Old page wikitext, before the edit (old_wikitext) | '{{short description|Inherited neurodegenerative disorder}}
{{Use dmy dates|date=December 2017}}
{{Use American English|date=December 2017}}
{{Infobox medical condition (new)
| name = Huntington's disease
| image = Neuron with mHtt inclusion.jpg
| alt = Several neurons colored yellow and having a large central core with up to two dozen tendrils branching out of them, the core of the neuron in the foreground contains an orange blob about a quarter of its diameter
| caption = An edited microscopic image of a [[medium spiny neuron]] (yellow) with an [[Inclusion bodies|inclusion body]] (orange), which occurs as part of the disease process (image width 360 [[micrometre|µm]])
| synonyms = Huntington's chorea
| field = [[Neurology]]
| symptoms = Problems with motor skills, including coordination and gait, mood, and mental abilities<ref name="Day20152"/><ref name=War2020/>
| complications = [[Pneumonia]], [[heart disease]], physical injury from falls, [[suicide]]<ref name=Frank2014/>
| onset = 30{{ndash}}50 years old<ref name=NIH2020/>
| duration = Long term<ref name=NIH2020/>
| causes = [[Genetics|Genetic]] (inherited or new mutation)<ref name=NIH2020/>
| risks =
| diagnosis = [[Genetic testing]]<ref name=Durr2012/>
| differential = [[Sydenham's chorea]], [[benign hereditary chorea]], [[lupus]], [[paraneoplastic syndrome]], [[Wilson's disease]]<ref>{{cite book| vauthors = Ferri FF |title=Ferri's differential diagnosis: a practical guide to the differential diagnosis of symptoms, signs, and clinical disorders|date=2010|publisher=Elsevier/Mosby|location=Philadelphia, PA|isbn=978-0323076999|page=Chapter H|edition=2nd}}</ref>
| prevention =
| treatment = [[Supportive care]]<ref name=War2020/>
| medication = [[Tetrabenazine]]<ref name=Frank2014/>
| prognosis = 15{{ndash}}20 years from onset of symptoms<ref name=NIH2020/>
| frequency = 4{{ndash}}15 in 100,000 (European descent)<ref name="Day20152"/>
| named after = [[George Huntington]]
}}
<!-- Definitions and symptoms -->
'''Huntington's disease''' ('''HD'''), also known as '''Huntington's chorea''', is an incurable [[neurodegenerative disease]]<ref>{{cite web | url=https://www.nhs.uk/conditions/huntingtons-disease/treatment/ | title=Huntington's disease - Treatment and support | date=23 October 2017 | access-date=6 May 2023 | archive-date=6 May 2023 | archive-url=https://web.archive.org/web/20230506014916/https://www.nhs.uk/conditions/huntingtons-disease/treatment/ | url-status=live }}</ref> that is mostly [[Genetic disorder#Autosomal dominant|inherited]].<ref name=msuRussia2018>{{cite web |title=Molecular Pathogenesis in Huntington's Disease |url=http://protein.bio.msu.ru/biokhimiya/contents/v83/full/83091299.html#Ref4 |website=protein.bio.msu.ru |access-date=8 November 2020 |archive-date=13 November 2020 |archive-url=https://web.archive.org/web/20201113121719/http://protein.bio.msu.ru/biokhimiya/contents/v83/full/83091299.html#Ref4 |url-status=live }}</ref> The earliest symptoms are often subtle problems with mood or mental/psychiatric abilities.<ref name="Gene Therapy for Neurodegenerative">{{cite journal | vauthors = Sudhakar V, Richardson RM | title = Gene Therapy for Neurodegenerative Diseases | journal = Neurotherapeutics | volume = 16 | issue = 1 | pages = 166–175 | date = January 2019 | pmid = 30542906 | pmc = 6361055 | doi = 10.1007/s13311-018-00694-0 }}</ref><ref name="Day20152"/> A general [[Ataxia|lack of coordination]] and an unsteady [[human gait|gait]] often follow.<ref name=War2020>{{cite journal | title = Huntington Disease | journal = GeneReviews | date = 2020 | pmid = 20301482 | veditors = Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A | last1 = Adam | first1 = M. P. | last2 = Mirzaa | first2 = G. M. | last3 = Pagon | first3 = R. A. | last4 = Wallace | first4 = S. E. | author5 = Bean LJH | last6 = Gripp | first6 = K. W. | last7 = Amemiya | first7 = A. | last8 = Caron | first8 = N. S. | author9 = Wright GEB | last10 = Hayden | first10 = M. R. }}</ref> It is also a [[Basal ganglia disease#Huntington's disease|basal ganglia disease]] causing a [[hyperkinesia|hyperkinetic]] [[movement disorder]] known as [[chorea]].<ref name="Robbins">{{cite book |title=Robbins basic pathology |vauthors=Kumar, Abbas A, Aster J |date=2018 |publisher=Elsevier |isbn=9780323353175 |edition=Tenth |location=Philadelphia, Pennsylvania |page=879}}</ref><ref name="Purves">{{cite book | vauthors = Purves D |title=Neuroscience |date=2012 |location=Sunderland, Mass. |isbn=9780878936953 |page=415 |edition=5th}}</ref> As the disease advances, uncoordinated, involuntary body movements of chorea become more apparent.<ref name="Day20152"/> Physical abilities gradually worsen until [[Motor coordination|coordinated movement]] becomes difficult and the person is unable to talk.<ref name="Day20152"/><ref name=War2020/> [[Neurocognition|Mental abilities]] generally decline into [[dementia]], depression, apathy, and impulsivity at times.<ref name="Gene Therapy for Neurodegenerative"/><ref name="The Biology of Huntingtin">{{cite journal | vauthors = Saudou F, Humbert S | title = The Biology of Huntingtin | journal = Neuron | volume = 89 | issue = 5 | pages = 910–926 | date = March 2016 | pmid = 26938440 | doi = 10.1016/j.neuron.2016.02.003 | s2cid = 8272667 | doi-access = free }}</ref><ref name="Frank2014" /> The specific symptoms vary somewhat between people.<ref name="Day20152"/> Symptoms usually begin between 30 and 50 years of age, and can start at any age but are usually seen around the age of 40.<ref name="The Biology of Huntingtin"/><ref name="Gene Therapy for Neurodegenerative"/><ref name="Frank2014" /><ref name="NIH2020">{{cite web |title=Huntington's Disease Information Page {{!}} National Institute of Neurological Disorders and Stroke |url=https://www.ninds.nih.gov/Disorders/All-Disorders/Huntingtons-Disease-Information-Page |website=www.ninds.nih.gov |access-date=14 December 2020 |archive-date=13 December 2020 |archive-url=https://web.archive.org/web/20201213025651/https://www.ninds.nih.gov/Disorders/All-Disorders/Huntingtons-Disease-Information-Page |url-status=live }}</ref> The disease may develop earlier in [[Anticipation (genetics)|each successive generation]].<ref name="Day20152"/> About eight percent of cases start before the age of 20 years, and are known as ''juvenile HD'', which typically present with the [[hypokinesia|slow movement symptoms]] of [[Parkinson's disease]] rather than those of chorea.<ref name=Frank2014/>
<!-- Cause and diagnosis -->
HD is typically [[Genetic disorder#Autosomal dominant|inherited from an affected parent]], who carries a [[mutation]] in the [[huntingtin gene]] (HTT).<ref name=NIH2020/> However, up to 10% of cases are due to a new mutation.<ref name="Day20152"/> The huntingtin gene provides the genetic information for [[huntingtin protein]] (Htt).<ref name="Day20152"/> Expansion of [[CAG repeat]]s of [[cytosine]]-[[adenine]]-[[guanine]] (known as a [[trinucleotide repeat expansion]]) in the gene coding for the huntingtin protein results in an abnormal mutant protein (mHtt), which gradually damages [[neuron|brain cells]] through a number of possible mechanisms.<ref name=msuRussia2018/><ref name="hdprimer"/> Diagnosis is by [[genetic testing]], which can be carried out at any time, regardless of whether or not symptoms are present.<ref name=Durr2012>{{cite journal | vauthors = Durr A, Gargiulo M, Feingold J | title = The presymptomatic phase of Huntington disease | journal = Revue Neurologique | volume = 168 | issue = 11 | pages = 806–808 | date = November 2012 | pmid = 22902173 | doi = 10.1016/j.neurol.2012.07.003 }}</ref> This fact raises several ethical debates: the age at which an individual is considered mature enough to choose testing; whether parents have the right to have their children tested; and managing confidentiality and disclosure of test results.<ref name=War2020/>
<!-- Treatment, epidemiology, and prognosis -->
No cure for HD is known, and full-time care is required in the later stages.<ref name=War2020/> Treatments can relieve some symptoms and in some, improve [[quality of life (healthcare)|quality of life]].<ref name=Frank2014/> The best evidence for treatment of the movement problems is with [[tetrabenazine]].<ref name=Frank2014/> HD affects about 4 to 15 in 100,000 people of European descent.<ref name="Day20152">{{cite journal | vauthors = Dayalu P, Albin RL | title = Huntington disease: pathogenesis and treatment | journal = Neurologic Clinics | volume = 33 | issue = 1 | pages = 101–114 | date = February 2015 | pmid = 25432725 | doi = 10.1016/j.ncl.2014.09.003 }}</ref><ref name=Frank2014/> It is rare among Japanese, while the occurrence rate in Africa is unknown.<ref name=Frank2014/> The disease affects men and women equally.<ref name=Frank2014>{{cite journal | vauthors = Frank S | title = Treatment of Huntington's disease | journal = Neurotherapeutics | volume = 11 | issue = 1 | pages = 153–160 | date = January 2014 | pmid = 24366610 | pmc = 3899480 | doi = 10.1007/s13311-013-0244-z }}</ref> Complications such as [[pneumonia]], [[heart disease]], and physical injury from falls reduce life expectancy; although fatal aspiration pneumonia is commonly cited as the ultimate cause of death for those with the condition.<ref>{{Cite web |title=Aspiration Pneumonia: What It Is, Causes, Diagnosis, Treatment |url=https://my.clevelandclinic.org/health/diseases/21954-aspiration-pneumonia |access-date=2023-06-12 |website=Cleveland Clinic |language=en |archive-date=12 June 2023 |archive-url=https://web.archive.org/web/20230612211926/https://my.clevelandclinic.org/health/diseases/21954-aspiration-pneumonia |url-status=live }}</ref><ref name="The Biology of Huntingtin"/><ref name=Frank2014/> [[Suicide]] is the cause of death in about 9% of cases.<ref name=Frank2014/> Death typically occurs 15–20 years from when the disease was first detected.<ref name=NIH2020/>
<!-- History and research -->
The earliest known description of the disease was in 1841 by American physician Charles Oscar Waters.<ref name=History2015/> The condition was described in further detail in 1872 by American physician [[George Huntington]].<ref name=History2015>{{cite journal | vauthors = Vale TC, Cardoso F | title = Chorea: A Journey through History | journal = Tremor and Other Hyperkinetic Movements | volume = 5 | date = 2015 | pmid = 26056609 | pmc = 4454991 | doi = 10.7916/D8WM1C98 }}</ref> The genetic basis was discovered in 1993 by an international collaborative effort led by the [[Hereditary Disease Foundation]].<ref name=Research2016>{{cite web |title=About Huntington's Disease |url=https://www.genome.gov/Genetic-Disorders/Huntingtons-Disease |website=Genome.gov |access-date=13 January 2021 |language=en |archive-date=9 January 2021 |archive-url=https://web.archive.org/web/20210109070041/https://www.genome.gov/Genetic-Disorders/Huntingtons-Disease |url-status=live }}</ref><ref name="HDF-About Us"/> Research and [[Support group|support organizations]] began forming in the late 1960s to increase public awareness, provide support for individuals and their families and promote research.<ref name="HDF-About Us">{{cite web|url=http://hdfoundation.org/history-of-the-hdf/|title=History of the HDF|publisher=Hereditary Disease Foundation|access-date=18 November 2015|url-status=dead|archive-url=https://web.archive.org/web/20151119025644/http://hdfoundation.org/history-of-the-hdf/|archive-date=19 November 2015}}</ref><ref name="HDSA12020">{{cite web |title=History and Genetics of Huntington's Disease {{!}} Huntington's Disease Society of America |date=March 2019 |url=https://hdsa.org/what-is-hd/history-and-genetics-of-huntingtons-disease/ |access-date=14 December 2020 |archive-date=1 December 2020 |archive-url=https://web.archive.org/web/20201201060837/https://hdsa.org/what-is-hd/history-and-genetics-of-huntingtons-disease/ |url-status=live }}</ref> Research directions include determining the exact mechanism of the disease, improving [[Genetically modified animal|animal models]] to aid with research, testing of medications and their [[Drug delivery|delivery]] to treat symptoms or slow the progression of the disease, and studying procedures such as [[stem-cell therapy]] with the goal of replacing damaged or lost neurons.<ref name=Research2016/>
==Signs and symptoms==
[[Signs and symptoms]] of Huntington's disease most commonly become noticeable between the ages of 30 and 50 years, but they can begin at any age<ref name=NIH2020/> and present as a [[Medical triad|triad]] of motor, cognitive, and psychiatric symptoms.<ref name=Jensen>{{cite journal | vauthors = Jensen RN, Bolwig T, Sørensen SA | title = [Psychiatric symptoms in patients with Huntington's disease] | language = da | journal = Ugeskrift for Laeger | volume = 180 | issue = 13 | date = March 2018 | pmid = 29587954 }}</ref> When developed in an early stage, it is known as juvenile Huntington's disease.<ref name=":1">{{Cite web |title=Huntington's disease - Symptoms and causes |url=https://www.mayoclinic.org/diseases-conditions/huntingtons-disease/symptoms-causes/syc-20356117 |access-date=2022-12-13 |website=Mayo Clinic |language=en |archive-date=5 March 2018 |archive-url=https://web.archive.org/web/20180305034543/https://www.mayoclinic.org/diseases-conditions/huntingtons-disease/symptoms-causes/syc-20356117 |url-status=live }}</ref> In 50% of cases, the psychiatric symptoms appear first.<ref name=Jensen/> Their progression is often described in early stages, middle stages, and late stages with an earlier [[Prodrome|prodromal]] phase.<ref name=War2020/> In the early stages, subtle personality changes, problems in [[cognition]] and physical skills, [[irritability]], and mood swings occur, all of which may go unnoticed,<ref name="NHSScot">{{cite web |title=Huntington's disease |url=https://www.nhsinform.scot/illnesses-and-conditions/brain-nerves-and-spinal-cord/huntingtons-disease |publisher=www.nhsinform.scot |access-date=12 July 2020 |language=en |archive-date=12 July 2020 |archive-url=https://web.archive.org/web/20200712181757/https://www.nhsinform.scot/illnesses-and-conditions/brain-nerves-and-spinal-cord/huntingtons-disease |url-status=live }}</ref><ref name="genereviews">{{cite journal | vauthors = Caron NS, Wright GE, Hayden MR | title = Huntington Disease | journal = Genereviews Bookshelf | date = June 2020 | pmid = 20301482 | url = https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=huntington#huntington.Management | access-date = 22 November 2020 | publisher = University of Washington | archive-date = 10 February 2009 | archive-url = https://web.archive.org/web/20090210161856/http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=huntington#huntington.Management | url-status = live }}</ref> and these usually precede the motor symptoms.<ref name="DSM5">{{cite book |title=Diagnostic and statistical manual of mental disorders: DSM-5. |date=2013 |publisher=American Psychiatric Association |location=Arlington, VA |isbn=9780890425541 |page=639 |edition=5th}}</ref> Almost everyone with HD eventually exhibits similar physical symptoms, but the onset, progression, and extent of cognitive and behavioral symptoms vary significantly between individuals.<ref name="OxfordMonographclinical">{{cite book | vauthors = Kremer B |chapter=Clinical neurology of Huntington's disease |veditors=Bates G, Harper P, Jones L | title=Huntington's Disease – Third Edition| publisher=Oxford University Press| location=Oxford| year=2002| isbn=978-0-19-851060-4|pages=28–53}}</ref><ref>{{cite journal|vauthors=Wagle AC, Wagle SA, Marková IS, Berrios GE |year=2000|title=Psychiatric Morbidity in Huntington's disease|journal=Neurology, Psychiatry and Brain Research|issue=8|pages=5–16}}</ref>
The most characteristic initial physical symptoms are jerky, random, and uncontrollable movements called [[chorea]].<ref name="Robbins"/> Many people are not aware of their involuntary movements, or impeded by them.<ref name="Day20152"/> Chorea may be initially exhibited as general restlessness, small unintentionally initiated or uncompleted motions, lack of coordination, or slowed [[Saccade|saccadic eye movements]].<ref name="lancet07">{{cite journal | vauthors = Walker FO | title = Huntington's disease | journal = Lancet | volume = 369 | issue = 9557 | pages = 218–228 | date = January 2007 | pmid = 17240289 | doi = 10.1016/S0140-6736(07)60111-1 | s2cid = 46151626 }}</ref> These minor motor abnormalities usually precede more obvious signs of motor dysfunction by at least three years.<ref name="OxfordMonographclinical2">{{cite book |title=Huntington's Disease – Third Edition |vauthors=Kremer B |publisher=Oxford University Press |year=2002 |isbn=978-0-19-851060-4 |veditors=Bates G, Harper P, Jones L |location=Oxford |pages=28–53 |chapter=Clinical neurology of Huntington's disease}}</ref> The clear appearance of symptoms such as rigidity, writhing motions, or [[Dystonia|abnormal posturing]] appear as the disorder progresses.<ref name="lancet07" /> These are signs that the system in the brain that is responsible for movement has been affected.<ref name="pmid16496032">{{cite journal | vauthors = Montoya A, Price BH, Menear M, Lepage M | title = Brain imaging and cognitive dysfunctions in Huntington's disease | journal = Journal of Psychiatry & Neuroscience | volume = 31 | issue = 1 | pages = 21–29 | date = January 2006 | pmid = 16496032 | pmc = 1325063 | url = http://www.cma.ca/multimedia/staticContent/HTML/N0/l2/jpn/vol-31/issue-1/pdf/pg21.pdf | url-status = dead | access-date = 17 September 2008 | archive-url = https://web.archive.org/web/20160323102506/https://www.cma.ca/multimedia/staticcontent/html/n0/l2/jpn/vol-31/issue-1/pdf/pg21.pdf | archive-date = 23 March 2016 }}</ref> [[Psychomotor retardation|Psychomotor]] functions become increasingly impaired, such that any action that requires muscle control is affected. When muscle control is affected such as rigidity or muscle contracture this is known as [[dystonia]]. Dystonia is a neurological hyperkinetic movement disorder that results in twisting or repetitive movements, that may resemble a tremor. Common consequences are physical instability, abnormal facial expression, and difficulties chewing, [[dysphagia|swallowing]], and [[dysarthria|speaking]].<ref name="lancet07" /> [[Sleep disorder|Sleep disturbances]] and [[weight loss]] are also associated symptoms.<ref name="Dickey3">{{cite journal | vauthors = Dickey AS, La Spada AR | title = Therapy development in Huntington disease: From current strategies to emerging opportunities | journal = American Journal of Medical Genetics. Part A | volume = 176 | issue = 4 | pages = 842–861 | date = April 2018 | pmid = 29218782 | pmc = 5975251 | doi = 10.1002/ajmg.a.38494 }}</ref> Eating difficulties commonly cause weight loss and may lead to malnutrition.<ref name="pmid191655312">{{cite journal | vauthors = Aziz NA, van der Marck MA, Pijl H, Olde Rikkert MG, Bloem BR, Roos RA | title = Weight loss in neurodegenerative disorders | journal = Journal of Neurology | volume = 255 | issue = 12 | pages = 1872–1880 | date = December 2008 | pmid = 19165531 | doi = 10.1007/s00415-009-0062-8 | s2cid = 26109381 }}</ref><ref>{{cite web |date=11 April 2007 |title=Booklet by the Huntington Society of Canada |url=http://www.hdac.org/caregiving/pdf/Caregiver_Handbook.pdf |url-status=dead |archive-url=https://web.archive.org/web/20080625160929/http://www.hdac.org/caregiving/pdf/Caregiver_Handbook.pdf |archive-date=25 June 2008 |access-date=10 August 2008 |work=Caregiver's Handbook for Advanced-Stage Huntington Disease |publisher=HD Society of Canada}}</ref> Weight loss is common in people with Huntington's disease, and it progresses with the disease. Juvenile HD generally progresses at a faster rate with greater cognitive decline, and chorea is exhibited briefly, if at all; the Westphal variant of [[Hypokinesia|slowness of movement]], rigidity, and tremors is more typical in juvenile HD, as are [[seizure]]s.<ref name="lancet07" /><ref name="Dickey3" />
Cognitive abilities are progressively impaired and tend to generally decline into [[dementia]].<ref name="Frank2014" /> Especially affected are [[executive functions]], which include planning, cognitive flexibility, [[abstract thinking]], rule acquisition, initiation of appropriate actions, and inhibition of inappropriate actions. Different cognitive impairments include difficulty focusing on tasks, lack of flexibility, a lack of impulse, a lack of awareness of one's own behaviors and abilities and difficulty learning or processing new information. As the disease progresses, [[memory]] deficits tend to appear. Reported impairments range from [[short-term memory]] deficits to [[long-term memory]] difficulties, including deficits in [[episodic memory|episodic]] (memory of one's life), [[procedural memory|procedural]] (memory of the body of how to perform an activity), and [[working memory]].<ref name="pmid16496032"/>
Reported [[neuropsychiatry|neuropsychiatric]] signs are [[anxiety]], [[major depressive disorder|depression]], a [[reduced affect display|reduced display of emotions]], [[egocentrism]], [[aggression]], and [[compulsive behavior]], the latter of which can cause or worsen [[Behavioral addiction|addictions]], including [[alcoholism]], [[gambling]], and [[hypersexuality]].<ref name="pmid180708482">{{cite journal | vauthors = van Duijn E, Kingma EM, van der Mast RC | title = Psychopathology in verified Huntington's disease gene carriers | journal = The Journal of Neuropsychiatry and Clinical Neurosciences | volume = 19 | issue = 4 | pages = 441–448 | year = 2007 | pmid = 18070848 | doi = 10.1176/appi.neuropsych.19.4.441 }}</ref> Other common psychiatric disorders could include [[obsessive–compulsive disorder]], [[mania]], [[insomnia]] and [[bipolar disorder]]. Difficulties in recognizing other people's negative expressions have also been observed.<ref name="pmid16496032"/> The [[prevalence]] of these symptoms is highly variable between studies, with estimated rates for lifetime prevalence of [[Mental illness|psychiatric disorders]] between 33 and 76%.<ref name="pmid180708482" /> For many with the disease and their families, these symptoms are among the most distressing aspects of the disease, often affecting daily functioning and constituting reason for [[institutionalisation|institutionalization]].<ref name="pmid180708482" /> Early behavioral changes in HD result in an increased risk of suicide.<ref name="Robbins"/> Often, individuals have reduced awareness of chorea, cognitive, and emotional impairments.<ref>{{cite book |title=Bradley's neurology in clinical practice |vauthors=Murray ED, Buttner N, Price BH |publisher=Elsevier/Saunders |year=2012 |isbn=978-1-4377-0434-1 |veditors=Bradley WG, Daroff RB, Fenichel GM, Jankovic J |edition=6th |location=Philadelphia, PA |page=108 |chapter=Depression and Psychosis in Neurological Practice}}</ref>
Mutant huntingtin is expressed throughout the body and associated with abnormalities in peripheral tissues that are directly caused by such expression outside the brain. These abnormalities include [[muscle atrophy]], [[cardiac failure]], [[impaired glucose tolerance]], [[weight loss]], [[osteoporosis]], and [[testicular atrophy]].<ref>{{cite journal | vauthors = van der Burg JM, Björkqvist M, Brundin P | title = Beyond the brain: widespread pathology in Huntington's disease | journal = The Lancet. Neurology | volume = 8 | issue = 8 | pages = 765–774 | date = August 2009 | pmid = 19608102 | doi = 10.1016/S1474-4422(09)70178-4 | s2cid = 14419437 }}</ref>
==Genetics==
<!-- Please note that although the disorder is spelled Huntington, the associated gene and protein are correctly spelled Huntingtin -->
Everyone has two copies of the [[huntingtin gene]] (''HTT''), which codes for the [[huntingtin protein]] (Htt). ''HTT'' is also called the HD gene, and the ''IT15'' gene, (interesting [[transcription (genetics)|transcript]] 15). Part of this gene is a repeated section called a [[trinucleotide repeat expansion]] – a [[copy number variation#Types and chromosomal rearrangements|short repeat]], which varies in length between individuals, and may change length between generations. If the repeat is present in a healthy gene, a dynamic mutation may increase the repeat count and result in a defective gene. When the length of this repeated section reaches a certain threshold, it produces an altered form of the protein, called mutant huntingtin protein (mHtt). The differing functions of these proteins are the cause of pathological changes, which in turn cause the disease symptoms. The Huntington's disease mutation is genetically dominant and almost fully [[penetrance|penetrant]]; mutation of either of a person's ''HTT'' alleles causes the disease. It is not inherited according to sex, but by the length of the repeated section of the gene, hence its severity can be influenced by the sex of the affected parent.<ref name="lancet07"/>
===Genetic mutation===
HD is one of several [[trinucleotide repeat disorder]]s that are caused by the length of a repeated section of a gene exceeding a normal range.<ref name="lancet07" /> The ''HTT'' gene is located on the [[Locus (genetics)|short arm]] of [[chromosome 4 (human)|chromosome 4]]<ref name="lancet07" /> at 4p16.3. ''HTT'' contains a sequence of three [[DNA base]]s—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ... CAGCAGCAG ...), known as a trinucleotide repeat.<ref name="lancet07" /> CAG is the three-letter [[genetic code]] ([[codon]]) for the [[amino acid]] [[glutamine]], so a series of them results in the production of a chain of glutamine known as a [[polyglutamine tract]] (or polyQ tract), and the repeated part of the gene, the ''polyQ region''.<ref>{{cite journal | vauthors = Katsuno M, Banno H, Suzuki K, Takeuchi Y, Kawashima M, Tanaka F, Adachi H, Sobue G | display-authors = 6 | title = Molecular genetics and biomarkers of polyglutamine diseases | journal = Current Molecular Medicine | volume = 8 | issue = 3 | pages = 221–234 | date = May 2008 | pmid = 18473821 | doi = 10.2174/156652408784221298 }}</ref>
[[File:Huntington's disease (5880985560).jpg|thumb|upright=1.4|Graphic showing at top normal range of repeats, and disease-causing range of repeats.]]
{| class="wikitable" style="float:right; margin-left:15px; margin-right:15px; text-align:center;"
|+Classification of trinucleotide repeats, and resulting disease status, depending on the number of CAG repeats<ref name="lancet07" />
|-
! Repeat count
! Classification
! Disease status
! Risk to offspring
|-
| <27
| Normal
| Will not be affected
| None
|-
| 27–35
| Intermediate
| Will not be affected
| Elevated, but <50%
|-
| 36–39
| Reduced Penetrance
| May or may not be affected
| 50%
|-
| 40+
| Full penetrance
| Will be affected
| 50%
|}
Generally, people have fewer than 36 repeated glutamines in the polyQ region, which results in the production of the [[cytoplasmic]] protein huntingtin.<ref name="lancet07" /> However, a sequence of 36 or more glutamines results in the production of a protein with different characteristics.<ref name="lancet07" /> This altered form, called mutant huntingtin (mHtt), increases the decay rate of certain types of [[medium spiny neurons|neurons]]. Regions of the brain have differing amounts and reliance on these types of neurons and are affected accordingly.<ref name="lancet07" /> Generally, the number of CAG repeats is related to how much this process is affected, and accounts for about 60% of the variation of the age of the onset of symptoms. The remaining variation is attributed to the environment and other genes that modify the mechanism of HD.<ref name="lancet07" /> About 36 to 39 repeats result in a reduced-penetrance form of the disease, with a much later onset and slower progression of symptoms. In some cases, the onset may be so late that symptoms are never noticed.<ref name="lancet07" /> With very large repeat counts (more than 60), HD onset can occur below the age of 20, known as juvenile HD. Juvenile HD is typically of the Westphal variant that is characterized by slowness of movement, rigidity, and tremors. This accounts for about 7% of HD carriers.<ref name="Squitieri">{{cite journal | vauthors = Squitieri F, Frati L, Ciarmiello A, Lastoria S, Quarrell O | title = Juvenile Huntington's disease: does a dosage-effect pathogenic mechanism differ from the classical adult disease? | journal = Mechanisms of Ageing and Development | volume = 127 | issue = 2 | pages = 208–212 | date = February 2006 | pmid = 16274727 | doi = 10.1016/j.mad.2005.09.012 | s2cid = 20523093 }}</ref><ref name="juvenile">{{cite journal | vauthors = Nance MA, Myers RH | title = Juvenile onset Huntington's disease--clinical and research perspectives | journal = Mental Retardation and Developmental Disabilities Research Reviews | volume = 7 | issue = 3 | pages = 153–157 | year = 2001 | pmid = 11553930 | doi = 10.1002/mrdd.1022 }}</ref>
===Inheritance===
[[File:Autosomal Dominant Pedigree Chart2.svg|thumb|upright|right|alt=Diagram showing a father carrying the gene and an unaffected mother, leading to some of their offspring being affected; those affected are also shown with some affected offspring; those unaffected have no affected offspring|Huntington's disease is inherited in an [[autosomal dominant]] fashion. The probability of each offspring inheriting an affected gene is 50%. Inheritance is independent of sex, and the phenotype does not skip generations.]]
