eMedicine Specialties > Neurology > Pediatric Neurology

Emery-Dreifuss Muscular Dystrophy

Author: Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCare, Consulting Staff, Barnes Jewish Hospital
Contributor Information and Disclosures

Updated: Jan 8, 2009

Introduction

Background

Although it was probably first described in the early 1900s, Emery-Dreifuss muscular dystrophy (EDMD) was not clearly delineated as a separate disease until the 1960s. In 1961, Dreifuss and Hogan described a large family with an X-linked form of muscular dystrophy that they considered to be a benign form of Duchenne muscular dystrophy. Subsequent evaluation of this family by Emery and Dreifuss in 1966 led to distinguishing this type of X-linked dystrophy from the more severe Duchenne and Becker muscular dystrophies. An autosomal dominant from of EDMD was described by several authors in the early 1980s. The genetic defects in both the X-linked recessive form and the autosomal dominant form of EDMD have been determined.

Pathophysiology

Both X-linked EDMD (EMD1) and autosomal EDMD (EMD2) are due to mutations of genes coding for proteins of the nuclear envelope. Even though these proteins are ubiquitously expressed, disease manifestations are tissue specific for as yet unclear reasons. EMD1 is caused by mutations in the EMD gene on the X chromosome that codes for the nuclear envelope protein emerin. Mutations occur throughout the gene and almost always result in complete absence of emerin from muscle or mislocalization of emerin. On rare occasions, a decreased amount of a modified form of emerin is produced in muscle. Emerin is a ubiquitous inner nuclear membrane protein, present in nearly all cell types, although its highest expression is in skeletal and cardiac muscle. Emerin binds to many nuclear proteins, including several gene-regulatory proteins (eg, barrier-to-autointegration factor, germ cell-less, Btf), nesprins (proteins that act as molecular scaffolds), F-actin, and lamins.

Interestingly, EMD2 is due to mutations in the LMNA gene that codes for lamins A and C. Mutations in LMNA occur throughout the gene and can cause several different phenotypes (see Causes). Lamins are intermediate filaments found in the inner nuclear membrane and nucleoplasm of almost all cells and have multiple functions including providing mechanical strength to the nucleus, helping to determine nuclear shape, and anchoring and spacing nuclear pore complexes; they are also essential for DNA replication and mRNA transcription. They bind to structural components (emerin, nesprin), chromatin components (histone), signal transduction molecules (protein kinase C), and several gene regulatory molecules.

New mutations have been found in the synaptic nuclear envelope protein 1 (SYNE1) gene in 3 patients in 3 families and in the synaptic nuclear envelope protein 2 (SYNE2) gene in 2 patients in 2 families, also termed Nesprin-1 and Nesprin-2, respectively.¹  Inheritance was autosomal dominant or sporadic. Phenotypes ranged from asymptomatic to limb girdle or in one case, scapular weakness with progression to a wheelchair by age 26 years. Cardiac involvement and contractures were present in some, but not all patients.   

How mutations in EMD, LMNA, SYNE1, and SYNE2 cause EDMD is unknown. Two main hypothesis have been suggested. The first suggests that disruption of the inner nuclear membrane and the nuclear lamina causes disorganization of nuclear chromatin and gene expression, while the second proposes that the mechanical strength of the cell nucleus is disrupted when the nuclear lamina is weakened leading to structural and signaling defects in mechanically stressed tissue such as muscle and heart. Mutations in all of these genes have been shown to result in defects in the nucleoskeleton and related structures that could cause the above pathologic abnormalities.

Whatever the true mechanism, the discovery of mutations in several different nuclear membrane proteins that cause similar diseases will likely eventually lead to a better understanding of nuclear membrane physiology and the pathophysiology of diseases caused by mutations in these proteins.

