Markedly different course of Friedreich's ataxia in sib pairs with similarGAA repeat expansions in the frataxin gene

Friedreich's ataxia (FA) is most frequently caused by intronic trinucleotid e repeat expansions in the frataxin gene on chromosome 9. The broad clinica l spectrum includes late-onset FA (LOFA) and FA with retained reflexes (FAR R). The size of the GAA expansions accounts for most, but not all, of the c linical variability. We report the unusual occurrence of LOFA and FARR in t wo siblings of patients with classical early-onset FA in two families. In s pite of the markedly different course of the disease, the respective siblin gs harboured GAA repeat expansions of similar size in leucocytes. Since hap lotype-related variability is not likely among siblings, we suppose that th is intrafamilial phenotype variability is due to somatic mosaicism, with th e more severely affected siblings harbouring the larger expansions in spina l cord and other affected tissues. In view of these results, genetic counse ling and predictions on the course of FA are particularly difficult, even i f an expansion mutation is found.