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Identification of three novel frameshift mutations in patients with Friedreich's ataxia
  1. MARK A POOK*,
  1. *Hereditary Ataxia Research Group, Department of Molecular Genetics, Division of Biomedical Sciences, Sir Alexander Fleming Building, Imperial College School of Science Technology and Medicine, Exhibition Road, London SW7 2AZ, UK
  2. †Paediatric Neurology, Child Health, Southampton General Hospital, Southampton, UK
  3. ‡Paediatric Neurology, Alder Hey Children's Hospital, Liverpool, UK
  4. §Clinical Genetics, Birmingham Women's Hospital, Birmingham, UK
  5. ¶Molecular Genetics Laboratory, Liverpool Women's Hospital, Liverpool, UK
  1. Dr Pook, m.pook{at}

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Editor—Friedreich's ataxia (FRDA, MIM 229300) is an autosomal recessive, progressive, neurodegenerative disorder. It is the most common of all hereditary ataxias, with an estimated prevalence of 1 in 50 000, and a carrier frequency calculated to be as high as 1 in 90 in white populations. Onset normally occurs between 8 and 15 years of age, presenting as ataxia of gait accompanied by dysarthria, areflexia, extensor plantar responses, and distal loss of position and vibration sense. The involvement of other systems is also apparent, and in particular most patients die prematurely from hypertrophic cardiomyopathy.

The FRDA gene encodes a highly conserved protein, designated frataxin, which localises to the mitochondrial matrix and appears to be involved in the efflux of iron from mitochondria.1-4 Patients with FRDA have reduced levels of frataxin expression, which probably leads to mitochondrial iron accumulation and free radical damage of oxidative phosphorylation processes.5-8 The predominant mutation, accounting for approximately 98% of FRDA chromosomes, is expansion of a GAA trinucleotide repeat located within intron 1 of theFRDA gene.1 9 Normal subjects have 6-36 GAA repeats at this position, whereas FRDA patients have expansions of 120-1700 repeats.10-12 The GAA expansion has been postulated to interfere with frataxin transcription by forming a triple helical based “sticky DNA” structure.13 14An estimated 96% of FRDA patients are homozygous for the GAA expansion and a correlation between severity of the disease phenotype and the size of the smaller of the two alleles has been identified.2 The remaining 4% of FRDA patients are compound heterozygotes, having a GAA expansion at one allele and either a known point mutation (2.5%) or an as yet unidentified mutation (1.5%) at the other allele.9 No instance of an FRDA patient carrying two frataxin point mutations has yet been …

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