Résumé :
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Emery-Dreifuss Muscular Dystrophy (EDMD) is a rare autosomal or X-linked recessive condition, associating muscular dystrophy, joint contractures and cardiac disease. Mutations in 2 genes, EMD (emerin) and LMNA (Lamins A/C) encoding nuclear envelope proteins account for only 40% of EDMD cases, suggesting additional genetic heterogeneity. Our objective was to estimate the respective contribution of LMNA and EMD mutations among an EDMD cohort screened in our labs. We reviewed medical records of 2200 patients screened for LMNA and/or EMD. EDMD clinical criteria were the coexistence of muscle involvement in a humeroperoneal, proximal or diffuse distribution; early tendons contractures; conduction defect and arrhythmias with or without dilated cardiomyopathy. EMD and LMNA genes were analyzed by dHPLC/sequencing with a preliminary analysis of emerin protein (western-blot, immuno-histochemistry). 656 patients matched with our EDMD inclusion criteria. This study revealed the respective proportion of LMNA mutations (176 patients, 27%), EMD mutations (48 patients, 7%) detected following an abnormal emerin expression. 90% of EMD mutations were truncating ones whereas 94% of those found in LMNA gene were nontruncating. No mutation of these 2 genes was identified for 432 EDMD patients (66%) underlining the large number of patients lacking genetic diagnosis. Of these, 28 patients (6.5%) were eventually found to be mutated in other genes, as EDMD clinically overlaps with several other myopathies (LGMDs, CMDs, collagenopathies…) thus highlighting the importance of an accurate and careful diagnosis of this disease. From 96 patients consistent with X-linked transmission and for whom emerin protein was normal, analysis of EMD gene did not identify any mutation, confirming that emerin protein analysis remains a powerful diagnostic tool to detect EMD mutations. We finally characterized a global cohort of 404 patients eligible to search new EDMD genes. Six informative families are currently being genotyped. Meanwhile, candidate genes are being sequenced among our global cohort.
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