Résumé :
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The number of genes associated with distal myopathies, i.e. muscle diseases showing a predominant distal weakness at onset or throughout the disease evolution, continues to increase. Currently 20 different entities of distal myopathy have been genetically determined, compared to just 5 entities delineated on clinical grounds 20 years ago. Half of these genes cause distal phenotypes only, whereas other genes are associated also with proximal, scapuloperoneal or generalized phenotypes. The presentation will give an overview of the diagnostic and clinical features of the different distal myopathies with emphasis on some recent findings. GNE-mutated distal myopathy DMRV/h-IBM, and the distal myopathies with myofibrillar myopathic pathology (MFM) will be covered in separate presentations and not further detailed in this presentation.Interestingly, most of the genes causing distal myopathy code for proteins of the sarcomeric machinery, in contrast to the proximal dystrophies, in which most of the genes cause defects in the cell membrane. Similarly rimmed vacuolar pathology is more frequent in the distal myopathies compared to the more necrotic myopathology in the proximal dystrophies. The highly selective involvement of muscles in many of the distal myopathies is even less well understood. Understanding why some muscles remain unaffected despite expression of the same gene mutation as in the affected muscles would open new options for therapeutic possibilities. So far, the further scientific advance in understanding molecular pathophysiology after initial gene identification has not delivered ready to use curative therapies." Early onset autosomal recessive forms Distal nebulin myopathy Oculopharyngeal distal myopathy, OPDM" Early adult onset autosomal recessive forms Dysferlinopathy (Miyoshi) Distal Anoctaminopathy GNE-mutated distal myopathy (DMRV, Nonaka) " Late adult onset autosomal dominant formsWelander distal myopathy Tibial muscular dystrophy (TMD titinopathy, Udd) Distal myotilinopathy ZASPopathy (Markesbery-Griggs) VCP-mutated distal myopathy Matrin3 distal myopathy (VCPDM, MPD2)" Adult onset autosomal dominant forms Desminopathy Finnish-MPD3 (Mahjneh) Italian 19p13-linked distal myopathy (Servidei) Distal non-MFM ABD-filaminopathy (Williams) Oculopharyngeal distal myopathy" Early onset autosomal dominant forms Myosinopathy MYH7 (MPD1, Laing) KLHL9-mutated distal myopathy (Cirak 2010) The future classification of distal myopathies may rely on the protein product or gene mutation rather than on clinical features. However, the current classification considering also age at onset, pattern of muscle involvement, and mode of inheritance and pathology is clinically useful and facilitates further diagnostic procedures.
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