title: Striking intrafamilial phenotypic variability and spastic paraplegia in the presence of similar homozygous expansions of the FRDA1 gene.
abstract: We report on a Friedreich's ataxia (FA) family with 3 affected siblings with markedly different phenotypic presentations, including one with spastic paraplegia. Molecular analysis showed midsize GAA repeat expansion sizes in all 3 individuals. Gait spasticity in FA, although rare, has been described in a few patients who are compound heterozygotes for a point mutation, or who had GAA expansions of less than 200 repeats. The occurrence of spastic paraplegia in our family, in the presence of homozygous midsize GAA repeat expansions, is an unusual finding. Spasticity can be the main feature in both sporadic and familial patients with FA, either as an isolated finding, or in addition to other neurological abnormalities, and should be included as a rare feature in the clinical spectrum of FA. This family also demonstrates that in FA, marked intrafamilial phenotypic variability can arise in the presence of similar GAA expansion sizes. Therefore, in familial FA, the disease course in relatives therefore cannot be predicted solely from repeat length. Factors such as somatic mosaicism, repeat interruptions, modifying mutations and environmental factors must also be considered.
authors.affiliation: Neurogenetics Unit, Montreal Neurological Hospital and Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Amanpreet
authors.initials: A
authors.lastname: Badhwar
authors.forename: An
authors.initials: A
authors.lastname: Jansen
authors.forename: Frederick
authors.initials: F
authors.lastname: Andermann
authors.forename: Massimo
authors.initials: M
authors.lastname: Pandolfo
authors.forename: Eva
authors.initials: E
authors.lastname: Andermann
mesh_terms: D000328:Adult; D001706:Biopsy; D005260:Female; D005621:Friedreich Ataxia / Q000235:genetics; D005684:Gait; D006720:Homozygote; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics*; D008297:Male; D010264:Paraplegia / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics; D013497:Sural Nerve / Q000473:pathology; D000096923:Frataxin
chemical_list: D033862:Iron-Binding Proteins; D000096923:Frataxin