Emery-Dreifuss Muscular Dystrophy

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 form 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.

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Pathophysiology

In 5 of 6 gene mutations that have been shown to cause EDMD, the affected protein is present in the LINC (linker of nucleoskeleton and cytoskeleton) complex. This complex includes nuclear membrane integral and associated proteins including emerin, lamin A/C, SUN1, SUN2, nesprin-1, and nesprin-2 that are proposed to form a mechanical link between the nucleoskeleton and cytoskeleton.^[1] Even though these proteins are ubiquitously expressed, disease manifestations are tissue specific for as yet unclear reasons. EDMD1 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 membraneprotein, presentin nearly all cell types, although its highest expression is in skeletal and cardiacmuscle.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.

EDMD2/EDMD3 is due to mutations (autosomal dominant and autosomal recessive, respectively) 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 and in the synaptic nuclear envelope protein 2 (SYNE2) gene in a few families, also termed Nesprin-1 and Nesprin-2, respectively.^[2] 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.

Lastly, mutations in the transmembrane protein 43 (TMEM43), also termed LUMA, which binds to emerin and SUN2, has also been reported to cause an EDMD phenotype in a few families.

How mutations in EMD, LMNA, SYNE1, SYNE2, and TMEM43 cause EDMD is unknown. Two main hypotheses 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.

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Epidemiology

Frequency

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.^[3] The combined prevalence of X-linked and autosomal EDMD has been estimated at about 1-2 cases per 100,000 people.

Only about 50% of patients with EDMD have a mutation in one of the known nuclear envelope genes, with about 20% each being caused by mutations in EMD and LMNA. This suggests that unknown genes also likely related to the nuclear envelope are involved in EDMD pathogenesis.^[1]

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.^[4]

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.

Demographics

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.

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.

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History

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

Contractures often present before weakness and may be more disabling. They include the following:

• Elbow (unusual except in EDMD)
• Spine

  • Posterior neck (unusual except in EDMD)
  • Low back (rigid spine)

   

  

   
• Ankle

Weakness

Weaknesses may include the following:

• 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.^[3]

Cardiac disease (nearly universal)

See the list below:

• 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.^[3]

In general, autosomal dominant EDMD is clinically indistinguishable from the X-linked form. A few differences have been noted to be more common in EDMD2 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.

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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 and rarely autosomal recessive 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 and include the following:

• EDMD2/EDMD3
• 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.^[5]

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.

EDMD4 is caused by a mutation on chromosome 6 in synaptic nuclear envelope protein 1 (SYNE1; Nesprin-1α) and EDMD5 is caused by a mutation in synaptic nuclear envelope protein 2 (SYNE2; Nesprin-2β).^[2] 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.

EDMD6 is caused by a mutation on the X chromosome in four-and-a-half-LIM protein 1.^[6]

Mutations in this protein also cause reducing body myopathy, scapuloperoneal myopathy, X-linked myopathy with postural muscle atrophy, and rigid spine syndrome. These syndromes have several common features, including progressive muscle loss, rigid spine, contractures, scapular winging, and cardiac involvement.^[7]

FHL-1 is highly expressed in cardiac and skeletal muscle and is likely involved in signaling pathways that regulate muscle growth and differentiation, detection of mechanical stress, and modulation of cardiac conduction through interaction with potassium channel KCNA5.

It is thought that FHL1 mutations may cause a toxic gain of function via the formation of FHL1 protein aggregates in muscle or a loss of function via reduced expression or impairment of protein partner binding. Both mechanisms may also play a role as aggregates because reduced FHL1 levels are noted in several of the above syndromes.

EDMD 7 is caused by a mutation on chromosome 3 in the transmembrane protein 43 (TMEM43) gene.^[8]

The TMEM43 gene encodes for a protein (also termed LUMA) that is located on the inner nuclear membrane and interacts with emerin and SUN2 (another inner nuclear membrane protein).

Titin mutations can cause early-onset myopathy/dystrophy with features that overlap with EDMD. Researchers described 3 patients with EDMD-like phenotype; limb-girdle weakness, early-onset joint contractures, and dystrophic muscle biopsy, but without cardiomyopathy.^[9]

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Laboratory Studies

The creatinine kinase (CK) level is mildly elevated to less than 10-times normal levels in most cases of Emery-Dreifuss muscular dystrophy (EDMD). If the CK level is extremely elevated, other disorders should be considered, including Duchenne/Becker or limb-girdle muscular dystrophy.

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Other Tests

Needle electromyography (EMG) and nerve conduction studies (NCSs)

EMG and NCSs should be obtained to confirm the myopathic nature of the disease and to exclude other neuromuscular syndromes.

In EDMD, EMG shows small amplitude narrow duration motor unit potentials (MUPs) with early recruitment (as is typical for myopathies).

Fibrillations and positive sharp waves are rare. NCSs are normal.

Electrocardiogram (ECG)

ECG should be obtained in all patients with EDMD.

Early changes include low amplitude P waves and a prolonged PR interval.

Progression to bradycardia, absent P waves, irregular atrial rhythm, atrial fibrillation and flutter, AV-conduction defects, and a late cardiomyopathy all have been reported.

A classic pattern is of a junctional escape rhythm at 40-50 beats per minute without P waves.

Confirmation of the diagnosis is obtained by demonstration of a lack of all electrical and mechanical activity of the atria and an inability to pace the atria confirming that the myocardium, not the conduction system, is affected.

Genetic testing

If emerin is absent or reduced on tissue sample or with a typical presentation and clear X-linked inheritance, EMD should be tested.

With a typical clinical presentation and autosomal dominant inheritance, LMNA should be tested.

Affected females should also undergo genetic testing.

A multi-gene panel that includes EMD, LMNA, and FHL1 (and others) could also be considered.