Huntington's disease has [[autosomal dominant]] inheritance, meaning that an affected individual typically inherits one copy of the gene with an expanded trinucleotide repeat (the mutant [[allele]]) from an affected parent.<ref name="lancet07" /> Since the penetrance of the mutation is very high, those who have a mutated copy of the gene will have the disease. In this type of inheritance pattern, each offspring of an affected individual has a 50% risk of inheriting the mutant allele, so are affected with the disorder (see figure). This probability is sex-independent.<ref name="basicgenetics">{{cite book | vauthors =Passarge E | title=Color Atlas of Genetics | url =https://archive.org/details/coloratlasofgene0000pass | url-access =registration | publisher=Thieme | edition=2nd | year=2001 | page=[https://archive.org/details/coloratlasofgene0000pass/page/n155 142] | isbn=978-0-86577-958-7}}</ref> Sex-dependent or sex-linked genes are traits that are found on the X or Y chromosomes.<ref>{{Cite web |title=Sex Linked |url=https://www.genome.gov/genetics-glossary/Sex-Linked |access-date=2022-12-13 |website=Genome.gov |language=en |archive-date=14 April 2022 |archive-url=https://web.archive.org/web/20220414183337/https://www.genome.gov/genetics-glossary/Sex-Linked |url-status=live }}</ref>
[[Trinucleotide repeat expansion|Trinucleotide CAG repeats]] numbering over 28 are unstable during [[DNA replication|replication]], and this instability increases with the number of repeats present.<ref name="lancet07" /> This usually leads to new expansions as generations pass ([[dynamic mutation]]s) instead of reproducing an exact copy of the trinucleotide repeat.<ref name="lancet07" /> This causes the number of repeats to change in successive generations, such that an unaffected parent with an "intermediate" number of repeats (28–35), or "reduced penetrance" (36–40), may pass on a copy of the gene with an increase in the number of repeats that produces fully penetrant HD.<ref name="lancet07" /> The earlier [[age of onset]] and greater severity of disease in successive generations due to increases in the number of repeats is known as genetic [[anticipation (genetics)|anticipation]].<ref name="Day20152"/> Instability is greater in [[spermatogenesis]] than [[oogenesis]];<ref name="lancet07" /> maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones have a higher chance of increasing in length.<ref name="lancet07" /><ref name="Ridley">{{cite journal | vauthors = Ridley RM, Frith CD, Crow TJ, Conneally PM | title = Anticipation in Huntington's disease is inherited through the male line but may originate in the female | journal = Journal of Medical Genetics | volume = 25 | issue = 9 | pages = 589–595 | date = September 1988 | pmid = 2972838 | pmc = 1051535 | doi = 10.1136/jmg.25.9.589 }}</ref> Rarely is Huntington's disease caused by a [[de novo mutation|new mutation]], where neither parent has over 36 CAG repeats.<ref name="pmid16965319">{{cite journal | vauthors = Semaka A, Creighton S, Warby S, Hayden MR | title = Predictive testing for Huntington disease: interpretation and significance of intermediate alleles | journal = Clinical Genetics | volume = 70 | issue = 4 | pages = 283–294 | date = October 2006 | pmid = 16965319 | doi = 10.1111/j.1399-0004.2006.00668.x | s2cid = 26007984 }}</ref>
In the rare situations where both parents have an expanded HD gene, the risk increases to 75%, and when either parent has two expanded copies, the risk is 100% (all children will be affected). Individuals with [[Homozygous|both genes affected]] are rare. For some time, HD was thought to be the only disease for which possession of a second mutated gene did not affect symptoms and progression,<ref name="pmid2881213">{{cite journal | vauthors = Wexler NS, Young AB, Tanzi RE, Travers H, Starosta-Rubinstein S, Penney JB, Snodgrass SR, Shoulson I, Gomez F, Ramos Arroyo MA | display-authors = 6 | title = Homozygotes for Huntington's disease | journal = Nature | volume = 326 | issue = 6109 | pages = 194–197 | year = 1987 | pmid = 2881213 | doi = 10.1038/326194a0 | hdl-access = free | s2cid = 4312171 | bibcode = 1987Natur.326..194W | hdl = 2027.42/62543 }}</ref> but it has since been found that it can affect the [[phenotype]] and the rate of progression.<ref name="lancet07" /><ref name="pmid12615650">{{cite journal | vauthors = Squitieri F, Gellera C, Cannella M, Mariotti C, Cislaghi G, Rubinsztein DC, Almqvist EW, Turner D, Bachoud-Lévi AC, Simpson SA, Delatycki M, Maglione V, Hayden MR, Donato SD | display-authors = 6 | title = Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course | journal = Brain | volume = 126 | issue = Pt 4 | pages = 946–955 | date = April 2003 | pmid = 12615650 | doi = 10.1093/brain/awg077 | doi-access = free }}</ref>
==Mechanisms==
Huntingtin protein interacts with over 100 other proteins, and appears to have multiple functions.<ref name="pmid15383276">{{cite journal | vauthors = Goehler H, Lalowski M, Stelzl U, Waelter S, Stroedicke M, Worm U, Droege A, Lindenberg KS, Knoblich M, Haenig C, Herbst M, Suopanki J, Scherzinger E, Abraham C, Bauer B, Hasenbank R, Fritzsche A, Ludewig AH, Büssow K, Coleman SH, Gutekunst CA, Landwehrmeyer BG, Lehrach H, Wanker EE | display-authors = 6 | title = A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease | journal = Molecular Cell | volume = 15 | issue = 6 | pages = 853–865 | date = September 2004 | pmid = 15383276 | doi = 10.1016/j.molcel.2004.09.016 | author23-link = Bernhard Landwehrmeyer | doi-access = free }}</ref> The behavior of the mutated protein (mHtt) is not completely understood, but it is toxic to certain cell types, particularly [[brain cells]]. Early damage is most evident in the [[subcortical]] [[basal ganglia]], initially in the [[striatum]], but as the disease progresses, other areas of the brain are also affected, including regions of the [[cerebral cortex]]. Early symptoms are attributable to functions of the striatum and its cortical connections—namely control over movement, mood, and higher cognitive function.<ref name="lancet07" /> [[DNA methylation]] also appears to be changed in HD.<ref>{{cite journal | vauthors = Glajch KE, Sadri-Vakili G | title = Epigenetic Mechanisms Involved in Huntington's Disease Pathogenesis | journal = Journal of Huntington's Disease | volume = 4 | issue = 1 | pages = 1–15 | date = 2015 | pmid = 25813218 | doi = 10.3233/JHD-159001 | doi-access = free }}</ref>
===Huntingtin function===
{{See also|Huntingtin#Function}}
Htt is [[gene expression|expressed]] in all cells, with the highest concentrations found in the brain and [[testes]], and moderate amounts in the [[liver]], [[heart]], and [[lung]]s. Its functions are unclear, but it does interact with proteins involved in [[Transcription (biology)|transcription]], [[cell signaling]], and [[Vesicle (biology)#Transport vesicles|intracellular transporting]].<ref name="Liu"/> In [[Genetically modified organism|animals genetically modified]] to exhibit HD, several functions of Htt have been identified.<ref name="Httfunction">{{cite journal | vauthors = Cattaneo E, Zuccato C, Tartari M | title = Normal huntingtin function: an alternative approach to Huntington's disease | journal = Nature Reviews. Neuroscience | volume = 6 | issue = 12 | pages = 919–930 | date = December 2005 | pmid = 16288298 | doi = 10.1038/nrn1806 | s2cid = 10119487 }}</ref> In these animals, Htt is important for embryonic development, as its absence is related to embryonic death. [[Caspase]], an enzyme which plays a role in catalyzing [[apoptosis]], is thought to be activated by the mutated gene through damaging the ubiquitin-protease system. It also acts as an [[Apoptosis|antiapoptotic]] agent preventing [[programmed cell death]] and controls the production of [[brain-derived neurotrophic factor]], a protein that protects neurons and regulates their creation during [[neurogenesis]]. Htt also facilitates [[Synaptic vesicle|synaptic vesicular transport]] and [[synaptic transmission]], and controls neuronal gene transcription.<ref name="Httfunction"/> If the expression of Htt is increased, [[Neuron|brain cell]] survival is improved and the effects of mHtt are reduced, whereas when the expression of Htt is reduced, the resulting characteristics are more as seen in the presence of mHtt.<ref name="Httfunction"/> Accordingly, the disease is thought not to be caused by [[haploinsufficiency|inadequate production]] of Htt, but by a [[Gain-of-function|toxic gain-of-function]] of mHtt in the body.<ref name="lancet07" />
===Cellular changes===
[[File:Neuron with mHTT inclusion zoomed.jpg|thumb|left|alt=Closer view of neuron having a large central core with several tendrils branching out some of which branch again, the core of the contains an orange blob about a quarter of its diameter | A microscope image of a neuron with an [[inclusion body]] (stained orange) caused by HD, image width 250 [[micrometre|µm]]]]
The toxic action of mHtt may manifest and produce the HD pathology through multiple cellular changes.<ref name="pmid14585171">{{cite journal | vauthors = Rubinsztein DC, Carmichael J | title = Huntington's disease: molecular basis of neurodegeneration | journal = Expert Reviews in Molecular Medicine | volume = 5 | issue = 20 | pages = 1–21 | date = August 2003 | pmid = 14585171 | doi = 10.1017/S1462399403006549 | s2cid = 28435830 }}</ref><ref name="pmid2136787">{{cite journal | vauthors = Bloch M, Hayden MR | title = Opinion: predictive testing for Huntington disease in childhood: challenges and implications | journal = American Journal of Human Genetics | volume = 46 | issue = 1 | pages = 1–4 | date = January 1990 | pmid = 2136787 | pmc = 1683548 }}</ref> In its mutant (polyglutamine expanded) form, the protein is more prone to cleavage that creates shorter fragments containing the polyglutamine expansion.<ref name="pmid14585171"/> These protein fragments have a propensity to undergo [[misfolding]] and aggregation, yielding fibrillar aggregates in which non-native polyglutamine β-strands from multiple proteins are bonded together by hydrogen bonds.<ref name="hdprimer">{{cite journal | vauthors = Bates GP, Dorsey R, Gusella JF, Hayden MR, Kay C, Leavitt BR, Nance M, Ross CA, Scahill RI, Wetzel R, Wild EJ, Tabrizi SJ | display-authors = 6 | title = Huntington disease | journal = Nature Reviews. Disease Primers | volume = 1 | pages = 15005 | date = April 2015 | pmid = 27188817 | doi = 10.1038/nrdp.2015.5 | author-link12 = Sarah Tabrizi | s2cid = 25759303 }}</ref> These aggregates share the same fundamental cross-beta [[amyloid]] architecture seen in other [[Proteopathies|protein deposition diseases]] .<ref name="fibrilstruc">{{cite journal | vauthors = Matlahov I, van der Wel PC | title = Conformational studies of pathogenic expanded polyglutamine protein deposits from Huntington's disease | journal = Experimental Biology and Medicine | volume = 244 | issue = 17 | pages = 1584–1595 | date = December 2019 | pmid = 31203656 | pmc = 6920524 | doi = 10.1177/1535370219856620 | s2cid = 189944779 }}</ref> Over time, the aggregates accumulate to form [[inclusion bodies]] within cells, ultimately interfering with neuronal function.<ref name="hdprimer"/><ref name="pmid14585171"/> Inclusion bodies have been found in both the [[cell nucleus]] and [[cytoplasm]].<ref name="pmid14585171"/> Inclusion bodies in cells of the brain are one of the earliest pathological changes, and some experiments have found that they can be [[neurotoxicity|toxic]] for the cell, but other experiments have shown that they may form as part of the body's defense mechanism and help protect cells.<ref name="pmid14585171"/>
Several pathways by which mHtt may cause cell death have been identified. These include effects on [[Chaperone (protein)|chaperone proteins]], which help fold proteins and remove misfolded ones; interactions with [[caspase]]s, which play a role in the [[apoptosis|process of removing cells]]; the [[excitotoxicity|toxic effects of glutamine on nerve cells]]; impairment of energy production within cells; and effects on the expression of genes.<ref name="hdprimer"/><ref name="urlNature Clinical Practice Neurology | Mechanisms of Disease: histone modifications in Huntingtons disease | Article">{{cite journal | vauthors = Sadri-Vakili G, Cha JH | title = Mechanisms of disease: Histone modifications in Huntington's disease | journal = Nature Clinical Practice. Neurology | volume = 2 | issue = 6 | pages = 330–338 | date = June 2006 | pmid = 16932577 | doi = 10.1038/ncpneuro0199 | s2cid = 12474262 }}</ref>
Mutant huntingtin protein has been found to play a key role in [[mitochondrial dysfunction]].<ref name="Liu">{{cite journal | vauthors = Liu Z, Zhou T, Ziegler AC, Dimitrion P, Zuo L | title = Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications | journal = Oxidative Medicine and Cellular Longevity | volume = 2017 | pages = 2525967 | date = 2017 | pmid = 28785371 | pmc = 5529664 | doi = 10.1155/2017/2525967 | doi-access = free }}</ref> The impairment of [[mitochondrial electron transport chains|mitochondrial electron transport]] can result in higher levels of [[oxidative stress]] and release of [[reactive oxygen species]].<ref name="pmid27662334">{{cite journal | vauthors = Kumar A, Ratan RR | title = Oxidative Stress and Huntington's Disease: The Good, The Bad, and The Ugly | journal = Journal of Huntington's Disease | volume = 5 | issue = 3 | pages = 217–237 | date = October 2016 | pmid = 27662334 | pmc = 5310831 | doi = 10.3233/JHD-160205 }}</ref>
Glutamine is known to be [[Excitotoxin|excitotoxic]] when present in large amounts, that can cause damage to numerous cellular structures. Excessive glutamine is not found in HD, but the interactions of the altered huntingtin protein with numerous proteins in neurons lead to an increased vulnerability to glutamine. The increased vulnerability is thought to result in excitotoxic effects from normal glutamine levels.<ref name="hdprimer"/>
===Macroscopic changes===
{{See also|Basal ganglia disease}}
[[File:Basal_ganglia_and_related_structures_(2).svg|thumb|upright=1.4|alt=Diagram of a side view of the brain and part of the spinal cord, the front of the brain is to the left, in the centre are red and blue masses, the red mass largely overlaps the blue and has an arm that starts at its leftmost region and forms a spiral a little way out tapering off and ending in a nodule directly below the main mass |The area of the brain most damaged in early Huntington's disease is the [[dorsal striatum]] made up of the [[caudate nucleus]] and the [[putamen]].]]
Initially, damage to the brain is regionally specific with the [[dorsal striatum]] in the subcortical [[basal ganglia]] being primarily affected, followed later by [[cerebral cortex|cortical]] involvement in all areas.<ref name="Nopoulos">{{cite journal | vauthors = Nopoulos PC | title = Huntington disease: a single-gene degenerative disorder of the striatum | journal = Dialogues in Clinical Neuroscience | volume = 18 | issue = 1 | pages = 91–98 | date = March 2016 | pmid = 27069383 | pmc = 4826775 | doi = 10.31887/DCNS.2016.18.1/pnopoulos }}</ref><ref name="McColgan">{{cite journal | vauthors = McColgan P, Tabrizi SJ | title = Huntington's disease: a clinical review | journal = European Journal of Neurology | volume = 25 | issue = 1 | pages = 24–34 | date = January 2018 | pmid = 28817209 | doi = 10.1111/ene.13413 | doi-access = free }}</ref> Other areas of the [[basal ganglia]] affected include the [[substantia nigra]]; cortical involvement includes [[Cortical layers|cortical layers 3, 5, and 6]]; also evident is involvement of the [[hippocampus]], [[Purkinje cell]]s in the [[Cerebellum#Purkinje layer|cerebellum]], lateral tuberal nuclei of the [[hypothalamus]] and parts of the [[thalamus]].<ref name="lancet07" /> These areas are affected according to their structure and the types of neurons they contain, reducing in size as they lose cells.<ref name="lancet07" /> Striatal [[medium spiny neuron]]s are the most vulnerable, particularly ones with [[Neural pathway|projections]] towards the [[external globus pallidus]], with [[interneuron]]s and spiny cells projecting to the [[internal globus pallidus]] being less affected.<ref name="lancet07" /><ref>{{cite book | vauthors = Purves D, Augustine GA, Fitzpatrick D, Hall W, LaMantia AS, McNamara JO, Williams SM | veditors = Purves D | title = Neuroscience | url = https://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=neurosci.TOC&depth=2 | edition = 2nd | publisher = Sinauer Associates | location = Sunderland, MA | isbn = 978-0-87893-742-4 | chapter = Modulation of Movement by the Basal Ganglia – Circuits within the Basal Ganglia System | chapter-url = https://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=Huntington's%20disease&rid=neurosci.section.1251 | access-date = 1 April 2009 | year = 2001 | url-status=live | archive-url = https://web.archive.org/web/20090218192801/http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=neurosci.TOC&depth=2 | archive-date = 18 February 2009}}</ref> HD also causes an [[astrogliosis|abnormal increase]] in [[astrocyte]]s and activation of the brain's immune cells, [[microglia]].<ref name="pmid17965655">{{cite journal | vauthors = Lobsiger CS, Cleveland DW | title = Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease | journal = Nature Neuroscience | volume = 10 | issue = 11 | pages = 1355–1360 | date = November 2007 | pmid = 17965655 | pmc = 3110080 | doi = 10.1038/nn1988 }}</ref>
The basal ganglia play a key role in movement and behavior control. Their functions are not fully understood, but theories propose that they are part of the cognitive [[executive function|executive system]]<ref name="pmid16496032"/> and the motor circuit.<ref name="pmid10923984"/> The basal ganglia ordinarily inhibit a large number of circuits that generate specific movements. To initiate a particular movement, the cerebral cortex sends a signal to the basal ganglia that causes the inhibition to be released. Damage to the basal ganglia can cause the release or reinstatement of the inhibitions to be erratic and uncontrolled, which results in an awkward start to the motion or motions to be unintentionally initiated or in a motion to be halted before or beyond its intended completion. The accumulating damage to this area causes the characteristic erratic movements associated with HD known as chorea, a [[dyskinesia]].<ref name="pmid10923984">{{cite journal | vauthors = Crossman AR | title = Functional anatomy of movement disorders | journal = Journal of Anatomy | volume = 196 ( Pt 4) | issue = Pt 4 | pages = 519–525 | date = May 2000 | pmid = 10923984 | pmc = 1468094 | doi = 10.1046/j.1469-7580.2000.19640519.x }}</ref> Because of the basal ganglia's inability to inhibit movements, individuals affected by it inevitably experience a reduced ability to produce speech and swallow foods and liquids (dysphagia).<ref>{{Cite book|title = Motor Speech Disorders: Substrates, Differential Diagnosis, and Management | edition = 3rd | vauthors = Duffy J |publisher = Elsevier|year = 2013|location = St. Louis, Missouri|pages = 196–7}}</ref>
===Transcriptional dysregulation===
[[CREB-binding protein]] (CBP), a transcriptional coregulator, is essential for cell function because as a coactivator at a significant number of promoters, it activates the transcription of genes for survival pathways.<ref name="urlNature Clinical Practice Neurology | Mechanisms of Disease: histone modifications in Huntingtons disease | Article"/> CBP contains an [[acetyltransferase]] domain to which HTT binds through its polyglutamine-containing domain.<ref>{{cite journal | vauthors = Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A, Apostol BL, Kazantsev A, Schmidt E, Zhu YZ, Greenwald M, Kurokawa R, Housman DE, Jackson GR, Marsh JL, Thompson LM | display-authors = 6 | title = Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila | journal = Nature | volume = 413 | issue = 6857 | pages = 739–743 | date = October 2001 | pmid = 11607033 | doi = 10.1038/35099568 | s2cid = 4419980 | bibcode = 2001Natur.413..739S | url = https://escholarship.org/uc/item/5q52298v | access-date = 28 June 2019 | archive-date = 1 August 2020 | archive-url = https://web.archive.org/web/20200801220516/https://escholarship.org/uc/item/5q52298v | url-status = live }}</ref> Autopsied brains of those who had Huntington's disease also have been found to have incredibly reduced amounts of CBP.<ref name="urlAnalysis of Strand Slippage in DNA Polymerase Expansions of CAG/CTG Triplet Repeats Associated with Neurodegenerative Disease – JBC">{{cite journal | vauthors = Petruska J, Hartenstine MJ, Goodman MF | title = Analysis of strand slippage in DNA polymerase expansions of CAG/CTG triplet repeats associated with neurodegenerative disease | journal = The Journal of Biological Chemistry | volume = 273 | issue = 9 | pages = 5204–5210 | date = February 1998 | pmid = 9478975 | doi = 10.1074/jbc.273.9.5204 | doi-access = free }}</ref> In addition, when CBP is overexpressed, polyglutamine-induced death is diminished, further demonstrating that CBP plays an important role in Huntington's disease and neurons in general.<ref name="urlNature Clinical Practice Neurology | Mechanisms of Disease: histone modifications in Huntingtons disease | Article"/>
==Diagnosis==
[[Medical diagnosis|Diagnosis]] of the onset of HD can be made following the appearance of physical symptoms specific to the disease.<ref name="lancet07" /> Genetic testing can be used to confirm a physical diagnosis if no family history of HD exists. Even before the onset of symptoms, genetic testing can confirm if an individual or [[embryo]] carries an expanded copy of the trinucleotide repeat (CAG) in the ''HTT'' gene that causes the disease. [[Genetic counseling]] is available to provide advice and guidance throughout the testing procedure and on the implications of a confirmed diagnosis. These implications include the impact on an individual's psychology, career, family-planning decisions, relatives, and relationships. Despite the availability of pre-symptomatic testing, only 5% of those at risk of inheriting HD choose to do so.<ref name="lancet07" />
===Clinical===
[[File:Huntington.jpg|thumb|upright|alt=Cross section of a brain showing undulating tissues with gaps between them, two large gaps are evenly spaced about the centre.| [[Coronal plane|Coronal]] section from an [[MRI|MR]] [[brain scan]] of a patient with HD, showing [[atrophy]] of the heads of the [[caudate nucleus|caudate nuclei]], enlargement of the frontal horns of the [[lateral ventricles]] (hydrocephalus ''ex vacuo''), and generalized cortical atrophy<ref>{{cite web |vauthors=Gaillard F |title=Huntington's disease |url=http://www.radpod.org/2007/05/01/huntingtons-disease/ |date=1 May 2007 |work=Radiology picture of the day |publisher=www.radpod.org |access-date=24 July 2009 |url-status=dead |archive-url=https://web.archive.org/web/20071022134552/http://radpod.org/2007/05/01/huntingtons-disease/ |archive-date=22 October 2007}}</ref>]]
A [[physical examination]], sometimes combined with a [[psychological examination]], can determine whether the onset of the disease has begun.<ref name="lancet07" /> Excessive unintentional movements of any part of the body are often the reason for seeking medical consultation. If these are abrupt and have random timing and distribution, they suggest a diagnosis of HD. Cognitive or behavioral symptoms are rarely the first symptoms diagnosed; they are usually only recognized in hindsight or when they develop further. How far the disease has progressed can be measured using the unified Huntington's disease rating scale, which provides an overall rating system based on motor, behavioral, cognitive, and functional assessments.<ref name="pmid19111470">{{cite journal | vauthors = Rao AK, Muratori L, Louis ED, Moskowitz CB, Marder KS | title = Clinical measurement of mobility and balance impairments in Huntington's disease: validity and responsiveness | journal = Gait & Posture | volume = 29 | issue = 3 | pages = 433–436 | date = April 2009 | pmid = 19111470 | doi = 10.1016/j.gaitpost.2008.11.002 }}</ref><ref>{{cite web |url=http://huntingtonstudygroup.org/tools-resources/uhdrs/ |title=Unified Huntington's Disease Rating Scale (UHDRS) |access-date=14 April 2009 |work=UHDRS and Database |publisher=HSG |date=1 February 2009 |url-status=live |archive-url=https://web.archive.org/web/20150811064639/http://huntingtonstudygroup.org/tools-resources/uhdrs/ |archive-date=11 August 2015}}</ref> [[Medical imaging]], such as a [[CT scan]] or [[magnetic resonance imaging|MRI scan]], can show atrophy of the caudate nuclei early in the disease, as seen in the illustration to the right, but these changes are not, by themselves, diagnostic of HD. [[Cerebral atrophy]] can be seen in the advanced stages of the disease. [[Functional neuroimaging]] techniques, such as [[functional magnetic resonance imaging]] (fMRI) and [[positron emission tomography]] (PET), can show changes in brain activity before the onset of physical symptoms, but they are experimental tools and are not used clinically.<ref name="lancet07" />
===Predictive genetic testing===
Because HD follows an autosomal dominant pattern of inheritance, a strong motivation exists for individuals who are at risk of inheriting it to seek a diagnosis. The genetic test for HD consists of a blood test, which counts the numbers of CAG repeats in each of the ''HTT'' alleles.<ref name="pmid15717026">{{cite journal | vauthors = Myers RH | title = Huntington's disease genetics | journal = NeuroRx | volume = 1 | issue = 2 | pages = 255–262 | date = April 2004 | pmid = 15717026 | pmc = 534940 | doi = 10.1602/neurorx.1.2.255 }}</ref> [[Cutoff (reference value)|Cutoffs]] are given as follows:
* At 40 or more CAG repeats, full [[penetrance]] allele (FPA) exists.<ref name=Die-Smulders2013>{{cite journal | vauthors = de Die-Smulders CE, de Wert GM, Liebaers I, Tibben A, Evers-Kiebooms G | title = Reproductive options for prospective parents in families with Huntington's disease: clinical, psychological and ethical reflections | journal = Human Reproduction Update | volume = 19 | issue = 3 | pages = 304–315 | date = May 2013 | pmid = 23377865 | doi = 10.1093/humupd/dms058 | doi-access = free }} {{cite journal | vauthors = de Die-Smulders CE, de Wert GM, Liebaers I, Tibben A, Evers-Kiebooms G | title = Reproductive options for prospective parents in families with Huntington's disease: clinical, psychological and ethical reflections | journal = Human Reproduction Update | volume = 19 | issue = 3 | pages = 304–315 | year = 2013 | pmid = 23377865 | doi = 10.1093/humupd/dms058 | doi-access = free }}</ref> A "[[positive test]]" or "positive result" generally refers to this case. A positive result is not considered a diagnosis, since it may be obtained decades before the symptoms begin. However, a negative test means that the individual does not carry the expanded copy of the gene and will not develop HD.<ref name="lancet07" /> The test will tell a person who originally had a 50% chance of inheriting the disease if their risk goes up to 100% or is eliminated. Persons who test positive for the disease will develop HD sometime within their lifetimes, provided they live long enough for the disease to appear.<ref name="lancet07" />
* At 36 to 39 repeats, incomplete or reduced penetrance allele (RPA) may cause symptoms, usually later in the adult life.<ref name=Die-Smulders2013/> The maximum risk is 60% that a person with an RPA will be symptomatic at age 65, and 70% at 75.<ref name=Die-Smulders2013/>
* At 27 to 35 repeats, intermediate allele (IA), or large normal allele, is not associated with symptomatic disease in the tested individual, but may expand upon further inheritance to give symptoms in offspring.<ref name=Die-Smulders2013/>
* With 26 or fewer repeats, the result is not associated with HD.<ref name=Die-Smulders2013/>
Testing before the onset of symptoms is a life-changing event and a very personal decision.<ref name="lancet07" /> The main reason given for choosing to test for HD is to aid in career and family decisions.<ref name="lancet07" /> Predictive testing for Huntington's disease has been available via linkage analysis (which requires testing multiple family members) since 1986 and via direct mutation analysis since 1993.<ref>{{cite journal | vauthors = Baig SS, Strong M, Rosser E, Taverner NV, Glew R, Miedzybrodzka Z, Clarke A, Craufurd D, Quarrell OW | display-authors = 6 | title = 22 Years of predictive testing for Huntington's disease: the experience of the UK Huntington's Prediction Consortium | journal = European Journal of Human Genetics | volume = 24 | issue = 10 | pages = 1396–1402 | date = October 2016 | pmid = 27165004 | pmc = 5027682 | doi = 10.1038/ejhg.2016.36 }}</ref> At that time, surveys indicated that 50–70% of at-risk individuals would have been interested in receiving testing, but since predictive testing has been offered far fewer choose to be tested.<ref name="pmid23297124">{{cite journal | vauthors = Forrest Keenan K, Simpson SA, Miedzybrodzka Z, Alexander DA, Semper J | title = How do partners find out about the risk of Huntington's disease in couple relationships? | journal = Journal of Genetic Counseling | volume = 22 | issue = 3 | pages = 336–344 | date = June 2013 | pmid = 23297124 | doi = 10.1007/s10897-012-9562-2 | s2cid = 15447709 }}</ref> Over 95% of individuals at risk of inheriting HD do not proceed with testing, mostly because it has no treatment.<ref name="lancet07" /> A key issue is the anxiety an individual experiences about not knowing whether they will eventually develop HD, compared to the impact of a positive result.<ref name="lancet07" /> Irrespective of the result, stress levels are lower two years after being tested, but the risk of suicide is increased after a positive test result.<ref name="lancet07" /> Individuals found to have not inherited the disorder may experience [[survivor guilt]] about family members who are affected.<ref name="lancet07" /> Other factors taken into account when considering testing include the possibility of discrimination and the implications of a positive result, which usually means a parent has an affected gene and that the individual's siblings will be at risk of inheriting it.<ref name="lancet07" /> In one study, genetic discrimination was found in 46% of individuals at risk for Huntington's disease. It occurred at higher rates within personal relationships than health insurance or employment relations.<ref name="pmid20468061">{{cite journal | vauthors = Erwin C, Williams JK, Juhl AR, Mengeling M, Mills JA, Bombard Y, Hayden MR, Quaid K, Shoulson I, Taylor S, Paulsen JS | display-authors = 6 | title = Perception, experience, and response to genetic discrimination in Huntington disease: the international RESPOND-HD study | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 153B | issue = 5 | pages = 1081–1093 | date = July 2010 | pmid = 20468061 | pmc = 3593716 | doi = 10.1002/ajmg.b.31079 }}</ref> [[Genetic counseling]] in HD can provide information, advice and support for initial decision-making, and then, if chosen, throughout all stages of the testing process.<ref name="geneticcounselling">{{cite journal | vauthors = Burson CM, Markey KR | title = Genetic counseling issues in predictive genetic testing for familial adult-onset neurologic diseases | journal = Seminars in Pediatric Neurology | volume = 8 | issue = 3 | pages = 177–186 | date = September 2001 | pmid = 11575847 | doi = 10.1053/spen.2001.26451 }}</ref> Because of the implications of this test, patients who wish to undergo testing must complete three counseling sessions which provide information about Huntington's.<ref name="pmid22114233">{{cite journal | vauthors = Smith JA, Michie S, Stephenson M, Quarrell O | title = Risk Perception and Decision-making Processes in Candidates for Genetic Testing for Huntington's Disease: An Interpretative Phenomenological Analysis | journal = Journal of Health Psychology | volume = 7 | issue = 2 | pages = 131–144 | date = March 2002 | pmid = 22114233 | doi = 10.1177/1359105302007002398 | s2cid = 40182214 }}</ref>
Counseling and guidelines on the use of genetic testing for HD have become models for other genetic disorders, such as autosomal dominant [[cerebellar ataxia]].<ref name="lancet07" /><ref name="pmid12849232">{{cite journal | vauthors = Hayden MR | title = Predictive testing for Huntington's disease: a universal model? | journal = The Lancet. Neurology | volume = 2 | issue = 3 | pages = 141–142 | date = March 2003 | pmid = 12849232 | doi = 10.1016/S1474-4422(03)00317-X | s2cid = 39581496 }}</ref><ref>{{cite journal | vauthors = | title = Guidelines for the molecular genetics predictive test in Huntington's disease. International Huntington Association (IHA) and the World Federation of Neurology (WFN) Research Group on Huntington's Chorea | journal = Neurology | volume = 44 | issue = 8 | pages = 1533–1536 | date = August 1994 | pmid = 8058167 | doi = 10.1212/WNL.44.8.1533 | s2cid = 28018134 }}</ref> [[Predictive testing|Presymptomatic testing]] for HD has also influenced testing for other illnesses with genetic variants such as [[polycystic kidney]] disease, familial [[Alzheimer's disease]] and [[breast cancer]].<ref name="pmid12849232"/> The European Molecular Genetics Quality Network have published yearly external quality assessment scheme for molecular genetic testing for this disease and have developed best practice guidelines for genetic testing for HD to assist in testing and reporting of results.<ref name=Losekoot2012>{{cite journal | vauthors = Losekoot M, van Belzen MJ, Seneca S, Bauer P, Stenhouse SA, Barton DE | title = EMQN/CMGS best practice guidelines for the molecular genetic testing of Huntington disease | journal = European Journal of Human Genetics | volume = 21 | issue = 5 | pages = 480–486 | date = May 2013 | pmid = 22990145 | pmc = 3641377 | doi = 10.1038/ejhg.2012.200 }}</ref>
===Preimplantation genetic diagnosis===
[[Embryo]]s produced using [[in vitro fertilisation|''in vitro'' fertilization]] may be genetically tested for HD using [[preimplantation genetic diagnosis]]. This technique, where one or two cells are extracted from a typically 4- to 8-cell embryo and then tested for the genetic abnormality, can then be used to ensure embryos affected with HD genes are not implanted, so any offspring will not inherit the disease. Some forms of preimplantation genetic diagnosis—non-disclosure or exclusion testing—allow at-risk people to have HD-free offspring ''without'' revealing their own parental genotype, giving no information about whether they themselves are destined to develop HD. In exclusion testing, the embryo's DNA is compared with that of the parents and grandparents to avoid inheritance of the chromosomal region containing the HD gene from the affected grandparent. In nondisclosure testing, only disease-free embryos are replaced in the uterus while the parental genotype and hence parental risk for HD are never disclosed.<ref>{{cite journal | vauthors = Schulman JD, Black SH, Handyside A, Nance WE | title = Preimplantation genetic testing for Huntington disease and certain other dominantly inherited disorders | journal = Clinical Genetics | volume = 49 | issue = 2 | pages = 57–58 | date = February 1996 | pmid = 8740912 | doi = 10.1111/j.1399-0004.1996.tb04327.x | s2cid = 45703511 }}</ref><ref>{{cite journal | vauthors = Stern HJ, Harton GL, Sisson ME, Jones SL, Fallon LA, Thorsell LP, Getlinger ME, Black SH, Schulman JD | display-authors = 6 | title = Non-disclosing preimplantation genetic diagnosis for Huntington disease | journal = Prenatal Diagnosis | volume = 22 | issue = 6 | pages = 503–507 | date = June 2002 | pmid = 12116316 | doi = 10.1002/pd.359 | s2cid = 33967835 }}</ref>
===Prenatal testing===
Obtaining a [[prenatal diagnosis]] for an embryo or [[fetus]] in the womb is also possible, using fetal genetic material acquired through [[chorionic villus sampling]]. An [[amniocentesis]] can be performed if the pregnancy is further along, within 14–18 weeks. This procedure looks at the amniotic fluid surrounding the baby for indicators of the HD mutation.<ref>{{cite web|title=Predictive Testing for Huntington's Disease|url=http://predictivetestingforhd.com/testing-for-hd/prenatal-testing/amniocentesis/|access-date=7 May 2013|year=2011|url-status=live|archive-url=https://web.archive.org/web/20130122124510/http://predictivetestingforhd.com/testing-for-hd/prenatal-testing/amniocentesis/|archive-date=22 January 2013}}</ref> This, too, can be paired with exclusion testing to avoid disclosure of parental genotype. Prenatal testing can be done when parents have been diagnosed with HD, when they have had genetic testing showing the expansion of the ''HTT'' gene, or when they have a 50% chance of inheriting the disease. The parents can be counseled on their options, which include [[termination of pregnancy]], and on the difficulties of a child with the identified gene.<ref name="pmid15758612">{{cite journal | vauthors = Kuliev A, Verlinsky Y | title = Preimplantation diagnosis: a realistic option for assisted reproduction and genetic practice | journal = Current Opinion in Obstetrics & Gynecology | volume = 17 | issue = 2 | pages = 179–183 | date = April 2005 | pmid = 15758612 | doi = 10.1097/01.gco.0000162189.76349.c5 | s2cid = 9382420 }}</ref><ref>{{cite web|title=Guidelines for Genetic Testing for Huntington's Disease|url=http://dwb4.unl.edu/chem/chem869n/chem869nlinks/www.hdfoundation.org/testread/hdsatest.htm|publisher=Heredity Disease Foundation|access-date=7 May 2013|url-status=dead|archive-url=https://web.archive.org/web/20150626005614/http://dwb4.unl.edu/Chem/CHEM869N/CHEM869NLinks/www.hdfoundation.org/testread/hdsatest.htm|archive-date=26 June 2015}}</ref>
In addition, in at-risk pregnancies due to an affected male partner, noninvasive prenatal diagnosis can be performed by analyzing [[cell-free fetal DNA]] in a blood sample taken from the mother (via [[venipuncture]]) between six and 12 weeks of pregnancy.<ref name=Die-Smulders2013/> It has no procedure-related risk of miscarriage.<ref name=Die-Smulders2013/>
===Differential diagnosis===
About 99% of HD diagnoses based on the typical symptoms and a [[family history (medicine)|family history]] of the disease are confirmed by genetic testing to have the expanded trinucleotide repeat that causes HD. Most of the remaining are called [[Huntington's disease-like syndrome|HD-like (HDL) syndromes]].<ref name="lancet07" /><ref name="HD-LIKE"/> The cause of most HDL diseases is unknown, but those with known causes are due to mutations in the [[PRNP|prion protein gene]] (HDL1), the [[JPH3|junctophilin 3 gene]] (HDL2), a recessively inherited unknown gene (HDL3—only found in two families and poorly understood), and the gene encoding the [[TATA binding protein|TATA box-binding protein]] ([[Spinocerebellar ataxia|SCA17, sometimes called HDL4]]). Other autosomal dominant diseases that can be misdiagnosed as HD are [[dentatorubral-pallidoluysian atrophy]] and [[Adult-onset basal ganglia disease|neuroferritinopathy]]. Also, some [[autosomal recessive]] disorders resemble sporadic cases of HD. These include [[chorea acanthocytosis]] and [[pantothenate kinase-associated neurodegeneration]]. One [[Sex linkage|X-linked]] disorder of this type is [[McLeod syndrome]].<ref name="HD-LIKE">{{cite journal | vauthors = Schneider SA, Walker RH, Bhatia KP | title = The Huntington's disease-like syndromes: what to consider in patients with a negative Huntington's disease gene test | journal = Nature Clinical Practice. Neurology | volume = 3 | issue = 9 | pages = 517–525 | date = September 2007 | pmid = 17805246 | doi = 10.1038/ncpneuro0606 | s2cid = 9052603 }}</ref>
==Management==
[[File:Report (IA report00comm 6).pdf|thumb|Illustration from a case report in 1977 of a person with Huntington's disease]]
Treatments are available to reduce the severity of some HD symptoms.<ref name="HDDRUGS">{{cite journal | vauthors = Frank S, Jankovic J | title = Advances in the pharmacological management of Huntington's disease | journal = Drugs | volume = 70 | issue = 5 | pages = 561–571 | date = March 2010 | pmid = 20329804 | doi = 10.2165/11534430-000000000-00000 | url = http://adisonline.com/drugs/Abstract/2010/70050/Advances_in_the_Pharmacological_Management_of.4.aspx | url-status = dead | s2cid = 42386743 | archive-url = https://web.archive.org/web/20111008155523/http://adisonline.com/drugs/Abstract/2010/70050/Advances_in_the_Pharmacological_Management_of.4.aspx | archive-date = 8 October 2011 }}</ref> For many of these treatments, evidence to confirm their effectiveness in treating symptoms of HD specifically are incomplete.<ref name="lancet07" /><ref name="pmid15076012">{{cite journal | vauthors = Bonelli RM, Wenning GK, Kapfhammer HP | title = Huntington's disease: present treatments and future therapeutic modalities | journal = International Clinical Psychopharmacology | volume = 19 | issue = 2 | pages = 51–62 | date = March 2004 | pmid = 15076012 | doi = 10.1097/00004850-200403000-00001 | s2cid = 1956458 }}</ref> As the disease progresses, the ability to care for oneself declines, and carefully managed [[multidisciplinary]] [[caregiving]] becomes increasingly necessary.<ref name="lancet07" /> Although relatively few studies of exercises and therapies have shown to be helpful to [[Rehabilitation (neuropsychology)|rehabilitate]] cognitive symptoms of HD, some evidence shows the usefulness of [[physical therapy]], [[occupational therapy]], and [[speech therapy]].<ref name="lancet07" />
===Therapy===
Weight loss and problems in eating due to [[dysphagia]] and other muscle discoordination are common, making nutrition management increasingly important as the disease advances.<ref name="lancet07" /> [[Thickening agent]]s can be added to liquids, as thicker fluids are easier and safer to swallow.<ref name="lancet07" /> Reminding the affected person to eat slowly and to take smaller pieces of food into the mouth may also be of use to prevent choking.<ref name="lancet07" /> If eating becomes too hazardous or uncomfortable, the option of using a [[percutaneous endoscopic gastrostomy]] is available. This feeding tube, permanently attached through the [[abdomen]] into the [[stomach]], reduces the risk of [[pulmonary aspiration|aspirating]] food and provides better nutritional management.<ref name="pmid18390785">{{cite journal | vauthors = Panagiotakis PH, DiSario JA, Hilden K, Ogara M, Fang JC | title = DPEJ tube placement prevents aspiration pneumonia in high-risk patients | journal = Nutrition in Clinical Practice | volume = 23 | issue = 2 | pages = 172–175 | year = 2008 | pmid = 18390785 | doi = 10.1177/0884533608314537 }}</ref> Assessment and management by [[speech-language pathologist]]s with experience in Huntington's disease is recommended.<ref name="lancet07" />
People with Huntington's disease may see a [[physical therapist]] for noninvasive and nonmedication-based ways of managing the physical symptoms. Physical therapists may implement fall risk assessment and prevention, as well as strengthening, stretching, and cardiovascular exercises. [[Walking aids]] may be prescribed as appropriate. Physical therapists also prescribe breathing exercises and [[airway clearance technique]]s with the development of respiratory problems.<ref name=ehdnphysio /> Consensus guidelines on physiotherapy in Huntington's disease have been produced by the European HD Network.<ref name=ehdnphysio>{{cite web|url=http://www.euro-hd.net/html/network/groups/physio/physiotherapy-guidance-doc-2009.pdf|title=EHDN Physiotherapy Guidance Document|publisher=European HD Network Physiotherapy Working Group|access-date=2015-11-15|url-status=dead|archive-url=https://web.archive.org/web/20160304030647/http://www.euro-hd.net/html/network/groups/physio/physiotherapy-guidance-doc-2009.pdf|archive-date=4 March 2016}}</ref> Goals of early [[Rehabilitation medicine|rehabilitation]] interventions are prevention of loss of function. Participation in rehabilitation programs during the early to middle stage of the disease may be beneficial as it translates into long-term maintenance of motor and functional performance. Rehabilitation during the late stage aims to compensate for motor and functional losses.<ref>{{cite journal|vauthors=Quin L, Busee M|title=Development of physiotherapy guidance and treatment-based classifications for people with Huntington's disease|journal=Neurodegenerative Disease Management|date=February 2012|volume=2|issue=1|pages=21–31|doi=10.2217/nmt.11.86|url=http://www.futuremedicine.com/doi/pdf/10.2217/nmt.11.67|doi-access=free|access-date=10 May 2012|archive-date=9 August 2020|archive-url=https://web.archive.org/web/20200809000845/https://www.futuremedicine.com/doi/pdf/10.2217/nmt.11.67|url-status=live}}</ref> For long-term independent management, the therapist may develop home exercise programs for appropriate people.<ref>{{cite journal | vauthors = Khalil H, Quinn L, van Deursen R, Martin R, Rosser A, Busse M | title = Adherence to use of a home-based exercise DVD in people with Huntington disease: participants' perspectives | journal = Physical Therapy | volume = 92 | issue = 1 | pages = 69–82 | date = January 2012 | pmid = 21960468 | doi = 10.2522/ptj.20100438 | doi-access = free }}</ref>
Additionally, an increasing number of people with HD are turning to [[palliative care]], which aims to improve quality of life through the treatment of the symptoms and stress of serious illness, in addition to their other treatments.<ref>{{cite journal | vauthors = Travers E, Jones K, Nichol J | title = Palliative care provision in Huntington's disease | journal = International Journal of Palliative Nursing | volume = 13 | issue = 3 | pages = 125–130 | date = March 2007 | pmid = 17505405 | doi = 10.12968/ijpn.2007.13.3.23274 }}</ref>
===Medications===
[[File:Tetrabenazine structure.svg|thumb|right|alt=diagram showing 19 carbon, 27 hydrogen, 3 oxygen and 1 nitrogen atom bonded together| Chemical structure of [[tetrabenazine]], an approved compound for the management of [[chorea]] in HD]]
[[Tetrabenazine]] was approved in 2000 for treatment of chorea in Huntington's disease in the EU, and in 2008 in the US.<ref name=autogenerated1>{{cite web |url=https://www.fda.gov/bbs/topics/NEWS/2008/NEW01874.html |title=FDA Approves First Drug for Treatment of Chorea in Huntington's Disease |access-date=10 August 2008 |publisher=U.S. Food and Drug Administration |date=15 August 2008 |url-status=live |archive-url=https://web.archive.org/web/20080821020643/https://www.fda.gov/bbs/topics/NEWS/2008/NEW01874.html |archive-date=21 August 2008}}</ref> Although other drugs had been used "[[off label]]," tetrabenazine was the first approved treatment for Huntington's disease in the U.S. The compound has been known since the 1950s. An alternative to tetrabenazine is [[amantadine]] but there is limited evidence for its safety and efficacy.<ref name="Coppen">{{cite journal | vauthors = Coppen EM, Roos RA | title = Current Pharmacological Approaches to Reduce Chorea in Huntington's Disease | journal = Drugs | volume = 77 | issue = 1 | pages = 29–46 | date = January 2017 | pmid = 27988871 | pmc = 5216093 | doi = 10.1007/s40265-016-0670-4 }}</ref>
Other drugs that help to reduce chorea include [[antipsychotic]]s and [[benzodiazepine]]s.<ref name="genereviews"/> [[Hypokinesia]] and rigidity, especially in juvenile cases, can be treated with [[antiparkinsonian]] drugs, and [[myoclonic]] hyperkinesia can be treated with [[valproic acid]].<ref name="genereviews"/> Tentative evidence has found [[ethyl eicosapentaenoic acid]] to improve motor symptoms at one year.<ref>{{cite journal | vauthors = Morsy S, Khalil SM, Doheim MF, Kamel MG, El-Basiony DS, Ahmed Hassan HI, Eisa AA, Anh Ngoc CT, Dang NP, Hirayama K, Huy NT | display-authors = 6 | title = Efficacy of ethyl-EPA as a treatment for Huntington disease: a systematic review and meta-analysis | journal = Acta Neuropsychiatrica | volume = 31 | issue = 4 | pages = 175–185 | date = August 2019 | pmid = 30890195 | doi = 10.1017/neu.2019.11 | hdl-access = free | hdl = 10069/39427| s2cid = 84183892 }}</ref> In 2017, [[deutetrabenazine]], a heavier form of tetrabenazine medication for the treatment of chorea in HD, was approved by the FDA.<ref name="CDE">{{cite web |author=Center for Drug Evaluation Research |title=In Pursuit of Tardive Dyskinesia: The Breakthrough Designation and Approval of Valbenazine |url=https://www.fda.gov/drugs/news-events-human-drugs/pursuit-tardive-dyskinesia-breakthrough-designation-and-approval-valbenazine |website=FDA |access-date=15 November 2020 |language=en |date=17 July 2019 |archive-date=3 December 2020 |archive-url=https://web.archive.org/web/20201203175104/https://www.fda.gov/drugs/news-events-human-drugs/pursuit-tardive-dyskinesia-breakthrough-designation-and-approval-valbenazine |url-status=live }}</ref> This is marketed as Austedo.
