Chapter 7 Friedreich Ataxia

Publisher Summary This chapter discusses the clinical features and pathology of Friedreich ataxia (FA) that is the most common of the early-onset hereditary ataxias in Caucasians. The identification of the FA gene (FRDA) and its most common mutation, the unstable hyperexpansion of a GAA triplet repeat sequence (TRS) allowed to better define the clinical and pathologic spectrum of the disease. Studies suggest that the disease shows a remarkable clinical variability, sometimes even within the same sibship that is a rather uncommon finding for recessive disorders. Variability involves age at onset, rate of progression, and overall severity. Cardiomyopathy, kyphoscoliosis, pes cavus, optic atrophy, hearing loss, and diabetes mellitus occur only in some patients. Atypical cases with an overall FA-like phenotype but missing some of the essential diagnostic features can be identified. These include late-onset FA (LOFA) that develops after the age of 25 years, sometimes as late as the sixth decade, and FA with retained tendon reflexes (FARR). The FRDA locus is in the proximal long arm of chromosome 9. The gene contains seven exons spanning 95 kb of genomic DNA. The major, and probably only, functionally relevant messenger RNA (mRNA) has a size of 1.3 kb, corresponding to the first five exons, numbered 1–5a.