Résumé :
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Background: Mutation p.Arg527Pro in the lamin A/C, encoded by LMNA gene, was identified several times in dominant Emery-Dreifuss muscular dystrophy and cases with muscular dystrophy, lipodystrophy, and cardiac rhythm disturbances. We found this p.Arg527Pro mutation in two sisters, from consanguineous unaffected parents, with a congenital muscular dystrophy (CMD) phenotype. Patients: Reduced fetal movements and neonatal hypotonia were reported in both affected children. The patients walked at age 4 and 2 years respectively and now ambulate with difficulty. Neurological examination at ages 13 and 7 years respectively showed generalised muscle weakness with scapular winging, no facial weakness, marked contractures, hyperlordosis and scoliosis. Electrocardiography and echocardiography were normal. Respiratory function tests and CK levels were normal. IQ and brain MRI were also normal. On muscle biopsy there was marked fibrosis in younger child. Immunohistochemical analysis showed normal dystrophin, sarcoglycans and merosin. Results: A Genome-wide 10 cM microsatellite screen and extra genotyping of specific loci excluded all know CMD loci. This included the LMNA locus for both classical autosomal recessive or autosomal dominant inheritance patterns as normal siblings shared the same haplotypes as the affected children. No new locus was seen on the 10 cM microsatellite screen. LMNA sequencing, requested based on the clinical phenotype, found both affected children are heterozygous for a missense mutation in the gene LMNA encoding Lamin A/C, p.Arg527Pro, which was not present in either parent in DNA samples derived from lymphocytes. This pattern is best explained by the presence of gonadal mosaicism in a parent. Conclusion: De novo mutations are common in LMNA and typically mimic the pattern of autosomal recessive inheritance. Linkage analysis is non-informative in this situation, therefore patients are best selected for LMNA sequencing on clinical features, bearing in mind the broad range of clinical phenotypes that exists (severe congenital CMD to LGMD).
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