Frequency

International

No good data exist concerning the frequency of EMD1 or EMD2, but more than 70 different mutations have been reported in the EMD gene and more than 100 in LMNA. Sporadic cases with a mutation in the EMD gene are uncommon but are becoming increasingly more recognized in LMNA. A European collaborative study found LMNA mutations in 18 families and 39 sporadic cases with an EMD2 phenotype. A Japanese study found that laminopathy was slightly more common than emerinopathy.²  The combined prevalence of X-linked and autosomal EDMD has been estimated at about 1-2 cases per 100,000 people.

Mortality/Morbidity

• The major cause of mortality and morbidity in EDMD is cardiac disease, which is consistently present.
  • The most common disturbances are a result of atrial conduction defects (eg, bradycardia, atrial arrhythmias, atrioventricular [AV] block, atrial paralysis).
  • Cardiomyopathy may be present as well, and it may be severe with only a mild myopathy. This phenotype is more common with EMD2.
  • In some studies, as many as 40% of patients with EDMD had sudden cardiac death. The timely insertion of a pacemaker can be lifesaving.
• Early onset of contractures (often before weakness has developed) is common in EDMD.
  • This can lead to even greater functional disability than that caused by weakness.
  • Early referral for physical therapy, bracing, or orthopedic surgery can help prevent the formation or lessen the severity of contractures.

Sex

• Males are affected in X-linked EDMD.
• About 10-20% of female carriers have cardiac conduction defects, weakness, or both, and they can die from sudden cardiac death.
• In autosomal dominant EDMD, males and females are affected in equal numbers.

Age

• In X-linked EDMD, contractures and weakness can occur at any time from the neonatal period to the third decade. The mean age of onset is in the teenaged years.
• Cardiac symptoms usually occur after weakness has developed (in teenaged persons to those aged 40 y) but occasionally present before the onset of weakness.
• The onset of symptoms in autosomal dominant EDMD is similar to that in the X-linked form.

Clinical

History

History and physical findings of Emery-Dreifuss muscular dystrophy are discussed in this section.

• The following triad of symptoms strongly suggests EDMD:
  • Slowly progressive muscle weakness and wasting in a scapulohumeroperoneal distribution
  • Early contractures of the elbow, ankle, and posterior neck
  • Cardiac conduction defects, cardiomyopathy, or both
• Onset is usually in the teenage years, but the condition can present with neonatal hypotonia or through the third decade. Patients typically develop weakness of peroneal muscles with toe-walking late in the first decade or in the early teenage years.
• Prominent interfamilial and intrafamilial variability can exist, even with the same mutation types. However, sometimes a clear difference between mutation types cannot be found in families.
• Contractures often present before weakness and may be more disabling.
  • Elbow (unusual except in EDMD)
  • Spine
    • Posterior neck (unusual except in EDMD)
    • Low back (rigid spine)
  • Ankle
• Weakness
  • Symmetric weakness of the biceps, triceps, and peroneal muscles
  • Scapular winging
  • Face, thigh, and hand weakness (uncommon but may occur late)
  • A limb girdle phenotype can be seen with mutations in EMD, but is more commonly due to a mutation in LMNA.²
• Cardiac disease (nearly universal)
  • Cardiac disease usually begins after onset of weakness and manifests as syncope in the second or third decade.
  • Pacemakers are often needed by age 30 years.
  • Cardiac disease may present with sudden cardiac death.
  • Bradycardia, atrial arrhythmias (including atrial fibrillation/flutter), AV conduction defect, and atrial paralysis have all been reported.
  • Late findings may include atrial or ventricular cardiomyopathy.
  • Of female carriers, 10-20% have atrial arrhythmias or conduction defects and need to be monitored with yearly ECG to try to prevent sudden cardiac death.
  • Conduction defects with minimal muscle and joint involvement may occur.²
• In general, autosomal dominant EDMD is clinically indistinguishable from the X-linked form. A few differences have been noted to be more common in EMD2 and include the following:
  • Muscle weakness is often the initial symptom, before contractures develop.
  • Calf hypertrophy may mimic other forms of childhood muscular dystrophy. 
  • Scapular winging is more common.
  • Loss of ambulation is more likely.
  • Isolated or more severe cardiac conduction defects or cardiomyopathy are more common.

