Broadened Friedreich's ataxia phenotype after gene cloning Minimal GAA expansion causes late-onset spastic ataxia z M. Ragno, MD; G. De Michele, MD; F. Cavalcanti, MD; L. Pianese, PhD; A. Monticelli, MD; L. Curatola, MD; F. Bollettini, MD; S. Cocozza, MD; G. Caruso, MD; L. Santoro, MD; and A. Filla, MD Article abstract-We describe three siblings from an Italian family affected by an autosomal recessive spinocerebellar degeneration. Gait ataxia, presenting between 38 and 45 years, was the first symptom in all three patients. Dysarthria, dysmetria, brisk tendon reflexes, extensor plantar response, and scoliosis were constant features. Disease progression was slow. Electrophysiologic studies demonstrated a slight reduction in sural nerve sensory action potential in only one patient. Analysis of GAA expansion within the X25 gene showed that patients were homozygous for the expansion, with the shorter expanded allele ranging from 120 to 156 triplets. The size of the zyxw GAA expansion may be smaller than we previously described. Such minimal expansions may result in atypical forms of Friedreich's ataxia. NEUROI,O(;Y 1997;49.1617-1620 Friedreich's ataxia (FA) is the most frequent autoso- ma1 recessive inherited ataxia. It is characterized by progressive ataxia with onset before 20 years, lower limb areflexia, dysarthria, extensor plantar re- sponse, weakness, decreased vibratory sensation, pes cavus, and scoliosis. In addition, cardiomyopathy and diabetes are often present.' Chamberlain et al.2 mapped the FA locus to chromosome 9 by tight link- age to anonymous marker D9S15. We reported link- age to the FA locus also in patients with onset between 21 and 36 years," and in patients with re- tained tendon reflexes,' demonstrating that onset be- fore 20 years and lower limb areflexia are not constant features of FA. In a cooperative study we recently identified the disease-causing gene (X25).? The gene encodes a 210- protein, frataxin, with an unknown function. The majority of patients (90%) were homozygous for an unstable GAA trinucleotide expansion in the first X25 intron. In addition, we described three rare point mutations in the remaining patients. Frataxin messenger RNA levels were reduced in FA patients.5 In patients homozygous for the expansion, disease severity strongly correlated with the length of the GAA repeat."7 A recent studyu suggested that X25 may comprise part of a larger gene (STM7). We studied patients affected by autosonial reces- sive or sporadic spinocerebellar ataxias phenotypi- cally different from FA to characterize further the boundaries of the FA phenotype. Here we describe the clinical and neurophysiologic aspects of three sib- lings from an Italian family with late-onset spastic ataxia who were homozygous for the GAA expansion. The size of the expansion is below the range reported previously.6 Methods. zyxwv Molecular analysis. DNA was prepared from fresh blood. We analyzed the GAA repeat in the first intron of t h e X25 gene using a method described previously." Ten percent glycerol was added to the polymerase ch.1' in reac- tion mixture to amplify better the largest expanded alleles. The estimated error in size determination was zy 2 30 trip- lets for the largest expanded alleles. The evoked potentials and nerve conduction recordings were performed using a Dan- tec Counterpoint electromyograph (Copenhagen, Den- mark). For motor cortex stimulation a Magstim Company Ltd. (Whitland, UK) (model zyx 200) magnetic stimulator was used. Somatosensory evoked potentials for median and tibial nerve stimulation were recorded according to standard technique. Orthodromic sensory conduction ve- locity (SCV) and motor conduction velocity (MCV) were measured along the median, tibial, and sural nerves. The classic technique and needle electrodes were used. Nerve conduction velocity was recorded twice, with a 4-year in- terval. Patient 11-1 gave informed consent to sural nerve biopsy. Under local anesthesia a specimen of sural nerve was removed in toto proximal to the lateral malleolus and was prepared for morphometric measurement. The teased fiber procedure was not per- formed. Neurophysiologic study. Neuropathologic study. Patient report. The family pedigree is shown in the upper part of figure 1. The parents originated from two close villages in the district of Ascoli, a town in central Prom the lkyartments of Neurological Sciences (Drs. De Michele, Santoro, Caruso, and Filla) and Molecular and Cellular Biology and Pathology zy t1)rs. Chvalcanti, F'i;rnese. Mtrnticelli, and Cocozza), Federico I1 University, Naples; the Division of Neurology, Mazzoni Hospital (Dr. Ragno), Ascoli Piccno; and thr Division 111' Nrurnlogy (Drs. Curatola and Bollettini), San Benedetto del Tronto Hospital, Italy. Supported in part by a grant from Italian Telethon (no. 9691. Itewivcd March 17, 1997. Accepted in final form July 9. 1997. Address correspondence and reprint requests to Dr. Alessandro Filla, Clinica Neurologica, Universita Fedcrico 11, via Pansini 5, 80131 Napoli, Italy. Copyright 0 1997 by the American Academy of Neurology 1617