AUTHOR INFORMATION

Section 1 of 12

Authored by Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCar; Consulting Staff, Barnes Jewish Hospital

Glenn Lopate, MD, is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and Phi Beta Kappa

Edited by James J Riviello, Jr, MD, Professor, Department of Neurology, Director of Epilepsy Program, Division of Epilepsy and Clinical Neurophysiology, Children's Hospital, Harvard University Medical School; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Kenneth J Mack, MD, PhD, Visiting Associate Professor, Department of Neurology, University of Wisconsin at Madison; Associate Professor and Consultant, Department of Neurology, Division of Child and Adolescent Neurology, Mayo Medical School; Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital; and Nicholas Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants

Author's Email:	Glenn Lopate, MD
Editor's Email:	James J Riviello, Jr, MD

eMedicine Journal, September 19 2006, VOLUME 7, Number 9

INTRODUCTION

Section 2 of 12

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 (newly discovered proteins that may 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.

One family with an autosomal recessive inheritance pattern and a more severe phenotype has been shown to harbor a mutation in LMNA and has been designated EDMD3.

How mutations in EMD and LMNA cause EDMD is unknown. One hypothesis suggests that muscle and cardiac cells that lack emerin or lamin A/C are more likely to be disrupted due to mechanical stress because of nuclear fragility. Another hypothesis suggests that altered gene expression/regulation in certain cells (muscle, cardiac, cartilage) may lead to specific alterations in these cell types. Similarly, alterations in signal transduction may lead to downstream effects on gene expression or chromatin remodeling at different time points of muscle (and cardiac) cell differentiation. Whatever the true mechanism, the discovery of mutations in two different nuclear membrane proteins that cause similar diseases will likely eventually lead to a better understanding of nuclear membrane physiology and diseases caused by mutations in these proteins.

Frequency:

• Internationally: 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 tham 100 in LMNA. Sporadic cases with a mutation in the EMD gene are uncommon but are becoming increasingly more recognized in LMNA. A recent European collaborative study found LMNA mutations in 18 families and 39 sporadic cases with an EMD2 phenotype. 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 slightly later than in the X-linked form.

CLINICAL

Section 3 of 12

History: History and Physical 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)
  
  
  
• Cardiac disease (nearly universal)
  • Usually begins after onset of weakness and manifests as syncope in the second or third decade

  • Pacemaker often needed by age 30 years

  • 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.



• In general, autosomal dominant EDMD is clinically indistinguishable from the X-linked form. A few minor differences have been noted to be more common in EMD2 and include the following:


• • Muscle weakness before contractures
  
  
  
  • More common scapular winging

  • Loss of ambulation more likely

  • Isolated or more severe cardiac conduction defects or cardiomyopathy
  
  
  

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.
  
  
  
  • Electron microscopy of patients with EMD1 shows an irregularly thickened nuclear lamina, rearranged heterochromatin, and chromatin condensation and extrusion into the sarcoplasm.
  
  
  
• Autosomal dominant EDMD is caused by a mutation on chromosome 1 in the gene that codes for lamin A/C (LMNA). One rare autosomal recessive case of EDMD has also been described (EMD3) and was found to be due to a mutation in 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 some mild and some severely affected patients reported within the same family. Furthermore, families have been reported with different members having different syndromes. 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.
  
  
  
  • 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.
  
  
  

DIFFERENTIALS

Section 4 of 12

Congenital Muscular Dystrophy
Congenital Myopathies
Dermatomyositis/Polymyositis
Facioscapulohumeral Dystrophy
Limb-Girdle Muscular Dystrophy
Myasthenia Gravis
Spinal Muscular Atrophy

Other Problems to be Considered:

Becker dystrophy
Bethlem myopathy
Duchenne dystrophy
Rigid spine syndrome
Scapuloperoneal muscular dystrophy
Scapuloperoneal neuronopathy

WORKUP

Section 5 of 12

Lab Studies:

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

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.
  
  
  

Procedures:

• Muscle biopsy: 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.

In X-linked EDMD, immunohistochemical staining using an antiemerin antibody shows the absence of normal staining of the inner nuclear membrane (see Image 1). 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.

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.

TREATMENT

Section 6 of 12

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.

    • 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.
  
  
  

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.

Consultations:

• 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

MEDICATION

Section 7 of 12

No specific treatment for EDMD exists.

FOLLOW-UP

Section 8 of 12

Further Inpatient Care:

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

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.

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.

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.

Patient Education:

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

MISCELLANEOUS

Section 9 of 12

Special Concerns:

• Additional information


• • Washington University Neuromuscular Disease Center
  
  
  
  • Muscular Dystrophy Association
  
  
  

TEST QUESTIONS

Section 10 of 12

CME Question 1: What finding is least expected on physical examination of a 12-year-old boy with Emery-Dreifuss muscular dystrophy (EDMD)?

A: Proximal leg weakness
B: Elbow contractures
C: Bradycardia
D: Scapular winging
E: Biceps and triceps weakness

The correct answer is A: Unlike limb-girdle and Duchenne/Becker muscular dystrophies, proximal leg weakness is not an early manifestation of EDMD. Weakness is in a scapulohumeroperoneal distribution. Contractures and cardiac disease are invariably present.

CME Question 2: Which of the following is not characteristic of emerin, the protein that is absent in Emery-Dreifuss muscular dystrophy (EDMD)?

A: Staining for emerin is usually absent when performing immunohistochemical studies of muscle in patients with EDMD.
B: Emerin interacts with the lamins.
C: Emerin is normally present on the inner nuclear membrane.
D: Emerin may play a role in stabilizing the inner nuclear membrane during the mechanical stress of muscle contraction.
E: Emerin is present in only skeletal and cardiac muscle.

The correct answer is E: 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, nesprins (newly discovered proteins that may act as molecular scaffolds), F-actin, and lamins.

Pearl Question 1 (T/F): The mode of inheritance in Emery-Dreifuss muscular dystrophy (EDMD) is most commonly autosomal recessive.

The correct answer is False: EDMD is inherited most commonly as an X-linked disorder, but it can also be inherited in an autosomal dominant fashion. Only one family has been described with an autosomal recessive inheritance pattern

Pearl Question 2 (T/F): Chest pain and shortness of breath are the most frequent presenting signs of cardiac disease in Emery-Dreifuss muscular dystrophy (EDMD).

The correct answer is False: Syncope is the most frequent presenting sign of cardiac disease in EDMD.

Pearl Question 3 (T/F): No major clinical differences exist between the X-linked form and the autosomal dominant form of Emery-Dreifuss muscular dystrophy (EDMD).

The correct answer is True: No clinical differences exist between the two disorders, although autosomal dominant EDMD may have more prominent weakness and/or present with isolated or more severe cardiac disease.

Pearl Question 4 (T/F): A 15-year-old adolescent boy presents with moderate scapulohumeroperoneal weakness, severe elbow and posterior neck contractures, and 2 episodes of bradycardia and syncope. Referral to a cardiologist is imperative.

The correct answer is True: This patient most likely has Emery-Dreifuss muscular dystrophy and should be referred to a cardiologist for placement of a permanent pacemaker.

PICTURES

Section 11 of 12

Caption: Picture 1. Right, The photomicrograph is a muscle biopsy with normal emerin immunostaining. Left, The micrograph is from a patient with X-linked Emery-Dreifuss muscular dystrophy. Note the absence of nuclear staining as well as the hypertrophied and atrophied muscle fibers.
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BIBLIOGRAPHY

Section 12 of 12

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