Résumé :
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Communication n° 523. Recently, we found that mutations of the SEPN1 gene, encoding the novel selenoprotein N, cause 3 early-onset myopathies: Rigid Spine Muscular Dystrophy (RSMD1), classical multiminicore disease (MmD) and desmin-related myopathy with Mallory Body-like inclusions (MB-DRM). We proposed that all 3 constitute a novel entity, termed SEPN-related myopathy (SEPN-RM). To define this emerging entity and to establish phenotype-genotype correlations, we analysed the clinical, morphological and molecular findings in a series of 80 patients (64 families) with SEPN1 mutations. Transmission was always autosomal recessive; 25 families were consanguineous. No neomutation was found. Most of the 42 mutations identified were insertions (6), deletions (10) or non-sense mutations (6). Exon 1 mutations were frequent (50 patients). Founder effects were identified for 3 mutations. Regardless of the initial diagnosis, all patients (aged 5-48 years) shared a consistent clinical phenotype, with early-onset axial muscle weakness and relatively preserved limb strength. Poor and delayed head control was constant but most patients walked at normal age. There were no congenital contractures. CK was usually normal. 90 % patients developed severe scoliosis and respiratory insufficiency at the mean ages of 9.75 and 11.74 y, respectively. A variable degree of spinal rigidity was seen in 92% cases. Arthrodesis (21 cases) and nasal ventilation led generally to clinical stability and preserved ambulation. Without respiratory assistance, 3 patients and 12 relatives died between 4 and 19 years. Most of the 42 muscle biopsies analysed showed multi-minicores (83.3%), either isolated (45%), associated with dystrophic findings (21%, mainly in axial muscles), or with Mallory body-like inclusions (17%, only in quadriceps). In conclusion, RSMD1, classical MmD and MB-DRM due to SEPN1 mutations are not allelic disorders, but the same entity. SEPN-RM is clinically homogenous but shows a large morphological spectrum.
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