Alkaptonuria

Clinical characteristics: Alkaptonuria is caused by deficiency of homogentisate 1,2-dioxygenase, an enzyme that converts homogentisic acid (HGA) to maleylacetoacetic acid in the tyrosine degradation pathway. The three major features of alkaptonuria are dark urine or urine that turns dark on standing, ochronosis (bluish-black pigmentation in connective tissue), and arthritis of the spine and larger joints. Ochronosis generally occurs after age 30 years; arthritis often begins in the third decade. Other manifestations can include pigment in the sclera, ear cartilage, and skin of the hands; aortic or mitral valve calcification or regurgitation and occasionally aortic dilatation; renal stones; prostate stones; and hypothyroidism.

Diagnosis/testing: The biochemical diagnosis of alkaptonuria in a proband is based on the detection of a significant amount of HGA in the urine (usually 1 to 8 grams per day).

The molecular diagnosis (needed to provide genetic counseling to family members) is based on identification of biallelic pathogenic variants in HGD.

Management: Treatment of manifestations: Symptomatic management of joint pain is tailored to the individual; physical and occupational therapy help promote optimal muscle strength and flexibility; knee, hip, and shoulder replacements are options when needed; surgical intervention for prostate stones and renal stones as needed; aortic stenosis may necessitate valve replacement; thyroid hormone replacement.

Treatment with nitisinone, which has been shown to slow the progression of symptoms, is approved for use in treatment of alkaptonuria in Europe but not the United States.

Surveillance: In individuals older than age 40 years, echocardiography to detect aortic dilatation, aortic or mitral valve calcification, and stenosis. In individuals with suggestive symptoms, consider CT imaging to detect coronary artery calcification. Assess thyroid function at the time of initial diagnosis, and monitor every 1-2 years thereafter.

Agents/circumstances to avoid: Physical stress to the spine and large joints (including heavy manual labor or high-impact sports) to try to reduce progression of severe arthritis.

Evaluation of relatives at risk: It is appropriate to evaluate apparently asymptomatic older and younger sibs of an affected individual in order to identify as early as possible those who would benefit from preventive measures to help preserve overall joint mobility and function.

Genetic counseling: Alkaptonuria is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an HGD pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. When both HGD pathogenic variants in the family are known, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.