Friedreich ataxia (FRDA1) is the most common autosomal recessive inherited ataxia with a prevalence of approximately 1:20,000 (in Southwestern Europe) to 1:250,000 (in Northern and Eastern Europe). First symptoms usually appear before the age of 20. The main symptoms include progressive gait ataxia, dysarthria, nystagmus, hollow high-arched foot feet (Friedreich's foot), predominantly sensory neuropathy with abnormalities in electrophysiology, lack of muscular reflexes, and pyramidal path tract signs. Initially, hypertrophic cardiomyopathy is often seen, later dilated cardiomyopathy is also observed. In the course of the disease initially hypertrophic, later also dilated cardiomyopathy is often observed. Not infrequently, visual acuity is impaired by optic atrophy, while hearing impairment is observed in less than 10%. Cognitive abilities are usually not impaired, and about 30% of those affected develop diabetes mellitus. Neuropathological findings include evidence of degeneration of the dorsal pathways, the spinocerebellar tract and the sensory neurons of the dorsal root cells. Death usually occurs in the 4th decade of life, often as a result of cardiomyopathy or impaired brain stem functions.
The disease is caused by a GAA triplet repeat expansion in intron 1 of the FXN gene. Normal persons have about 7-33 GAA repeats. In healthy premutation carriers, 34-65 uninterrupted GAA triplets can be detected, which may be extended when passed on to the next generation. Patients have 66 to about 1,700 repeats. In more than 95-98% of cases the disease is caused by two alleles with the GAA triplet repeat expansion, while in about 2-3% the cause is expansion on one allele and a point mutation, more rarely a deletion, on the other FXN allele. GAA expansion reduces the expression of frataxin, a protein involved in mitochondrial iron homeostasis.
Cook et al. 2017, Br Med Bull.; 124:19 / Bürk, 2017, Cerebellum Ataxias; 4: 4 / Schulz et al. 2009, Nat Rev Neurol 5:222 / Pandolfo et al. 2009, J Neurol 256:Suppl 1 / Wilson 2006, Semin Pediatr Neurol 13:166 / Delatycki et al. 2000, J Med Genet 37:1 / Montermini et al. 1997, Hum Mol Genet 6:1261 / Dürr et al. 1996, New Eng J Med 335:1169 / Campuzano et al. 1996, Science 271:1423