Emery-Dreifuss Muscular Dystrophy Clinical Presentation

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.

• 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.