Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Friedreich's Ataxia (FRDA1) [G11.1]

OMIM numbers: 229300, 606829 (FXN)

Dr. rer. biol. hum. Soheyla Chahrokh-Zadeh

Scientific Background

Friedreich's ataxia is the most frequently occurring autosomal recessive ataxia and has a prevalence of approx. 1 in 50,000. First signs and symptoms usually occur before 20 years of age. Major signs include progressive gait ataxia, dysarthria, nystagmus, hollow feet (Friedreich's foot), predominantly sensory neuropathy with abnormalities in electrophysiology, absence of muscular reflexes, pyramidal tract signs. Furthermore, cardiomyopathy, initially hypertrophic, later dilatative, is observed in the course of the disease. Frequently, the vision is impaired due to optic atrophy, while hearing impairment is observed in less than 10% of all patients. Cognitive skills are usually not impaired; approx. 30% of all patients develop diabetes mellitus. Neuropathological signs mainly include degeneration of the dorsal tracts, the spinocerebellar tract and the sensory neurons of the dorsal root cells. Death usually occurs within the 4th decade of life, frequently as a consequence of cardiomyopathy or impaired functioning of the brain stem.

The disease is caused by a GAA triplet-repeat expansion in intron 1 of the FXN gene. Healthy persons carry approximately 7–33 GAA repeats. In healthy carriers of premutations, 34–65 GAA uninterrupted triplets can be detected, which may expand when passed on to the next generation. Affected patients have 66 to approx. 1,700 repeats. In more than 95–98% of all cases, the disease is caused by two alleles with a GAA triplet-repeat expansion, while in 2–3% of all cases it is caused by the expansion on one allele and a point mutation or less frequently a deletion on the other FXN allele. The GAA expansion seems to reduce the expression of frataxin, a protein which is involved in the mitochondrial homeostasis of iron.