Friedreich Ataxia

Clinical characteristics: Typical Friedreich ataxia (FRDA) is characterized by progressive ataxia with onset from early childhood to early adulthood with mean age at onset from 10 to 15 years (range: age two years to the eighth decade). Ataxia, manifesting initially as poor balance when walking, is typically followed by upper-limb ataxia, dysarthria, dysphagia, peripheral motor and sensory neuropathy, spasticity, autonomic disturbance, and often abnormal eye movements and optic atrophy. Hypertrophic cardiomyopathy is present in about two thirds of individuals; occasionally it is diagnosed prior to the onset of ataxia. Diabetes mellitus and impaired glucose tolerance can also occur.

Among individuals with FRDA, about 75% have "typical Friedreich ataxia" and about 25% of individuals with biallelic FXN full-penetrance GAA repeat expansions have "atypical Friedreich ataxia" that includes late-onset FRDA (LOFA) (i.e., onset after age 25 years), very late-onset FRDA (VLOFA) (i.e., onset after age 40 years), and FRDA with retained reflexes (FARR).

Diagnosis/testing: The diagnosis of Friedreich ataxia is established in a proband with suggestive findings and biallelic pathogenic variants in FXN identified by molecular genetic testing. The two classes of FXN pathogenic variants are (1) GAA repeat expansions and (2) FXN pathogenic sequence variants, including base substitutions and small indels or large deletions. Approximately 96% of individuals with FRDA have biallelic FXN GAA repeat expansions in intron 1; approximately 4% are compound heterozygotes for an FXN GAA repeat expansion and either an intragenic FXN pathogenic variant or a large deletion.

Management: Targeted therapy: Omaveloxolone, an Nrf2 activator, has been shown to slow the progression of FRDA; it is approved in the United States and Europe for individuals age 16 years and older.

Supportive care: Multidisciplinary care by specialists in relevant fields, such as neurologists, ophthalmologists, orthoptists, physical therapists, occupational therapists, cardiologists, endocrinologists, speech and language therapists, and psychologists.

Surveillance: Routinely scheduled evaluations by the treating multidisciplinary specialists.

Agents/circumstances to avoid: Use and misuse of illegal and controlled drugs, as they may affect neuronal well-being and, thus, exacerbate disease manifestations; medications that are toxic or potentially toxic to people with neuropathy; circumstances that increase the risk of falling (e.g., rough surfaces).

Evaluation of relatives at risk: If at-risk minor and adult sibs of an individual with FRDA have not had testing for the FXN pathogenic variant(s) in their family, they should be offered echocardiography surveillance to determine if treatable cardiac manifestations of presymptomatic disease are present.

Pregnancy management: Worsening, improving, or unchanged manifestations during pregnancy were each reported with equal frequency by women with FRDA. Close cardiac monitoring and regular testing for diabetes mellitus during pregnancy is recommended in any woman with FRDA. If cesarean section is required, epidural or spinal anesthesia is recommended rather than general anesthesia if possible.

Genetic counseling: FRDA is inherited in an autosomal recessive manner. If both parents are heterozygous for a pathogenic variant in FXN, each sib of an affected individual has at conception a 25% chance of inheriting biallelic FRDA-related genetic alterations, a 50% chance of inheriting one FRDA-related genetic alteration, and a 25% chance of inheriting neither of the familial FRDA-related genetic alterations. Sibs who inherit biallelic FXN pathogenic variants will be affected. Once the FRDA-related genetic alterations have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.