Emery–Dreifuss muscular dystrophy

doi:10.1016/S0960-8966(00)00105-X

Neuromuscular Disorders

Volume 10, Issues 4–5, 1 June 2000, Pages 228-232

https://doi.org/10.1016/S0960-8966(00)00105-X Get rights and content

Abstract

Emery–Dreifuss muscular dystrophy (EDMD) was delineated as a separate form of muscular dystrophy nearly 40 years ago, based on the distinctive clinical features of early contractures and humero-peroneal weakness, and cardiac conduction defects. The gene, STA at Xq28, for the commoner X-linked EDMD encodes a 34 kD nuclear membrane protein designated ‘emerin’, and in almost all cases on immunostaining is absent in muscle, skin fibroblasts, leucocytes and even exfoliative buccal cells, and a mosaic pattern in female carriers. The gene, LMNA at 1q21, for the autosomal dominant Emery–Dreifuss muscular dystrophy encodes other nuclear membrane proteins, lamins A/C. The diagnosis (at present) depends on mutation analysis rather than protein immunohistochemistry. It is still not at all clear how defects in these nuclear membrane proteins are related to the phenotype, even less clear that LMNA mutations can also be associated with familial dilated cardiomyopathy with no weakness, and even familial partial lipodystrophy with diabetes mellitus and coronary heart disease! What began as clinical studies in a relatively rare form of dystrophy has progressed to detailed research into the functions of nuclear membrane proteins particularly in regard to various forms of heart disease.

Introduction

The X-linked form of this muscular dystrophy was first studied by the author in 1962 [1] and was considered at the time to be possibly a distinct entity. Details were published some years later [2]. This same disorder, however, seems likely to have been described in two affected brothers in 1902 [3], and the rarer autosomal form in 1941 in a family of French–Canadian descent [4] though in neither of these reports are the distinctive cardiac features of the disease mentioned. The eponymous association (Emery–Dreifuss muscular dystrophy or EDMD) was first suggested in 1979 by Rowland [5]. A listing of all references to the disease in the neuromuscular and cardiological literature is now maintained by Merlini and colleagues in Bologna (www.affari.com/smanet/edmd.htm).

Section snippets

Clinical features

In the last few years the existence of the disorder has been increasingly recognized. The clinical features of this relatively benign form of dystrophy, with onset in early childhood and thereafter relatively slow progression, are now clearly defined. The disorder is characterized by the triad of:

1.
Early contractures, often before there is any significant weakness, of the Achilles tendons, elbows and post-cervical muscles (with subsequent limitation of neck flexion, but later forward flexion of

Investigations

The serum level of creatine kinase is usually moderately elevated but can be normal. Electromyography may be indicative of a myopathy but does not contribute to the diagnosis. Muscle histology may occasionally reveal frank dystrophic changes (with fibre necrosis and phagocytosis) but often there is little more than increased variation in fibre size with occasional atrophic fibres. Immunohistochemistry of muscle biopsy tissue, leucocytes, fibroblasts or exfoliative buccal cells for emerin

Genetics

Most cases of EDMD are inherited as an X-linked recessive trait including the large family in which the disorder was first recognized as a distinct entity [2]. Female carriers rarely have any weakness but a proportion of otherwise healthy carriers may exhibit varying degrees of heart block and may require a pacemaker. Sudden death has been reported in a female carrier and cardiac transplantation has been carried out on a carrier [11].

A rarer autosomal dominant form of EDMD (AD-EDMD) has also

Molecular pathology

The gene locus for XL-EDMD is located at Xq28, and the gene (STA) is 2100 bp in length and consists of six exons. Its novel 34 kD protein product of 254 amino acids has been designated ‘emerin’ [14]. It is expressed on the inner nuclear membrane in skeletal, cardiac and smooth muscle [15], [16] but with diffuse cytoplasmic localization in some other tissues [17]. A mutation database is maintained [18], and approaching a hundred mutations in the STA gene have now been reported. A complete

Pathophysiology

Many forms of muscular dystrophy are associated with defects in structural proteins (Fig. 3) directly associated with the sarcolemma (dystrophin, various sarcoglycans, dysferlin, lamin α-2 (merosin), caveolin-3). Defects in any of these proteins result in disruption of the sarcolemma protein complex with the resultant loss of muscle proteins, and this would seem a likely explanation for the muscle weakness associated with these disorders. However, the important role of the lipid bilayer itself

Management and treatment

As with all the dystrophies the essentials of management are the promotion of good health in general, limitation of deformities through exercise, physiotherapy, orthoses and surgery, and the preservation of respiratory function. The contractures in EDMD occur early and are not the result of prolonged immobilization as in other dystrophies. Their prevention is, therefore, not possible and it is very doubtful if surgical correction can provide any benefit for the patient apart perhaps from

Summary and conclusions

The clinical features of EDMD are quite distinctive: early contractures of the Achilles tendons, elbows and post-cervical muscles; slowly progressive muscle weakness with an essentially humero-peroneal distribution at the beginning; and cardiac conduction defects. The X-linked and autosomal dominant forms of the disease are clinically similar and are caused by defects of the nuclear membrane proteins emerin and lamins A/C, respectively. In the case of XL-EDMD through protein immunohistochemical

Acknowledgements

The author is very grateful to all those who, over the years, have shared with me their knowledge and expertise about the disease. He is especially grateful to Kiichi Arahata, Juliet Ellis, Caroline Sewry, Daniela Toniolo and Stephen Warren. Finally, the author should like to thank Bill Hopkins and his colleagues of Edinburgh University Department of Medical Illustration for preparing the illustrations.

References (39)

M. Hoeltzenbein et al.
Severe clinical expression in X-linked Emery–Dreifuss muscular dystrophy
Neuromusc Disord
(1999)
F. Muntoni et al.
Early presentation of X-linked Emery–Dreifuss muscular dystrophy resembling limb-girdle muscular dystrophy
Neuromusc Disord
(1998)
D. Toniolo et al.
Muscular dystrophies: alterations in a limited number of cellular pathways
Curr Opin Genet Dev
(1999)
J.R.W. Yates et al.
Genotype-phenotype analysis in X-linked Emery–Dreifuss muscular dystrophy and identification of a missense mutation associated with a milder phenotype
Neuromusc Disord
(1999)
S. Manilal et al.
Diagnosis of X-linked Emery–Dreifuss muscular dystrophy by protein analysis of leucocytes and skin with monoclonal antibodies
Neuromusc Disord
(1997)
P. Sabatelli et al.
Oral exfoliative cytology for the non-invasive diagnosis in X-linked Emery–Dreifuss muscular dystrophy patients and carriers
Neuromusc Disord
(1998)
M.C. Dabauvalle et al.
Distribution of emerin during the cell cycle
Eur J Cell Biol
(1999)
M. Funakoshi et al.
Emerin and cardiomyopathy in Emery–Dreifuss muscular dystrophy
Neuromusc Disord
(1999)
A.E.H. Emery et al.
A.E.H. Emery et al.
Unusual type of benign X-linked muscular dystrophy
J Neurol Neurosurg Psychiatr
(1966)

R. Cestan et al.

Une myopathie avec rétractions familiales

Nouvelle Iconographie de la Salpêtrière

(1902)

A. Hauptmann et al.

Muscular shortening and dystrophy – a heredofamilial disease

Arch Neurol Psychiatr

(1941)

L.P. Rowland et al.

Ann Neurol

(1979)

A.E. Buckley et al.

Cardiac involvement in Emery Dreifuss muscular dystrophy: a case series

Heart

(1999)

T. Voit et al.