Causes

• X-linked recessive EDMD is caused by a mutation on the X chromosome in the gene encoding emerin (EMD).
  • More than 70 unique mutations throughout the coding and promoter regions have been identified that are most often point mutations, small deletions, or insertions that usually result in stop codons.
  • Emerin protein is usually absent, but, in a few cases, the protein is present but in a reduced amount.
  • Emerin is a 34-kd protein that belongs to a family of nuclear proteins that bind a variety DNA regulatory molecules and to molecules thought to be important in maintaining nuclear membrane structure.
  • Emerin is not essential to cell survival and several animal models that have an emerin knock-out have no overt myopathic phenotype.
• Autosomal dominant EDMD is caused by a mutation on chromosome 1 in the gene that codes for lamin A/C (LMNA). Sporadic cases are common in large series describing patients with LMNA mutations.
  • Most mutations are missense, nonsense, inframe deletions, or at a splice site.
  • Several diseases are caused by mutations in the LMNA gene; these are termed laminopathies.
    • EMD2
    • Limb-girdle muscular dystrophy with cardiac conduction disturbances (LGMD1B)
    • Dilated cardiomyopathy with conduction system disease (CMD1A)
    • Autosomal recessive axonal neuropathy (CMT2B1)
    • Familial partial lipodystrophy (FPLD)
    • Mandibuloacral dysplasia (MAD)
    • Restrictive dermopathy
    • Progeria syndromes - Hutchinson-Gilford progeria, Werner syndrome (atypical)
  • Interestingly, the same mutation can result in different EDMD phenotypes between individuals and even between siblings with both mild and severely affected patients reported within the same family. Furthermore, the same mutation can also cause different laminopathy syndromes even within the same family. For example, one patient was described with both EDMD and progeria. Another family had EDMD and neuropathy in one member and just neuropathy in another member. In another family, some patients had EDMD, others had LGMD, and still others had dilated cardiomyopathy. The mutation R644C has extreme phenotypic diversity and low penetrance. All of the above syndromes (except restrictive dermopathy) have been reported, at least in part, to be caused by this mutation.³     
  • No clear correlation exists between clinical phenotype and the site of the mutation, although a few points are worth noting. The most common mutation in EMD2 is at R453W and accounts for about 15% of cases. The most common mutation in FPLD is at R482W/Q/L and accounts for about 85% of cases.
  • The lamin A/C tail region between amino acids 430 and 545 adopts an immunoglobulinlike fold, which is likely important in the interaction of lamin A/C with other proteins (or DNA). Many mutations that cause muscle disease (EMD, LGMD1B) affect buried residues at the core of the immunoglobulin structure, which are believed to play a role in the integrity of the immunoglobulinlike fold and may destabilize the carboxyl-terminus tail of lamin A/C, resulting in a loss of structurally functional lamin A/C. Other mutations throughout lamin A/C in muscle disease also suggest a change in protein structure. Mutations in the immunoglobulinlike domain that cause FPLD affect only solvent-accessible amino acids that lead to a decrease in positive surface charge.
• EMD3 is caused by a mutation on chromosome 6 in synaptic nuclear envelope protein 1 (SYNE1; Nesprin-1 α) and EMD4 is caused by a mutation in synaptic nuclear envelope protein 2 (SYNE2; Nesprin-2 β).¹
  • Nesprins are spectrin-repeat proteins that are present in many subcellular locations, including the nucleus, the inner and outer nuclear membranes, in association with mitochondria and the Golgi apparatus, throughout the sarcomere, and at the plasma membrane. The nesprins form a network linking these structures to the actin cytoskeleton.
  • By binding to lamins and emerin, nesprins link the nucleoskeleton and inner nuclear membrane to the outer nuclear membrane and cytoskeleton. Disruption of this interaction may be responsible for the complex phenotypes associated with EDMD.         

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