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Neurogenetics

, Volume 5, Issue 1, pp 27–34 | Cite as

New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunisian families

  • Nacim Louhichi
  • Chahnez Triki
  • Susana Quijano-Roy
  • Pascale Richard
  • Samira Makri
  • Mériem Méziou
  • Brigitte Estournet
  • Slah Mrad
  • Norma B. Romero
  • Hammadi Ayadi
  • Pascale Guicheney
  • Faiza FakhfakhEmail author
Original Article

Abstract

The congenital muscular dystrophies (CMD) constitute a clinically and genetically heterogeneous group of autosomal recessive myopathies. Patients show congenital hypotonia, muscle weakness, and dystrophic changes on muscle biopsy. Mutations in four genes (FKT1, POMGnT1, POMT1, FKRP) encoding putative glycosyltransferases have been identified in a subset of patients characterized by a deficient glycosylation of α-dystroglycan on muscle biopsy. FKRP mutations account for a broad spectrum of patients with muscular dystrophy, from a severe congenital form with or without mental retardation (MDC1C) to a much milder limb-girdle muscular dystrophy (LGMD2I). We identified two novel homozygous missense FKRP mutations, one, A455D, in six unrelated Tunisian patients and the other, V405L, in an Algerian boy. The patients, between the ages of 3 and 12 years, presented with a severe form of MDC1C with calf hypertrophy and high serum creatine kinase levels. None had ever walked. Two had cardiac dysfunction and one strabismus. They all had mental retardation, microcephaly, cerebellar cysts, and hypoplasia of the vermis. White matter abnormalities were found in five, mostly when cranial magnetic resonance imaging was performed at a young age. These abnormalities were shown to regress in one patient, as has been observed in patients with Fukuyama CMD. Identification of a new microsatellite close to the FKRP gene allowed us to confirm the founder origin of the Tunisian mutation. These results strongly suggest that particular FKRP mutations in the homozygous state induce structural and clinical neurological lesions in addition to muscular dystrophy. They also relate MDC1C to other CMD with abnormal protein glycosylation and disordered brain function.

Keywords

Congenital muscular dystrophy FKRP gene Founder haplotype Mental retardation Cerebellar cysts 

Notes

Acknowledgements

We thank the patients and their families for their participation. This work was supported by funds from the Secrétariat d’Etat à la Recherche Scientifique et à la Technologie (Tunisia), the Institut National de la Santé et de la Recherche Médicale (INSERM), Association Française contre les Myopathies (AFM), and the European Commission (contract no. QLG1-CT1999-00870).

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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Nacim Louhichi
    • 1
  • Chahnez Triki
    • 2
  • Susana Quijano-Roy
    • 3
  • Pascale Richard
    • 4
  • Samira Makri
    • 5
  • Mériem Méziou
    • 2
  • Brigitte Estournet
    • 3
  • Slah Mrad
    • 3
  • Norma B. Romero
    • 6
  • Hammadi Ayadi
    • 1
  • Pascale Guicheney
    • 6
  • Faiza Fakhfakh
    • 1
    Email author
  1. 1.Laboratoire de Génétique Moléculaire HumaineFaculté de Médecine de SfaxTunisia
  2. 2.Service de NeurologieCHU Habib BourguibaSfaxTunisia
  3. 3.Service de Pédiatrie, Rééducation et Réanimation NeurorespiratoireHôpital Raymond-PoincaréFrance
  4. 4.UF Cardio-MyoGénétiqueGroupe Hospitalier Pitié-SalpêtrièreParisFrance
  5. 5.Etablissement Hospitalier Spécialisé Ali Ait IdirAlgerAlgeria
  6. 6.INSERM U582 Institut de MyologieGroupe Hospitalier Pitié-SalpêtrièreParisFrance

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