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Journal Articles Annals of Neurology Year : 1999

Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes

Mireille Cossée
  • Function : Author
Alexandra Dürr
  • Function : Author
Michèle Schmitt
  • Function : Author
Niklas Dahl
  • Function : Author
Paul Trouillas
  • Function : Author
Patricia Allinson
  • Function : Author
Markus Kostrzewa
  • Function : Author
Annie Nivelon-Chevallier
  • Function : Author
Karl-Henrik Gustavson
  • Function : Author
Alfried Kohlschütter
  • Function : Author
Ulrich Müller
  • Function : Author
Alexis Brice
  • Function : Author
Francesca Cavalcanti
  • Function : Author
Angela Tammaro
  • Function : Author
Giuseppe de Michele
  • Function : Author
Alessandro Filla
  • Function : Author
Sergio Cocozza
  • Function : Author
Malgorzata Labuda
  • Function : Author
Laura Montermini
  • Function : Author
Josée Poirier
  • Function : Author
Massimo Pandolfo
  • Function : Author

Abstract

Friedreich's ataxia is the most common inherited ataxia. Ninety-six percent of patients are homozygous for GAA trinucleotide repeat expansions in the first intron of the frataxin gene. The remaining cases are compound heterozygotes for a GAA expansion and a frataxin point mutation. We report here the identification of 10 novel frataxin point mutations, and the detection of a previously described mutation (G130V) in two additional families. Most truncating mutations were in exon 1. All missense mutations were in the last three exons coding for the mature frataxin protein. The clinical features of 25 patients with identified frataxin point mutations were compared with those of 196 patients homozygous for the GAA expansion. A similar phenotype resulted from truncating mutations and from missense mutations in the carboxy-terminal half of mature frataxin, suggesting that they cause a comparable loss of function. In contrast, the only two missense mutations located in the amino-terminal half of mature frataxin (D122Y and G130V) cause an atypical and milder clinical presentation (early-onset spastic gait with slow disease progression, absence of dysarthria, retained or brisk tendon reflexes, and mild or no cerebellar ataxia), suggesting that they only partially affect frataxin function. The incidence of optic disk pallor was higher in compound heterozygotes than in expansion homozygotes, which might correlate with a very low residual level of normal frataxin produced from the expanded allele.

Dates and versions

hal-04027653 , version 1 (13-03-2023)

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Mireille Cossée, Alexandra Dürr, Michèle Schmitt, Niklas Dahl, Paul Trouillas, et al.. Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes. Annals of Neurology, 1999, 45 (2), pp.200-206. ⟨10.1002/1531-8249(199902)45:2<200::aid-ana10>3.0.co;2-u⟩. ⟨hal-04027653⟩
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