Psychiatric symptoms can be treated with medications similar to those used in the general population.<ref name="lancet07" /><ref name="pmid15076012"/> [[Selective serotonin reuptake inhibitor]]s and [[mirtazapine]] have been recommended for depression, while [[atypical antipsychotic]]s are recommended for [[psychosis]] and behavioral problems.<ref name="pmid15076012"/> Specialist neuropsychiatric input is recommended since people may require long-term treatment with multiple medications in combination.<ref name="lancet07" />
=== Plant based medications ===
{{Fringe section|date=August 2023}}
There has been a number of alternative therapies experimented in ayurvedic medicine with plant based products, though none have good evidence of efficacy. Ayurvedic formulations of Indian gooseberry - amla rasayana (Emblica officinalis ) and rasa-sindoor (an organo-metallic ash in the form of nano-sized crystals of mercuric sulphide) is said to suppress the neurodegeneration of Huntington and Alzheimer's diseases.<ref>{{Cite journal |last=Jayaraman |first=K. S. |date=30 December 2013 |title=Ayurveda for Huntington's and Alzheimer's? |url=https://www.nature.com/articles/nindia.2013.172 |journal=Nature India |doi=10.1038/nindia.2013.172 |access-date=19 July 2023 |archive-date=17 July 2023 |archive-url=https://web.archive.org/web/20230717071100/https://www.nature.com/articles/nindia.2013.172 |url-status=live }}</ref><ref>{{Cite journal |last1=Dwivedi |first1=Vibha |last2=Tripathi |first2=Bipin |last3=Mutsuddi |first3=Mousumi |last4=Lakhotia |first4=Subhash Chandra |date=December 2013 |title=Ayurvedic Amalaki Rasayana and Rasa-Sindoor suppress neurodegeneration in fly models of Huntington's and Alzheimer's diseases |url=https://www.researchgate.net/publication/259694504 |journal=Current Science |volume=105 |issue=12 |pages=1711–1723 |access-date=July 19, 2023 |via=Researchgate}}</ref>
===Education===
The families of individuals, and society at large, who have inherited or are at risk of inheriting HD have generations of experience of HD but may be unaware of recent breakthroughs in understanding the disease, and of the availability of genetic testing. Genetic counseling benefits these individuals by updating their knowledge, seeking to dispel any unfounded beliefs that they may have, and helping them consider their future options and plans. The Patient Education Program for Huntington's Disease has been created to help educate family members, caretakers, and those diagnosed with Huntington's disease.<ref name="PEP">{{cite journal |vauthors=A'Campo LE, Spliethoff-Kamminga NG, Roos RA |title=The Patient Education Program for Huntington's Disease (PEP-HD) |journal=J Huntingtons Dis |volume=1 |issue=1 |pages=47–56 |date=2012 |pmid=25063190 |doi=10.3233/JHD-2012-120002 |url=|doi-access=free }}</ref> Also covered is information concerning family planning choices, care management, and other considerations.<ref name="lancet07" /><ref name="OxfordMonographtesting">{{cite book | vauthors = Harper P|chapter=Genetic counselling and presymptomatic testing |veditors=Bates G, Harper P, Jones L | title=Huntington's Disease – Third Edition| publisher=Oxford University Press| location=Oxford| year=2002| isbn=978-0-19-851060-4|pages= 198–242}}</ref>
==Prognosis==
The length of the trinucleotide repeat accounts for 60% of the variation of the age of symptoms onset and their rate of progress. A longer repeat results in an earlier age of onset and a faster progression of symptoms.<ref name="lancet07" /><ref>{{cite journal | vauthors = Harper PS | title = Huntington's disease: a clinical, genetic and molecular model for polyglutamine repeat disorders | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 354 | issue = 1386 | pages = 957–61 | date = June 1999 | pmid = 10434293 | pmc = 1692597 | doi = 10.1098/rstb.1999.0446}}</ref> Individuals with more than sixty repeats often develop the disease before age 20, while those with fewer than 40 repeats may remain asymptomatic.<ref>{{cite journal | vauthors = Andrew SE, Goldberg YP, Kremer B, Telenius H, Theilmann J, Adam S, Starr E, Squitieri F, Lin B, Kalchman MA | title = The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease | journal = Nature Genetics | volume = 4 | issue = 4 | pages = 398–403 | date = August 1993 | pmid = 8401589 | doi = 10.1038/ng0893-398 | s2cid = 20645822}}</ref> The remaining variation is due to environmental factors and other genes that influence the mechanism of the disease.<ref name="lancet07" />
Life expectancy in HD is generally around 10 to 30 years following the onset of visible symptoms.<ref name="lancet07"/> Juvenile Huntington's disease has a life expectancy rate of 10 years after onset of visible symptoms. Most life-threatening complications result from muscle coordination, and to a lesser extent, behavioral changes induced by declining cognitive function. The largest risk is [[pneumonia]], which causes death in one third of those with HD. As the ability to synchronize movements deteriorates, difficulty clearing the lungs, and an increased risk of aspirating food or drink both increase the risk of contracting [[pneumonia]]. The second-greatest risk is [[heart disease]], which causes almost a quarter of fatalities of those with HD.<ref name="lancet072">{{cite journal |vauthors=Walker FO |date=January 2007 |title=Huntington's disease |journal=Lancet |volume=369 |issue=9557 |pages=218–28 |doi=10.1016/S0140-6736(07)60111-1 |pmid=17240289 |s2cid=46151626}}</ref> [[Suicide]] is the third greatest cause of fatalities, with 7.3% of those with HD taking their own lives and up to 27% attempting to do so. To what extent suicidal thoughts are influenced by behavioral symptoms is unclear, as they signify a desire to avoid the later stages of the disease.<ref name="OxfordMonographNeuro2">{{cite book |title=Huntington's Disease – Third Edition |vauthors=Crauford D, Snowden J |publisher=Oxford University Press |year=2002 |isbn=978-0-19-851060-4 |veditors=Bates G, Harper P, Jones L |location=Oxford |pages=62–87 |chapter=Neuropyschological and neuropsychiatric aspects of Huntington's disease}}</ref><ref>{{cite journal |vauthors=Di Maio L, Squitieri F, Napolitano G, Campanella G, Trofatter JA, Conneally PM |date=April 1993 |title=Suicide risk in Huntington's disease |journal=Journal of Medical Genetics |volume=30 |issue=4 |pages=293–5 |doi=10.1136/jmg.30.4.293 |pmc=1016335 |pmid=8487273}}</ref><ref name="OxfordMonographepi">{{cite book |title=Huntington's Disease – Third Edition |vauthors=Harper P |publisher=Oxford University Press |year=2002 |isbn=978-0-19-851060-4 |veditors=Bates G, Harper P, Jones L |location=Oxford |pages=159–189 |chapter=The epidemiology of Huntington's disease}}</ref> Suicide is the greatest risk of this disease before the diagnosis is made and in the middle stages of development throughout the disease. Other associated risks include choking; due to the inability to swallow, [[Injury|physical injury]] from falls, and malnutrition.<ref name="lancet072" /><ref name=":1" />
==Epidemiology==
The late onset of Huntington's disease means it does not usually affect reproduction.<ref name="lancet07" /> The worldwide [[prevalence]] of HD is 5–10 cases per 100,000 persons,<ref name="emedicine">{{cite web |url=http://emedicine.medscape.com/article/289706-overview |title=Huntington Disease Dementia | vauthors = Sharon I, Sharon R, Wilkens JP, Ersan T |year=2010 |work=emedicine, WebMD |publisher=Medscape |access-date=16 May 2010 |url-status=live |archive-url=https://web.archive.org/web/20100305050654/http://emedicine.medscape.com/article/289706-overview |archive-date=5 March 2010}}</ref><ref name="Driver-Dunckley2007">{{cite book |vauthors=Driver-Dunckley E, Caviness JN |chapter=Huntington's disease| veditors = Schapira AH | title=Neurology and Clinical Neuroscience| publisher=Mosby Elsevier|year=2007| isbn=978-0-323-03354-1|pages=879–885}}</ref> but varies greatly geographically as a result of ethnicity, local migration and past immigration patterns.<ref name="lancet07" /> Prevalence is similar for men and women. The rate of occurrence is highest in [[Ethnic group|peoples]] of Western European descent, averaging around seven per 100,000 people, and is lower in the rest of the world; e.g., one per million people of Asian and African descent. A 2013 epidemiological study of the prevalence of Huntington's disease in the UK between 1990 and 2010 found that the average prevalence for the UK was 12.3 per 100,000.<ref name="lancet07" /><ref name="pmid23482661">{{cite journal | vauthors = Evans SJ, Douglas I, Rawlins MD, Wexler NS, Tabrizi SJ, Smeeth L | title = Prevalence of adult Huntington's disease in the UK based on diagnoses recorded in general practice records | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 84 | issue = 10 | pages = 1156–60 | date = October 2013 | pmid = 23482661 | pmc = 3786631 | doi = 10.1136/jnnp-2012-304636}}</ref> Additionally, some localized areas have a much higher prevalence than their regional average.<ref name="lancet07" /> One of the highest incidences is in the isolated populations of the [[Lake Maracaibo]] region of [[Venezuela]], where HD affects up to 700 per 100,000 persons.<ref name="lancet07" /><ref>{{cite journal | vauthors = Avila-Giróo R |title=Medical and Social Aspects of Huntington's chorea in the state of Zulia, Venezuela |journal=Advances in Neurology |volume=1 |pages=261–6 |year=1973 |issn=0091-3952 |id=NAID 10021247802}}</ref> Other areas of high localization have been found in [[Tasmania]] and specific regions of [[Scotland]], [[Wales]] and [[Sweden]].<ref name="OxfordMonographepi"/> Increased prevalence in some cases occurs due to a local [[founder effect]], a historical migration of carriers into an area of [[geographic isolation]].<ref name="OxfordMonographepi"/><ref name="dnamark">{{cite journal | vauthors = Gusella JF, Wexler NS, Conneally PM, Naylor SL, Anderson MA, Tanzi RE, Watkins PC, Ottina K, Wallace MR, Sakaguchi AY | title = A polymorphic DNA marker genetically linked to Huntington's disease | journal = Nature | volume = 306 | issue = 5940 | pages = 234–8 | year = 1983 | pmid = 6316146 | doi = 10.1038/306234a0 | bibcode = 1983Natur.306..234G | s2cid = 4320711}}</ref> Some of these carriers have been traced back hundreds of years using [[genealogy|genealogical]] studies.<ref name="OxfordMonographepi"/> Genetic [[haplotype]]s can also give clues for the geographic variations of prevalence.<ref name="OxfordMonographepi"/><ref name="pmid7881406">{{cite journal | vauthors = Squitieri F, Andrew SE, Goldberg YP, Kremer B, Spence N, Zeisler J, Nichol K, Theilmann J, Greenberg J, Goto J | title = DNA haplotype analysis of Huntington disease reveals clues to the origins and mechanisms of CAG expansion and reasons for geographic variations of prevalence | journal = Human Molecular Genetics | volume = 3 | issue = 12 | pages = 2103–14 | date = December 1994 | pmid = 7881406 | doi = 10.1093/hmg/3.12.2103}}</ref> [[Iceland]], on the contrary, has a rather low prevalence of 1 per 100,000, despite the fact that [[Icelanders]] as a people are descended from the early Germanic tribes of Scandinavia which also gave rise to the [[Swedes]]; all cases with the exception of one going back nearly two centuries having derived from the offspring of a couple living early in the 19th century.<ref>{{cite journal | vauthors = Sveinsson O, Halldórsson S, Olafsson E | title = An unusually low prevalence of Huntington's disease in Iceland | journal = European Neurology | volume = 68 | issue = 1 | pages = 48–51 | date = July 2012 | pmid = 22722209 | doi = 10.1159/000337680 | s2cid = 207551998}}</ref> [[Finland]], as well, has a low incidence of only 2.2 per 100,000 people.<ref>{{cite journal | vauthors = Sipilä JO, Hietala M, Siitonen A, Päivärinta M, Majamaa K | title = Epidemiology of Huntington's disease in Finland | journal = Parkinsonism & Related Disorders | volume = 21 | issue = 1 | pages = 46–9 | date = January 2015 | pmid = 25466405 | doi = 10.1016/j.parkreldis.2014.10.025}}</ref>
Until the discovery of a genetic test, statistics could only include [[clinical diagnosis]] based on physical symptoms and a family history of HD, excluding those who died of other causes before diagnosis. These cases can now be included in statistics; and, as the test becomes more widely available, estimates of the prevalence and incidence of the disorder are likely to increase.<ref name="OxfordMonographepi"/><ref name="pmid11595021">{{cite journal | vauthors = Almqvist EW, Elterman DS, MacLeod PM, Hayden MR | title = High incidence rate and absent family histories in one quarter of patients newly diagnosed with Huntington disease in British Columbia | journal = Clinical Genetics | volume = 60 | issue = 3 | pages = 198–205 | date = September 2001 | pmid = 11595021 | doi = 10.1034/j.1399-0004.2001.600305.x | s2cid = 19786394}}</ref>
==History==
[[File:On Chorea with photo.jpg|thumb|alt=On the right is a young man, dressed in suit and tie, sporting a moustache and tuft of hair on the chin; on the left is the top half of a medical journal titled 'Medical and Surgical Reporter' |In 1872, [[George Huntington]] described the disorder in his first paper "[[s:On Chorea|On Chorea]]" at the age of 22.<ref name="onchorea">{{cite journal |vauthors=Huntington G |title=On Chorea |url=https://babel.hathitrust.org/cgi/pt?id=mdp.39015010956335&view=1up&seq=343&skin=2021 |journal=Medical and Surgical Reporter of Philadelphia |volume=26 |issue=15 |year=1872 |pages=317–321 |isbn=978-90-6186-011-2 |access-date=21 April 2022 |archive-date=21 April 2022 |archive-url=https://web.archive.org/web/20220421034757/https://babel.hathitrust.org/cgi/pt?id=mdp.39015010956335&view=1up&seq=343&skin=2021 |url-status=live }}</ref>]]
In centuries past, various kinds of chorea were at times called by names such as ''[[Saint Vitus' dance (disambiguation)|Saint Vitus' dance]]'', with little or no understanding of their cause or type in each case.
The first definite mention of HD was in a letter by [[Charles Oscar Waters]] (1816–1892), published in the first edition of [[Robley Dunglison]]'s ''Practice of Medicine'' in 1842.<ref>{{cite book |vauthors=Dunglison R |title=The Practice of Medicine ... |date=1842 |publisher=Lea & Blanchard |location=Philadelphia, Pennsylvania, USA |volume=2 |pages=312–313 |url=https://babel.hathitrust.org/cgi/pt?id=chi.092041301&view=1up&seq=316&skin=2021 |access-date=20 April 2022 |archive-date=20 April 2022 |archive-url=https://web.archive.org/web/20220420233417/https://babel.hathitrust.org/cgi/pt?id=chi.092041301&view=1up&seq=316&skin=2021 |url-status=live }}</ref> Waters described "a form of chorea, vulgarly called magrums", including accurate descriptions of the chorea, its progression, and the strong heredity of the disease.<ref name="OxfordMonographHistory">{{cite book | vauthors = Harper P |chapter=Huntington's disease: a historical background |veditors=Bates G, Harper P, Jones L | title=Huntington's Disease – Third Edition| publisher=Oxford University Press| location=Oxford| year=2002| isbn=978-0-19-851060-4|pages= 3–24}}</ref> In 1846 [[Charles Gorman (physician)|Charles Rollin Gorman]] (1817–1879) observed how higher prevalence seemed to occur in localized regions.<ref>Gorman, Charles R. (1846) Thesis for the degree Doctor of Medicine: ''"On a Form of Chorea, Vulgarly called Magrums"''
* [https://jdc.jefferson.edu/cgi/viewcontent.cgi?article=1071&context=jmc_catalogs ''Catalogue of Jefferson Medical College of Philadelphia: Session of 1846-7''] {{Webarchive|url=https://web.archive.org/web/20220626050233/https://jdc.jefferson.edu/cgi/viewcontent.cgi?article=1071&context=jmc_catalogs |date=26 June 2022 }}, p. 14.
* {{cite book |vauthors=Dunglison R |title=The Practice of Medicine ... |date=1848 |publisher=Lea & Blanchard |location=Philadelphia, Pennsylvania, USA |volume=2 |page=218 |edition=3rd |url=https://archive.org/details/practiceofmedici248dung/page/218/mode/2up?ref=ol&view=theater }}
* {{cite journal |vauthors=Boyd WA |title=Hereditary chorea with report of a case |journal=Boston Medical and Surgical Journal |date=6 November 1913 |volume=169 |issue=19 |pages=680–685 |doi=10.1056/NEJM191311061691904 |url=https://books.google.com/books?id=Q80EAAAAYAAJ&pg=RA1-PP12 |access-date=21 April 2022 |archive-date=2 August 2023 |archive-url=https://web.archive.org/web/20230802171644/https://books.google.com/books?id=Q80EAAAAYAAJ&pg=RA1-PP12 |url-status=live }} See p. 680.</ref><ref name="OxfordMonographHistory"/> Independently of Gorman and Waters, both students of Dunglison at [[Jefferson Medical College]] in Philadelphia,<ref name="Wexler2008">{{cite book |title=The Woman Who Walked Into the Sea. Huntington's and the Making of a Genetic Disease|year=2008 |publisher=Yale University Press|isbn=978-0-300-10502-5 |page=288 |url=https://archive.org/details/womanwhowalkedin0000wexl|url-access=registration|vauthors=Wexler A, Wexler N |access-date=15 November 2015}}</ref> {{interlanguage link|Johan Christian Lund|no}} (1830–1906) also produced an early description in 1860.<ref name="OxfordMonographHistory"/> He specifically noted that in [[Setesdalen]], a secluded mountain valley in [[Norway]], the high prevalence of dementia was associated with a pattern of jerking movement disorders that ran in families.<ref>{{cite journal | vauthors = Lund JC| title= Chorea Sti Viti i Sætersdalen. Uddrag af Distriktslæge J. C. Lunds Medicinalberetning for 1860| journal=Beretning Om Sundhedstilstanden| year=1860 | pages=137–138}}</ref>
The first thorough description of the disease was by [[George Huntington]] in 1872. Examining the combined medical history of several generations of a family exhibiting similar symptoms, he realized their conditions must be linked; he presented his detailed and accurate definition of the disease as his first paper. Huntington described the exact pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of [[Mendelian inheritance]].
{{blockquote|Of its hereditary nature. When either or both the parents have shown manifestations of the disease ... one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease.<ref name="onchorea"/><ref>{{cite journal | vauthors = Lanska DJ | title = George Huntington (1850–1916) and hereditary chorea | journal = Journal of the History of the Neurosciences | volume = 9 | issue = 1 | pages = 76–89 | date = April 2000 | pmid = 11232352 | doi = 10.1076/0964-704X(200004)9:1;1-2;FT076| s2cid = 22659368 }}</ref>}}
Sir [[William Osler]] was interested in the disorder and chorea in general, and was impressed with Huntington's paper, stating, "In the history of medicine, there are few instances in which a disease has been more accurately, more graphically or more briefly described."<ref>{{cite journal |vauthors=Osler W |title=Historical notes on hereditary chorea |journal=Neurographs |date=1908 |volume=1 |issue=2 |pages=113–116 |url=https://wellcomecollection.org/works/sa3gzpxh/items?canvas=35 |access-date=21 April 2022 |archive-date=21 April 2022 |archive-url=https://web.archive.org/web/20220421021137/https://wellcomecollection.org/works/sa3gzpxh/items?canvas=35 |url-status=live }} See p. 115.
* See also: {{cite journal |vauthors=Osler W |title=Remarks on the varieties of chronic chorea, and a report upon two families of the hereditary form, with one autopsy |journal=The Journal of Nervous and Mental Disease |date=February 1893 |volume=20 |issue=2 |pages=97–111 |url=https://babel.hathitrust.org/cgi/pt?id=hvd.32044103072369&view=1up&seq=113&skin=2021 |access-date=21 April 2022 |archive-date=21 April 2022 |archive-url=https://web.archive.org/web/20220421030701/https://babel.hathitrust.org/cgi/pt?id=hvd.32044103072369&view=1up&seq=113&skin=2021 |url-status=live }} See p. 97.</ref><ref name="OxfordMonographHistory"/><ref>{{cite journal | vauthors = Brody IA, Wilkins RH | title = Huntington's chorea | journal = Archives of Neurology | volume = 17 | issue = 3 | pages = 331 | date = September 1967 | pmid = 4228262 | doi = 10.1001/archneur.1967.00470270109013 }}</ref> Osler's continued interest in HD, combined with his influence in the field of medicine, helped to rapidly spread awareness and knowledge of the disorder throughout the medical community.<ref name="OxfordMonographHistory"/> Great interest was shown by scientists in Europe, including [[Louis Théophile Joseph Landouzy]], [[Désiré-Magloire Bourneville]], [[Camillo Golgi]], and [[Joseph Jules Dejerine]], and until the end of the century, much of the research into HD was European in origin.<ref name="OxfordMonographHistory"/> By the end of the 19th century, research and reports on HD had been published in many countries and the disease was recognized as a worldwide condition.<ref name="OxfordMonographHistory"/>
During the rediscovery of Mendelian inheritance at the turn of the 20th century, HD was used tentatively as an example of autosomal dominant inheritance.<ref name="OxfordMonographHistory"/> English biologist [[William Bateson]] used the pedigrees of affected families to establish that HD had an autosomal dominant inheritance pattern.<ref>{{cite book | vauthors = Bateson W |title=Mendel's Principles of Heredity |date=1909 |publisher=Cambridge University Press |location=Cambridge, England |page=229 |url=https://archive.org/details/mendelsprinciple00bate/page/228/mode/2up}} Bateson refers to "Huntington's disease" as "Hereditary Chorea".</ref><ref name="Wexler2008"/> The strong inheritance pattern prompted several researchers, including [[Smith Ely Jelliffe]], to attempt to trace and connect family members of previous studies.<ref name="OxfordMonographHistory"/> Jelliffe collected information from across [[New York (state)|New York]] and published several articles regarding the genealogy of HD in [[New England]].<ref>{{cite journal |vauthors=Jelliffe SE, Muncey EB, Davenport CB |title=Huntington's Chorea: A Study in Heredity |journal=The Journal of Nervous and Mental Disease |volume=40 |issue=12 |pages=796–799 |year=1913 |doi=10.1097/00005053-191312000-00010 |url=https://zenodo.org/record/1432003 |access-date=19 September 2020 |archive-date=5 April 2022 |archive-url=https://web.archive.org/web/20220405071433/https://zenodo.org/record/1432003 |url-status=live }}</ref> Jelliffe's research roused the interest of his college friend, [[Charles Davenport]], who commissioned Elizabeth Muncey to produce the first field study on the [[East Coast of the United States]] of families with HD and to construct their pedigrees.<ref name="davenportmuncey">{{cite journal |doi=10.1176/ajp.73.2.195 |pmid=<!--none--> |pmc=<!--none--> |vauthors=Davenport CB, Muncey EB |title=Huntington's chorea in relation to heredity and eugenics |journal=American Journal of Insanity|volume=73 |pages=195–222 |year=1916 |issue=2}}</ref> Davenport used this information to document the variable age of onset and range of symptoms of HD; he claimed that most cases of HD in the US could be traced back to a handful of individuals.<ref name="davenportmuncey"/> This research was further embellished in 1932 by [[P. R. Vessie]], who popularized the idea that three brothers who left [[England]] in 1630 bound for [[Boston]] were the progenitors of HD in the US.<ref>{{Cite journal | vauthors=Vessie PR | title=On the transmission of Huntington's chorea for 300 years – the Bures family group | journal=Nervous and Mental Disease | volume=76 | issue=6 | year=1932 | pages=553–573 | url=https://scholar.google.co.uk/scholar?q=info:12mCk4CjFKAJ:scholar.google.com/&output=viewport&pg=1 | access-date=1 April 2009 | doi=10.1097/00005053-193212000-00001 | s2cid=147656032 | archive-date=28 August 2021 | archive-url=https://web.archive.org/web/20210828112759/https://scholar.google.co.uk/scholar_host?q=info%3A12mCk4CjFKAJ%3Ascholar.google.com%2F&hl=en&as_sdt=0%2C5&output=viewport | url-status=live }}</ref> The claim that the earliest progenitors had been established and [[eugenic]] bias of Muncey's, Davenport's, and Vessie's work contributed to misunderstandings and prejudice about HD.<ref name="Wexler2008"/> Muncey and Davenport also popularized the idea that in the past, some with HD may have been thought to be possessed by spirits or victims of [[witchcraft]], and were sometimes [[shunning|shunned]] or [[exile]]d by society.<ref name="pmid12486915">{{cite journal | vauthors = Wexler AR | title = Chorea and community in a nineteenth-century town | journal = Bulletin of the History of Medicine | volume = 76 | issue = 3 | pages = 495–527 | year = 2002 | pmid = 12486915 | doi = 10.1353/bhm.2002.0150 | s2cid = 30791504}}</ref><ref name="pmid6233902">{{cite journal | vauthors = Conneally PM | title = Huntington disease: genetics and epidemiology | journal = American Journal of Human Genetics | volume = 36 | issue = 3 | pages = 506–26 | date = May 1984 | pmid = 6233902 | pmc = 1684448}}</ref> This idea has not been proven. Researchers have found contrary evidence; for instance, the community of the family studied by George Huntington openly accommodated those who exhibited symptoms of HD.<ref name="Wexler2008"/><ref name="pmid12486915"/>
The search for the cause of this condition was enhanced considerably in 1968, when the [[Hereditary Disease Foundation]] (HDF) was created by [[Milton Wexler]], a [[psychoanalyst]] based in [[Los Angeles]], [[California]], whose wife Leonore Sabin had been diagnosed earlier that year with Huntington's disease.<ref name=Wexler2012>{{cite journal | vauthors = Wexler NS | title = Huntington's disease: advocacy driving science | journal = Annual Review of Medicine | volume = 63 | pages = 1–22 | year = 2012 | doi = 10.1146/annurev-med-050710-134457 | pmid = 22248319 | doi-access = free}}</ref> The three brothers of Wexler's wife also had this disease.
