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

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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.

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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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Authors and Affiliations

  1. Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, Avenue Majida Boulila, 3029 Sfax, Tunisia

    Nacim Louhichi, Hammadi Ayadi & Faiza Fakhfakh

  2. Service de Neurologie, CHU Habib Bourguiba, 3029, Sfax, Tunisia

    Chahnez Triki & Mériem Méziou

  3. Service de Pédiatrie, Rééducation et Réanimation Neurorespiratoire, Hôpital Raymond-Poincaré, 92380 Garches, France

    Susana Quijano-Roy, Brigitte Estournet & Slah Mrad

  4. UF Cardio-MyoGénétique, Groupe Hospitalier Pitié-Salpêtrière, Paris, France

    Pascale Richard

  5. Etablissement Hospitalier Spécialisé Ali Ait Idir, 16000 Hahad, Alger, Algeria

    Samira Makri

  6. INSERM U582 Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France

    Norma B. Romero & Pascale Guicheney

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  1. Nacim Louhichi
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  2. Chahnez Triki
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  3. Susana Quijano-Roy
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  4. Pascale Richard
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  6. Mériem Méziou
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  7. Brigitte Estournet
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  8. Slah Mrad
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  9. Norma B. Romero
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  10. Hammadi Ayadi
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  11. Pascale Guicheney
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  12. Faiza Fakhfakh
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Corresponding author

Correspondence to Faiza Fakhfakh.

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Louhichi, N., Triki, C., Quijano-Roy, S. et al. New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunisian families. Neurogenetics 5, 27–34 (2004). https://doi.org/10.1007/s10048-003-0165-9

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  • DOI: https://doi.org/10.1007/s10048-003-0165-9

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