title: Intrafamilial phenotypic variability in Friedreich ataxia associated with a G130V mutation in the FRDA gene.
abstract: BACKGROUND
  Most patients with Friedreich ataxia (FA) have a GAA trinucleotide repeat expansion in intron 1 of the FA gene (FRDA) on both arms of chromosome 9. However, some patients are compound heterozygotes and harbor a GAA expansion on one allele and a point mutation on the other. Compound heterozygous patients with FA who have a GAA expansion and a G130V mutation have been reported to have an atypical phenotype with a slow disease progression, minimal or no ataxia, or gait spasticity.
  
  
  OBJECTIVE
  To describe intrafamilial phenotypic variability in a GAA expansion/G130V mutation compound heterozygous family with FA.
  
  
  METHODS
  Tertiary referral university hospital setting.
  
  
  METHODS
  A 34-year-old man presented to our hospital with a 24-year history of stiff legs and mild unsteadiness of gait. Clinical examination showed a spastic paraparesis with normal to pathologically brisk deep tendon reflexes and mild left upper limb ataxia. His 27-year-old sister presented with a slowly progressive early-onset ataxic syndrome. She had ataxia of gait, mild to severe limb ataxia, and reduced or absent deep tendon reflexes, but no evidence of spasticity on examination.
  
  
  RESULTS
  Neurophysiologic investigations showed evidence of a sensory axonal neuropathy, and molecular genetic analysis showed that both siblings were compound heterozygotes with a GAA expansion and a G130V mutation.
  
  
  CONCLUSIONS
  This report confirms that compound heterozygous patients with FA who have a GAA expansion and a G130V mutation may present with an ataxic phenotype and that intrafamilial phenotypic variability in these pedigrees can occur. It also emphasizes the importance of performing molecular genetic analysis for the GAA trinucleotide expansion in patients presenting with a spastic paraparesis of undetermined etiology, especially when there is neurophysiologic evidence of a sensory axonal neuropathy.
authors.affiliation: Department of Clinical Neurology, Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, England. d.mccabe@ion.ucl.ac.uk
authors.forename: Dominick J H
authors.initials: DJ
authors.lastname: McCabe
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.forename: Fergus
authors.initials: F
authors.lastname: Ryan
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hanna
authors.forename: Sean
authors.initials: S
authors.lastname: Connolly
authors.forename: David P
authors.initials: DP
authors.lastname: Moore
authors.forename: Janice
authors.initials: J
authors.lastname: Redmond
authors.forename: David E
authors.initials: DE
authors.lastname: Barton
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Murphy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D001259:Ataxia / Q000209:etiology; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005621:Friedreich Ataxia / Q000235:genetics*; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D018911:Trinucleotide Repeats / Q000235:genetics*
chemical_list: C079091:APBA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D009419:Nerve Tissue Proteins