title: Different phenotypes of Friedreich's ataxia within one 'pseudo-dominant' genealogy: relationships between trinucleotide (GAA) repeat lengths and clinical features.
abstract: We examined a large Turkmen family with 'pseudo-dominant' inheritance of Friedreich'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 ataxia with onset of symptoms before 10 years and a rapidly progressive course. In contrast, three patients (two sisters from the younger generation and their father) had a more benign phenotype of late-onset Friedreich's ataxia 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 common ancestral expanded allele of the X25 gene containing 700-800 GAA repeats, while the patients with late-onset Friedreich's ataxia had two different mutated alleles, the shorter 250-repeat expansion of paternal origin and the longer 700-repeat expansion of maternal origin. One may conclude that clinical variability of Friedreich's ataxia in our patients is accounted for predominantly by a modifying effect of one of the two (shorter or longer) expanded alleles inherited from their affected father. Our observation clearly demonstrates the significance of variable-sized alleles for the phenotypic expression of the disease.
authors.affiliation: Department of Neurogenetics, Institute of Neurology, Russian Academy of Medical Sciences, Moscow, Russia. neurogen@online.ru
authors.forename: S N
authors.initials: SN
authors.lastname: Illarioshkin
authors.forename: G K
authors.initials: GK
authors.lastname: Bagieva
authors.forename: S A
authors.initials: SA
authors.lastname: Klyushnikov
authors.forename: I V
authors.initials: IV
authors.lastname: Ovchinnikov
authors.forename: E D
authors.initials: ED
authors.lastname: Markova
authors.forename: I A
authors.initials: IA
authors.lastname: Ivanova-Smolenskaya
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D005621:Friedreich Ataxia / Q000453:epidemiology / Q000235:genetics*; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D018911:Trinucleotide Repeats / Q000235:genetics*; D014421:Turkey / Q000453:epidemiology