The foundation was involved in the recruitment of more than 100 scientists in the US-Venezuela Huntington's Disease Collaborative Project, which over a 10-year period from 1979, worked to locate the genetic cause.<ref name=HDFP/> This was achieved in 1983 when a causal gene was approximately located,<ref name="dnamark"/> and in 1993, the gene was precisely located at chromosome 4 (4p16.3).<ref name="pmid8458085">{{cite journal | vauthors = | title = A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group | journal = Cell | volume = 72 | issue = 6 | pages = 971–983 | date = March 1993 | pmid = 8458085 | doi = 10.1016/0092-8674(93)90585-E | hdl-access = free | s2cid = 802885 | hdl = 2027.42/30901 }}</ref> The study had focused on the populations of two isolated [[Venezuela]]n villages, Barranquitas and Lagunetas, where there was an unusually high prevalence of HD, and involved over 18,000 people, mostly from a single extended family, and resulted in making HD the first [[autosomal]] disease [[Locus (genetics)|locus]] found using [[Genetic linkage#Linkage analysis|genetic linkage analysis]].<ref name="pmid8458085"/><ref name="pmid15931380">{{cite journal | vauthors = Bertram L, Tanzi RE | title = The genetic epidemiology of neurodegenerative disease | journal = The Journal of Clinical Investigation | volume = 115 | issue = 6 | pages = 1449–1457 | date = June 2005 | pmid = 15931380 | pmc = 1137006 | doi = 10.1172/JCI24761 }}</ref> Among other innovations, the project developed [[Genetic marker|DNA-marking]] methods which were an important step in making the [[Human Genome Project]] possible.<ref name=HDFP>{{cite web |url=http://hdfoundation.org/the-venezuela-huntingtons-disease-project/ |title=The Venezuela Huntington's disease project |access-date=8 September 2008 |work=Hereditary Disease Foundation website |publisher=Hereditary Disease Foundation |year=2008 |url-status=dead |archive-url=https://web.archive.org/web/20150810153514/http://hdfoundation.org/the-venezuela-huntingtons-disease-project/ |archive-date=10 August 2015}}</ref>
In the same time, key discoveries concerning the mechanisms of the disorder were being made, including the findings by [[Anita Harding]]'s research group on the effects of the gene's length.<ref name="pmid1303283">{{cite journal | vauthors = La Spada AR, Roling DB, Harding AE, Warner CL, Spiegel R, [[Hausmanowa-Petrusewicz I]], Yee WC, Fischbeck KH | title = Meiotic stability and genotype–phenotype correlation of the trinucleotide repeat in X-linked spinal and bulbar muscular atrophy | journal = Nature Genetics | volume = 2 | issue = 4 | pages = 301–4 | date = December 1992 | pmid = 1303283 | doi = 10.1038/ng1292-301 | s2cid = 6603129}}</ref>
Modelling the disease in various types of animals, such as the [[transgenic]] mouse developed in 1996, enabled larger-scale experiments. As these animals have faster [[metabolism]]s and much shorter lifespans than humans results from experiments are received sooner, speeding research. The 1997 discovery that mHtt fragments [[Protein folding|misfold]] led to the discovery of the nuclear inclusions they cause. These advances have led to increasingly extensive research into the proteins involved with the disease, potential drug treatments, care methods, and the gene itself.<ref name="OxfordMonographHistory"/><ref name=ross-tabrizi />
The networks of care and support that had developed in Venezuela and Colombia during the research projects there in the 1970s through 2000s were eventually eroded by various forces, such as the ongoing [[crisis in Venezuela]] and the death of a lead researcher in Colombia (Jorge Daza Barriga).<ref name="Smith-NYT-2023-05-23">{{cite news |vauthors=Smith JE, Cordero C |title=Sought Out by Science, and Then Forgotten |url=https://www.nytimes.com/2023/05/23/science/huntingtons-disease-colombia.html |access-date=2023-05-23 |work=The New York Times |date=2023-05-23 |archive-date=23 May 2023 |archive-url=https://web.archive.org/web/20230523222910/https://www.nytimes.com/2023/05/23/science/huntingtons-disease-colombia.html |url-status=live }}</ref> Doctors are working toward rekindling these networks because the people who have contributed to the science of Huntington's disease by participating in these studies deserve adequate follow-up care; societies elsewhere in the world who benefit from the scientific advances thus achieved owe at least that much to those who participated in the research.<ref name="Smith-NYT-2023-05-23"/>
The condition was formerly called Huntington's chorea, but this term has been replaced by Huntington's disease because not all patients develop chorea and due to the importance of cognitive and behavioral problems.<ref name=huntchorea>{{cite web|title=What is HD?|url=http://www.hda.org.uk/huntingtons/what-is-hd.html|publisher=Huntington's disease association|access-date=18 December 2011|url-status=dead|archive-url=https://web.archive.org/web/20111213133025/http://www.hda.org.uk/huntingtons/what-is-hd.html|archive-date=13 December 2011}}</ref>
==Society and culture==
{{See also|List of Huntington's disease media depictions}}
===Ethics===
{{See also|In vitro fertilisation#Ethics|Stem cell controversy}}
[[Genetic testing]] for Huntington's disease has raised several ethical issues. The issues for genetic testing include defining how mature an individual should be before being considered eligible for testing, ensuring the confidentiality of results, and whether companies should be allowed to use test results for decisions on employment, life insurance or other financial matters. There was controversy when [[Charles Davenport]] proposed in 1910 that [[compulsory sterilization]] and [[immigration]] control be used for people with certain diseases, including HD, as part of the [[eugenics]] movement.<ref>{{cite journal | vauthors = Davenport CB | title = Huntington's Chorea in Relation to Heredity and Eugenics | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 1 | issue = 5 | pages = 283–5 | date = May 1915 | pmid = 16575999 | pmc = 1090803 | doi = 10.1073/pnas.1.5.283 | bibcode = 1915PNAS....1..283D| doi-access = free }}</ref> [[In vitro fertilization]] has some issues regarding its use of embryos. Some HD research has ethical issues due to its use of [[Ethics of animal research|animal testing]] and [[embryonic stem cells]].<ref>{{cite journal | vauthors = Rollin BE | title = The regulation of animal research and the emergence of animal ethics: a conceptual history | url = https://org.uib.no/dyreavd/handouts/Rollin__B._2006._Animal_Research_Regulation_in_Theoret._Medicin_....PDF | journal = Theoretical Medicine and Bioethics | volume = 27 | issue = 4 | pages = 285–304 | year = 2006 | pmid = 16937023 | doi = 10.1007/s11017-006-9007-8 | s2cid = 18620094 | access-date = 1 December 2019 | archive-date = 8 October 2020 | archive-url = https://web.archive.org/web/20201008152801/https://org.uib.no/dyreavd/handouts/Rollin__B._2006._Animal_Research_Regulation_in_Theoret._Medicin_....PDF | url-status = dead }}</ref><ref name="pmid18181947">{{cite journal | vauthors = Doerflinger RM | title = The problem of deception in embryonic stem cell research | journal = Cell Proliferation | volume = 41 | issue = Suppl 1 | pages = 65–70 | date = February 2008 | pmid = 18181947 | doi = 10.1111/j.1365-2184.2008.00492.x | pmc = 6496399}}</ref>
The development of an accurate diagnostic test for Huntington's disease has caused social, legal, and ethical concerns over access to and use of a person's results.<ref>{{cite journal | vauthors = Chapman MA | title = Predictive testing for adult-onset genetic disease: ethical and legal implications of the use of linkage analysis for Huntington disease | journal = American Journal of Human Genetics | volume = 47 | issue = 1 | pages = 1–3 | date = July 1990 | pmid = 2140926 | pmc = 1683745}}</ref><ref>{{cite journal | vauthors = Huggins M, Bloch M, Kanani S, Quarrell OW, Theilman J, Hedrick A, Dickens B, Lynch A, Hayden M | title = Ethical and legal dilemmas arising during predictive testing for adult-onset disease: the experience of Huntington disease | journal = American Journal of Human Genetics | volume = 47 | issue = 1 | pages = 4–12 | date = July 1990 | pmid = 1971997 | pmc = 1683755}}</ref>
Many guidelines and testing procedures have strict procedures for disclosure and confidentiality to allow individuals to decide when and how to receive their results and also to whom the results are made available.<ref name="lancet07" /> Insurance companies and businesses are faced with the question of whether to use genetic test results when assessing an individual, such as for life insurance or employment. The United Kingdom's insurance companies agreed with the [[Department of Health and Social Care]] that until 2017 customers would not need to disclose predictive genetics tests to them, but this agreement explicitly excluded the government-approved test for Huntington's when writing policies with a value over {{GBP|500,000}}.<ref>{{cite press release |url=https://www.abi.org.uk/News/News-releases/2011/04/Insurance-Genetics-Moratorium-extended-to-2017 |title=Insurance Genetics Moratorium extended to 2017 |access-date=13 January 2016 |publisher=Association of British Insurers |date=5 April 2011 |url-status=live |archive-url=https://web.archive.org/web/20160304043951/https://www.abi.org.uk/News/News-releases/2011/04/Insurance-Genetics-Moratorium-extended-to-2017 |archive-date=4 March 2016}}</ref><ref name="Expert backs gene test disclosure">{{cite news|title=Expert backs gene test disclosure|url=http://news.bbc.co.uk/1/hi/health/6731623.stm|publisher=BBC article|date=7 June 2007|url-status=live|archive-url=https://web.archive.org/web/20080226155310/http://news.bbc.co.uk/1/hi/health/6731623.stm|archive-date=26 February 2008}}</ref> As with other untreatable genetic conditions with a later onset, it is ethically questionable to perform presymptomatic testing on a child or adolescent since there would be no medical benefit for that individual. There is consensus for testing only individuals who are considered cognitively mature, although there is a counter-argument that parents have a right to make the decision on their child's behalf. With the lack of effective treatment, testing a person under [[Age of majority|legal age]] who is not judged to be [[Gillick competence|competent]] is considered unethical in most cases.<ref name="pmid2136787"/><ref name="pmid8950670">{{cite journal | vauthors = Binedell J, Soldan JR, Scourfield J, Harper PS | title = Huntington's disease predictive testing: the case for an assessment approach to requests from adolescents | journal = Journal of Medical Genetics | volume = 33 | issue = 11 | pages = 912–8 | date = November 1996 | pmid = 8950670 | pmc = 1050784 | doi = 10.1136/jmg.33.11.912}}</ref><ref name="pmid18704981">{{cite journal | vauthors = Borry P, Goffin T, Nys H, Dierickx K | title = Predictive genetic testing in minors for adult-onset genetic diseases | journal = The Mount Sinai Journal of Medicine, New York | volume = 75 | issue = 3 | pages = 287–96 | year = 2008 | pmid = 18704981 | doi = 10.1002/msj.20038 | url = https://lirias.kuleuven.be/handle/123456789/223776}}</ref>
There are ethical concerns related to [[Prenatal diagnosis|prenatal genetic testing]] or [[preimplantation genetic diagnosis]] to ensure a child is not born with a given disease.<ref name="pmid9949442">{{cite journal | vauthors = Braude PR, De Wert GM, Evers-Kiebooms G, Pettigrew RA, Geraedts JP | title = Non-disclosure preimplantation genetic diagnosis for Huntington's disease: practical and ethical dilemmas | journal = Prenatal Diagnosis | volume = 18 | issue = 13 | pages = 1422–6 | date = December 1998 | pmid = 9949442 | doi = 10.1002/(SICI)1097-0223(199812)18:13<1422::AID-PD499>3.0.CO;2-R| s2cid = 39977672 }}</ref> For example, prenatal testing raises the issue of selective abortion, a choice considered unacceptable by some.<ref name="pmid9949442"/> As it is a dominant disease, there are difficulties in situations in which a parent does not want to know his or her own diagnosis. This would require parts of the process to be kept secret from the parent.<ref name="pmid9949442"/>
===Support organizations===
[[File:Woody Guthrie NYWTS.jpg|thumb|upright|The death of [[Woody Guthrie]] led to the foundation of the [[Huntington's Disease Society of America|Committee to Combat Huntington's Disease]]|alt=A black-and-white photograph taken indoors of Woody Guthrie wearing pinstripe trousers, a tartan shirt with the top button undone, and a cap. He sits playing a six-string acoustic guitar, which is supported on one knee, and he appears to be singing. 'This Machine Kills Fascists' is written in all capital letters on a rectangular sticker, which is fixed onto the guitar.]]
In 1968, after experiencing HD in his wife's family, Dr. Milton Wexler was inspired to start the [[Hereditary Disease Foundation]] (HDF), with the aim of curing genetic illnesses by coordinating and supporting research.<ref name="HDF-About Us"/> The foundation and Wexler's daughter, [[Nancy Wexler]], were key parts of the research team in Venezuela which discovered the HD gene.<ref name="HDF-About Us"/>
At roughly the same time as the HDF formed, [[Marjorie Guthrie]] helped to found the committee to Combat Huntington's Disease (now the [[Huntington's Disease Society of America]]), after her husband, folk singer-songwriter [[Woody Guthrie]] died from complications of HD.<ref name="HDSA12020"/>
Since then, support and research organizations have formed in many countries around the world and have helped to increase public awareness of HD. A number of these collaborate in umbrella organizations, like the International Huntington Association and the European HD network.<ref>{{cite web |url=http://www.huntington-assoc.com/ |title=The International Huntington Association |access-date=3 April 2009 |publisher=International Huntington Association |year=2013 |url-status=live |archive-url=https://web.archive.org/web/20090418154858/http://www.huntington-assoc.com/ |archive-date=18 April 2009}}</ref> Many support organizations hold an annual HD awareness event, some of which have been endorsed by their respective governments. For example, 6 June is designated "National Huntington's Disease Awareness Day" by the [[United States Senate|US Senate]].<ref>{{cite web|url=https://www.congress.gov/bill/110th-congress/senate-resolution/531|title=US Senate s. resolution 531|access-date=10 August 2008|work=S. Res. 531|publisher=US Senate|date=6 April 2008|url-status=live|archive-url=https://web.archive.org/web/20151117063126/https://www.congress.gov/bill/110th-congress/senate-resolution/531|archive-date=17 November 2015}}</ref> Many organizations exist to support and inform those affected by HD, including the [[Huntington's Disease Association]] in the UK. The largest funder of research is provided by the [[CHDI Foundation|Cure Huntington's Disease Initiative Foundation]] (CHDI).<ref name=chdi-nature-moneytree>{{cite journal| vauthors = Odling-Smee L|title=Biomedical philanthropy: The money tree|journal=Nature|date=17 May 2007|volume=447|issue=7142|page=251|doi=10.1038/447251a|bibcode=2007Natur.447..251.|s2cid=4357517|doi-access=free}}</ref>
==Research directions==
Research into the mechanism of HD is focused on identifying the functioning of Htt, how mHtt differs or interferes with it, and the brain pathology that the disease produces.<ref name="NIHHope2020">{{cite web |title=Huntington's Disease: Hope Through Research |url=https://www.ninds.nih.gov/disorders/patient-caregiver-education/hope-through-research/huntingtons-disease-hope-through |website=www.ninds.nih.gov |access-date=16 November 2020 |archive-date=25 October 2020 |archive-url=https://web.archive.org/web/20201025060231/https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Huntingtons-Disease-Hope-Through |url-status=live }}</ref> Research is conducted using ''[[in vitro]]'' methods, [[genetically modified animal]]s, (also called [[transgene|transgenic animal models]]), and human volunteers. Animal models are critical for understanding the fundamental mechanisms causing the disease, and for supporting the early stages of [[drug development]].<ref name=ross-tabrizi /> The identification of the causative gene has enabled the development of many [[genetically modified organism]]s including [[nematode]]s (roundworms), ''[[Drosophila melanogaster|Drosophila]]'' [[Drosophila melanogaster|fruit flies]], and [[genetically modified mammal]]s including mice, rats, sheep, pigs and monkeys that express mutant huntingtin and develop progressive [[neurodegeneration]] and HD-like symptoms.<ref name=ross-tabrizi>{{cite journal | vauthors = Ross CA, Tabrizi SJ | title = Huntington's disease: from molecular pathogenesis to clinical treatment | journal = The Lancet. Neurology | volume = 10 | issue = 1 | pages = 83–98 | date = January 2011 | pmid = 21163446 | doi = 10.1016/S1474-4422(10)70245-3 | s2cid = 17488174}}</ref>
Research is being conducted using many approaches to either prevent Huntington's disease or slow its progression.<ref name="NIHHope2020"/> Disease-modifying strategies can be broadly grouped into three categories: reducing the level of the mutant huntingtin protein (including [[gene splicing]] and [[gene silencing]]); approaches aimed at improving neuronal survival by reducing the harm caused by the protein to specific cellular pathways and mechanisms (including [[protein homeostasis]] and [[histone deacetylase inhibitor|histone deacetylase inhibition]]); and strategies to replace lost neurons. In addition, novel therapies to improve brain functioning are under development; these seek to produce symptomatic rather than [[Disease-modifying treatment|disease-modifying therapies]], and include [[phosphodiesterase inhibitors]].<ref name="ReferenceA">{{cite journal | vauthors = Wild EJ, Tabrizi SJ | title = Targets for future clinical trials in Huntington's disease: what's in the pipeline? | journal = Movement Disorders | volume = 29 | issue = 11 | pages = 1434–45 | date = September 2014 | pmid = 25155142 | pmc = 4265300 | doi = 10.1002/mds.26007}}</ref><ref name="20170503TOI">{{cite news| vauthors = Solomon S |title=Taube to fund $3m Huntington's disease research in US|url=http://www.timesofisrael.com/taube-to-fund-3m-huntingtons-disease-research-in-us/|access-date=5 May 2017|work=[[The Times of Israel]]|date=3 May 2017|url-status=live|archive-url=https://web.archive.org/web/20170503135635/http://www.timesofisrael.com/taube-to-fund-3m-huntingtons-disease-research-in-us/|archive-date=3 May 2017}}</ref>
The [[CHDI Foundation]] funds a great many research initiatives providing many publications.<ref name="CHDIA">{{cite web |title=Scientific Publications {{!}} CHDI Foundation |url=https://chdifoundation.org/scientific-publications/ |website=chdifoundation.org |access-date=12 December 2021 |archive-date=12 December 2021 |archive-url=https://web.archive.org/web/20211212175055/https://chdifoundation.org/scientific-publications/ |url-status=live }}</ref> The CHDI foundation is the largest funder of Huntington's disease research globally and aims to find and develop drugs that will slow the progression of HD.<ref name=chdi-nature-moneytree/><ref name="CHDI">{{cite web |title=CHDI Foundation |url=https://chdifoundation.org/ |website=chdifoundation.org |access-date=13 November 2020 |archive-date=14 November 2020 |archive-url=https://web.archive.org/web/20201114214504/https://chdifoundation.org/ |url-status=live }}</ref> CHDI was formerly known as the High Q Foundation. In 2006, it spent $50 million on Huntington's disease research.<ref name=chdi-nature-moneytree /> CHDI collaborates with many academic and commercial laboratories globally and engages in oversight and management of research projects as well as funding.<ref name=chdi-nature-philanthropy>{{cite journal | vauthors = Check E | title = Biomedical philanthropy: love or money | journal = Nature | volume = 447 | issue = 7142 | pages = 252–3 | date = May 2007 | pmid = 17507955 | doi = 10.1038/447252a | bibcode = 2007Natur.447..252C| s2cid = 4318384 | doi-access = free }}</ref>
===Reducing huntingtin production===
[[Gene silencing]] aims to reduce the production of the mutant protein, since HD is caused by a [[Genetic disorder#Single-gene|single dominant gene]] encoding a toxic protein. Gene silencing experiments in mouse models have shown that when the expression of mHtt is reduced, symptoms improve.<ref name=munoz-bates-jci>{{cite journal | vauthors = Munoz-Sanjuan I, Bates GP | title = The importance of integrating basic and clinical research toward the development of new therapies for Huntington disease | journal = The Journal of Clinical Investigation | volume = 121 | issue = 2 | pages = 476–83 | date = February 2011 | pmid = 21285520 | pmc = 3026740 | doi = 10.1172/JCI45364}}</ref> The safety of [[RNA interference]], and [[allele-specific oligonucleotide]] (ASO) methods of gene silencing has been demonstrated in mice and the larger primate macaque brain.<ref>{{cite journal | vauthors = McBride JL, Pitzer MR, Boudreau RL, Dufour B, Hobbs T, Ojeda SR, Davidson BL | title = Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington's disease | journal = Molecular Therapy | volume = 19 | issue = 12 | pages = 2152–62 | date = December 2011 | pmid = 22031240 | pmc = 3242667 | doi = 10.1038/mt.2011.219}}</ref><ref>{{cite journal | vauthors = Kordasiewicz HB, Stanek LM, Wancewicz EV, Mazur C, McAlonis MM, Pytel KA, Artates JW, Weiss A, Cheng SH, Shihabuddin LS, Hung G, Bennett CF, Cleveland DW | title = Sustained therapeutic reversal of Huntington's disease by transient repression of huntingtin synthesis | journal = Neuron | volume = 74 | issue = 6 | pages = 1031–44 | date = June 2012 | pmid = 22726834 | pmc = 3383626 | doi = 10.1016/j.neuron.2012.05.009 }}</ref> Allele-specific silencing attempts to silence mutant htt while leaving wild-type Htt untouched. One way of accomplishing this is to identify polymorphisms present on only one allele and produce gene silencing drugs that target polymorphisms in only the mutant allele.<ref name=sah-aronin>{{cite journal | vauthors = Barnes DW, Whitley RJ | title = Antiviral therapy and pulmonary disease | journal = Chest | volume = 91 | issue = 2 | pages = 246–51 | date = February 1987 | doi=10.1378/chest.91.2.246| pmid = 3026739 }}</ref> The first gene silencing trial involving humans with HD began in 2015, testing the safety of IONIS-HTTRx, produced by [[Ionis Pharmaceuticals]] and led by [[UCL Institute of Neurology]].<ref name=bbc-news-gene-silencing-trial-starts>{{cite news|title=Landmark Huntington's trial starts|url=https://www.bbc.com/news/health-34552041|access-date=19 October 2015|url-status=live|archive-url=https://web.archive.org/web/20151021214158/http://www.bbc.com/news/health-34552041|archive-date=21 October 2015}}</ref><ref>{{cite web|title=Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IONIS-HTTRx in Patients With Early Manifest Huntington's Disease - Full Text View |url=https://clinicaltrials.gov/ct2/show/NCT02519036|publisher=ClinicalTrials.gov |access-date=18 April 2016|url-status=live|archive-url=https://web.archive.org/web/20150929080905/https://clinicaltrials.gov/ct2/show/NCT02519036|archive-date=29 September 2015}}</ref> Mutant huntingtin was detected and quantified for the first time in [[cerebrospinal fluid]] from Huntington's disease mutation-carriers in 2015 using a novel "single-molecule counting" [[immunoassay]],<ref name="mhtt-detection-jci-2015">{{cite journal | vauthors = Wild EJ, Boggio R, Langbehn D, Robertson N, Haider S, Miller JR, Zetterberg H, Leavitt BR, Kuhn R, Tabrizi SJ, Macdonald D, Weiss A | title = Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington's disease patients | journal = The Journal of Clinical Investigation | volume = 125 | issue = 5 | pages = 1979–86 | date = May 2015 | pmid = 25844897 | pmc = 4463213 | doi = 10.1172/jci80743}}</ref> providing a direct way to assess whether huntingtin-lowering treatments are achieving the desired effect.<ref>{{cite journal | vauthors = Chase A | title = Huntington disease: cerebrospinal fluid and MRI biomarkers for prodromal HD | journal = Nature Reviews Neurology | volume = 11 | issue = 5 | page = 245 | date = May 2015 | pmid = 25896083 | doi = 10.1038/nrneurol.2015.63 | s2cid = 38300571}}</ref><ref>{{cite journal | vauthors = Keiser MS, Kordasiewicz HB, McBride JL | title = Gene suppression strategies for dominantly inherited neurodegenerative diseases: lessons from Huntington's disease and spinocerebellar ataxia | journal = Human Molecular Genetics | volume = 25 | issue = R1 | pages = R53–64 | date = April 2016 | pmid = 26503961 | pmc = 4802374 | doi = 10.1093/hmg/ddv442}}</ref> A phase 3 trial of this compound, renamed tominersen and sponsored by [[Hoffmann-La Roche|Roche Pharmaceuticals]], began in 2019 but was halted in 2021 after the safety monitoring board concluded that the risk-benefit balance was unfavourable.<ref>{{Cite journal| vauthors = Kwon D |date=2021-04-06|title=Genetic therapies offer new hope against incurable brain diseases|journal=Nature|language=en|volume=592|issue=7853|pages=180–183|doi=10.1038/d41586-021-00870-x|pmid=33824521|bibcode=2021Natur.592..180K|doi-access=free}}</ref> A huntingtin-lowering gene therapy trial run by Uniqure began in 2019, and several trials of orally administered huntingtin-lowering splicing modulator compounds have been announced.<ref>{{Cite web|title=Huntington's disease clinical trial round up|url=https://en.hdbuzz.net/303|access-date=2021-05-05|website=HDBuzz|language=en|archive-date=5 May 2021|archive-url=https://web.archive.org/web/20210505134715/https://en.hdbuzz.net/303|url-status=live}}</ref> [[Gene splicing]] techniques are being looked at to try to repair a genome with the erroneous gene that causes HD, using tools such as [[CRISPR#Cas9|CRISPR/Cas9]].<ref name="20170503TOI" />
===Increasing huntingtin clearance===
Another strategy to reduce the level of mutant huntingtin is to increase the rate at which cells are able to clear it.<ref name=":0">{{cite journal | vauthors = Djajadikerta A, Keshri S, Pavel M, Prestil R, Ryan L, Rubinsztein DC | title = Autophagy Induction as a Therapeutic Strategy for Neurodegenerative Diseases | journal = Journal of Molecular Biology | volume = 432 | issue = 8 | pages = 2799–2821 | date = April 2020 | pmid = 31887286 | doi = 10.1016/j.jmb.2019.12.035 | series = Autophagy in Neurodegenerative Diseases | s2cid = 209518157 | url = https://www.repository.cam.ac.uk/handle/1810/299796 | access-date = 20 June 2023 | archive-date = 23 May 2022 | archive-url = https://web.archive.org/web/20220523210125/https://www.repository.cam.ac.uk/handle/1810/299796 | url-status = live }}</ref> As mHtt (and many other [[Protein aggregation|protein aggregates]]) are degraded by [[autophagy]], increasing the rate of autophagy has the potential to reduce levels of mHtt and thereby ameliorate disease.<ref>{{cite journal | vauthors = Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O'Kane CJ, Rubinsztein DC | display-authors = 6 | title = Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease | journal = Nature Genetics | volume = 36 | issue = 6 | pages = 585–595 | date = June 2004 | pmid = 15146184 | doi = 10.1038/ng1362 | s2cid = 7749825 | doi-access = free }}</ref> Pharmacological and genetic inducers of autophagy have been tested in a variety of Huntington's disease models; many have been shown to reduce mHtt levels and decrease toxicity.<ref name=":0" />
===Improving cell survival===
Among the approaches aimed at improving cell survival in the presence of mutant huntingtin are correction of [[transcriptional regulation]] using [[histone deacetylase inhibitor]]s, modulating [[Protein aggregation|aggregation]] of huntingtin, improving [[metabolism]] and [[Mitochondria|mitochondrial function]] and restoring function of [[synapses]].<ref name=munoz-bates-jci/>
===Neuronal replacement===
[[Stem-cell therapy]] is used to replace damaged neurons by transplantation of [[stem cell]]s into affected regions of the brain. Experiments in animal models (rats and mice only) have yielded positive results.<ref name="Holley Kamdjou Reidling Fury pp. 329–342">{{cite journal | vauthors = Holley SM, Kamdjou T, Reidling JC, Fury B, Coleal-Bergum D, Bauer G, Thompson LM, Levine MS, Cepeda C | display-authors = 6 | title = Therapeutic effects of stem cells in rodent models of Huntington's disease: Review and electrophysiological findings | journal = CNS Neuroscience & Therapeutics | volume = 24 | issue = 4 | pages = 329–342 | date = April 2018 | pmid = 29512295 | pmc = 6489814 | doi = 10.1111/cns.12839 | publisher = Wiley }}</ref>
Whatever their future therapeutic potential, stem cells are already a valuable tool for studying Huntington's disease in the laboratory.<ref>{{cite journal | vauthors = Cundiff PE, Anderson SA | title = Impact of induced pluripotent stem cells on the study of central nervous system disease | journal = Current Opinion in Genetics & Development | volume = 21 | issue = 3 | pages = 354–61 | date = June 2011 | pmid = 21277194 | pmc = 3932563 | doi = 10.1016/j.gde.2011.01.008}}</ref>
===Clinical trials===
In 2020, there were 197 [[clinical trial]]s related to varied therapies and biomarkers for Huntington's disease listed as either underway, recruiting or newly completed.<ref name="Trials">{{cite web |title=Search of: Huntington Disease - List Results - ClinicalTrials.gov |url=https://clinicaltrials.gov/ct2/results?cond=Huntington+Disease&term=&cntry=&state=&city=&dist= |website=clinicaltrials.gov |language=en |access-date=16 November 2020 |archive-date=11 November 2021 |archive-url=https://web.archive.org/web/20211111192242/https://clinicaltrials.gov/ct2/results?cond=Huntington+Disease&term=&cntry=&state=&city=&dist= |url-status=live }}</ref> Compounds [[clinical trial|trialled]], that have failed to prevent or slow the progression of Huntington's disease include [[remacemide]], [[coenzyme Q10]], [[riluzole]], [[creatine]], [[minocycline]], [[ethyl-EPA]], [[phenylbutyrate]] and [[dimebon]].<ref>{{cite web|title=Completed Clinical Trials|url=http://www.huntington-study-group.org/ClinicalResearch/CompletedClinicalTrials/tabid/65/Default.aspx|publisher=Huntington Study Group|access-date=4 February 2012|archive-url=https://web.archive.org/web/20120628020904/http://www.huntington-study-group.org/ClinicalResearch/CompletedClinicalTrials/tabid/65/Default.aspx|archive-date=28 June 2012}}</ref>
==See also==
* {{Portal inline|Medicine}}
==References==
{{reflist|colwidth=30em}}
==External links==
<!-- External links should be limited to major international organizations and the support organizations of English-speaking nations. Sites should be up-to-date and reliable. Please discuss changes at the talk page to ensure this section does not become unmanageable. -->
{{sister project links|collapsible=true|q=no}}
