Different phenotypes of Friedreich's ataxia within one 'pseudo-dominant' genealogy: relationships between trinucleotide (GAA) repeat lengths and clinical features

We examined a large Turkmen family with 'pseudo-dominant' inheritance of Fr iedreich's ataxia resulting from consanguineous marriage of a Friedreich's ataxia patient to a heterozygote carrying an ancestral mutated allele. Two distinct phenotypes of the disease co-segregated within this genealogy. Two brothers from the younger generation exhibited 'classical' Friedreich's at axia with onset of symptoms before 10 years and a rapidly progressive cours e. In contrast, three patients (two sisters from the younger generation and their father) had a more benign phenotype of late-onset Friedreich's ataxi a with the onset at 26, 45 and 48 years and slow progression over decades. The patients with 'classical' Friedreich's ataxia were homozygous for a com mon ancestral expanded allele of the X25 gene containing 700-800 GAA repeat s, while the patients with late-onset Friedreich's ataxia had two different mutated alleles, the shorter 250-repeat expansion of paternal origin and t he longer 700-repeat expansion of maternal origin. One may conclude that cl inical variability of Friedreich's ataxia in our patients is accounted for predominantly by a modifying effect of one of the two (shorter or longer) e xpanded alleles inherited from their affected father. Our observation clear ly demonstrates the significance of variable-sized alleles for the phenotyp ic expression of the disease.