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Article Dans Une Revue Annals of Neurology Année : 1999

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

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

Résumé

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 et 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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