* {{curlie|Health/Conditions_and_Diseases/Neurological_Disorders/Huntington%27s_Disease/}}
* [http://hopes.stanford.edu/ HOPES project] – [[HOPES|Stanford University's HD information project]]
* [http://hdbuzz.net/ HDBuzz] – HD research news written by scientists in plain language
* [http://hddrugworks.org/ HD Drug Works] – news about current treatments and planned trials
{{Medical condition classification and resources
| DiseasesDB = 6060
| ICD10 = {{ICD10|G|10||g|10}}, {{ICD10|F|02|2|f|00}}
| ICD9 = {{ICD9|333.4}}, {{ICD9|294.1}}
| ICDO =
| OMIM = 143100
| MedlinePlus = 000770
| eMedicineSubj = article
| eMedicineTopic = 1150165
| eMedicine_mult = {{eMedicine2|article|792600}} {{eMedicine2|article|289706}}
| MeshID = D006816
| GeneReviewsName=Huntington Disease
| GeneReviewsNBK=NBK1305
| Orphanet=399
}}
{{Mental and behavioural disorders|selected = neurological}}
{{Diseases of the nervous system}}
{{Trinucleotide repeat disorders}}
{{authority control}}
[[Category:Huntington's disease| ]]
[[Category:Autosomal dominant disorders]]
[[Category:Disorders causing seizures]]
[[Category:Extrapyramidal and movement disorders]]
[[Category:Genetic diseases and disorders]]
[[Category:Wikipedia medicine articles ready to translate]]
[[Category:Wikipedia neurology articles ready to translate]]
[[Category:Systemic atrophies primarily affecting the central nervous system]]
[[Category:Trinucleotide repeat disorders]]
[[Category:Diseases named for discoverer]]' |
New page wikitext, after the edit (new_wikitext) | '{{short description|Inherited neurodegenerative disorder}}
{{Use dmy dates|date=December 2017}}
{{Use American English|date=December 2017}}
{{Infobox medical condition (new)
| name = Huntington's disease
| image = Neuron with mHtt inclusion.jpg
| alt = Several neurons colored yellow and having a large central core with up to two dozen tendrils branching out of them, the core of the neuron in the foreground contains an orange blob about a quarter of its diameter
| caption = An edited microscopic image of a [[medium spiny neuron]] (yellow) with an [[Inclusion bodies|inclusion body]] (orange), which occurs as part of the disease process (image width 360 [[micrometre|µm]])
| synonyms = Huntington's chorea
| field = [[Neurology]]
| symptoms = Problems with motor skills, including coordination and gait, mood, and mental abilities<ref name="Day20152"/><ref name=War2020/>
| complications = [[Pneumonia]], [[heart disease]], physical injury from falls, [[suicide]]<ref name=Frank2014/>
| onset = 30{{ndash}}50 years old<ref name=NIH2020/>
| duration = Long term<ref name=NIH2020/>
| causes = [[Genetics|Genetic]] (inherited or new mutation)<ref name=NIH2020/>
| risks =
| diagnosis = [[Genetic testing]]<ref name=Durr2012/>
| differential = [[Sydenham's chorea]], [[benign hereditary chorea]], [[lupus]], [[paraneoplastic syndrome]], [[Wilson's disease]]<ref>{{cite book| vauthors = Ferri FF |title=Ferri's differential diagnosis: a practical guide to the differential diagnosis of symptoms, signs, and clinical disorders|date=2010|publisher=Elsevier/Mosby|location=Philadelphia, PA|isbn=978-0323076999|page=Chapter H|edition=2nd}}</ref>
| prevention =
| treatment = [[Supportive care]]<ref name=War2020/>
| medication = [[Tetrabenazine]]<ref name=Frank2014/>
| prognosis = 15{{ndash}}20 years from onset of symptoms<ref name=NIH2020/>
| frequency = 4{{ndash}}15 in 100,000 (European descent)<ref name="Day20152"/>
| named after = [[George Huntington]]
}}
<!-- Definitions and symptoms -->
'''Huntington's disease''' ('''HD'''), also known as '''Huntington's chorea''', is an incurable [[neurodegenerative disease]]<ref>{{cite web | url=https://www.nhs.uk/conditions/huntingtons-disease/treatment/ | title=Huntington's disease - Treatment and support | date=23 October 2017 | access-date=6 May 2023 | archive-date=6 May 2023 | archive-url=https://web.archive.org/web/20230506014916/https://www.nhs.uk/conditions/huntingtons-disease/treatment/ | url-status=live }}</ref> that is mostly [[Genetic disorder#Autosomal dominant|inherited]].<ref name=msuRussia2018>{{cite web |title=Molecular Pathogenesis in Huntington's Disease |url=http://protein.bio.msu.ru/biokhimiya/contents/v83/full/83091299.html#Ref4 |website=protein.bio.msu.ru |access-date=8 November 2020 |archive-date=13 November 2020 |archive-url=https://web.archive.org/web/20201113121719/http://protein.bio.msu.ru/biokhimiya/contents/v83/full/83091299.html#Ref4 |url-status=live }}</ref> The earliest symptoms are often subtle problems with mood or mental/psychiatric abilities.<ref name="Gene Therapy for Neurodegenerative">{{cite journal | vauthors = Sudhakar V, Richardson RM | title = Gene Therapy for Neurodegenerative Diseases | journal = Neurotherapeutics | volume = 16 | issue = 1 | pages = 166–175 | date = January 2019 | pmid = 30542906 | pmc = 6361055 | doi = 10.1007/s13311-018-00694-0 }}</ref><ref name="Day20152"/> A general [[Ataxia|lack of coordination]] and an unsteady [[human gait|gait]] often follow.<ref name=War2020>{{cite journal | title = Huntington Disease | journal = GeneReviews | date = 2020 | pmid = 20301482 | veditors = Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A | last1 = Adam | first1 = M. P. | last2 = Mirzaa | first2 = G. M. | last3 = Pagon | first3 = R. A. | last4 = Wallace | first4 = S. E. | author5 = Bean LJH | last6 = Gripp | first6 = K. W. | last7 = Amemiya | first7 = A. | last8 = Caron | first8 = N. S. | author9 = Wright GEB | last10 = Hayden | first10 = M. R. }}</ref> It is also a [[Basal ganglia disease#Huntington's disease|basal ganglia disease]] causing a [[hyperkinesia|hyperkinetic]] [[movement disorder]] known as [[chorea]].<ref name="Robbins">{{cite book |title=Robbins basic pathology |vauthors=Kumar, Abbas A, Aster J |date=2018 |publisher=Elsevier |isbn=9780323353175 |edition=Tenth |location=Philadelphia, Pennsylvania |page=879}}</ref><ref name="Purves">{{cite book | vauthors = Purves D |title=Neuroscience |date=2012 |location=Sunderland, Mass. |isbn=9780878936953 |page=415 |edition=5th}}</ref> As the disease advances, uncoordinated, involuntary body movements of chorea become more apparent.<ref name="Day20152"/> Physical abilities gradually worsen until [[Motor coordination|coordinated movement]] becomes difficult and the person is unable to talk.<ref name="Day20152"/><ref name=War2020/> [[Neurocognition|Mental abilities]] generally decline into [[dementia]], depression, apathy, and impulsivity at times.<ref name="Gene Therapy for Neurodegenerative"/><ref name="The Biology of Huntingtin">{{cite journal | vauthors = Saudou F, Humbert S | title = The Biology of Huntingtin | journal = Neuron | volume = 89 | issue = 5 | pages = 910–926 | date = March 2016 | pmid = 26938440 | doi = 10.1016/j.neuron.2016.02.003 | s2cid = 8272667 | doi-access = free }}</ref><ref name="Frank2014" /> The specific symptoms vary somewhat between people.<ref name="Day20152"/> Symptoms usually begin between 30 and 50 years of age, and can start at any age but are usually seen around the age of 40.<ref name="The Biology of Huntingtin"/><ref name="Gene Therapy for Neurodegenerative"/><ref name="Frank2014" /><ref name="NIH2020">{{cite web |title=Huntington's Disease Information Page {{!}} National Institute of Neurological Disorders and Stroke |url=https://www.ninds.nih.gov/Disorders/All-Disorders/Huntingtons-Disease-Information-Page |website=www.ninds.nih.gov |access-date=14 December 2020 |archive-date=13 December 2020 |archive-url=https://web.archive.org/web/20201213025651/https://www.ninds.nih.gov/Disorders/All-Disorders/Huntingtons-Disease-Information-Page |url-status=live }}</ref> The disease may develop earlier in [[Anticipation (genetics)|each successive generation]].<ref name="Day20152"/> About eight percent of cases start before the age of 20 years, and are known as ''juvenile HD'', which typically present with the [[hypokinesia|slow movement symptoms]] of [[Parkinson's disease]] rather than those of chorea.<ref name=Frank2014/>
<!-- Cause and diagnosis -->
HD is typically [[Genetic disorder#Autosomal dominant|inherited from an affected parent]], who carries a [[mutation]] in the [[huntingtin gene]] (HTT).<ref name=NIH2020/> However, up to 10% of cases are due to a new mutation.<ref name="Day20152"/> The huntingtin gene provides the genetic information for [[huntingtin protein]] (Htt).<ref name="Day20152"/> Expansion of [[CAG repeat]]s of [[cytosine]]-[[adenine]]-[[guanine]] (known as a [[trinucleotide repeat expansion]]) in the gene coding for the huntingtin protein results in an abnormal mutant protein (mHtt), which gradually damages [[neuron|brain cells]] through a number of possible mechanisms.<ref name=msuRussia2018/><ref name="hdprimer"/> Diagnosis is by [[genetic testing]], which can be carried out at any time, regardless of whether or not symptoms are present.<ref name=Durr2012>{{cite journal | vauthors = Durr A, Gargiulo M, Feingold J | title = The presymptomatic phase of Huntington disease | journal = Revue Neurologique | volume = 168 | issue = 11 | pages = 806–808 | date = November 2012 | pmid = 22902173 | doi = 10.1016/j.neurol.2012.07.003 }}</ref> This fact raises several ethical debates: the age at which an individual is considered mature enough to choose testing; whether parents have the right to have their children tested; and managing confidentiality and disclosure of test results.<ref name=War2020/>
<!-- Treatment, epidemiology, and prognosis -->
No cure for HD is known, and full-time care is required in the later stages.<ref name=War2020/> Treatments can relieve some symptoms and in some, improve [[quality of life (healthcare)|quality of life]].<ref name=Frank2014/> The best evidence for treatment of the movement problems is with [[tetrabenazine]].<ref name=Frank2014/> HD affects about 4 to 15 in 100,000 people of European descent.<ref name="Day20152">{{cite journal | vauthors = Dayalu P, Albin RL | title = Huntington disease: pathogenesis and treatment | journal = Neurologic Clinics | volume = 33 | issue = 1 | pages = 101–114 | date = February 2015 | pmid = 25432725 | doi = 10.1016/j.ncl.2014.09.003 }}</ref><ref name=Frank2014/> It is rare among Japanese, while the occurrence rate in Africa is unknown.<ref name=Frank2014/> The disease affects men and women equally.<ref name=Frank2014>{{cite journal | vauthors = Frank S | title = Treatment of Huntington's disease | journal = Neurotherapeutics | volume = 11 | issue = 1 | pages = 153–160 | date = January 2014 | pmid = 24366610 | pmc = 3899480 | doi = 10.1007/s13311-013-0244-z }}</ref> Complications such as [[pneumonia]], [[heart disease]], and physical injury from falls reduce life expectancy; although fatal aspiration pneumonia is commonly cited as the ultimate cause of death for those with the condition.<ref>{{Cite web |title=Aspiration Pneumonia: What It Is, Causes, Diagnosis, Treatment |url=https://my.clevelandclinic.org/health/diseases/21954-aspiration-pneumonia |access-date=2023-06-12 |website=Cleveland Clinic |language=en |archive-date=12 June 2023 |archive-url=https://web.archive.org/web/20230612211926/https://my.clevelandclinic.org/health/diseases/21954-aspiration-pneumonia |url-status=live }}</ref><ref name="The Biology of Huntingtin"/><ref name=Frank2014/> [[Suicide]] is the cause of death in about 9% of cases.<ref name=Frank2014/> Death typically occurs 15–20 years from when the disease was first detected.<ref name=NIH2020/>
<!-- History and research -->
The earliest known description of the disease was in 1841 by American physician Charles Oscar Waters.<ref name=History2015/> The condition was described in further detail in 1872 by American physician [[George Huntington]].<ref name=History2015>{{cite journal | vauthors = Vale TC, Cardoso F | title = Chorea: A Journey through History | journal = Tremor and Other Hyperkinetic Movements | volume = 5 | date = 2015 | pmid = 26056609 | pmc = 4454991 | doi = 10.7916/D8WM1C98 }}</ref> The genetic basis was discovered in 1993 by an international collaborative effort led by the [[Hereditary Disease Foundation]].<ref name=Research2016>{{cite web |title=About Huntington's Disease |url=https://www.genome.gov/Genetic-Disorders/Huntingtons-Disease |website=Genome.gov |access-date=13 January 2021 |language=en |archive-date=9 January 2021 |archive-url=https://web.archive.org/web/20210109070041/https://www.genome.gov/Genetic-Disorders/Huntingtons-Disease |url-status=live }}</ref><ref name="HDF-About Us"/> Research and [[Support group|support organizations]] began forming in the late 1960s to increase public awareness, provide support for individuals and their families and promote research.<ref name="HDF-About Us">{{cite web|url=http://hdfoundation.org/history-of-the-hdf/|title=History of the HDF|publisher=Hereditary Disease Foundation|access-date=18 November 2015|url-status=dead|archive-url=https://web.archive.org/web/20151119025644/http://hdfoundation.org/history-of-the-hdf/|archive-date=19 November 2015}}</ref><ref name="HDSA12020">{{cite web |title=History and Genetics of Huntington's Disease {{!}} Huntington's Disease Society of America |date=March 2019 |url=https://hdsa.org/what-is-hd/history-and-genetics-of-huntingtons-disease/ |access-date=14 December 2020 |archive-date=1 December 2020 |archive-url=https://web.archive.org/web/20201201060837/https://hdsa.org/what-is-hd/history-and-genetics-of-huntingtons-disease/ |url-status=live }}</ref> Research directions include determining the exact mechanism of the disease, improving [[Genetically modified animal|animal models]] to aid with research, testing of medications and their [[Drug delivery|delivery]] to treat symptoms or slow the progression of the disease, and studying procedures such as [[stem-cell therapy]] with the goal of replacing damaged or lost neurons.<ref name=Research2016/>
==Signs and symptoms==
[[Signs and symptoms]] of Huntington's disease most commonly become noticeable between the ages of 30 and 50 years, but they can begin at any age<ref name=NIH2020/> and present as a [[Medical triad|triad]] of motor, cognitive, and psychiatric symptoms.<ref name=Jensen>{{cite journal | vauthors = Jensen RN, Bolwig T, Sørensen SA | title = [Psychiatric symptoms in patients with Huntington's disease] | language = da | journal = Ugeskrift for Laeger | volume = 180 | issue = 13 | date = March 2018 | pmid = 29587954 }}</ref> When developed in an early stage, it is known as juvenile Huntington's disease.<ref name=":1">{{Cite web |title=Huntington's disease - Symptoms and causes |url=https://www.mayoclinic.org/diseases-conditions/huntingtons-disease/symptoms-causes/syc-20356117 |access-date=2022-12-13 |website=Mayo Clinic |language=en |archive-date=5 March 2018 |archive-url=https://web.archive.org/web/20180305034543/https://www.mayoclinic.org/diseases-conditions/huntingtons-disease/symptoms-causes/syc-20356117 |url-status=live }}</ref> In 50% of cases, the psychiatric symptoms appear first.<ref name=Jensen/> Their progression is often described in early stages, middle stages, and late stages with an earlier [[Prodrome|prodromal]] phase.<ref name=War2020/> In the early stages, subtle personality changes, problems in [[cognition]] and physical skills, [[irritability]], and mood swings occur, all of which may go unnoticed,<ref name="NHSScot">{{cite web |title=Huntington's disease |url=https://www.nhsinform.scot/illnesses-and-conditions/brain-nerves-and-spinal-cord/huntingtons-disease |publisher=www.nhsinform.scot |access-date=12 July 2020 |language=en |archive-date=12 July 2020 |archive-url=https://web.archive.org/web/20200712181757/https://www.nhsinform.scot/illnesses-and-conditions/brain-nerves-and-spinal-cord/huntingtons-disease |url-status=live }}</ref><ref name="genereviews">{{cite journal | vauthors = Caron NS, Wright GE, Hayden MR | title = Huntington Disease | journal = Genereviews Bookshelf | date = June 2020 | pmid = 20301482 | url = https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=huntington#huntington.Management | access-date = 22 November 2020 | publisher = University of Washington | archive-date = 10 February 2009 | archive-url = https://web.archive.org/web/20090210161856/http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=huntington#huntington.Management | url-status = live }}</ref> and these usually precede the motor symptoms.<ref name="DSM5">{{cite book |title=Diagnostic and statistical manual of mental disorders: DSM-5. |date=2013 |publisher=American Psychiatric Association |location=Arlington, VA |isbn=9780890425541 |page=639 |edition=5th}}</ref> Almost everyone with HD eventually exhibits similar physical symptoms, but the onset, progression, and extent of cognitive and behavioral symptoms vary significantly between individuals.<ref name="OxfordMonographclinical">{{cite book | vauthors = Kremer B |chapter=Clinical neurology of Huntington's disease |veditors=Bates G, Harper P, Jones L | title=Huntington's Disease – Third Edition| publisher=Oxford University Press| location=Oxford| year=2002| isbn=978-0-19-851060-4|pages=28–53}}</ref><ref>{{cite journal|vauthors=Wagle AC, Wagle SA, Marková IS, Berrios GE |year=2000|title=Psychiatric Morbidity in Huntington's disease|journal=Neurology, Psychiatry and Brain Research|issue=8|pages=5–16}}</ref>
The most characteristic initial physical symptoms are jerky, random, and uncontrollable movements called [[chorea]].<ref name="Robbins"/> Many people are not aware of their involuntary movements, or impeded by them.<ref name="Day20152"/> Chorea may be initially exhibited as general restlessness, small unintentionally initiated or uncompleted motions, lack of coordination, or slowed [[Saccade|saccadic eye movements]].<ref name="lancet07">{{cite journal | vauthors = Walker FO | title = Huntington's disease | journal = Lancet | volume = 369 | issue = 9557 | pages = 218–228 | date = January 2007 | pmid = 17240289 | doi = 10.1016/S0140-6736(07)60111-1 | s2cid = 46151626 }}</ref> These minor motor abnormalities usually precede more obvious signs of motor dysfunction by at least three years.<ref name="OxfordMonographclinical2">{{cite book |title=Huntington's Disease – Third Edition |vauthors=Kremer B |publisher=Oxford University Press |year=2002 |isbn=978-0-19-851060-4 |veditors=Bates G, Harper P, Jones L |location=Oxford |pages=28–53 |chapter=Clinical neurology of Huntington's disease}}</ref> The clear appearance of symptoms such as rigidity, writhing motions, or [[Dystonia|abnormal posturing]] appear as the disorder progresses.<ref name="lancet07" /> These are signs that the system in the brain that is responsible for movement has been affected.<ref name="pmid16496032">{{cite journal | vauthors = Montoya A, Price BH, Menear M, Lepage M | title = Brain imaging and cognitive dysfunctions in Huntington's disease | journal = Journal of Psychiatry & Neuroscience | volume = 31 | issue = 1 | pages = 21–29 | date = January 2006 | pmid = 16496032 | pmc = 1325063 | url = http://www.cma.ca/multimedia/staticContent/HTML/N0/l2/jpn/vol-31/issue-1/pdf/pg21.pdf | url-status = dead | access-date = 17 September 2008 | archive-url = https://web.archive.org/web/20160323102506/https://www.cma.ca/multimedia/staticcontent/html/n0/l2/jpn/vol-31/issue-1/pdf/pg21.pdf | archive-date = 23 March 2016 }}</ref> [[Psychomotor retardation|Psychomotor]] functions become increasingly impaired, such that any action that requires muscle control is affected. When muscle control is affected such as rigidity or muscle contracture this is known as [[dystonia]]. Dystonia is a neurological hyperkinetic movement disorder that results in twisting or repetitive movements, that may resemble a tremor. Common consequences are physical instability, abnormal facial expression, and difficulties chewing, [[dysphagia|swallowing]], and [[dysarthria|speaking]].<ref name="lancet07" /> [[Sleep disorder|Sleep disturbances]] and [[weight loss]] are also associated symptoms.<ref name="Dickey3">{{cite journal | vauthors = Dickey AS, La Spada AR | title = Therapy development in Huntington disease: From current strategies to emerging opportunities | journal = American Journal of Medical Genetics. Part A | volume = 176 | issue = 4 | pages = 842–861 | date = April 2018 | pmid = 29218782 | pmc = 5975251 | doi = 10.1002/ajmg.a.38494 }}</ref> Eating difficulties commonly cause weight loss and may lead to malnutrition.<ref name="pmid191655312">{{cite journal | vauthors = Aziz NA, van der Marck MA, Pijl H, Olde Rikkert MG, Bloem BR, Roos RA | title = Weight loss in neurodegenerative disorders | journal = Journal of Neurology | volume = 255 | issue = 12 | pages = 1872–1880 | date = December 2008 | pmid = 19165531 | doi = 10.1007/s00415-009-0062-8 | s2cid = 26109381 }}</ref><ref>{{cite web |date=11 April 2007 |title=Booklet by the Huntington Society of Canada |url=http://www.hdac.org/caregiving/pdf/Caregiver_Handbook.pdf |url-status=dead |archive-url=https://web.archive.org/web/20080625160929/http://www.hdac.org/caregiving/pdf/Caregiver_Handbook.pdf |archive-date=25 June 2008 |access-date=10 August 2008 |work=Caregiver's Handbook for Advanced-Stage Huntington Disease |publisher=HD Society of Canada}}</ref> Weight loss is common in people with Huntington's disease, and it progresses with the disease. Juvenile HD generally progresses at a faster rate with greater cognitive decline, and chorea is exhibited briefly, if at all; the Westphal variant of [[Hypokinesia|slowness of movement]], rigidity, and tremors is more typical in juvenile HD, as are [[seizure]]s.<ref name="lancet07" /><ref name="Dickey3" />
Cognitive abilities are progressively impaired and tend to generally decline into [[dementia]].<ref name="Frank2014" /> Especially affected are [[executive functions]], which include planning, cognitive flexibility, [[abstract thinking]], rule acquisition, initiation of appropriate actions, and inhibition of inappropriate actions. Different cognitive impairments include difficulty focusing on tasks, lack of flexibility, a lack of impulse, a lack of awareness of one's own behaviors and abilities and difficulty learning or processing new information. As the disease progresses, [[memory]] deficits tend to appear. Reported impairments range from [[short-term memory]] deficits to [[long-term memory]] difficulties, including deficits in [[episodic memory|episodic]] (memory of one's life), [[procedural memory|procedural]] (memory of the body of how to perform an activity), and [[working memory]].<ref name="pmid16496032"/>
Reported [[neuropsychiatry|neuropsychiatric]] signs are [[anxiety]], [[major depressive disorder|depression]], a [[reduced affect display|reduced display of emotions]], [[egocentrism]], [[aggression]], and [[compulsive behavior]], the latter of which can cause or worsen [[Behavioral addiction|addictions]], including [[alcoholism]], [[gambling]], and [[hypersexuality]].<ref name="pmid180708482">{{cite journal | vauthors = van Duijn E, Kingma EM, van der Mast RC | title = Psychopathology in verified Huntington's disease gene carriers | journal = The Journal of Neuropsychiatry and Clinical Neurosciences | volume = 19 | issue = 4 | pages = 441–448 | year = 2007 | pmid = 18070848 | doi = 10.1176/appi.neuropsych.19.4.441 }}</ref> Other common psychiatric disorders could include [[obsessive–compulsive disorder]], [[mania]], [[insomnia]] and [[bipolar disorder]]. Difficulties in recognizing other people's negative expressions have also been observed.<ref name="pmid16496032"/> The [[prevalence]] of these symptoms is highly variable between studies, with estimated rates for lifetime prevalence of [[Mental illness|psychiatric disorders]] between 33 and 76%.<ref name="pmid180708482" /> For many with the disease and their families, these symptoms are among the most distressing aspects of the disease, often affecting daily functioning and constituting reason for [[institutionalisation|institutionalization]].<ref name="pmid180708482" /> Early behavioral changes in HD result in an increased risk of suicide.<ref name="Robbins"/> Often, individuals have reduced awareness of chorea, cognitive, and emotional impairments.<ref>{{cite book |title=Bradley's neurology in clinical practice |vauthors=Murray ED, Buttner N, Price BH |publisher=Elsevier/Saunders |year=2012 |isbn=978-1-4377-0434-1 |veditors=Bradley WG, Daroff RB, Fenichel GM, Jankovic J |edition=6th |location=Philadelphia, PA |page=108 |chapter=Depression and Psychosis in Neurological Practice}}</ref>
Mutant huntingtin is expressed throughout the body and associated with abnormalities in peripheral tissues that are directly caused by such expression outside the brain. These abnormalities include [[muscle atrophy]], [[cardiac failure]], [[impaired glucose tolerance]], [[weight loss]], [[osteoporosis]], and [[testicular atrophy]].<ref>{{cite journal | vauthors = van der Burg JM, Björkqvist M, Brundin P | title = Beyond the brain: widespread pathology in Huntington's disease | journal = The Lancet. Neurology | volume = 8 | issue = 8 | pages = 765–774 | date = August 2009 | pmid = 19608102 | doi = 10.1016/S1474-4422(09)70178-4 | s2cid = 14419437 }}</ref>
==Genetics==
<!-- Please note that although the disorder is spelled Huntington, the associated gene and protein are correctly spelled Huntingtin -->
Everyone has two copies of the [[huntingtin gene]] (''HTT''), which codes for the [[huntingtin protein]] (Htt). ''HTT'' is also called the HD gene, and the ''IT15'' gene, (interesting [[transcription (genetics)|transcript]] 15). Part of this gene is a repeated section called a [[trinucleotide repeat expansion]] – a [[copy number variation#Types and chromosomal rearrangements|short repeat]], which varies in length between individuals, and may change length between generations. If the repeat is present in a healthy gene, a dynamic mutation may increase the repeat count and result in a defective gene. When the length of this repeated section reaches a certain threshold, it produces an altered form of the protein, called mutant huntingtin protein (mHtt). The differing functions of these proteins are the cause of pathological changes, which in turn cause the disease symptoms. The Huntington's disease mutation is genetically dominant and almost fully [[penetrance|penetrant]]; mutation of either of a person's ''HTT'' alleles causes the disease. It is not inherited according to sex, but by the length of the repeated section of the gene, hence its severity can be influenced by the sex of the affected parent.<ref name="lancet07"/>
===Genetic mutation===
HD is one of several [[trinucleotide repeat disorder]]s that are caused by the length of a repeated section of a gene exceeding a normal range.<ref name="lancet07" /> The ''HTT'' gene is located on the [[Locus (genetics)|short arm]] of [[chromosome 4 (human)|chromosome 4]]<ref name="lancet07" /> at 4p16.3. ''HTT'' contains a sequence of three [[DNA base]]s—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ... CAGCAGCAG ...), known as a trinucleotide repeat.<ref name="lancet07" /> CAG is the three-letter [[genetic code]] ([[codon]]) for the [[amino acid]] [[glutamine]], so a series of them results in the production of a chain of glutamine known as a [[polyglutamine tract]] (or polyQ tract), and the repeated part of the gene, the ''polyQ region''.<ref>{{cite journal | vauthors = Katsuno M, Banno H, Suzuki K, Takeuchi Y, Kawashima M, Tanaka F, Adachi H, Sobue G | display-authors = 6 | title = Molecular genetics and biomarkers of polyglutamine diseases | journal = Current Molecular Medicine | volume = 8 | issue = 3 | pages = 221–234 | date = May 2008 | pmid = 18473821 | doi = 10.2174/156652408784221298 }}</ref>
[[File:Huntington's disease (5880985560).jpg|thumb|upright=1.4|Graphic showing at top normal range of repeats, and disease-causing range of repeats.]]
{| class="wikitable" style="float:right; margin-left:15px; margin-right:15px; text-align:center;"
|+Classification of trinucleotide repeats, and resulting disease status, depending on the number of CAG repeats<ref name="lancet07" />
|-
! Repeat count
! Classification
! Disease status
! Risk to offspring
|-
| <27
| Normal
| Will not be affected
| None
|-
| 27–35
| Intermediate
| Will not be affected
| Elevated, but <50%
|-
| 36–39
| Reduced Penetrance
| May or may not be affected
| 50%
|-
| 40+
| Full penetrance
| Will be affected
| 50%
|}
Generally, people have fewer than 36 repeated glutamines in the polyQ region, which results in the production of the [[cytoplasmic]] protein huntingtin.<ref name="lancet07" /> However, a sequence of 36 or more glutamines results in the production of a protein with different characteristics.<ref name="lancet07" /> This altered form, called mutant huntingtin (mHtt), increases the decay rate of certain types of [[medium spiny neurons|neurons]]. Regions of the brain have differing amounts and reliance on these types of neurons and are affected accordingly.<ref name="lancet07" /> Generally, the number of CAG repeats is related to how much this process is affected, and accounts for about 60% of the variation of the age of the onset of symptoms. The remaining variation is attributed to the environment and other genes that modify the mechanism of HD.<ref name="lancet07" /> About 36 to 39 repeats result in a reduced-penetrance form of the disease, with a much later onset and slower progression of symptoms. In some cases, the onset may be so late that symptoms are never noticed.<ref name="lancet07" /> With very large repeat counts (more than 60), HD onset can occur below the age of 20, known as juvenile HD. Juvenile HD is typically of the Westphal variant that is characterized by slowness of movement, rigidity, and tremors. This accounts for about 7% of HD carriers.<ref name="Squitieri">{{cite journal | vauthors = Squitieri F, Frati L, Ciarmiello A, Lastoria S, Quarrell O | title = Juvenile Huntington's disease: does a dosage-effect pathogenic mechanism differ from the classical adult disease? | journal = Mechanisms of Ageing and Development | volume = 127 | issue = 2 | pages = 208–212 | date = February 2006 | pmid = 16274727 | doi = 10.1016/j.mad.2005.09.012 | s2cid = 20523093 }}</ref><ref name="juvenile">{{cite journal | vauthors = Nance MA, Myers RH | title = Juvenile onset Huntington's disease--clinical and research perspectives | journal = Mental Retardation and Developmental Disabilities Research Reviews | volume = 7 | issue = 3 | pages = 153–157 | year = 2001 | pmid = 11553930 | doi = 10.1002/mrdd.1022 }}</ref>
===Inheritance===
[[File:Autosomal Dominant Pedigree Chart2.svg|thumb|upright|right|alt=Diagram showing a father carrying the gene and an unaffected mother, leading to some of their offspring being affected; those affected are also shown with some affected offspring; those unaffected have no affected offspring|Huntington's disease is inherited in an [[autosomal dominant]] fashion. The probability of each offspring inheriting an affected gene is 50%. Inheritance is independent of sex, and the phenotype does not skip generations.]]
