Molecular Genetics of Emery–Dreifuss Muscular Dystrophy

Abstract

Abstract Emery–Dreifuss muscular dystrophy (EDMD) is a rare neuromuscular disorder typically characterised by early contractures, slowly progressive muscular wasting, and life‐threatening heart conduction disturbances, which can develop into a cardiomyopathy. Some severe neonatal cases have also been identified. There is a wide intrafamilial and interfamilial clinical variability. Genetically, X‐linked recessive ( EMD1 and EDMD6 ), autosomal dominant ( EMD2 , EDMD4 and EDMD5 ) and autosomal recessive (EMD3) forms can be distinguished. By molecular genetic methods, EDMD can be associated with mutations in the STA (emerin gene symbol), LMNA (lamin A/C gene symbol), SYNE (nesprin gene symbol) 1 , SYNE2 and Four and a Half LIM Domain 1 ( FHL1 ) genes. Female carriers of the X‐linked forms may manifest with cardiac symptoms but heterozygous carriers of the autosomal forms do not show symptoms. Only approximately 46% of unrelated EDMD patients have a mutation in known genes pointing to further genetic heterogeneity in EDMD. The molecular pathogenesis is unresolved, but there is evidence for gene expression changes via altered nuclear signalling and for reduced resistance of muscles to physical damage during contraction. Key Concepts: Emery–Dreifuss muscular dystrophy (EDMD) is a neuromuscular disorder recognised clinically by three features: early contractures, a characteristic pattern of muscle wasting and cardiac conduction defects. EDMD was originally described as an X‐linked disorder, later found to be caused by mutations in the STA gene encoding a nuclear membrane protein, emerin. Molecular genetic analysis allows precise subtyping of EDMD into X‐linked forms ( STA and FHL1 associated), autosomal dominant forms ( LMNA , SYNE1/SYNE2 associated) and an autosomal recessive form ( LMNA associated). Wide clinical variability of EDMD and clinical overlap with other clinical entities frequently require consideration of patients not completely fulfilling the EDMD diagnostic criteria for molecular genetic differentiation in STA , LMNA , SYNE1/SYNE2 and FHL1 . Digenic pathogenesis has been observed including LMNA / STA , LMNA / DES and SYNE1/SYNE2 . In most cases, EDMD mutations affect proteins located in the nuclear membrane where they interact with each other. Many patients do not have mutations in genes identified so far, so further genes are expected to be involved in the pathogenesis of EDMD.