Friedreich's ataxia is an autosomal recessively inherited neurodegener
ative disorder caused by expansions of an unstable GAA trinucleotide r
epeat in the STM7/X25 gene on chromosome 9q. We studied the (GAA)(n) p
olymorphism in 178 healthy controls and 102 patients with idiopathic a
taxia. The repeat size ranged from 7 to 29 (GAA)(n) motifs on normal c
hromosomes and from 66 to 1360 trinucleotide repetitions in Friedreich
's ataxia patients. Meiotic instability of expanded alleles was observ
ed without significant differences in maternal and paternal transmissi
ons. Thirty-six of 102 patients were typed homozygous for expanded (GA
A)(n) alleles. Twenty-seven of these presented with the typical Friedr
eich's ataxia symptoms and nine patients with an atypical Friedreich's
ataxia phenotype. Before molecular genetic diagnosis had been perform
ed seven of these patients had been classified as early onset cerebell
ar ataxia and two as idiopathic sporadic cerebellar ataxia of late ons
et. In contrast, in one family with typical Friedreich's ataxia phenot
ype we did not find an expanded allele; this suggests that there can b
e either point mutations in the X25 gene on both chromosomes or locus
heterogeneity in Friedreich's ataxia. The phenotypic spectrum of Fried
reich's ataxia is much broader than considered before. Early onset, ar
eflexia, extensor plantar responses and reduced vibration sense should
no longer be considered essential diagnostic criteria of Friedreich's
ataxia. In comparison with the non-Friedreich's ataxia group hypertro
phic cardiomyopathy seems to be the only symptom specific for Friedrei
ch's ataxia. However it is not obligatory The phenotype is significant
ly influenced by the number of GAA repeats with close genotype-phenoty
pe relationships when the smaller of the two alleles is considered. Re
peat length correlated inversely with age at onset, onset of dysarthri
a and progression rate. In conclusion, molecular genetic analysis appe
ars mandatory for the diagnosis and genetic counselling of Friedreich'
s ataxia. The molecular genetic test should be applied not only to pat
ients with typical Friedreich's ataxia phenotype but also in all cases
of idiopathic autosomal recessive or sporadic ataxia.