Huntington's disease has [[autosomal dominant]] inheritance, meaning that an affected individual typically inherits one copy of the gene with an expanded trinucleotide repeat (the mutant [[allele]]) from an affected parent.<ref name="lancet07" /> Since the penetrance of the mutation is very high, those who have a mutated copy of the gene will have the disease. In this type of inheritance pattern, each offspring of an affected individual has a 50% risk of inheriting the mutant allele, so are affected with the disorder (see figure). This probability is sex-independent.<ref name="basicgenetics">{{cite book | vauthors =Passarge E | title=Color Atlas of Genetics | url =https://archive.org/details/coloratlasofgene0000pass | url-access =registration | publisher=Thieme | edition=2nd | year=2001 | page=[https://archive.org/details/coloratlasofgene0000pass/page/n155 142] | isbn=978-0-86577-958-7}}</ref> Sex-dependent or sex-linked genes are traits that are found on the X or Y chromosomes.<ref>{{Cite web |title=Sex Linked |url=https://www.genome.gov/genetics-glossary/Sex-Linked |access-date=2022-12-13 |website=Genome.gov |language=en |archive-date=14 April 2022 |archive-url=https://web.archive.org/web/20220414183337/https://www.genome.gov/genetics-glossary/Sex-Linked |url-status=live }}</ref>
[[Trinucleotide repeat expansion|Trinucleotide CAG repeats]] numbering over 28 are unstable during [[DNA replication|replication]], and this instability increases with the number of repeats present.<ref name="lancet07" /> This usually leads to new expansions as generations pass ([[dynamic mutation]]s) instead of reproducing an exact copy of the trinucleotide repeat.<ref name="lancet07" /> This causes the number of repeats to change in successive generations, such that an unaffected parent with an "intermediate" number of repeats (28–35), or "reduced penetrance" (36–40), may pass on a copy of the gene with an increase in the number of repeats that produces fully penetrant HD.<ref name="lancet07" /> The earlier [[age of onset]] and greater severity of disease in successive generations due to increases in the number of repeats is known as genetic [[anticipation (genetics)|anticipation]].<ref name="Day20152"/> Instability is greater in [[spermatogenesis]] than [[oogenesis]];<ref name="lancet07" /> maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones have a higher chance of increasing in length.<ref name="lancet07" /><ref name="Ridley">{{cite journal | vauthors = Ridley RM, Frith CD, Crow TJ, Conneally PM | title = Anticipation in Huntington's disease is inherited through the male line but may originate in the female | journal = Journal of Medical Genetics | volume = 25 | issue = 9 | pages = 589–595 | date = September 1988 | pmid = 2972838 | pmc = 1051535 | doi = 10.1136/jmg.25.9.589 }}</ref> Rarely is Huntington's disease caused by a [[de novo mutation|new mutation]], where neither parent has over 36 CAG repeats.<ref name="pmid16965319">{{cite journal | vauthors = Semaka A, Creighton S, Warby S, Hayden MR | title = Predictive testing for Huntington disease: interpretation and significance of intermediate alleles | journal = Clinical Genetics | volume = 70 | issue = 4 | pages = 283–294 | date = October 2006 | pmid = 16965319 | doi = 10.1111/j.1399-0004.2006.00668.x | s2cid = 26007984 }}</ref>
In the rare situations where both parents have an expanded HD gene, the risk increases to 75%, and when either parent has two expanded copies, the risk is 100% (all children will be affected). Individuals with [[Homozygous|both genes affected]] are rare. For some time, HD was thought to be the only disease for which possession of a second mutated gene did not affect symptoms and progression,<ref name="pmid2881213">{{cite journal | vauthors = Wexler NS, Young AB, Tanzi RE, Travers H, Starosta-Rubinstein S, Penney JB, Snodgrass SR, Shoulson I, Gomez F, Ramos Arroyo MA | display-authors = 6 | title = Homozygotes for Huntington's disease | journal = Nature | volume = 326 | issue = 6109 | pages = 194–197 | year = 1987 | pmid = 2881213 | doi = 10.1038/326194a0 | hdl-access = free | s2cid = 4312171 | bibcode = 1987Natur.326..194W | hdl = 2027.42/62543 }}</ref> but it has since been found that it can affect the [[phenotype]] and the rate of progression.<ref name="lancet07" /><ref name="pmid12615650">{{cite journal | vauthors = Squitieri F, Gellera C, Cannella M, Mariotti C, Cislaghi G, Rubinsztein DC, Almqvist EW, Turner D, Bachoud-Lévi AC, Simpson SA, Delatycki M, Maglione V, Hayden MR, Donato SD | display-authors = 6 | title = Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course | journal = Brain | volume = 126 | issue = Pt 4 | pages = 946–955 | date = April 2003 | pmid = 12615650 | doi = 10.1093/brain/awg077 | doi-access = free }}</ref>
==Mechanisms==
Huntingtin protein interacts with over 100 other proteins, and appears to have multiple functions.<ref name="pmid15383276">{{cite journal | vauthors = Goehler H, Lalowski M, Stelzl U, Waelter S, Stroedicke M, Worm U, Droege A, Lindenberg KS, Knoblich M, Haenig C, Herbst M, Suopanki J, Scherzinger E, Abraham C, Bauer B, Hasenbank R, Fritzsche A, Ludewig AH, Büssow K, Coleman SH, Gutekunst CA, Landwehrmeyer BG, Lehrach H, Wanker EE | display-authors = 6 | title = A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease | journal = Molecular Cell | volume = 15 | issue = 6 | pages = 853–865 | date = September 2004 | pmid = 15383276 | doi = 10.1016/j.molcel.2004.09.016 | author23-link = Bernhard Landwehrmeyer | doi-access = free }}</ref> The behavior of the mutated protein (mHtt) is not completely understood, but it is toxic to certain cell types, particularly [[brain cells]]. Early damage is most evident in the [[subcortical]] [[basal ganglia]], initially in the [[striatum]], but as the disease progresses, other areas of the brain are also affected, including regions of the [[cerebral cortex]]. Early symptoms are attributable to functions of the striatum and its cortical connections—namely control over movement, mood, and higher cognitive function.<ref name="lancet07" /> [[DNA methylation]] also appears to be changed in HD.<ref>{{cite journal | vauthors = Glajch KE, Sadri-Vakili G | title = Epigenetic Mechanisms Involved in Huntington's Disease Pathogenesis | journal = Journal of Huntington's Disease | volume = 4 | issue = 1 | pages = 1–15 | date = 2015 | pmid = 25813218 | doi = 10.3233/JHD-159001 | doi-access = free }}</ref>
===Huntingtin function===
{{See also|Huntingtin#Function}}
Htt is [[gene expression|expressed]] in all cells, with the highest concentrations found in the brain and [[testes]], and moderate amounts in the [[liver]], [[heart]], and [[lung]]s. Its functions are unclear, but it does interact with proteins involved in [[Transcription (biology)|transcription]], [[cell signaling]], and [[Vesicle (biology)#Transport vesicles|intracellular transporting]].<ref name="Liu"/> In [[Genetically modified organism|animals genetically modified]] to exhibit HD, several functions of Htt have been identified.<ref name="Httfunction">{{cite journal | vauthors = Cattaneo E, Zuccato C, Tartari M | title = Normal huntingtin function: an alternative approach to Huntington's disease | journal = Nature Reviews. Neuroscience | volume = 6 | issue = 12 | pages = 919–930 | date = December 2005 | pmid = 16288298 | doi = 10.1038/nrn1806 | s2cid = 10119487 }}</ref> In these animals, Htt is important for embryonic development, as its absence is related to embryonic death. [[Caspase]], an enzyme which plays a role in catalyzing [[apoptosis]], is thought to be activated by the mutated gene through damaging the ubiquitin-protease system. It also acts as an [[Apoptosis|antiapoptotic]] agent preventing [[programmed cell death]] and controls the production of [[brain-derived neurotrophic factor]], a protein that protects neurons and regulates their creation during [[neurogenesis]]. Htt also facilitates [[Synaptic vesicle|synaptic vesicular transport]] and [[synaptic transmission]], and controls neuronal gene transcription.<ref name="Httfunction"/> If the expression of Htt is increased, [[Neuron|brain cell]] survival is improved and the effects of mHtt are reduced, whereas when the expression of Htt is reduced, the resulting characteristics are more as seen in the presence of mHtt.<ref name="Httfunction"/> Accordingly, the disease is thought not to be caused by [[haploinsufficiency|inadequate production]] of Htt, but by a [[Gain-of-function|toxic gain-of-function]] of mHtt in the body.<ref name="lancet07" />
===Cellular changes===
[[File:Neuron with mHTT inclusion zoomed.jpg|thumb|left|alt=Closer view of neuron having a large central core with several tendrils branching out some of which branch again, the core of the contains an orange blob about a quarter of its diameter | A microscope image of a neuron with an [[inclusion body]] (stained orange) caused by HD, image width 250 [[micrometre|µm]]]]
The toxic action of mHtt may manifest and produce the HD pathology through multiple cellular changes.<ref name="pmid14585171">{{cite journal | vauthors = Rubinsztein DC, Carmichael J | title = Huntington's disease: molecular basis of neurodegeneration | journal = Expert Reviews in Molecular Medicine | volume = 5 | issue = 20 | pages = 1–21 | date = August 2003 | pmid = 14585171 | doi = 10.1017/S1462399403006549 | s2cid = 28435830 }}</ref><ref name="pmid2136787">{{cite journal | vauthors = Bloch M, Hayden MR | title = Opinion: predictive testing for Huntington disease in childhood: challenges and implications | journal = American Journal of Human Genetics | volume = 46 | issue = 1 | pages = 1–4 | date = January 1990 | pmid = 2136787 | pmc = 1683548 }}</ref> In its mutant (polyglutamine expanded) form, the protein is more prone to cleavage that creates shorter fragments containing the polyglutamine expansion.<ref name="pmid14585171"/> These protein fragments have a propensity to undergo [[misfolding]] and aggregation, yielding fibrillar aggregates in which non-native polyglutamine β-strands from multiple proteins are bonded together by hydrogen bonds.<ref name="hdprimer">{{cite journal | vauthors = Bates GP, Dorsey R, Gusella JF, Hayden MR, Kay C, Leavitt BR, Nance M, Ross CA, Scahill RI, Wetzel R, Wild EJ, Tabrizi SJ | display-authors = 6 | title = Huntington disease | journal = Nature Reviews. Disease Primers | volume = 1 | pages = 15005 | date = April 2015 | pmid = 27188817 | doi = 10.1038/nrdp.2015.5 | author-link12 = Sarah Tabrizi | s2cid = 25759303 }}</ref> These aggregates share the same fundamental cross-beta [[amyloid]] architecture seen in other [[Proteopathies|protein deposition diseases]] .<ref name="fibrilstruc">{{cite journal | vauthors = Matlahov I, van der Wel PC | title = Conformational studies of pathogenic expanded polyglutamine protein deposits from Huntington's disease | journal = Experimental Biology and Medicine | volume = 244 | issue = 17 | pages = 1584–1595 | date = December 2019 | pmid = 31203656 | pmc = 6920524 | doi = 10.1177/1535370219856620 | s2cid = 189944779 }}</ref> Over time, the aggregates accumulate to form [[inclusion bodies]] within cells, ultimately interfering with neuronal function.<ref name="hdprimer"/><ref name="pmid14585171"/> Inclusion bodies have been found in both the [[cell nucleus]] and [[cytoplasm]].<ref name="pmid14585171"/> Inclusion bodies in cells of the brain are one of the earliest pathological changes, and some experiments have found that they can be [[neurotoxicity|toxic]] for the cell, but other experiments have shown that they may form as part of the body's defense mechanism and help protect cells.<ref name="pmid14585171"/>
Several pathways by which mHtt may cause cell death have been identified. These include effects on [[Chaperone (protein)|chaperone proteins]], which help fold proteins and remove misfolded ones; interactions with [[caspase]]s, which play a role in the [[apoptosis|process of removing cells]]; the [[excitotoxicity|toxic effects of glutamine on nerve cells]]; impairment of energy production within cells; and effects on the expression of genes.<ref name="hdprimer"/><ref name="urlNature Clinical Practice Neurology | Mechanisms of Disease: histone modifications in Huntingtons disease | Article">{{cite journal | vauthors = Sadri-Vakili G, Cha JH | title = Mechanisms of disease: Histone modifications in Huntington's disease | journal = Nature Clinical Practice. Neurology | volume = 2 | issue = 6 | pages = 330–338 | date = June 2006 | pmid = 16932577 | doi = 10.1038/ncpneuro0199 | s2cid = 12474262 }}</ref>
Mutant huntingtin protein has been found to play a key role in [[mitochondrial dysfunction]].<ref name="Liu">{{cite journal | vauthors = Liu Z, Zhou T, Ziegler AC, Dimitrion P, Zuo L | title = Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications | journal = Oxidative Medicine and Cellular Longevity | volume = 2017 | pages = 2525967 | date = 2017 | pmid = 28785371 | pmc = 5529664 | doi = 10.1155/2017/2525967 | doi-access = free }}</ref> The impairment of [[mitochondrial electron transport chains|mitochondrial electron transport]] can result in higher levels of [[oxidative stress]] and release of [[reactive oxygen species]].<ref name="pmid27662334">{{cite journal | vauthors = Kumar A, Ratan RR | title = Oxidative Stress and Huntington's Disease: The Good, The Bad, and The Ugly | journal = Journal of Huntington's Disease | volume = 5 | issue = 3 | pages = 217–237 | date = October 2016 | pmid = 27662334 | pmc = 5310831 | doi = 10.3233/JHD-160205 }}</ref>
Glutamine is known to be [[Excitotoxin|excitotoxic]] when present in large amounts, that can cause damage to numerous cellular structures. Excessive glutamine is not found in HD, but the interactions of the altered huntingtin protein with numerous proteins in neurons lead to an increased vulnerability to glutamine. The increased vulnerability is thought to result in excitotoxic effects from normal glutamine levels.<ref name="hdprimer"/>
===Macroscopic changes===
{{See also|Basal ganglia disease}}
[[File:Basal_ganglia_and_related_structures_(2).svg|thumb|upright=1.4|alt=Diagram of a side view of the brain and part of the spinal cord, the front of the brain is to the left, in the centre are red and blue masses, the red mass largely overlaps the blue and has an arm that starts at its leftmost region and forms a spiral a little way out tapering off and ending in a nodule directly below the main mass |The area of the brain most damaged in early Huntington's disease is the [[dorsal striatum]] made up of the [[caudate nucleus]] and the [[putamen]].]]
Initially, damage to the brain is regionally specific with the [[dorsal striatum]] in the subcortical [[basal ganglia]] being primarily affected, followed later by [[cerebral cortex|cortical]] involvement in all areas.<ref name="Nopoulos">{{cite journal | vauthors = Nopoulos PC | title = Huntington disease: a single-gene degenerative disorder of the striatum | journal = Dialogues in Clinical Neuroscience | volume = 18 | issue = 1 | pages = 91–98 | date = March 2016 | pmid = 27069383 | pmc = 4826775 | doi = 10.31887/DCNS.2016.18.1/pnopoulos }}</ref><ref name="McColgan">{{cite journal | vauthors = McColgan P, Tabrizi SJ | title = Huntington's disease: a clinical review | journal = European Journal of Neurology | volume = 25 | issue = 1 | pages = 24–34 | date = January 2018 | pmid = 28817209 | doi = 10.1111/ene.13413 | doi-access = free }}</ref> Other areas of the [[basal ganglia]] affected include the [[substantia nigra]]; cortical involvement includes [[Cortical layers|cortical layers 3, 5, and 6]]; also evident is involvement of the [[hippocampus]], [[Purkinje cell]]s in the [[Cerebellum#Purkinje layer|cerebellum]], lateral tuberal nuclei of the [[hypothalamus]] and parts of the [[thalamus]].<ref name="lancet07" /> These areas are affected according to their structure and the types of neurons they contain, reducing in size as they lose cells.<ref name="lancet07" /> Striatal [[medium spiny neuron]]s are the most vulnerable, particularly ones with [[Neural pathway|projections]] towards the [[external globus pallidus]], with [[interneuron]]s and spiny cells projecting to the [[internal globus pallidus]] being less affected.<ref name="lancet07" /><ref>{{cite book | vauthors = Purves D, Augustine GA, Fitzpatrick D, Hall W, LaMantia AS, McNamara JO, Williams SM | veditors = Purves D | title = Neuroscience | url = https://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=neurosci.TOC&depth=2 | edition = 2nd | publisher = Sinauer Associates | location = Sunderland, MA | isbn = 978-0-87893-742-4 | chapter = Modulation of Movement by the Basal Ganglia – Circuits within the Basal Ganglia System | chapter-url = https://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=Huntington's%20disease&rid=neurosci.section.1251 | access-date = 1 April 2009 | year = 2001 | url-status=live | archive-url = https://web.archive.org/web/20090218192801/http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=neurosci.TOC&depth=2 | archive-date = 18 February 2009}}</ref> HD also causes an [[astrogliosis|abnormal increase]] in [[astrocyte]]s and activation of the brain's immune cells, [[microglia]].<ref name="pmid17965655">{{cite journal | vauthors = Lobsiger CS, Cleveland DW | title = Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease | journal = Nature Neuroscience | volume = 10 | issue = 11 | pages = 1355–1360 | date = November 2007 | pmid = 17965655 | pmc = 3110080 | doi = 10.1038/nn1988 }}</ref>
The basal ganglia play a key role in movement and behavior control. Their functions are not fully understood, but theories propose that they are part of the cognitive [[executive function|executive system]]<ref name="pmid16496032"/> and the motor circuit.<ref name="pmid10923984"/> The basal ganglia ordinarily inhibit a large number of circuits that generate specific movements. To initiate a particular movement, the cerebral cortex sends a signal to the basal ganglia that causes the inhibition to be released. Damage to the basal ganglia can cause the release or reinstatement of the inhibitions to be erratic and uncontrolled, which results in an awkward start to the motion or motions to be unintentionally initiated or in a motion to be halted before or beyond its intended completion. The accumulating damage to this area causes the characteristic erratic movements associated with HD known as chorea, a [[dyskinesia]].<ref name="pmid10923984">{{cite journal | vauthors = Crossman AR | title = Functional anatomy of movement disorders | journal = Journal of Anatomy | volume = 196 ( Pt 4) | issue = Pt 4 | pages = 519–525 | date = May 2000 | pmid = 10923984 | pmc = 1468094 | doi = 10.1046/j.1469-7580.2000.19640519.x }}</ref> Because of the basal ganglia's inability to inhibit movements, individuals affected by it inevitably experience a reduced ability to produce speech and swallow foods and liquids (dysphagia).<ref>{{Cite book|title = Motor Speech Disorders: Substrates, Differential Diagnosis, and Management | edition = 3rd | vauthors = Duffy J |publisher = Elsevier|year = 2013|location = St. Louis, Missouri|pages = 196–7}}</ref>
===Transcriptional dysregulation===
[[CREB-binding protein]] (CBP), a transcriptional coregulator, is essential for cell function because as a coactivator at a significant number of promoters, it activates the transcription of genes for survival pathways.<ref name="urlNature Clinical Practice Neurology | Mechanisms of Disease: histone modifications in Huntingtons disease | Article"/> CBP contains an [[acetyltransferase]] domain to which HTT binds through its polyglutamine-containing domain.<ref>{{cite journal | vauthors = Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A, Apostol BL, Kazantsev A, Schmidt E, Zhu YZ, Greenwald M, Kurokawa R, Housman DE, Jackson GR, Marsh JL, Thompson LM | display-authors = 6 | title = Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila | journal = Nature | volume = 413 | issue = 6857 | pages = 739–743 | date = October 2001 | pmid = 11607033 | doi = 10.1038/35099568 | s2cid = 4419980 | bibcode = 2001Natur.413..739S | url = https://escholarship.org/uc/item/5q52298v | access-date = 28 June 2019 | archive-date = 1 August 2020 | archive-url = https://web.archive.org/web/20200801220516/https://escholarship.org/uc/item/5q52298v | url-status = live }}</ref> Autopsied brains of those who had Huntington's disease also have been found to have incredibly reduced amounts of CBP.<ref name="urlAnalysis of Strand Slippage in DNA Polymerase Expansions of CAG/CTG Triplet Repeats Associated with Neurodegenerative Disease – JBC">{{cite journal | vauthors = Petruska J, Hartenstine MJ, Goodman MF | title = Analysis of strand slippage in DNA polymerase expansions of CAG/CTG triplet repeats associated with neurodegenerative disease | journal = The Journal of Biological Chemistry | volume = 273 | issue = 9 | pages = 5204–5210 | date = February 1998 | pmid = 9478975 | doi = 10.1074/jbc.273.9.5204 | doi-access = free }}</ref> In addition, when CBP is overexpressed, polyglutamine-induced death is diminished, further demonstrating that CBP plays an important role in Huntington's disease and neurons in general.<ref name="urlNature Clinical Practice Neurology | Mechanisms of Disease: histone modifications in Huntingtons disease | Article"/>
==Diagnosis==
[[Medical diagnosis|Diagnosis]] of the onset of HD can be made following the appearance of physical symptoms specific to the disease.<ref name="lancet07" /> Genetic testing can be used to confirm a physical diagnosis if no family history of HD exists. Even before the onset of symptoms, genetic testing can confirm if an individual or [[embryo]] carries an expanded copy of the trinucleotide repeat (CAG) in the ''HTT'' gene that causes the disease. [[Genetic counseling]] is available to provide advice and guidance throughout the testing procedure and on the implications of a confirmed diagnosis. These implications include the impact on an individual's psychology, career, family-planning decisions, relatives, and relationships. Despite the availability of pre-symptomatic testing, only 5% of those at risk of inheriting HD choose to do so.<ref name="lancet07" />
===Clinical===
[[File:Huntington.jpg|thumb|upright|alt=Cross section of a brain showing undulating tissues with gaps between them, two large gaps are evenly spaced about the centre.| [[Coronal plane|Coronal]] section from an [[MRI|MR]] [[brain scan]] of a patient with HD, showing [[atrophy]] of the heads of the [[caudate nucleus|caudate nuclei]], enlargement of the frontal horns of the [[lateral ventricles]] (hydrocephalus ''ex vacuo''), and generalized cortical atrophy<ref>{{cite web |vauthors=Gaillard F |title=Huntington's disease |url=http://www.radpod.org/2007/05/01/huntingtons-disease/ |date=1 May 2007 |work=Radiology picture of the day |publisher=www.radpod.org |access-date=24 July 2009 |url-status=dead |archive-url=https://web.archive.org/web/20071022134552/http://radpod.org/2007/05/01/huntingtons-disease/ |archive-date=22 October 2007}}</ref>]]
A [[physical examination]], sometimes combined with a [[psychological examination]], can determine whether the onset of the disease has begun.<ref name="lancet07" /> Excessive unintentional movements of any part of the body are often the reason for seeking medical consultation. If these are abrupt and have random timing and distribution, they suggest a diagnosis of HD. Cognitive or behavioral symptoms are rarely the first symptoms diagnosed; they are usually only recognized in hindsight or when they develop further. How far the disease has progressed can be measured using the unified Huntington's disease rating scale, which provides an overall rating system based on motor, behavioral, cognitive, and functional assessments.<ref name="pmid19111470">{{cite journal | vauthors = Rao AK, Muratori L, Louis ED, Moskowitz CB, Marder KS | title = Clinical measurement of mobility and balance impairments in Huntington's disease: validity and responsiveness | journal = Gait & Posture | volume = 29 | issue = 3 | pages = 433–436 | date = April 2009 | pmid = 19111470 | doi = 10.1016/j.gaitpost.2008.11.002 }}</ref><ref>{{cite web |url=http://huntingtonstudygroup.org/tools-resources/uhdrs/ |title=Unified Huntington's Disease Rating Scale (UHDRS) |access-date=14 April 2009 |work=UHDRS and Database |publisher=HSG |date=1 February 2009 |url-status=live |archive-url=https://web.archive.org/web/20150811064639/http://huntingtonstudygroup.org/tools-resources/uhdrs/ |archive-date=11 August 2015}}</ref> [[Medical imaging]], such as a [[CT scan]] or [[magnetic resonance imaging|MRI scan]], can show atrophy of the caudate nuclei early in the disease, as seen in the illustration to the right, but these changes are not, by themselves, diagnostic of HD. [[Cerebral atrophy]] can be seen in the advanced stages of the disease. [[Functional neuroimaging]] techniques, such as [[functional magnetic resonance imaging]] (fMRI) and [[positron emission tomography]] (PET), can show changes in brain activity before the onset of physical symptoms, but they are experimental tools and are not used clinically.<ref name="lancet07" />
===Predictive genetic testing===
Because HD follows an autosomal dominant pattern of inheritance, a strong motivation exists for individuals who are at risk of inheriting it to seek a diagnosis. The genetic test for HD consists of a blood test, which counts the numbers of CAG repeats in each of the ''HTT'' alleles.<ref name="pmid15717026">{{cite journal | vauthors = Myers RH | title = Huntington's disease genetics | journal = NeuroRx | volume = 1 | issue = 2 | pages = 255–262 | date = April 2004 | pmid = 15717026 | pmc = 534940 | doi = 10.1602/neurorx.1.2.255 }}</ref> [[Cutoff (reference value)|Cutoffs]] are given as follows:
* At 40 or more CAG repeats, full [[penetrance]] allele (FPA) exists.<ref name=Die-Smulders2013>{{cite journal | vauthors = de Die-Smulders CE, de Wert GM, Liebaers I, Tibben A, Evers-Kiebooms G | title = Reproductive options for prospective parents in families with Huntington's disease: clinical, psychological and ethical reflections | journal = Human Reproduction Update | volume = 19 | issue = 3 | pages = 304–315 | date = May 2013 | pmid = 23377865 | doi = 10.1093/humupd/dms058 | doi-access = free }} {{cite journal | vauthors = de Die-Smulders CE, de Wert GM, Liebaers I, Tibben A, Evers-Kiebooms G | title = Reproductive options for prospective parents in families with Huntington's disease: clinical, psychological and ethical reflections | journal = Human Reproduction Update | volume = 19 | issue = 3 | pages = 304–315 | year = 2013 | pmid = 23377865 | doi = 10.1093/humupd/dms058 | doi-access = free }}</ref> A "[[positive test]]" or "positive result" generally refers to this case. A positive result is not considered a diagnosis, since it may be obtained decades before the symptoms begin. However, a negative test means that the individual does not carry the expanded copy of the gene and will not develop HD.<ref name="lancet07" /> The test will tell a person who originally had a 50% chance of inheriting the disease if their risk goes up to 100% or is eliminated. Persons who test positive for the disease will develop HD sometime within their lifetimes, provided they live long enough for the disease to appear.<ref name="lancet07" />
* At 36 to 39 repeats, incomplete or reduced penetrance allele (RPA) may cause symptoms, usually later in the adult life.<ref name=Die-Smulders2013/> The maximum risk is 60% that a person with an RPA will be symptomatic at age 65, and 70% at 75.<ref name=Die-Smulders2013/>
* At 27 to 35 repeats, intermediate allele (IA), or large normal allele, is not associated with symptomatic disease in the tested individual, but may expand upon further inheritance to give symptoms in offspring.<ref name=Die-Smulders2013/>
* With 26 or fewer repeats, the result is not associated with HD.<ref name=Die-Smulders2013/>
Testing before the onset of symptoms is a life-changing event and a very personal decision.<ref name="lancet07" /> The main reason given for choosing to test for HD is to aid in career and family decisions.<ref name="lancet07" /> Predictive testing for Huntington's disease has been available via linkage analysis (which requires testing multiple family members) since 1986 and via direct mutation analysis since 1993.<ref>{{cite journal | vauthors = Baig SS, Strong M, Rosser E, Taverner NV, Glew R, Miedzybrodzka Z, Clarke A, Craufurd D, Quarrell OW | display-authors = 6 | title = 22 Years of predictive testing for Huntington's disease: the experience of the UK Huntington's Prediction Consortium | journal = European Journal of Human Genetics | volume = 24 | issue = 10 | pages = 1396–1402 | date = October 2016 | pmid = 27165004 | pmc = 5027682 | doi = 10.1038/ejhg.2016.36 }}</ref> At that time, surveys indicated that 50–70% of at-risk individuals would have been interested in receiving testing, but since predictive testing has been offered far fewer choose to be tested.<ref name="pmid23297124">{{cite journal | vauthors = Forrest Keenan K, Simpson SA, Miedzybrodzka Z, Alexander DA, Semper J | title = How do partners find out about the risk of Huntington's disease in couple relationships? | journal = Journal of Genetic Counseling | volume = 22 | issue = 3 | pages = 336–344 | date = June 2013 | pmid = 23297124 | doi = 10.1007/s10897-012-9562-2 | s2cid = 15447709 }}</ref> Over 95% of individuals at risk of inheriting HD do not proceed with testing, mostly because it has no treatment.<ref name="lancet07" /> A key issue is the anxiety an individual experiences about not knowing whether they will eventually develop HD, compared to the impact of a positive result.<ref name="lancet07" /> Irrespective of the result, stress levels are lower two years after being tested, but the risk of suicide is increased after a positive test result.<ref name="lancet07" /> Individuals found to have not inherited the disorder may experience [[survivor guilt]] about family members who are affected.<ref name="lancet07" /> Other factors taken into account when considering testing include the possibility of discrimination and the implications of a positive result, which usually means a parent has an affected gene and that the individual's siblings will be at risk of inheriting it.<ref name="lancet07" /> In one study, genetic discrimination was found in 46% of individuals at risk for Huntington's disease. It occurred at higher rates within personal relationships than health insurance or employment relations.<ref name="pmid20468061">{{cite journal | vauthors = Erwin C, Williams JK, Juhl AR, Mengeling M, Mills JA, Bombard Y, Hayden MR, Quaid K, Shoulson I, Taylor S, Paulsen JS | display-authors = 6 | title = Perception, experience, and response to genetic discrimination in Huntington disease: the international RESPOND-HD study | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 153B | issue = 5 | pages = 1081–1093 | date = July 2010 | pmid = 20468061 | pmc = 3593716 | doi = 10.1002/ajmg.b.31079 }}</ref> [[Genetic counseling]] in HD can provide information, advice and support for initial decision-making, and then, if chosen, throughout all stages of the testing process.<ref name="geneticcounselling">{{cite journal | vauthors = Burson CM, Markey KR | title = Genetic counseling issues in predictive genetic testing for familial adult-onset neurologic diseases | journal = Seminars in Pediatric Neurology | volume = 8 | issue = 3 | pages = 177–186 | date = September 2001 | pmid = 11575847 | doi = 10.1053/spen.2001.26451 }}</ref> Because of the implications of this test, patients who wish to undergo testing must complete three counseling sessions which provide information about Huntington's.<ref name="pmid22114233">{{cite journal | vauthors = Smith JA, Michie S, Stephenson M, Quarrell O | title = Risk Perception and Decision-making Processes in Candidates for Genetic Testing for Huntington's Disease: An Interpretative Phenomenological Analysis | journal = Journal of Health Psychology | volume = 7 | issue = 2 | pages = 131–144 | date = March 2002 | pmid = 22114233 | doi = 10.1177/1359105302007002398 | s2cid = 40182214 }}</ref>
Counseling and guidelines on the use of genetic testing for HD have become models for other genetic disorders, such as autosomal dominant [[cerebellar ataxia]].<ref name="lancet07" /><ref name="pmid12849232">{{cite journal | vauthors = Hayden MR | title = Predictive testing for Huntington's disease: a universal model? | journal = The Lancet. Neurology | volume = 2 | issue = 3 | pages = 141–142 | date = March 2003 | pmid = 12849232 | doi = 10.1016/S1474-4422(03)00317-X | s2cid = 39581496 }}</ref><ref>{{cite journal | vauthors = | title = Guidelines for the molecular genetics predictive test in Huntington's disease. International Huntington Association (IHA) and the World Federation of Neurology (WFN) Research Group on Huntington's Chorea | journal = Neurology | volume = 44 | issue = 8 | pages = 1533–1536 | date = August 1994 | pmid = 8058167 | doi = 10.1212/WNL.44.8.1533 | s2cid = 28018134 }}</ref> [[Predictive testing|Presymptomatic testing]] for HD has also influenced testing for other illnesses with genetic variants such as [[polycystic kidney]] disease, familial [[Alzheimer's disease]] and [[breast cancer]].<ref name="pmid12849232"/> The European Molecular Genetics Quality Network have published yearly external quality assessment scheme for molecular genetic testing for this disease and have developed best practice guidelines for genetic testing for HD to assist in testing and reporting of results.<ref name=Losekoot2012>{{cite journal | vauthors = Losekoot M, van Belzen MJ, Seneca S, Bauer P, Stenhouse SA, Barton DE | title = EMQN/CMGS best practice guidelines for the molecular genetic testing of Huntington disease | journal = European Journal of Human Genetics | volume = 21 | issue = 5 | pages = 480–486 | date = May 2013 | pmid = 22990145 | pmc = 3641377 | doi = 10.1038/ejhg.2012.200 }}</ref>
===Preimplantation genetic diagnosis===
[[Embryo]]s produced using [[in vitro fertilisation|''in vitro'' fertilization]] may be genetically tested for HD using [[preimplantation genetic diagnosis]]. This technique, where one or two cells are extracted from a typically 4- to 8-cell embryo and then tested for the genetic abnormality, can then be used to ensure embryos affected with HD genes are not implanted, so any offspring will not inherit the disease. Some forms of preimplantation genetic diagnosis—non-disclosure or exclusion testing—allow at-risk people to have HD-free offspring ''without'' revealing their own parental genotype, giving no information about whether they themselves are destined to develop HD. In exclusion testing, the embryo's DNA is compared with that of the parents and grandparents to avoid inheritance of the chromosomal region containing the HD gene from the affected grandparent. In nondisclosure testing, only disease-free embryos are replaced in the uterus while the parental genotype and hence parental risk for HD are never disclosed.<ref>{{cite journal | vauthors = Schulman JD, Black SH, Handyside A, Nance WE | title = Preimplantation genetic testing for Huntington disease and certain other dominantly inherited disorders | journal = Clinical Genetics | volume = 49 | issue = 2 | pages = 57–58 | date = February 1996 | pmid = 8740912 | doi = 10.1111/j.1399-0004.1996.tb04327.x | s2cid = 45703511 }}</ref><ref>{{cite journal | vauthors = Stern HJ, Harton GL, Sisson ME, Jones SL, Fallon LA, Thorsell LP, Getlinger ME, Black SH, Schulman JD | display-authors = 6 | title = Non-disclosing preimplantation genetic diagnosis for Huntington disease | journal = Prenatal Diagnosis | volume = 22 | issue = 6 | pages = 503–507 | date = June 2002 | pmid = 12116316 | doi = 10.1002/pd.359 | s2cid = 33967835 }}</ref>
===Prenatal testing===
