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GENATLAS PHENOTYPE
last update : 29-01-20121
Symbol FRDA
Location 9q21.11
Name Friedreich ataxia
Corresponding gene FXN
Other symbol(s) FRDA1, DA
Main clinical features
  • primary degeneration of the dorsal root ganglia (DRG), associated with axonal degeneration in the posterior columns, spinocerebellar tracts, and corticospinal tracts of the spinal cord and large myelinated fibers in the peripheral nerves
  • most often between the ages of 8 and 15 years
  • characterized by dysarthria, areflexia, pyramidal weakness of the legs, extensor palmar response, distal loss of joint position and vibration sense
  • complicated by a cardiomyopathy which is the most frequent cause of death, and diabetes
  • main histological lesion in the brain patients is neuronal atrophy and a peculiar proliferation of synaptic terminals in the dentate nucleus termed grumose degeneration, which is is the morphological manifestation of mitochondrial iron dysmetabolism in the terminals of corticonuclear fibers (Koeppen (2007)
    • Genetic determination autosomal recessive
    Prevalence 1/50000
    Related entries including Acadian late onset forms and early onset ataxia with hypoalbuminemia (EOAHA), presenting as a gait ataxia
    Function/system disorder neurology
    Type disease
    Gene product
    Name expansion of an GAA repeat in the first intron (FRDA) gene, in almost all of the patients (95–98p100)
    Mechanism(s)
    Gene mutationChromosome rearrangementEffectComments
    repeat expansion   abnormal protein/loss of function expansion of an GAA repeat(66-1700) in the first intron accounting for 98p100 of cases, causing alterations in transcripts and flux and heme metabolites
    missense   unknown in the other 2p100 of the cases the most frequent being I154F, another mutation (G130V) in an heterozygous state is associated to an expansion on the other allele, a correlation between the size of the expansion and the type of the mutation has been found in compound heterozygotes
    Remark(s)
  • frataxin absence leading to mitochondrial iron accumulation and subsequent defect of respiratory chain and aconitase, not due to cellular sensitivity to oxidant stress
  • point mutations I154F and W155R are clustered to one surface of the protein, and these mutations decrease the interaction of frataxin with LYRM4
  • the expanded GAA triplet-repeat sequence displays an age-dependent increase in mutation load in somatic cells; progressive somatic instability may contribute to disease pathogenesis in Friedreich ataxia
  • increased mitochondrial and nuclear DNA damage, as well as gene expression patterns consistent with DNA damage, in peripheral blood cells of patients with FRDA (Haugen 2010)
  • excess iron is imported and accumulated in mitochondria, which leads to iron deficiency in the cytosol; IRP proteins are activated, and cellular iron homeostasis is impaired (PMID: 20481466 )
  • FXN promoter silencing in FRDA is dependent on the length of the expanded GAA-TR mutation (PMID: 25112975))
  • HAX1 could be considered as a potential biomarker of cardiac disease in FRDA (PMID: 31943004))