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Friedreich ataxia

Puneet Opal, MD, PhD
Huda Y Zoghbi, MD
Section Editors
Marc C Patterson, MD, FRACP
Helen V Firth, DM, FRCP, DCH
Deputy Editor
John F Dashe, MD, PhD


The hereditary ataxias are a genetically heterogeneous group of diseases characterized by motor incoordination resulting from dysfunction of the cerebellum and its connections. This topic will review the clinical aspects of Friedreich ataxia, a neurodegenerative disorder that is the most common of the hereditary ataxias.

Other hereditary ataxias are discussed separately. (See "Overview of the hereditary ataxias" and "Overview of cerebellar ataxia in adults", section on 'Chronic progressive ataxias'.)


Most cases of Friedreich ataxia are caused by loss of function mutations in the frataxin (FXN) gene located on chromosome 9q13 [1-3]. The great majority of patients have an expanded trinucleotide (GAA) repeat in intron 1 of both alleles of the frataxin gene. The repeat expansion results in reduced transcription of the gene (ie, silencing) and decreased expression of the gene product frataxin [4,5].

The number of GAA repeats can vary from 66 to 1700 [1,6], compared with 7 to 34 in normal alleles [2,7]. Most patients have repeats between 600 and 1200 triplets. Repeat numbers between 34 and 100 seldom result in disease, but their significance is mainly determined by whether or not they are interrupted by non-GAA repeats. Interruption stabilizes the repeat against expansions in subsequent generations. On the other hand, uninterrupted repeat tracts of this size are not stable; they are considered to be premutations because they can expand to over 300 repeats in just a single generation [7].

The manifestations of Friedreich ataxia vary in part with the number of GAA expansions. Larger GAA expansions, particularly on the smaller allele, correlate with earlier age at onset, shorter times to loss of ambulation, a greater frequency of cardiomyopathy, and loss of reflexes in the upper limbs [1,8]. Patients with late-onset cerebellar ataxia and retained reflexes tend to have smaller repeats [1]. True heterozygotes (eg, first-degree relatives) have no neurologic or cardiac abnormalities that can be ascribed to Friedreich ataxia [9].


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Literature review current through: Sep 2016. | This topic last updated: Mar 17, 2016.
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