Friedreich ataxia

Friedreich ataxia is a progressive multisystem disorder predominantly affecting the cerebellum, dorsal columns, dorsal root ganglia, corticospinal tracts, and peripheral nerves. Ataxia manifests initially as poor balance when walking, followed by slurred speech and upper-limb ataxia. Mean age at onset lies between 10 and 15 years, with a documented range from age 2 years to the eighth decade. About 75% of individuals show typical FRDA, while around 25% present with atypical forms including late-onset FRDA, very late-onset FRDA, and FRDA with retained reflexes. Extraneurological involvement includes hypertrophic cardiomyopathy in roughly two thirds of individuals, diabetes mellitus in up to 30%, scoliosis, pes cavus, sensorineural hearing loss in 13%, and asymptomatic optic atrophy in approximately 25%. The rate of progression is variable; the average time from onset to wheelchair dependence is about ten years, and earlier onset is associated with more rapid progression.

The estimated prevalence is 1:200,000 in countries with predominant European ancestry. FRDA is the most common early-onset inherited ataxia in Europe, the Middle East, South Asia, and North Africa, with a reported carrier frequency of 1:60 to 1:100.

Friedreich ataxia is caused by germline pathogenic variants in FXN (9q21.11). Approximately 96% of affected individuals carry biallelic intronic GAA repeat expansions in intron 1 of FXN, while about 4% are compound heterozygous for a GAA expansion and an intragenic FXN pathogenic sequence variant or deletion. Frataxin, the nuclear-encoded mitochondrial protein encoded by FXN, is an iron-binding protein required for the synthesis of iron-sulphur clusters and for the activity of mitochondrial respiratory chain enzymes. Its deficiency leads to secondary loss of iron-sulphur cluster-containing enzymes, mislocalisation of cellular iron, increased sensitivity to oxidative stress, and impaired mitochondrial respiratory function.

Friedreich ataxia is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes and therefore carry one pathogenic FXN variant. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a heterozygous carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes are asymptomatic and not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the FXN pathogenic variants in an affected family member. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

The diagnosis of Friedreich ataxia is established in a proband with suggestive clinical findings by the identification of biallelic pathogenic variants in FXN on molecular genetic testing. Brain MRI is often normal in early stages; with advanced disease, atrophy of the cervical spinal cord and cerebellum, and of the superior cerebellar peduncle, may be observed. Imaging findings are supportive but not diagnostic.

Main differential diagnoses include:

• Ataxia with vitamin E deficiency (AVED): clinical overlap with FRDA, but titubation and hyperkinesia are more frequent and cardiomyopathy is much less common; plasma vitamin E differentiates AVED; TTPA.
• : childhood-onset cerebellar ataxia with oculomotor apraxia, severe axonal sensorimotor neuropathy, chorea, and cerebellar atrophy on MRI; APTX.
• : childhood clumsiness, areflexia, and minimal distal muscle weakness can mimic early FRDA before dysarthria or extensor plantar responses develop; >80 genes, e.g. PMP22, MFN2, GJB1.

• Establishing the diagnosis in an individual with suggestive clinical findings, thereby ending the diagnostic odyssey and clarifying the underlying molecular cause.
• Enabling specific and individualised surveillance covering neurological progression, cardiomyopathy, diabetes mellitus, hearing, sleep apnoea, osteoporosis, and psychological well-being, as the prerequisite for targeted medical care defined by the treating physicians in consultation with the affected individual.
• Identification of the familial pathogenic variants permits carrier testing of at-risk relatives and informs reproductive counselling.

• Bidichandani SI, Delatycki MB, Napierala M, Duquette A. Friedreich ataxia. 1998 Dec 18 [updated 2024 Oct 31]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: PMID:20301458.
• Corben LA, Collins V, Milne S, Farmer J, Musheno A, Lynch D, et al. Clinical management guidelines for Friedreich ataxia: best practice in rare diseases. Orphanet J Rare Dis. 2022;17(1):415. doi:10.1186/s13023-022-02568-3. PMID:; PMCID:PMC9644683.