Whole exome sequencing should be used if the above fails to show abnormality.

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Procedures

A muscle biopsy should be obtained in all patients with presumed EDMD for routine histologic staining. For immunohistochemical studies, antibodies to emerin can help confirm the diagnosis.

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Histologic Findings

Routine histochemical stains show typical myopathic features, including variability in muscle fiber size with small round fibers and occasional necrotic and regenerating fibers. A mild increase in endomysial connective tissue and internal nuclei are often present. Myosin adenosine triphosphatase (ATPase) stains may show type I fiber smallness or type I fiber predominance.

In X-linked EDMD, immunohistochemical staining using an antiemerin antibody shows the absence of normal staining of the inner nuclear membrane in 95% of patients (see image below). A similar pattern is obtained upon staining of peripheral leukocytes, skin fibroblasts, and buccal cells. Furthermore, detection of female carriers is possible because emerin immunostaining is lost from a percentage of muscle fibers.

View Image

Left: The photomicrograph is a muscle biopsy with normal emerin immunostaining. Right: The micrograph is from a patient with X-linked Emery-Dreifuss m....

Immunostaining for lamin A/C is normal in patients with EMD2 as well as in patients with EMD1; therefore, immunostaining results can not be used to diagnose EMD2.

Electron microscopy of patients with EMD1 and EMD2 can show irregularly thickened nuclear lamina, rearranged heterochromatin, chromatin condensation and decondensation, focal chromatin loss or extrusion into the sarcoplasm, nuclear disintegration/fragmentation and tubulofilamentous inclusions within the nuclear matrix.^[10]

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Imaging Studies

In a  study utilizing MRI imaging, researchers found that all patients with Emery-Dreifuss muscular dystrophy type 2 showed a characteristic involvement of the posterior calf muscles. They observed that while the medial head of the gastrocnemius was always predominantly involved, the lateral head was relatively spared. This pattern was more obvious in mildly affected patients in whom the other calf muscles were spared or only mildly involved. However, it was also recognizable in the patients with more advanced disease. In contrast, none of the patients with the X-linked EDMD or with Emery-Dreifuss-like phenotype but no mutation in either genes showed this pattern of muscle involvement. Findings suggest that patients with EDMD2 have a specific pattern of muscle involvement and therefore muscle MRI, in combination with other techniques, can be used to distinguish various genetic forms of the disease.^[11]

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Medical Care

No specific treatment for EDMD exists, but aggressive supportive care is essential to preserve muscle activity, to provide for maximal functional ability, and to prolong life expectancy.

The primary concern is preventing sudden cardiac death.

• Pacemakers should be inserted in patients with bradycardia. The European Society of Cardiology recommends pacing at the first appearance of bradyarrhythmias or conduction disturbances, in general before the age of 30 years.^[12]
• Intra-atrial thrombus, cerebral embolization, and cardiomyopathy may still occur even in patients treated with pacemaker.
• Cardiac transplantation should be considered in patients with progressive untreatable cardiomyopathy.
• Ventricular arrhythmias may occur late in the disease and for this reason a cardioverter-defibrillator may be preferable to a simple pacemaker.

The other main concern is prevention and correction of skeletal abnormalities (contractures) and to maintain ambulation.

• Achilles tenotomy may help stabilize ankle contractures.
• Neck and spine contractures may benefit from surgical intervention (internal fixation with rods), but the benefit must be weighed against the risk of loss of ambulation.

Aggressive use of passive stretching, bracing, and orthopedic procedures allows the patient to remain independent for as long as possible.

As in other hereditary myopathies, a team approach including a neurologist, pulmonologist, cardiologist, orthopedic surgeon, physiatrist, physical therapist, orthotist, and counselors ensures the best possible therapy.

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Surgical Care

The goal is to keep the patient as mobile as possible for as long as possible.

Orthopedic surgery (eg, tendon release) may be needed to correct or prevent contractures and to increase range of motion.

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Consultations

Consultations with the following may be helpful:

• Cardiologist: Early referral and evaluation by a cardiologist is mandatory for persons with EDMD, immediately after diagnosis. Not only is cardiac disease always present, it may manifest unexpectedly as syncope or sudden death. Typically, ECG, 24 hour Holter-monitoring, and echocardiography should be performed yearly. Treatment with a pacemaker if the patient is symptomatic or if the ECG shows significant bradycardia or rhythm disturbances can be lifesaving. However, sudden cardiac death has been reported in patients with a pacemaker, and the insertion of a defibrillator has been recommended. As many as 20% of female carriers may have significant cardiac disease and should be monitored with annual ECGs.
• Pulmonologist
• Orthopedic surgeon
• Physical medicine specialist and a physical therapist
• Orthotist
• Anesthesiologist experienced in the care of patients with MD

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Medication Summary

No specific treatment for EDMD exists.

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Further Outpatient Care

Patients with EDMD should be seen at least yearly by a neurologist and cardiologist, especially if placement of a permanent cardiac pacemaker is being considered.

At each visit, monitor muscle function, contractures, ability to perform activities of daily living (ADLs), and cardiac function.

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Further Inpatient Care

Further inpatient care may be needed for orthopedic or cardiac evaluation and treatment.

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Complications

Atrial cardiac conduction defects that manifest as syncope or sudden death are the main complications of EDMD.

Severe contractures can cause significant orthopedic problems.

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Prognosis

Early cardiac pacing will prevent sudden cardiac death, which is a frequent cause of early mortality.

EDMD is progressive, and patients often die in mid adulthood from progressive pulmonary or cardiac failure.

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Patient Education

Genetic counseling concerning the risk of cardiac disease in asymptomatic female carriers of the X-linked EDMD gene or the autosomal LMNA gene mutation can prevent sudden cardiac death in family members.

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