Molecular Genetics of Emery–Dreifuss Muscular Dystrophy


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. There is a wide intrafamilial and interfamilial clinical variability. Genetically, X‐linked recessive, autosomal dominant and autosomal recessive forms can be distinguished. Female carriers of the X‐linked forms may manifest with cardiac symptoms. By molecular genetic methods, EDMD can be associated with mutations in several genes encoding nuclear envelope proteins. These proteins are lamin A, emerin, FHL1, nesprins and SUN proteins. Still only approximately half of unrelated patients diagnosed with EDMD have a mutation in known genes pointing to further genetic heterogeneity in EDMD. The molecular pathogenesis is not fully resolved, but there are effects on signalling, mechanical stability and gene expression.

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 EMD gene encoding a nuclear membrane protein, emerin.
  • Molecular genetic analysis allows precise subtyping of EDMD into X‐linked forms (EMD and FHL1 associated), autosomal dominant forms (LMNA, SYNE1/SYNE2 associated) and autosomal recessive forms (LMNA and SUN1 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 EMD, LMNA, SYNE1/SYNE2, SUN1 and FHL1.
  • Digenic pathogenesis has been observed including LMNA/EMD, LMNA/DES, SYNE1/SYNE2, LMNA/SUN1, LMNA/SUN2 and EMD/SUN1.
  • In all cases, EDMD mutations affect proteins located at the nuclear envelope 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.

Keywords: Emery–Dreifuss muscular dystrophy; contractures; cardiomyopathy; EMD; SYNE; SUN; FHL1; emerin; lamin A/C; LINC complex; nuclear envelope

Figure 1. Clinical picture of Emery–Dreifuss muscular dystrophy (EDMD). (a) X‐EDMD patient at age 11 showing contractures of elbow and Achilles tendons as well as remarkable humero‐peroneal muscular wasting. (b) Typical posture of the arms of a patient at age 31 caused by contractures of the elbow tendons. (c) Contractures of the spine (‘rigid spine’). (d) Holter monitoring of a patient at ages 7 and 12 showing intraventricular conduction disturbances, irregular atrial beats, sinoatrial blocks and supraventricular arrhythmia with moving atrial pace maker and polytopic early beats. Medizinische Genetik, Emery‐Dreifuss Muskeldystrophie: Klinische Variabilität und genetische Heterogenität, 21, 2009, 343–348, Wehnert M. With permission of Springer.
Figure 2. Modifying mutations in EDMD: Two patients carry the same EMD mutation: p.L84Pfs6*, (a) typical EDMD phenotype (reproduced by permission of Manfred Wehnert) and unusual severe clinical manifestation, this patient carries the additional SUN1 mutation p.A203V (reprinted from Neuromuscular Disorders, 9(3), Hoeltzenbein et al., Severe clinical expression in X‐linked Emery–Dreifuss muscular dystrophy, 166–170, Copyright (1999), with permission from Elsevier).


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Further Reading

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Worman HJ and Schirmer EC (2015) Nuclear membrane diversity: underlying tissue‐specific pathologies in disease? Current Opinion in Cell Biology 34: 101–112.

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Meinke, Peter(Jan 2018) Molecular Genetics of Emery–Dreifuss Muscular Dystrophy. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022438.pub2]