title: New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunisian families.
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 alpha-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.
authors.affiliation: Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, Avenue Majida Boulila, 3029 Sfax, Tunisia.
authors.forename: Nacim
authors.initials: N
authors.lastname: Louhichi
authors.forename: Chahnez
authors.initials: C
authors.lastname: Triki
authors.forename: Susana
authors.initials: S
authors.lastname: Quijano-Roy
authors.forename: Pascale
authors.initials: P
authors.lastname: Richard
authors.forename: Samira
authors.initials: S
authors.lastname: Makri
authors.forename: Mériem
authors.initials: M
authors.lastname: Méziou
authors.forename: Brigitte
authors.initials: B
authors.lastname: Estournet
authors.forename: Slah
authors.initials: S
authors.lastname: Mrad
authors.forename: Norma B
authors.initials: NB
authors.lastname: Romero
authors.forename: Hammadi
authors.initials: H
authors.lastname: Ayadi
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
authors.forename: Faiza
authors.initials: F
authors.lastname: Fakhfakh
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D002531:Cerebellum / Q000002:abnormalities*; D002648:Child; D002675:Child, Preschool; D005192:Family Health; D005260:Female; D018703:Founder Effect; D006031:Glycosylation; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000150:complications / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D009136:Muscular Dystrophies / Q000150:complications / Q000151:congenital / Q000235:genetics*; D010375:Pedigree; D010430:Pentosyltransferases; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D014416:Tunisia
chemical_list: D011506:Proteins; C443107:FKRP protein, human; D010430:Pentosyltransferases