Obtaining a [[prenatal diagnosis]] for an embryo or [[fetus]] in the womb is also possible, using fetal genetic material acquired through [[chorionic villus sampling]]. An [[amniocentesis]] can be performed if the pregnancy is further along, within 14–18 weeks. This procedure looks at the amniotic fluid surrounding the baby for indicators of the HD mutation.<ref>{{cite web|title=Predictive Testing for Huntington's Disease|url=http://predictivetestingforhd.com/testing-for-hd/prenatal-testing/amniocentesis/|access-date=7 May 2013|year=2011|url-status=live|archive-url=https://web.archive.org/web/20130122124510/http://predictivetestingforhd.com/testing-for-hd/prenatal-testing/amniocentesis/|archive-date=22 January 2013}}</ref> This, too, can be paired with exclusion testing to avoid disclosure of parental genotype. Prenatal testing can be done when parents have been diagnosed with HD, when they have had genetic testing showing the expansion of the ''HTT'' gene, or when they have a 50% chance of inheriting the disease. The parents can be counseled on their options, which include [[termination of pregnancy]], and on the difficulties of a child with the identified gene.<ref name="pmid15758612">{{cite journal | vauthors = Kuliev A, Verlinsky Y | title = Preimplantation diagnosis: a realistic option for assisted reproduction and genetic practice | journal = Current Opinion in Obstetrics & Gynecology | volume = 17 | issue = 2 | pages = 179–183 | date = April 2005 | pmid = 15758612 | doi = 10.1097/01.gco.0000162189.76349.c5 | s2cid = 9382420 }}</ref><ref>{{cite web|title=Guidelines for Genetic Testing for Huntington's Disease|url=http://dwb4.unl.edu/chem/chem869n/chem869nlinks/www.hdfoundation.org/testread/hdsatest.htm|publisher=Heredity Disease Foundation|access-date=7 May 2013|url-status=dead|archive-url=https://web.archive.org/web/20150626005614/http://dwb4.unl.edu/Chem/CHEM869N/CHEM869NLinks/www.hdfoundation.org/testread/hdsatest.htm|archive-date=26 June 2015}}</ref>
In addition, in at-risk pregnancies due to an affected male partner, noninvasive prenatal diagnosis can be performed by analyzing [[cell-free fetal DNA]] in a blood sample taken from the mother (via [[venipuncture]]) between six and 12 weeks of pregnancy.<ref name=Die-Smulders2013/> It has no procedure-related risk of miscarriage.<ref name=Die-Smulders2013/>
===Differential diagnosis===
About 99% of HD diagnoses based on the typical symptoms and a [[family history (medicine)|family history]] of the disease are confirmed by genetic testing to have the expanded trinucleotide repeat that causes HD. Most of the remaining are called [[Huntington's disease-like syndrome|HD-like (HDL) syndromes]].<ref name="lancet07" /><ref name="HD-LIKE"/> The cause of most HDL diseases is unknown, but those with known causes are due to mutations in the [[PRNP|prion protein gene]] (HDL1), the [[JPH3|junctophilin 3 gene]] (HDL2), a recessively inherited unknown gene (HDL3—only found in two families and poorly understood), and the gene encoding the [[TATA binding protein|TATA box-binding protein]] ([[Spinocerebellar ataxia|SCA17, sometimes called HDL4]]). Other autosomal dominant diseases that can be misdiagnosed as HD are [[dentatorubral-pallidoluysian atrophy]] and [[Adult-onset basal ganglia disease|neuroferritinopathy]]. Also, some [[autosomal recessive]] disorders resemble sporadic cases of HD. These include [[chorea acanthocytosis]] and [[pantothenate kinase-associated neurodegeneration]]. One [[Sex linkage|X-linked]] disorder of this type is [[McLeod syndrome]].<ref name="HD-LIKE">{{cite journal | vauthors = Schneider SA, Walker RH, Bhatia KP | title = The Huntington's disease-like syndromes: what to consider in patients with a negative Huntington's disease gene test | journal = Nature Clinical Practice. Neurology | volume = 3 | issue = 9 | pages = 517–525 | date = September 2007 | pmid = 17805246 | doi = 10.1038/ncpneuro0606 | s2cid = 9052603 }}</ref>
==Management==
[[File:Report (IA report00comm 6).pdf|thumb|Illustration from a case report in 1977 of a person with Huntington's disease]]
Treatments are available to reduce the severity of some HD symptoms.<ref name="HDDRUGS">{{cite journal | vauthors = Frank S, Jankovic J | title = Advances in the pharmacological management of Huntington's disease | journal = Drugs | volume = 70 | issue = 5 | pages = 561–571 | date = March 2010 | pmid = 20329804 | doi = 10.2165/11534430-000000000-00000 | url = http://adisonline.com/drugs/Abstract/2010/70050/Advances_in_the_Pharmacological_Management_of.4.aspx | url-status = dead | s2cid = 42386743 | archive-url = https://web.archive.org/web/20111008155523/http://adisonline.com/drugs/Abstract/2010/70050/Advances_in_the_Pharmacological_Management_of.4.aspx | archive-date = 8 October 2011 }}</ref> For many of these treatments, evidence to confirm their effectiveness in treating symptoms of HD specifically are incomplete.<ref name="lancet07" /><ref name="pmid15076012">{{cite journal | vauthors = Bonelli RM, Wenning GK, Kapfhammer HP | title = Huntington's disease: present treatments and future therapeutic modalities | journal = International Clinical Psychopharmacology | volume = 19 | issue = 2 | pages = 51–62 | date = March 2004 | pmid = 15076012 | doi = 10.1097/00004850-200403000-00001 | s2cid = 1956458 }}</ref> As the disease progresses, the ability to care for oneself declines, and carefully managed [[multidisciplinary]] [[caregiving]] becomes increasingly necessary.<ref name="lancet07" /> Although relatively few studies of exercises and therapies have shown to be helpful to [[Rehabilitation (neuropsychology)|rehabilitate]] cognitive symptoms of HD, some evidence shows the usefulness of [[physical therapy]], [[occupational therapy]], and [[speech therapy]].<ref name="lancet07" />
===Therapy===
Weight loss and problems in eating due to [[dysphagia]] and other muscle discoordination are common, making nutrition management increasingly important as the disease advances.<ref name="lancet07" /> [[Thickening agent]]s can be added to liquids, as thicker fluids are easier and safer to swallow.<ref name="lancet07" /> Reminding the affected person to eat slowly and to take smaller pieces of food into the mouth may also be of use to prevent choking.<ref name="lancet07" /> If eating becomes too hazardous or uncomfortable, the option of using a [[percutaneous endoscopic gastrostomy]] is available. This feeding tube, permanently attached through the [[abdomen]] into the [[stomach]], reduces the risk of [[pulmonary aspiration|aspirating]] food and provides better nutritional management.<ref name="pmid18390785">{{cite journal | vauthors = Panagiotakis PH, DiSario JA, Hilden K, Ogara M, Fang JC | title = DPEJ tube placement prevents aspiration pneumonia in high-risk patients | journal = Nutrition in Clinical Practice | volume = 23 | issue = 2 | pages = 172–175 | year = 2008 | pmid = 18390785 | doi = 10.1177/0884533608314537 }}</ref> Assessment and management by [[speech-language pathologist]]s with experience in Huntington's disease is recommended.<ref name="lancet07" />
People with Huntington's disease may see a [[physical therapist]] for noninvasive and nonmedication-based ways of managing the physical symptoms. Physical therapists may implement fall risk assessment and prevention, as well as strengthening, stretching, and cardiovascular exercises. [[Walking aids]] may be prescribed as appropriate. Physical therapists also prescribe breathing exercises and [[airway clearance technique]]s with the development of respiratory problems.<ref name=ehdnphysio /> Consensus guidelines on physiotherapy in Huntington's disease have been produced by the European HD Network.<ref name=ehdnphysio>{{cite web|url=http://www.euro-hd.net/html/network/groups/physio/physiotherapy-guidance-doc-2009.pdf|title=EHDN Physiotherapy Guidance Document|publisher=European HD Network Physiotherapy Working Group|access-date=2015-11-15|url-status=dead|archive-url=https://web.archive.org/web/20160304030647/http://www.euro-hd.net/html/network/groups/physio/physiotherapy-guidance-doc-2009.pdf|archive-date=4 March 2016}}</ref> Goals of early [[Rehabilitation medicine|rehabilitation]] interventions are prevention of loss of function. Participation in rehabilitation programs during the early to middle stage of the disease may be beneficial as it translates into long-term maintenance of motor and functional performance. Rehabilitation during the late stage aims to compensate for motor and functional losses.<ref>{{cite journal|vauthors=Quin L, Busee M|title=Development of physiotherapy guidance and treatment-based classifications for people with Huntington's disease|journal=Neurodegenerative Disease Management|date=February 2012|volume=2|issue=1|pages=21–31|doi=10.2217/nmt.11.86|url=http://www.futuremedicine.com/doi/pdf/10.2217/nmt.11.67|doi-access=free|access-date=10 May 2012|archive-date=9 August 2020|archive-url=https://web.archive.org/web/20200809000845/https://www.futuremedicine.com/doi/pdf/10.2217/nmt.11.67|url-status=live}}</ref> For long-term independent management, the therapist may develop home exercise programs for appropriate people.<ref>{{cite journal | vauthors = Khalil H, Quinn L, van Deursen R, Martin R, Rosser A, Busse M | title = Adherence to use of a home-based exercise DVD in people with Huntington disease: participants' perspectives | journal = Physical Therapy | volume = 92 | issue = 1 | pages = 69–82 | date = January 2012 | pmid = 21960468 | doi = 10.2522/ptj.20100438 | doi-access = free }}</ref>
Additionally, an increasing number of people with HD are turning to [[palliative care]], which aims to improve quality of life through the treatment of the symptoms and stress of serious illness, in addition to their other treatments.<ref>{{cite journal | vauthors = Travers E, Jones K, Nichol J | title = Palliative care provision in Huntington's disease | journal = International Journal of Palliative Nursing | volume = 13 | issue = 3 | pages = 125–130 | date = March 2007 | pmid = 17505405 | doi = 10.12968/ijpn.2007.13.3.23274 }}</ref>
===Medications===
[[File:Tetrabenazine structure.svg|thumb|right|alt=diagram showing 19 carbon, 27 hydrogen, 3 oxygen and 1 nitrogen atom bonded together| Chemical structure of [[tetrabenazine]], an approved compound for the management of [[chorea]] in HD]]
[[Tetrabenazine]] was approved in 2000 for treatment of chorea in Huntington's disease in the EU, and in 2008 in the US.<ref name=autogenerated1>{{cite web |url=https://www.fda.gov/bbs/topics/NEWS/2008/NEW01874.html |title=FDA Approves First Drug for Treatment of Chorea in Huntington's Disease |access-date=10 August 2008 |publisher=U.S. Food and Drug Administration |date=15 August 2008 |url-status=live |archive-url=https://web.archive.org/web/20080821020643/https://www.fda.gov/bbs/topics/NEWS/2008/NEW01874.html |archive-date=21 August 2008}}</ref> Although other drugs had been used "[[off label]]," tetrabenazine was the first approved treatment for Huntington's disease in the U.S. The compound has been known since the 1950s. An alternative to tetrabenazine is [[amantadine]] but there is limited evidence for its safety and efficacy.<ref name="Coppen">{{cite journal | vauthors = Coppen EM, Roos RA | title = Current Pharmacological Approaches to Reduce Chorea in Huntington's Disease | journal = Drugs | volume = 77 | issue = 1 | pages = 29–46 | date = January 2017 | pmid = 27988871 | pmc = 5216093 | doi = 10.1007/s40265-016-0670-4 }}</ref>
Other drugs that help to reduce chorea include [[antipsychotic]]s and [[benzodiazepine]]s.<ref name="genereviews"/> [[Hypokinesia]] and rigidity, especially in juvenile cases, can be treated with [[antiparkinsonian]] drugs, and [[myoclonic]] hyperkinesia can be treated with [[valproic acid]].<ref name="genereviews"/> Tentative evidence has found [[ethyl eicosapentaenoic acid]] to improve motor symptoms at one year.<ref>{{cite journal | vauthors = Morsy S, Khalil SM, Doheim MF, Kamel MG, El-Basiony DS, Ahmed Hassan HI, Eisa AA, Anh Ngoc CT, Dang NP, Hirayama K, Huy NT | display-authors = 6 | title = Efficacy of ethyl-EPA as a treatment for Huntington disease: a systematic review and meta-analysis | journal = Acta Neuropsychiatrica | volume = 31 | issue = 4 | pages = 175–185 | date = August 2019 | pmid = 30890195 | doi = 10.1017/neu.2019.11 | hdl-access = free | hdl = 10069/39427| s2cid = 84183892 }}</ref> In 2017, [[deutetrabenazine]], a heavier form of tetrabenazine medication for the treatment of chorea in HD, was approved by the FDA.<ref name="CDE">{{cite web |author=Center for Drug Evaluation Research |title=In Pursuit of Tardive Dyskinesia: The Breakthrough Designation and Approval of Valbenazine |url=https://www.fda.gov/drugs/news-events-human-drugs/pursuit-tardive-dyskinesia-breakthrough-designation-and-approval-valbenazine |website=FDA |access-date=15 November 2020 |language=en |date=17 July 2019 |archive-date=3 December 2020 |archive-url=https://web.archive.org/web/20201203175104/https://www.fda.gov/drugs/news-events-human-drugs/pursuit-tardive-dyskinesia-breakthrough-designation-and-approval-valbenazine |url-status=live }}</ref> This is marketed as Austedo.
Psychiatric symptoms can be treated with medications similar to those used in the general population.<ref name="lancet07" /><ref name="pmid15076012"/> [[Selective serotonin reuptake inhibitor]]s and [[mirtazapine]] have been recommended for depression, while [[atypical antipsychotic]]s are recommended for [[psychosis]] and behavioral problems.<ref name="pmid15076012"/> Specialist neuropsychiatric input is recommended since people may require long-term treatment with multiple medications in combination.<ref name="lancet07" />
=== Plant based medications ===
There has been a number of alternative therapies experimented in ayurvedic medicine with plant based products, though none have good evidence of efficacy.
===Education===
The families of individuals, and society at large, who have inherited or are at risk of inheriting HD have generations of experience of HD but may be unaware of recent breakthroughs in understanding the disease, and of the availability of genetic testing. Genetic counseling benefits these individuals by updating their knowledge, seeking to dispel any unfounded beliefs that they may have, and helping them consider their future options and plans. The Patient Education Program for Huntington's Disease has been created to help educate family members, caretakers, and those diagnosed with Huntington's disease.<ref name="PEP">{{cite journal |vauthors=A'Campo LE, Spliethoff-Kamminga NG, Roos RA |title=The Patient Education Program for Huntington's Disease (PEP-HD) |journal=J Huntingtons Dis |volume=1 |issue=1 |pages=47–56 |date=2012 |pmid=25063190 |doi=10.3233/JHD-2012-120002 |url=|doi-access=free }}</ref> Also covered is information concerning family planning choices, care management, and other considerations.<ref name="lancet07" /><ref name="OxfordMonographtesting">{{cite book | vauthors = Harper P|chapter=Genetic counselling and presymptomatic testing |veditors=Bates G, Harper P, Jones L | title=Huntington's Disease – Third Edition| publisher=Oxford University Press| location=Oxford| year=2002| isbn=978-0-19-851060-4|pages= 198–242}}</ref>
==Prognosis==
The length of the trinucleotide repeat accounts for 60% of the variation of the age of symptoms onset and their rate of progress. A longer repeat results in an earlier age of onset and a faster progression of symptoms.<ref name="lancet07" /><ref>{{cite journal | vauthors = Harper PS | title = Huntington's disease: a clinical, genetic and molecular model for polyglutamine repeat disorders | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 354 | issue = 1386 | pages = 957–61 | date = June 1999 | pmid = 10434293 | pmc = 1692597 | doi = 10.1098/rstb.1999.0446}}</ref> Individuals with more than sixty repeats often develop the disease before age 20, while those with fewer than 40 repeats may remain asymptomatic.<ref>{{cite journal | vauthors = Andrew SE, Goldberg YP, Kremer B, Telenius H, Theilmann J, Adam S, Starr E, Squitieri F, Lin B, Kalchman MA | title = The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease | journal = Nature Genetics | volume = 4 | issue = 4 | pages = 398–403 | date = August 1993 | pmid = 8401589 | doi = 10.1038/ng0893-398 | s2cid = 20645822}}</ref> The remaining variation is due to environmental factors and other genes that influence the mechanism of the disease.<ref name="lancet07" />
Life expectancy in HD is generally around 10 to 30 years following the onset of visible symptoms.<ref name="lancet07"/> Juvenile Huntington's disease has a life expectancy rate of 10 years after onset of visible symptoms. Most life-threatening complications result from muscle coordination, and to a lesser extent, behavioral changes induced by declining cognitive function. The largest risk is [[pneumonia]], which causes death in one third of those with HD. As the ability to synchronize movements deteriorates, difficulty clearing the lungs, and an increased risk of aspirating food or drink both increase the risk of contracting [[pneumonia]]. The second-greatest risk is [[heart disease]], which causes almost a quarter of fatalities of those with HD.<ref name="lancet072">{{cite journal |vauthors=Walker FO |date=January 2007 |title=Huntington's disease |journal=Lancet |volume=369 |issue=9557 |pages=218–28 |doi=10.1016/S0140-6736(07)60111-1 |pmid=17240289 |s2cid=46151626}}</ref> [[Suicide]] is the third greatest cause of fatalities, with 7.3% of those with HD taking their own lives and up to 27% attempting to do so. To what extent suicidal thoughts are influenced by behavioral symptoms is unclear, as they signify a desire to avoid the later stages of the disease.<ref name="OxfordMonographNeuro2">{{cite book |title=Huntington's Disease – Third Edition |vauthors=Crauford D, Snowden J |publisher=Oxford University Press |year=2002 |isbn=978-0-19-851060-4 |veditors=Bates G, Harper P, Jones L |location=Oxford |pages=62–87 |chapter=Neuropyschological and neuropsychiatric aspects of Huntington's disease}}</ref><ref>{{cite journal |vauthors=Di Maio L, Squitieri F, Napolitano G, Campanella G, Trofatter JA, Conneally PM |date=April 1993 |title=Suicide risk in Huntington's disease |journal=Journal of Medical Genetics |volume=30 |issue=4 |pages=293–5 |doi=10.1136/jmg.30.4.293 |pmc=1016335 |pmid=8487273}}</ref><ref name="OxfordMonographepi">{{cite book |title=Huntington's Disease – Third Edition |vauthors=Harper P |publisher=Oxford University Press |year=2002 |isbn=978-0-19-851060-4 |veditors=Bates G, Harper P, Jones L |location=Oxford |pages=159–189 |chapter=The epidemiology of Huntington's disease}}</ref> Suicide is the greatest risk of this disease before the diagnosis is made and in the middle stages of development throughout the disease. Other associated risks include choking; due to the inability to swallow, [[Injury|physical injury]] from falls, and malnutrition.<ref name="lancet072" /><ref name=":1" />
==Epidemiology==
The late onset of Huntington's disease means it does not usually affect reproduction.<ref name="lancet07" /> The worldwide [[prevalence]] of HD is 5–10 cases per 100,000 persons,<ref name="emedicine">{{cite web |url=http://emedicine.medscape.com/article/289706-overview |title=Huntington Disease Dementia | vauthors = Sharon I, Sharon R, Wilkens JP, Ersan T |year=2010 |work=emedicine, WebMD |publisher=Medscape |access-date=16 May 2010 |url-status=live |archive-url=https://web.archive.org/web/20100305050654/http://emedicine.medscape.com/article/289706-overview |archive-date=5 March 2010}}</ref><ref name="Driver-Dunckley2007">{{cite book |vauthors=Driver-Dunckley E, Caviness JN |chapter=Huntington's disease| veditors = Schapira AH | title=Neurology and Clinical Neuroscience| publisher=Mosby Elsevier|year=2007| isbn=978-0-323-03354-1|pages=879–885}}</ref> but varies greatly geographically as a result of ethnicity, local migration and past immigration patterns.<ref name="lancet07" /> Prevalence is similar for men and women. The rate of occurrence is highest in [[Ethnic group|peoples]] of Western European descent, averaging around seven per 100,000 people, and is lower in the rest of the world; e.g., one per million people of Asian and African descent. A 2013 epidemiological study of the prevalence of Huntington's disease in the UK between 1990 and 2010 found that the average prevalence for the UK was 12.3 per 100,000.<ref name="lancet07" /><ref name="pmid23482661">{{cite journal | vauthors = Evans SJ, Douglas I, Rawlins MD, Wexler NS, Tabrizi SJ, Smeeth L | title = Prevalence of adult Huntington's disease in the UK based on diagnoses recorded in general practice records | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 84 | issue = 10 | pages = 1156–60 | date = October 2013 | pmid = 23482661 | pmc = 3786631 | doi = 10.1136/jnnp-2012-304636}}</ref> Additionally, some localized areas have a much higher prevalence than their regional average.<ref name="lancet07" /> One of the highest incidences is in the isolated populations of the [[Lake Maracaibo]] region of [[Venezuela]], where HD affects up to 700 per 100,000 persons.<ref name="lancet07" /><ref>{{cite journal | vauthors = Avila-Giróo R |title=Medical and Social Aspects of Huntington's chorea in the state of Zulia, Venezuela |journal=Advances in Neurology |volume=1 |pages=261–6 |year=1973 |issn=0091-3952 |id=NAID 10021247802}}</ref> Other areas of high localization have been found in [[Tasmania]] and specific regions of [[Scotland]], [[Wales]] and [[Sweden]].<ref name="OxfordMonographepi"/> Increased prevalence in some cases occurs due to a local [[founder effect]], a historical migration of carriers into an area of [[geographic isolation]].<ref name="OxfordMonographepi"/><ref name="dnamark">{{cite journal | vauthors = Gusella JF, Wexler NS, Conneally PM, Naylor SL, Anderson MA, Tanzi RE, Watkins PC, Ottina K, Wallace MR, Sakaguchi AY | title = A polymorphic DNA marker genetically linked to Huntington's disease | journal = Nature | volume = 306 | issue = 5940 | pages = 234–8 | year = 1983 | pmid = 6316146 | doi = 10.1038/306234a0 | bibcode = 1983Natur.306..234G | s2cid = 4320711}}</ref> Some of these carriers have been traced back hundreds of years using [[genealogy|genealogical]] studies.<ref name="OxfordMonographepi"/> Genetic [[haplotype]]s can also give clues for the geographic variations of prevalence.<ref name="OxfordMonographepi"/><ref name="pmid7881406">{{cite journal | vauthors = Squitieri F, Andrew SE, Goldberg YP, Kremer B, Spence N, Zeisler J, Nichol K, Theilmann J, Greenberg J, Goto J | title = DNA haplotype analysis of Huntington disease reveals clues to the origins and mechanisms of CAG expansion and reasons for geographic variations of prevalence | journal = Human Molecular Genetics | volume = 3 | issue = 12 | pages = 2103–14 | date = December 1994 | pmid = 7881406 | doi = 10.1093/hmg/3.12.2103}}</ref> [[Iceland]], on the contrary, has a rather low prevalence of 1 per 100,000, despite the fact that [[Icelanders]] as a people are descended from the early Germanic tribes of Scandinavia which also gave rise to the [[Swedes]]; all cases with the exception of one going back nearly two centuries having derived from the offspring of a couple living early in the 19th century.<ref>{{cite journal | vauthors = Sveinsson O, Halldórsson S, Olafsson E | title = An unusually low prevalence of Huntington's disease in Iceland | journal = European Neurology | volume = 68 | issue = 1 | pages = 48–51 | date = July 2012 | pmid = 22722209 | doi = 10.1159/000337680 | s2cid = 207551998}}</ref> [[Finland]], as well, has a low incidence of only 2.2 per 100,000 people.<ref>{{cite journal | vauthors = Sipilä JO, Hietala M, Siitonen A, Päivärinta M, Majamaa K | title = Epidemiology of Huntington's disease in Finland | journal = Parkinsonism & Related Disorders | volume = 21 | issue = 1 | pages = 46–9 | date = January 2015 | pmid = 25466405 | doi = 10.1016/j.parkreldis.2014.10.025}}</ref>
Until the discovery of a genetic test, statistics could only include [[clinical diagnosis]] based on physical symptoms and a family history of HD, excluding those who died of other causes before diagnosis. These cases can now be included in statistics; and, as the test becomes more widely available, estimates of the prevalence and incidence of the disorder are likely to increase.<ref name="OxfordMonographepi"/><ref name="pmid11595021">{{cite journal | vauthors = Almqvist EW, Elterman DS, MacLeod PM, Hayden MR | title = High incidence rate and absent family histories in one quarter of patients newly diagnosed with Huntington disease in British Columbia | journal = Clinical Genetics | volume = 60 | issue = 3 | pages = 198–205 | date = September 2001 | pmid = 11595021 | doi = 10.1034/j.1399-0004.2001.600305.x | s2cid = 19786394}}</ref>
==History==
[[File:On Chorea with photo.jpg|thumb|alt=On the right is a young man, dressed in suit and tie, sporting a moustache and tuft of hair on the chin; on the left is the top half of a medical journal titled 'Medical and Surgical Reporter' |In 1872, [[George Huntington]] described the disorder in his first paper "[[s:On Chorea|On Chorea]]" at the age of 22.<ref name="onchorea">{{cite journal |vauthors=Huntington G |title=On Chorea |url=https://babel.hathitrust.org/cgi/pt?id=mdp.39015010956335&view=1up&seq=343&skin=2021 |journal=Medical and Surgical Reporter of Philadelphia |volume=26 |issue=15 |year=1872 |pages=317–321 |isbn=978-90-6186-011-2 |access-date=21 April 2022 |archive-date=21 April 2022 |archive-url=https://web.archive.org/web/20220421034757/https://babel.hathitrust.org/cgi/pt?id=mdp.39015010956335&view=1up&seq=343&skin=2021 |url-status=live }}</ref>]]
In centuries past, various kinds of chorea were at times called by names such as ''[[Saint Vitus' dance (disambiguation)|Saint Vitus' dance]]'', with little or no understanding of their cause or type in each case.
The first definite mention of HD was in a letter by [[Charles Oscar Waters]] (1816–1892), published in the first edition of [[Robley Dunglison]]'s ''Practice of Medicine'' in 1842.<ref>{{cite book |vauthors=Dunglison R |title=The Practice of Medicine ... |date=1842 |publisher=Lea & Blanchard |location=Philadelphia, Pennsylvania, USA |volume=2 |pages=312–313 |url=https://babel.hathitrust.org/cgi/pt?id=chi.092041301&view=1up&seq=316&skin=2021 |access-date=20 April 2022 |archive-date=20 April 2022 |archive-url=https://web.archive.org/web/20220420233417/https://babel.hathitrust.org/cgi/pt?id=chi.092041301&view=1up&seq=316&skin=2021 |url-status=live }}</ref> Waters described "a form of chorea, vulgarly called magrums", including accurate descriptions of the chorea, its progression, and the strong heredity of the disease.<ref name="OxfordMonographHistory">{{cite book | vauthors = Harper P |chapter=Huntington's disease: a historical background |veditors=Bates G, Harper P, Jones L | title=Huntington's Disease – Third Edition| publisher=Oxford University Press| location=Oxford| year=2002| isbn=978-0-19-851060-4|pages= 3–24}}</ref> In 1846 [[Charles Gorman (physician)|Charles Rollin Gorman]] (1817–1879) observed how higher prevalence seemed to occur in localized regions.<ref>Gorman, Charles R. (1846) Thesis for the degree Doctor of Medicine: ''"On a Form of Chorea, Vulgarly called Magrums"''
* [https://jdc.jefferson.edu/cgi/viewcontent.cgi?article=1071&context=jmc_catalogs ''Catalogue of Jefferson Medical College of Philadelphia: Session of 1846-7''] {{Webarchive|url=https://web.archive.org/web/20220626050233/https://jdc.jefferson.edu/cgi/viewcontent.cgi?article=1071&context=jmc_catalogs |date=26 June 2022 }}, p. 14.
* {{cite book |vauthors=Dunglison R |title=The Practice of Medicine ... |date=1848 |publisher=Lea & Blanchard |location=Philadelphia, Pennsylvania, USA |volume=2 |page=218 |edition=3rd |url=https://archive.org/details/practiceofmedici248dung/page/218/mode/2up?ref=ol&view=theater }}
* {{cite journal |vauthors=Boyd WA |title=Hereditary chorea with report of a case |journal=Boston Medical and Surgical Journal |date=6 November 1913 |volume=169 |issue=19 |pages=680–685 |doi=10.1056/NEJM191311061691904 |url=https://books.google.com/books?id=Q80EAAAAYAAJ&pg=RA1-PP12 |access-date=21 April 2022 |archive-date=2 August 2023 |archive-url=https://web.archive.org/web/20230802171644/https://books.google.com/books?id=Q80EAAAAYAAJ&pg=RA1-PP12 |url-status=live }} See p. 680.</ref><ref name="OxfordMonographHistory"/> Independently of Gorman and Waters, both students of Dunglison at [[Jefferson Medical College]] in Philadelphia,<ref name="Wexler2008">{{cite book |title=The Woman Who Walked Into the Sea. Huntington's and the Making of a Genetic Disease|year=2008 |publisher=Yale University Press|isbn=978-0-300-10502-5 |page=288 |url=https://archive.org/details/womanwhowalkedin0000wexl|url-access=registration|vauthors=Wexler A, Wexler N |access-date=15 November 2015}}</ref> {{interlanguage link|Johan Christian Lund|no}} (1830–1906) also produced an early description in 1860.<ref name="OxfordMonographHistory"/> He specifically noted that in [[Setesdalen]], a secluded mountain valley in [[Norway]], the high prevalence of dementia was associated with a pattern of jerking movement disorders that ran in families.<ref>{{cite journal | vauthors = Lund JC| title= Chorea Sti Viti i Sætersdalen. Uddrag af Distriktslæge J. C. Lunds Medicinalberetning for 1860| journal=Beretning Om Sundhedstilstanden| year=1860 | pages=137–138}}</ref>
The first thorough description of the disease was by [[George Huntington]] in 1872. Examining the combined medical history of several generations of a family exhibiting similar symptoms, he realized their conditions must be linked; he presented his detailed and accurate definition of the disease as his first paper. Huntington described the exact pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of [[Mendelian inheritance]].
{{blockquote|Of its hereditary nature. When either or both the parents have shown manifestations of the disease ... one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease.<ref name="onchorea"/><ref>{{cite journal | vauthors = Lanska DJ | title = George Huntington (1850–1916) and hereditary chorea | journal = Journal of the History of the Neurosciences | volume = 9 | issue = 1 | pages = 76–89 | date = April 2000 | pmid = 11232352 | doi = 10.1076/0964-704X(200004)9:1;1-2;FT076| s2cid = 22659368 }}</ref>}}
Sir [[William Osler]] was interested in the disorder and chorea in general, and was impressed with Huntington's paper, stating, "In the history of medicine, there are few instances in which a disease has been more accurately, more graphically or more briefly described."<ref>{{cite journal |vauthors=Osler W |title=Historical notes on hereditary chorea |journal=Neurographs |date=1908 |volume=1 |issue=2 |pages=113–116 |url=https://wellcomecollection.org/works/sa3gzpxh/items?canvas=35 |access-date=21 April 2022 |archive-date=21 April 2022 |archive-url=https://web.archive.org/web/20220421021137/https://wellcomecollection.org/works/sa3gzpxh/items?canvas=35 |url-status=live }} See p. 115.
* See also: {{cite journal |vauthors=Osler W |title=Remarks on the varieties of chronic chorea, and a report upon two families of the hereditary form, with one autopsy |journal=The Journal of Nervous and Mental Disease |date=February 1893 |volume=20 |issue=2 |pages=97–111 |url=https://babel.hathitrust.org/cgi/pt?id=hvd.32044103072369&view=1up&seq=113&skin=2021 |access-date=21 April 2022 |archive-date=21 April 2022 |archive-url=https://web.archive.org/web/20220421030701/https://babel.hathitrust.org/cgi/pt?id=hvd.32044103072369&view=1up&seq=113&skin=2021 |url-status=live }} See p. 97.</ref><ref name="OxfordMonographHistory"/><ref>{{cite journal | vauthors = Brody IA, Wilkins RH | title = Huntington's chorea | journal = Archives of Neurology | volume = 17 | issue = 3 | pages = 331 | date = September 1967 | pmid = 4228262 | doi = 10.1001/archneur.1967.00470270109013 }}</ref> Osler's continued interest in HD, combined with his influence in the field of medicine, helped to rapidly spread awareness and knowledge of the disorder throughout the medical community.<ref name="OxfordMonographHistory"/> Great interest was shown by scientists in Europe, including [[Louis Théophile Joseph Landouzy]], [[Désiré-Magloire Bourneville]], [[Camillo Golgi]], and [[Joseph Jules Dejerine]], and until the end of the century, much of the research into HD was European in origin.<ref name="OxfordMonographHistory"/> By the end of the 19th century, research and reports on HD had been published in many countries and the disease was recognized as a worldwide condition.<ref name="OxfordMonographHistory"/>
During the rediscovery of Mendelian inheritance at the turn of the 20th century, HD was used tentatively as an example of autosomal dominant inheritance.<ref name="OxfordMonographHistory"/> English biologist [[William Bateson]] used the pedigrees of affected families to establish that HD had an autosomal dominant inheritance pattern.<ref>{{cite book | vauthors = Bateson W |title=Mendel's Principles of Heredity |date=1909 |publisher=Cambridge University Press |location=Cambridge, England |page=229 |url=https://archive.org/details/mendelsprinciple00bate/page/228/mode/2up}} Bateson refers to "Huntington's disease" as "Hereditary Chorea".</ref><ref name="Wexler2008"/> The strong inheritance pattern prompted several researchers, including [[Smith Ely Jelliffe]], to attempt to trace and connect family members of previous studies.<ref name="OxfordMonographHistory"/> Jelliffe collected information from across [[New York (state)|New York]] and published several articles regarding the genealogy of HD in [[New England]].<ref>{{cite journal |vauthors=Jelliffe SE, Muncey EB, Davenport CB |title=Huntington's Chorea: A Study in Heredity |journal=The Journal of Nervous and Mental Disease |volume=40 |issue=12 |pages=796–799 |year=1913 |doi=10.1097/00005053-191312000-00010 |url=https://zenodo.org/record/1432003 |access-date=19 September 2020 |archive-date=5 April 2022 |archive-url=https://web.archive.org/web/20220405071433/https://zenodo.org/record/1432003 |url-status=live }}</ref> Jelliffe's research roused the interest of his college friend, [[Charles Davenport]], who commissioned Elizabeth Muncey to produce the first field study on the [[East Coast of the United States]] of families with HD and to construct their pedigrees.<ref name="davenportmuncey">{{cite journal |doi=10.1176/ajp.73.2.195 |pmid=<!--none--> |pmc=<!--none--> |vauthors=Davenport CB, Muncey EB |title=Huntington's chorea in relation to heredity and eugenics |journal=American Journal of Insanity|volume=73 |pages=195–222 |year=1916 |issue=2}}</ref> Davenport used this information to document the variable age of onset and range of symptoms of HD; he claimed that most cases of HD in the US could be traced back to a handful of individuals.<ref name="davenportmuncey"/> This research was further embellished in 1932 by [[P. R. Vessie]], who popularized the idea that three brothers who left [[England]] in 1630 bound for [[Boston]] were the progenitors of HD in the US.<ref>{{Cite journal | vauthors=Vessie PR | title=On the transmission of Huntington's chorea for 300 years – the Bures family group | journal=Nervous and Mental Disease | volume=76 | issue=6 | year=1932 | pages=553–573 | url=https://scholar.google.co.uk/scholar?q=info:12mCk4CjFKAJ:scholar.google.com/&output=viewport&pg=1 | access-date=1 April 2009 | doi=10.1097/00005053-193212000-00001 | s2cid=147656032 | archive-date=28 August 2021 | archive-url=https://web.archive.org/web/20210828112759/https://scholar.google.co.uk/scholar_host?q=info%3A12mCk4CjFKAJ%3Ascholar.google.com%2F&hl=en&as_sdt=0%2C5&output=viewport | url-status=live }}</ref> The claim that the earliest progenitors had been established and [[eugenic]] bias of Muncey's, Davenport's, and Vessie's work contributed to misunderstandings and prejudice about HD.<ref name="Wexler2008"/> Muncey and Davenport also popularized the idea that in the past, some with HD may have been thought to be possessed by spirits or victims of [[witchcraft]], and were sometimes [[shunning|shunned]] or [[exile]]d by society.<ref name="pmid12486915">{{cite journal | vauthors = Wexler AR | title = Chorea and community in a nineteenth-century town | journal = Bulletin of the History of Medicine | volume = 76 | issue = 3 | pages = 495–527 | year = 2002 | pmid = 12486915 | doi = 10.1353/bhm.2002.0150 | s2cid = 30791504}}</ref><ref name="pmid6233902">{{cite journal | vauthors = Conneally PM | title = Huntington disease: genetics and epidemiology | journal = American Journal of Human Genetics | volume = 36 | issue = 3 | pages = 506–26 | date = May 1984 | pmid = 6233902 | pmc = 1684448}}</ref> This idea has not been proven. Researchers have found contrary evidence; for instance, the community of the family studied by George Huntington openly accommodated those who exhibited symptoms of HD.<ref name="Wexler2008"/><ref name="pmid12486915"/>
The search for the cause of this condition was enhanced considerably in 1968, when the [[Hereditary Disease Foundation]] (HDF) was created by [[Milton Wexler]], a [[psychoanalyst]] based in [[Los Angeles]], [[California]], whose wife Leonore Sabin had been diagnosed earlier that year with Huntington's disease.<ref name=Wexler2012>{{cite journal | vauthors = Wexler NS | title = Huntington's disease: advocacy driving science | journal = Annual Review of Medicine | volume = 63 | pages = 1–22 | year = 2012 | doi = 10.1146/annurev-med-050710-134457 | pmid = 22248319 | doi-access = free}}</ref> The three brothers of Wexler's wife also had this disease.
