Molecular Genetics of Emery–Dreifuss Muscular Dystrophy

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.

Keywords: Emery–Dreifuss muscular dystrophy; contractures; cardiomyopathy; STA; SYNE; FHL1; emerin; lamin A/C; nesprin; nuclear membrane

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. Wehnert M (2009) Emery‐Dreifuss Muskeldystrophie: Klinische Variabilität und genetische Heterogenität. Medizinische Genetik21: 343–348, doi:10.1007/s11825‐009‐0173‐8. Reproduced by permission of Springer.

Figure 2.

Segregation of LMNA p.M348I and STA p.0 mutations in family Antwerpen‐EMD‐2. (a) Pedigree; (b) Sequence analysis in LMNA; (c) Restriction digestion with SmuI validating LMNA p.M348I. Wehnert M (2009) Emery‐Dreifuss Muskeldystrophie: Klinische Variabilität und genetische Heterogenität. Medizinische Genetik21: 343–348, doi:10.1007/s11825‐009‐0173‐8. Reproduced by permission of Springer.

close

References

Attali R, Warwar N, Israel A et al. (2009) Mutation of SYNE‐1, encoding an essential component of the nuclear lamina, is responsible for autosomal recessive arthrogryposis. Human Molecular Genetics 18: 3462–3469.

di Barletta R, Ricci M, Galluzzi E et al. (2000) Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery–Dreifuss muscular dystrophy. American Journal of Human Genetics 66: 1407–1412.

Ben Yaou R, Toutain A, Arimura T et al. (2007) Multitissular involvement in a family with LMNA and EMD mutations: role of digenic mechanism? Neurology 68: 1883–1894.

Bione S, Maestrini E, Rivella S et al. (1994) Identification of a novel X‐linked gene responsible for Emery–Dreifuss muscular dystrophy. Nature Genetics 8: 323–327.

Bonne G, Di Barletta MR, Varnous S et al. (1999) Mutations in the gene encoding lamin A/C cause autosomal dominant Emery–Dreifuss muscular dystrophy. Nature Genetics 21: 285–288.

Bonne G, Mercuri E, Muchir A et al. (2000) Clinical and molecular genetic spectrum of autosomal dominant Emery–Dreifuss muscular dystrophy due to mutations of the lamin A/C gene. Annals of Neurology 2: 170–180.

Clements L, Manilal S, Love DR and Morris GE (2000) Direct interaction between emerin and lamin A. Biochemical and Biophysical Research Communications 267: 709–714.

Dubowitz V and Sewry CA (2007) Muscle Biopsy: A Practical Approach, 3rd edn. Edinburgh: Saunders‐Elsevier.

Emery AEH (1989) Emery–Dreifuss syndrome. Journal of Medical Genetics 26: 637–641.

Emery AEH and Dreifuss FE (1966) Unusual benign X‐linked muscular dystrophy. Journal of Neurology, Neurosurgery, and Psychiatry 29: 338–342.

Gueneau L, Bertrand AT, Jais J‐P et al. (2009) Mutations of FHL1 gene cause Emery–Dreifuss muscular dystrophy. American Journal of Human Genetics 85: 338–353.

Knoblauch H, Geier C, Adams S et al. (2009) Contractures and hypertrophic cardiomyopathy in a novel FHL1 mutation. Annals of Neurology 67: 136–140.

Manilal S, Nguyen TM, Sewry CA and Morris GE (1996) The Emery–Dreifuss muscular dystrophy protein, emerin, is a nuclear membrane protein. Human Molecular Genetics 5: 801–808.

Markiewicz E, Tilgner K, Barker N et al. (2006) The inner nuclear membrane protein emerin regulates beta‐catenin activity by restricting its accumulation in the nucleus. EMBO Journal 25: 3275–3285.

Morris GE (2001) The role of the nuclear envelope in Emery–Dreifuss muscular dystrophy. Trends in Molecular Medicine 7: 572–577.

Muchir A and Worman HJ (2007) Emery–Dreifuss muscular dystrophy. Current Neurology and Neuroscience Reports 7: 78–83.

Muntoni F, Bonne G, Goldfarb LG et al. (2006) Disease severity in dominant Emery–Dreifuss is increased by mutations in both emerin and desmin proteins. Brain: A Journal of Neurology 129: 1260–1268.

Schessl J, Taratuto AL, Sewry C et al. (2009) Clinical, histological and genetic characterization of reducing body myopathy caused by mutations in FHL1. Brain: A Journal of Neurology 132: 452–464.

Wehnert M and Muntoni F (1999) 60th ENMC International workshop: non‐X‐linked Emery–Dreifuss muscular dystrophy. Neuromuscular Disorders 9: 115–121.

Windpassinger C, Schoser B, Straub V et al. (2007) A novel X‐linked myopathy with postural muscle atrophy and generalized hypertrophy, termed XMPMA, is caused by mutations in FHL1. American Journal of Human Genetics 82: 88–99.

Worman HJ and Bonne G (2007) Laminopathies: a wide spectrum of human disease. Experimental Cell Research 313: 2121–2133.

Zhang Q, Bethmann C, Worth NF et al. (2007) Nesprin‐1 and ‐2 are involved in the pathogenesis of Emery–Dreifuss muscular dystrophy and are critical for nuclear envelope integrity. Human Molecular Genetics 16: 2816–2833.

Further Reading

Ellis J (ed.) (2008) Nuclear envelope diseases and chromatin organization. Biochemical Society Transactions 36: 1329–1392.

Hutchison CJ (ed.) (2010) Nuclear envelope disease and chromatin organization. Biochemical Society Transactions 38: 253–311.

Randles K and Morris GE (eds) (2006) Workshop on the nuclear envelope and Emery–Dreifuss muscular dystrophy. Neuromuscular Disorders 16: 608–612.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Morris, Glenn E, Sewry, Caroline A, and Wehnert, Manfred(Sep 2010) Molecular Genetics of Emery–Dreifuss Muscular Dystrophy. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022438]