The foundation was involved in the recruitment of more than 100 scientists in the US-Venezuela Huntington's Disease Collaborative Project, which over a 10-year period from 1979, worked to locate the genetic cause.<ref name=HDFP/> This was achieved in 1983 when a causal gene was approximately located,<ref name="dnamark"/> and in 1993, the gene was precisely located at chromosome 4 (4p16.3).<ref name="pmid8458085">{{cite journal | vauthors = | title = A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group | journal = Cell | volume = 72 | issue = 6 | pages = 971–983 | date = March 1993 | pmid = 8458085 | doi = 10.1016/0092-8674(93)90585-E | hdl-access = free | s2cid = 802885 | hdl = 2027.42/30901 }}</ref> The study had focused on the populations of two isolated [[Venezuela]]n villages, Barranquitas and Lagunetas, where there was an unusually high prevalence of HD, and involved over 18,000 people, mostly from a single extended family, and resulted in making HD the first [[autosomal]] disease [[Locus (genetics)|locus]] found using [[Genetic linkage#Linkage analysis|genetic linkage analysis]].<ref name="pmid8458085"/><ref name="pmid15931380">{{cite journal | vauthors = Bertram L, Tanzi RE | title = The genetic epidemiology of neurodegenerative disease | journal = The Journal of Clinical Investigation | volume = 115 | issue = 6 | pages = 1449–1457 | date = June 2005 | pmid = 15931380 | pmc = 1137006 | doi = 10.1172/JCI24761 }}</ref> Among other innovations, the project developed [[Genetic marker|DNA-marking]] methods which were an important step in making the [[Human Genome Project]] possible.<ref name=HDFP>{{cite web |url=http://hdfoundation.org/the-venezuela-huntingtons-disease-project/ |title=The Venezuela Huntington's disease project |access-date=8 September 2008 |work=Hereditary Disease Foundation website |publisher=Hereditary Disease Foundation |year=2008 |url-status=dead |archive-url=https://web.archive.org/web/20150810153514/http://hdfoundation.org/the-venezuela-huntingtons-disease-project/ |archive-date=10 August 2015}}</ref>
In the same time, key discoveries concerning the mechanisms of the disorder were being made, including the findings by [[Anita Harding]]'s research group on the effects of the gene's length.<ref name="pmid1303283">{{cite journal | vauthors = La Spada AR, Roling DB, Harding AE, Warner CL, Spiegel R, [[Hausmanowa-Petrusewicz I]], Yee WC, Fischbeck KH | title = Meiotic stability and genotype–phenotype correlation of the trinucleotide repeat in X-linked spinal and bulbar muscular atrophy | journal = Nature Genetics | volume = 2 | issue = 4 | pages = 301–4 | date = December 1992 | pmid = 1303283 | doi = 10.1038/ng1292-301 | s2cid = 6603129}}</ref>
Modelling the disease in various types of animals, such as the [[transgenic]] mouse developed in 1996, enabled larger-scale experiments. As these animals have faster [[metabolism]]s and much shorter lifespans than humans results from experiments are received sooner, speeding research. The 1997 discovery that mHtt fragments [[Protein folding|misfold]] led to the discovery of the nuclear inclusions they cause. These advances have led to increasingly extensive research into the proteins involved with the disease, potential drug treatments, care methods, and the gene itself.<ref name="OxfordMonographHistory"/><ref name=ross-tabrizi />
The networks of care and support that had developed in Venezuela and Colombia during the research projects there in the 1970s through 2000s were eventually eroded by various forces, such as the ongoing [[crisis in Venezuela]] and the death of a lead researcher in Colombia (Jorge Daza Barriga).<ref name="Smith-NYT-2023-05-23">{{cite news |vauthors=Smith JE, Cordero C |title=Sought Out by Science, and Then Forgotten |url=https://www.nytimes.com/2023/05/23/science/huntingtons-disease-colombia.html |access-date=2023-05-23 |work=The New York Times |date=2023-05-23 |archive-date=23 May 2023 |archive-url=https://web.archive.org/web/20230523222910/https://www.nytimes.com/2023/05/23/science/huntingtons-disease-colombia.html |url-status=live }}</ref> Doctors are working toward rekindling these networks because the people who have contributed to the science of Huntington's disease by participating in these studies deserve adequate follow-up care; societies elsewhere in the world who benefit from the scientific advances thus achieved owe at least that much to those who participated in the research.<ref name="Smith-NYT-2023-05-23"/>
The condition was formerly called Huntington's chorea, but this term has been replaced by Huntington's disease because not all patients develop chorea and due to the importance of cognitive and behavioral problems.<ref name=huntchorea>{{cite web|title=What is HD?|url=http://www.hda.org.uk/huntingtons/what-is-hd.html|publisher=Huntington's disease association|access-date=18 December 2011|url-status=dead|archive-url=https://web.archive.org/web/20111213133025/http://www.hda.org.uk/huntingtons/what-is-hd.html|archive-date=13 December 2011}}</ref>
==Society and culture==
{{See also|List of Huntington's disease media depictions}}
===Ethics===
{{See also|In vitro fertilisation#Ethics|Stem cell controversy}}
[[Genetic testing]] for Huntington's disease has raised several ethical issues. The issues for genetic testing include defining how mature an individual should be before being considered eligible for testing, ensuring the confidentiality of results, and whether companies should be allowed to use test results for decisions on employment, life insurance or other financial matters. There was controversy when [[Charles Davenport]] proposed in 1910 that [[compulsory sterilization]] and [[immigration]] control be used for people with certain diseases, including HD, as part of the [[eugenics]] movement.<ref>{{cite journal | vauthors = Davenport CB | title = Huntington's Chorea in Relation to Heredity and Eugenics | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 1 | issue = 5 | pages = 283–5 | date = May 1915 | pmid = 16575999 | pmc = 1090803 | doi = 10.1073/pnas.1.5.283 | bibcode = 1915PNAS....1..283D| doi-access = free }}</ref> [[In vitro fertilization]] has some issues regarding its use of embryos. Some HD research has ethical issues due to its use of [[Ethics of animal research|animal testing]] and [[embryonic stem cells]].<ref>{{cite journal | vauthors = Rollin BE | title = The regulation of animal research and the emergence of animal ethics: a conceptual history | url = https://org.uib.no/dyreavd/handouts/Rollin__B._2006._Animal_Research_Regulation_in_Theoret._Medicin_....PDF | journal = Theoretical Medicine and Bioethics | volume = 27 | issue = 4 | pages = 285–304 | year = 2006 | pmid = 16937023 | doi = 10.1007/s11017-006-9007-8 | s2cid = 18620094 | access-date = 1 December 2019 | archive-date = 8 October 2020 | archive-url = https://web.archive.org/web/20201008152801/https://org.uib.no/dyreavd/handouts/Rollin__B._2006._Animal_Research_Regulation_in_Theoret._Medicin_....PDF | url-status = dead }}</ref><ref name="pmid18181947">{{cite journal | vauthors = Doerflinger RM | title = The problem of deception in embryonic stem cell research | journal = Cell Proliferation | volume = 41 | issue = Suppl 1 | pages = 65–70 | date = February 2008 | pmid = 18181947 | doi = 10.1111/j.1365-2184.2008.00492.x | pmc = 6496399}}</ref>
The development of an accurate diagnostic test for Huntington's disease has caused social, legal, and ethical concerns over access to and use of a person's results.<ref>{{cite journal | vauthors = Chapman MA | title = Predictive testing for adult-onset genetic disease: ethical and legal implications of the use of linkage analysis for Huntington disease | journal = American Journal of Human Genetics | volume = 47 | issue = 1 | pages = 1–3 | date = July 1990 | pmid = 2140926 | pmc = 1683745}}</ref><ref>{{cite journal | vauthors = Huggins M, Bloch M, Kanani S, Quarrell OW, Theilman J, Hedrick A, Dickens B, Lynch A, Hayden M | title = Ethical and legal dilemmas arising during predictive testing for adult-onset disease: the experience of Huntington disease | journal = American Journal of Human Genetics | volume = 47 | issue = 1 | pages = 4–12 | date = July 1990 | pmid = 1971997 | pmc = 1683755}}</ref>
Many guidelines and testing procedures have strict procedures for disclosure and confidentiality to allow individuals to decide when and how to receive their results and also to whom the results are made available.<ref name="lancet07" /> Insurance companies and businesses are faced with the question of whether to use genetic test results when assessing an individual, such as for life insurance or employment. The United Kingdom's insurance companies agreed with the [[Department of Health and Social Care]] that until 2017 customers would not need to disclose predictive genetics tests to them, but this agreement explicitly excluded the government-approved test for Huntington's when writing policies with a value over {{GBP|500,000}}.<ref>{{cite press release |url=https://www.abi.org.uk/News/News-releases/2011/04/Insurance-Genetics-Moratorium-extended-to-2017 |title=Insurance Genetics Moratorium extended to 2017 |access-date=13 January 2016 |publisher=Association of British Insurers |date=5 April 2011 |url-status=live |archive-url=https://web.archive.org/web/20160304043951/https://www.abi.org.uk/News/News-releases/2011/04/Insurance-Genetics-Moratorium-extended-to-2017 |archive-date=4 March 2016}}</ref><ref name="Expert backs gene test disclosure">{{cite news|title=Expert backs gene test disclosure|url=http://news.bbc.co.uk/1/hi/health/6731623.stm|publisher=BBC article|date=7 June 2007|url-status=live|archive-url=https://web.archive.org/web/20080226155310/http://news.bbc.co.uk/1/hi/health/6731623.stm|archive-date=26 February 2008}}</ref> As with other untreatable genetic conditions with a later onset, it is ethically questionable to perform presymptomatic testing on a child or adolescent since there would be no medical benefit for that individual. There is consensus for testing only individuals who are considered cognitively mature, although there is a counter-argument that parents have a right to make the decision on their child's behalf. With the lack of effective treatment, testing a person under [[Age of majority|legal age]] who is not judged to be [[Gillick competence|competent]] is considered unethical in most cases.<ref name="pmid2136787"/><ref name="pmid8950670">{{cite journal | vauthors = Binedell J, Soldan JR, Scourfield J, Harper PS | title = Huntington's disease predictive testing: the case for an assessment approach to requests from adolescents | journal = Journal of Medical Genetics | volume = 33 | issue = 11 | pages = 912–8 | date = November 1996 | pmid = 8950670 | pmc = 1050784 | doi = 10.1136/jmg.33.11.912}}</ref><ref name="pmid18704981">{{cite journal | vauthors = Borry P, Goffin T, Nys H, Dierickx K | title = Predictive genetic testing in minors for adult-onset genetic diseases | journal = The Mount Sinai Journal of Medicine, New York | volume = 75 | issue = 3 | pages = 287–96 | year = 2008 | pmid = 18704981 | doi = 10.1002/msj.20038 | url = https://lirias.kuleuven.be/handle/123456789/223776}}</ref>
There are ethical concerns related to [[Prenatal diagnosis|prenatal genetic testing]] or [[preimplantation genetic diagnosis]] to ensure a child is not born with a given disease.<ref name="pmid9949442">{{cite journal | vauthors = Braude PR, De Wert GM, Evers-Kiebooms G, Pettigrew RA, Geraedts JP | title = Non-disclosure preimplantation genetic diagnosis for Huntington's disease: practical and ethical dilemmas | journal = Prenatal Diagnosis | volume = 18 | issue = 13 | pages = 1422–6 | date = December 1998 | pmid = 9949442 | doi = 10.1002/(SICI)1097-0223(199812)18:13<1422::AID-PD499>3.0.CO;2-R| s2cid = 39977672 }}</ref> For example, prenatal testing raises the issue of selective abortion, a choice considered unacceptable by some.<ref name="pmid9949442"/> As it is a dominant disease, there are difficulties in situations in which a parent does not want to know his or her own diagnosis. This would require parts of the process to be kept secret from the parent.<ref name="pmid9949442"/>
===Support organizations===
[[File:Woody Guthrie NYWTS.jpg|thumb|upright|The death of [[Woody Guthrie]] led to the foundation of the [[Huntington's Disease Society of America|Committee to Combat Huntington's Disease]]|alt=A black-and-white photograph taken indoors of Woody Guthrie wearing pinstripe trousers, a tartan shirt with the top button undone, and a cap. He sits playing a six-string acoustic guitar, which is supported on one knee, and he appears to be singing. 'This Machine Kills Fascists' is written in all capital letters on a rectangular sticker, which is fixed onto the guitar.]]
In 1968, after experiencing HD in his wife's family, Dr. Milton Wexler was inspired to start the [[Hereditary Disease Foundation]] (HDF), with the aim of curing genetic illnesses by coordinating and supporting research.<ref name="HDF-About Us"/> The foundation and Wexler's daughter, [[Nancy Wexler]], were key parts of the research team in Venezuela which discovered the HD gene.<ref name="HDF-About Us"/>
At roughly the same time as the HDF formed, [[Marjorie Guthrie]] helped to found the committee to Combat Huntington's Disease (now the [[Huntington's Disease Society of America]]), after her husband, folk singer-songwriter [[Woody Guthrie]] died from complications of HD.<ref name="HDSA12020"/>
Since then, support and research organizations have formed in many countries around the world and have helped to increase public awareness of HD. A number of these collaborate in umbrella organizations, like the International Huntington Association and the European HD network.<ref>{{cite web |url=http://www.huntington-assoc.com/ |title=The International Huntington Association |access-date=3 April 2009 |publisher=International Huntington Association |year=2013 |url-status=live |archive-url=https://web.archive.org/web/20090418154858/http://www.huntington-assoc.com/ |archive-date=18 April 2009}}</ref> Many support organizations hold an annual HD awareness event, some of which have been endorsed by their respective governments. For example, 6 June is designated "National Huntington's Disease Awareness Day" by the [[United States Senate|US Senate]].<ref>{{cite web|url=https://www.congress.gov/bill/110th-congress/senate-resolution/531|title=US Senate s. resolution 531|access-date=10 August 2008|work=S. Res. 531|publisher=US Senate|date=6 April 2008|url-status=live|archive-url=https://web.archive.org/web/20151117063126/https://www.congress.gov/bill/110th-congress/senate-resolution/531|archive-date=17 November 2015}}</ref> Many organizations exist to support and inform those affected by HD, including the [[Huntington's Disease Association]] in the UK. The largest funder of research is provided by the [[CHDI Foundation|Cure Huntington's Disease Initiative Foundation]] (CHDI).<ref name=chdi-nature-moneytree>{{cite journal| vauthors = Odling-Smee L|title=Biomedical philanthropy: The money tree|journal=Nature|date=17 May 2007|volume=447|issue=7142|page=251|doi=10.1038/447251a|bibcode=2007Natur.447..251.|s2cid=4357517|doi-access=free}}</ref>
==Research directions==
Research into the mechanism of HD is focused on identifying the functioning of Htt, how mHtt differs or interferes with it, and the brain pathology that the disease produces.<ref name="NIHHope2020">{{cite web |title=Huntington's Disease: Hope Through Research |url=https://www.ninds.nih.gov/disorders/patient-caregiver-education/hope-through-research/huntingtons-disease-hope-through |website=www.ninds.nih.gov |access-date=16 November 2020 |archive-date=25 October 2020 |archive-url=https://web.archive.org/web/20201025060231/https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Huntingtons-Disease-Hope-Through |url-status=live }}</ref> Research is conducted using ''[[in vitro]]'' methods, [[genetically modified animal]]s, (also called [[transgene|transgenic animal models]]), and human volunteers. Animal models are critical for understanding the fundamental mechanisms causing the disease, and for supporting the early stages of [[drug development]].<ref name=ross-tabrizi /> The identification of the causative gene has enabled the development of many [[genetically modified organism]]s including [[nematode]]s (roundworms), ''[[Drosophila melanogaster|Drosophila]]'' [[Drosophila melanogaster|fruit flies]], and [[genetically modified mammal]]s including mice, rats, sheep, pigs and monkeys that express mutant huntingtin and develop progressive [[neurodegeneration]] and HD-like symptoms.<ref name=ross-tabrizi>{{cite journal | vauthors = Ross CA, Tabrizi SJ | title = Huntington's disease: from molecular pathogenesis to clinical treatment | journal = The Lancet. Neurology | volume = 10 | issue = 1 | pages = 83–98 | date = January 2011 | pmid = 21163446 | doi = 10.1016/S1474-4422(10)70245-3 | s2cid = 17488174}}</ref>
Research is being conducted using many approaches to either prevent Huntington's disease or slow its progression.<ref name="NIHHope2020"/> Disease-modifying strategies can be broadly grouped into three categories: reducing the level of the mutant huntingtin protein (including [[gene splicing]] and [[gene silencing]]); approaches aimed at improving neuronal survival by reducing the harm caused by the protein to specific cellular pathways and mechanisms (including [[protein homeostasis]] and [[histone deacetylase inhibitor|histone deacetylase inhibition]]); and strategies to replace lost neurons. In addition, novel therapies to improve brain functioning are under development; these seek to produce symptomatic rather than [[Disease-modifying treatment|disease-modifying therapies]], and include [[phosphodiesterase inhibitors]].<ref name="ReferenceA">{{cite journal | vauthors = Wild EJ, Tabrizi SJ | title = Targets for future clinical trials in Huntington's disease: what's in the pipeline? | journal = Movement Disorders | volume = 29 | issue = 11 | pages = 1434–45 | date = September 2014 | pmid = 25155142 | pmc = 4265300 | doi = 10.1002/mds.26007}}</ref><ref name="20170503TOI">{{cite news| vauthors = Solomon S |title=Taube to fund $3m Huntington's disease research in US|url=http://www.timesofisrael.com/taube-to-fund-3m-huntingtons-disease-research-in-us/|access-date=5 May 2017|work=[[The Times of Israel]]|date=3 May 2017|url-status=live|archive-url=https://web.archive.org/web/20170503135635/http://www.timesofisrael.com/taube-to-fund-3m-huntingtons-disease-research-in-us/|archive-date=3 May 2017}}</ref>
The [[CHDI Foundation]] funds a great many research initiatives providing many publications.<ref name="CHDIA">{{cite web |title=Scientific Publications {{!}} CHDI Foundation |url=https://chdifoundation.org/scientific-publications/ |website=chdifoundation.org |access-date=12 December 2021 |archive-date=12 December 2021 |archive-url=https://web.archive.org/web/20211212175055/https://chdifoundation.org/scientific-publications/ |url-status=live }}</ref> The CHDI foundation is the largest funder of Huntington's disease research globally and aims to find and develop drugs that will slow the progression of HD.<ref name=chdi-nature-moneytree/><ref name="CHDI">{{cite web |title=CHDI Foundation |url=https://chdifoundation.org/ |website=chdifoundation.org |access-date=13 November 2020 |archive-date=14 November 2020 |archive-url=https://web.archive.org/web/20201114214504/https://chdifoundation.org/ |url-status=live }}</ref> CHDI was formerly known as the High Q Foundation. In 2006, it spent $50 million on Huntington's disease research.<ref name=chdi-nature-moneytree /> CHDI collaborates with many academic and commercial laboratories globally and engages in oversight and management of research projects as well as funding.<ref name=chdi-nature-philanthropy>{{cite journal | vauthors = Check E | title = Biomedical philanthropy: love or money | journal = Nature | volume = 447 | issue = 7142 | pages = 252–3 | date = May 2007 | pmid = 17507955 | doi = 10.1038/447252a | bibcode = 2007Natur.447..252C| s2cid = 4318384 | doi-access = free }}</ref>
===Reducing huntingtin production===
[[Gene silencing]] aims to reduce the production of the mutant protein, since HD is caused by a [[Genetic disorder#Single-gene|single dominant gene]] encoding a toxic protein. Gene silencing experiments in mouse models have shown that when the expression of mHtt is reduced, symptoms improve.<ref name=munoz-bates-jci>{{cite journal | vauthors = Munoz-Sanjuan I, Bates GP | title = The importance of integrating basic and clinical research toward the development of new therapies for Huntington disease | journal = The Journal of Clinical Investigation | volume = 121 | issue = 2 | pages = 476–83 | date = February 2011 | pmid = 21285520 | pmc = 3026740 | doi = 10.1172/JCI45364}}</ref> The safety of [[RNA interference]], and [[allele-specific oligonucleotide]] (ASO) methods of gene silencing has been demonstrated in mice and the larger primate macaque brain.<ref>{{cite journal | vauthors = McBride JL, Pitzer MR, Boudreau RL, Dufour B, Hobbs T, Ojeda SR, Davidson BL | title = Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington's disease | journal = Molecular Therapy | volume = 19 | issue = 12 | pages = 2152–62 | date = December 2011 | pmid = 22031240 | pmc = 3242667 | doi = 10.1038/mt.2011.219}}</ref><ref>{{cite journal | vauthors = Kordasiewicz HB, Stanek LM, Wancewicz EV, Mazur C, McAlonis MM, Pytel KA, Artates JW, Weiss A, Cheng SH, Shihabuddin LS, Hung G, Bennett CF, Cleveland DW | title = Sustained therapeutic reversal of Huntington's disease by transient repression of huntingtin synthesis | journal = Neuron | volume = 74 | issue = 6 | pages = 1031–44 | date = June 2012 | pmid = 22726834 | pmc = 3383626 | doi = 10.1016/j.neuron.2012.05.009 }}</ref> Allele-specific silencing attempts to silence mutant htt while leaving wild-type Htt untouched. One way of accomplishing this is to identify polymorphisms present on only one allele and produce gene silencing drugs that target polymorphisms in only the mutant allele.<ref name=sah-aronin>{{cite journal | vauthors = Barnes DW, Whitley RJ | title = Antiviral therapy and pulmonary disease | journal = Chest | volume = 91 | issue = 2 | pages = 246–51 | date = February 1987 | doi=10.1378/chest.91.2.246| pmid = 3026739 }}</ref> The first gene silencing trial involving humans with HD began in 2015, testing the safety of IONIS-HTTRx, produced by [[Ionis Pharmaceuticals]] and led by [[UCL Institute of Neurology]].<ref name=bbc-news-gene-silencing-trial-starts>{{cite news|title=Landmark Huntington's trial starts|url=https://www.bbc.com/news/health-34552041|access-date=19 October 2015|url-status=live|archive-url=https://web.archive.org/web/20151021214158/http://www.bbc.com/news/health-34552041|archive-date=21 October 2015}}</ref><ref>{{cite web|title=Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IONIS-HTTRx in Patients With Early Manifest Huntington's Disease - Full Text View |url=https://clinicaltrials.gov/ct2/show/NCT02519036|publisher=ClinicalTrials.gov |access-date=18 April 2016|url-status=live|archive-url=https://web.archive.org/web/20150929080905/https://clinicaltrials.gov/ct2/show/NCT02519036|archive-date=29 September 2015}}</ref> Mutant huntingtin was detected and quantified for the first time in [[cerebrospinal fluid]] from Huntington's disease mutation-carriers in 2015 using a novel "single-molecule counting" [[immunoassay]],<ref name="mhtt-detection-jci-2015">{{cite journal | vauthors = Wild EJ, Boggio R, Langbehn D, Robertson N, Haider S, Miller JR, Zetterberg H, Leavitt BR, Kuhn R, Tabrizi SJ, Macdonald D, Weiss A | title = Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington's disease patients | journal = The Journal of Clinical Investigation | volume = 125 | issue = 5 | pages = 1979–86 | date = May 2015 | pmid = 25844897 | pmc = 4463213 | doi = 10.1172/jci80743}}</ref> providing a direct way to assess whether huntingtin-lowering treatments are achieving the desired effect.<ref>{{cite journal | vauthors = Chase A | title = Huntington disease: cerebrospinal fluid and MRI biomarkers for prodromal HD | journal = Nature Reviews Neurology | volume = 11 | issue = 5 | page = 245 | date = May 2015 | pmid = 25896083 | doi = 10.1038/nrneurol.2015.63 | s2cid = 38300571}}</ref><ref>{{cite journal | vauthors = Keiser MS, Kordasiewicz HB, McBride JL | title = Gene suppression strategies for dominantly inherited neurodegenerative diseases: lessons from Huntington's disease and spinocerebellar ataxia | journal = Human Molecular Genetics | volume = 25 | issue = R1 | pages = R53–64 | date = April 2016 | pmid = 26503961 | pmc = 4802374 | doi = 10.1093/hmg/ddv442}}</ref> A phase 3 trial of this compound, renamed tominersen and sponsored by [[Hoffmann-La Roche|Roche Pharmaceuticals]], began in 2019 but was halted in 2021 after the safety monitoring board concluded that the risk-benefit balance was unfavourable.<ref>{{Cite journal| vauthors = Kwon D |date=2021-04-06|title=Genetic therapies offer new hope against incurable brain diseases|journal=Nature|language=en|volume=592|issue=7853|pages=180–183|doi=10.1038/d41586-021-00870-x|pmid=33824521|bibcode=2021Natur.592..180K|doi-access=free}}</ref> A huntingtin-lowering gene therapy trial run by Uniqure began in 2019, and several trials of orally administered huntingtin-lowering splicing modulator compounds have been announced.<ref>{{Cite web|title=Huntington's disease clinical trial round up|url=https://en.hdbuzz.net/303|access-date=2021-05-05|website=HDBuzz|language=en|archive-date=5 May 2021|archive-url=https://web.archive.org/web/20210505134715/https://en.hdbuzz.net/303|url-status=live}}</ref> [[Gene splicing]] techniques are being looked at to try to repair a genome with the erroneous gene that causes HD, using tools such as [[CRISPR#Cas9|CRISPR/Cas9]].<ref name="20170503TOI" />
===Increasing huntingtin clearance===
Another strategy to reduce the level of mutant huntingtin is to increase the rate at which cells are able to clear it.<ref name=":0">{{cite journal | vauthors = Djajadikerta A, Keshri S, Pavel M, Prestil R, Ryan L, Rubinsztein DC | title = Autophagy Induction as a Therapeutic Strategy for Neurodegenerative Diseases | journal = Journal of Molecular Biology | volume = 432 | issue = 8 | pages = 2799–2821 | date = April 2020 | pmid = 31887286 | doi = 10.1016/j.jmb.2019.12.035 | series = Autophagy in Neurodegenerative Diseases | s2cid = 209518157 | url = https://www.repository.cam.ac.uk/handle/1810/299796 | access-date = 20 June 2023 | archive-date = 23 May 2022 | archive-url = https://web.archive.org/web/20220523210125/https://www.repository.cam.ac.uk/handle/1810/299796 | url-status = live }}</ref> As mHtt (and many other [[Protein aggregation|protein aggregates]]) are degraded by [[autophagy]], increasing the rate of autophagy has the potential to reduce levels of mHtt and thereby ameliorate disease.<ref>{{cite journal | vauthors = Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O'Kane CJ, Rubinsztein DC | display-authors = 6 | title = Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease | journal = Nature Genetics | volume = 36 | issue = 6 | pages = 585–595 | date = June 2004 | pmid = 15146184 | doi = 10.1038/ng1362 | s2cid = 7749825 | doi-access = free }}</ref> Pharmacological and genetic inducers of autophagy have been tested in a variety of Huntington's disease models; many have been shown to reduce mHtt levels and decrease toxicity.<ref name=":0" />
===Improving cell survival===
Among the approaches aimed at improving cell survival in the presence of mutant huntingtin are correction of [[transcriptional regulation]] using [[histone deacetylase inhibitor]]s, modulating [[Protein aggregation|aggregation]] of huntingtin, improving [[metabolism]] and [[Mitochondria|mitochondrial function]] and restoring function of [[synapses]].<ref name=munoz-bates-jci/>
===Neuronal replacement===
[[Stem-cell therapy]] is used to replace damaged neurons by transplantation of [[stem cell]]s into affected regions of the brain. Experiments in animal models (rats and mice only) have yielded positive results.<ref name="Holley Kamdjou Reidling Fury pp. 329–342">{{cite journal | vauthors = Holley SM, Kamdjou T, Reidling JC, Fury B, Coleal-Bergum D, Bauer G, Thompson LM, Levine MS, Cepeda C | display-authors = 6 | title = Therapeutic effects of stem cells in rodent models of Huntington's disease: Review and electrophysiological findings | journal = CNS Neuroscience & Therapeutics | volume = 24 | issue = 4 | pages = 329–342 | date = April 2018 | pmid = 29512295 | pmc = 6489814 | doi = 10.1111/cns.12839 | publisher = Wiley }}</ref>
Whatever their future therapeutic potential, stem cells are already a valuable tool for studying Huntington's disease in the laboratory.<ref>{{cite journal | vauthors = Cundiff PE, Anderson SA | title = Impact of induced pluripotent stem cells on the study of central nervous system disease | journal = Current Opinion in Genetics & Development | volume = 21 | issue = 3 | pages = 354–61 | date = June 2011 | pmid = 21277194 | pmc = 3932563 | doi = 10.1016/j.gde.2011.01.008}}</ref>
===Clinical trials===
In 2020, there were 197 [[clinical trial]]s related to varied therapies and biomarkers for Huntington's disease listed as either underway, recruiting or newly completed.<ref name="Trials">{{cite web |title=Search of: Huntington Disease - List Results - ClinicalTrials.gov |url=https://clinicaltrials.gov/ct2/results?cond=Huntington+Disease&term=&cntry=&state=&city=&dist= |website=clinicaltrials.gov |language=en |access-date=16 November 2020 |archive-date=11 November 2021 |archive-url=https://web.archive.org/web/20211111192242/https://clinicaltrials.gov/ct2/results?cond=Huntington+Disease&term=&cntry=&state=&city=&dist= |url-status=live }}</ref> Compounds [[clinical trial|trialled]], that have failed to prevent or slow the progression of Huntington's disease include [[remacemide]], [[coenzyme Q10]], [[riluzole]], [[creatine]], [[minocycline]], [[ethyl-EPA]], [[phenylbutyrate]] and [[dimebon]].<ref>{{cite web|title=Completed Clinical Trials|url=http://www.huntington-study-group.org/ClinicalResearch/CompletedClinicalTrials/tabid/65/Default.aspx|publisher=Huntington Study Group|access-date=4 February 2012|archive-url=https://web.archive.org/web/20120628020904/http://www.huntington-study-group.org/ClinicalResearch/CompletedClinicalTrials/tabid/65/Default.aspx|archive-date=28 June 2012}}</ref>
==See also==
* {{Portal inline|Medicine}}
==References==
{{reflist|colwidth=30em}}
==External links==
<!-- External links should be limited to major international organizations and the support organizations of English-speaking nations. Sites should be up-to-date and reliable. Please discuss changes at the talk page to ensure this section does not become unmanageable. -->
{{sister project links|collapsible=true|q=no}}
* {{curlie|Health/Conditions_and_Diseases/Neurological_Disorders/Huntington%27s_Disease/}}
* [http://hopes.stanford.edu/ HOPES project] – [[HOPES|Stanford University's HD information project]]
* [http://hdbuzz.net/ HDBuzz] – HD research news written by scientists in plain language
* [http://hddrugworks.org/ HD Drug Works] – news about current treatments and planned trials
{{Medical condition classification and resources
| DiseasesDB = 6060
| ICD10 = {{ICD10|G|10||g|10}}, {{ICD10|F|02|2|f|00}}
| ICD9 = {{ICD9|333.4}}, {{ICD9|294.1}}
| ICDO =
| OMIM = 143100
| MedlinePlus = 000770
| eMedicineSubj = article
| eMedicineTopic = 1150165
| eMedicine_mult = {{eMedicine2|article|792600}} {{eMedicine2|article|289706}}
| MeshID = D006816
| GeneReviewsName=Huntington Disease
| GeneReviewsNBK=NBK1305
| Orphanet=399
}}
{{Mental and behavioural disorders|selected = neurological}}
{{Diseases of the nervous system}}
{{Trinucleotide repeat disorders}}
{{authority control}}
[[Category:Huntington's disease| ]]
[[Category:Autosomal dominant disorders]]
[[Category:Disorders causing seizures]]
[[Category:Extrapyramidal and movement disorders]]
[[Category:Genetic diseases and disorders]]
[[Category:Wikipedia medicine articles ready to translate]]
[[Category:Wikipedia neurology articles ready to translate]]
[[Category:Systemic atrophies primarily affecting the central nervous system]]
[[Category:Trinucleotide repeat disorders]]
[[Category:Diseases named for discoverer]]' |
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9 => 'https://pubmed.ncbi.nlm.nih.gov/22902173',
10 => 'https://www.nhs.uk/conditions/huntingtons-disease/treatment/',
11 => 'https://web.archive.org/web/20230506014916/https://www.nhs.uk/conditions/huntingtons-disease/treatment/',
12 => 'http://protein.bio.msu.ru/biokhimiya/contents/v83/full/83091299.html#Ref4',
13 => 'https://web.archive.org/web/20201113121719/http://protein.bio.msu.ru/biokhimiya/contents/v83/full/83091299.html#Ref4',
14 => 'https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361055',
15 => 'https://doi.org/10.1007%2Fs13311-018-00694-0',
16 => 'https://pubmed.ncbi.nlm.nih.gov/30542906',
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