Emery-Dreifuss muscular dystrophy

INTRODUCTION — The muscular dystrophies are an inherited group of progressive myopathic disorders resulting from defects in a number of genes required for normal muscle function. Some of the genes responsible for these conditions have been identified. Muscle weakness is the primary symptom.

Clinical aspects of Emery-Dreifuss muscular dystrophy (EDMD), also known as humeroperoneal muscular dystrophy, are discussed here. Other muscular dystrophies are presented separately. (See "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis" and "Myotonic dystrophy: Etiology, clinical features, and diagnosis" and "Facioscapulohumeral muscular dystrophy" and "Limb-girdle muscular dystrophy" and "Oculopharyngeal, distal, and congenital muscular dystrophies".)

EPIDEMIOLOGY — EDMD is an uncommon if not rare disorder, although its overall incidence and prevalence are not known [1]. In a meta-analysis, the pooled prevalence of EDMD in all age groups was 0.39 per 100,000 [2].  

GENETICS — EDMD is a genetically heterogenous disorder with X-linked recessive, autosomal dominant, and autosomal recessive forms [3]. Several forms are considered nuclear envelopathies because they are associated with mutations in genes encoding nuclear membrane proteins, including the EMD gene that encodes for emerin, the LMNA gene that encodes for lamin A and lamin C, and the SYNE1 and SYNE2 genes that encode for nesprin 1 and nesprin 2, respectively [4]. The most common type is autosomal dominant EDMD caused by a heterozygous LMNA mutation, followed by X-linked EDMD caused by EMD or FHL1 mutations [1]. There are only a few reports of autosomal recessive EDMD. In a high proportion of EDMD cases, the genetic defect remains unknown [5].

X-linked forms — The X-linked forms of the disorder are EDMD1 and EDMD6:

●The EMD gene on Xq28 (EDMD1) encodes emerin, a protein that is localized to the nuclear envelope [6-9]. Most mutations are null mutations resulting in complete loss of emerin expression in muscle. Missense mutations are associated with decreased or even normal amounts of emerin and result in a milder phenotype.

●The FHL1 gene on Xq26.3 (EDMD6) encodes the four-and-a-half LIM domains protein 1 and is associated with an X-linked EDMD phenotype with hypertrophic cardiomyopathy [10,11]. Mutations in the FHL1 gene result in delayed myotube formation [10].

The nomenclature and classification of FHL1-linked myopathies/muscular dystrophies is still evolving. In addition to EDMD6, FHL1 mutations have also been identified in patients with X-linked myopathy with postural muscle atrophy, X-linked dominant scapuloperoneal myopathy, X-linked reducing body myopathy with early childhood onset, and myofibrillar myopathy [12,13]. Common features of FHL1 disorders include joint contractures, spinal rigidity, and cardiac involvement. Reducing body aggregates in muscle biopsies are a characteristic feature of reducing body myopathy and scapuloperoneal myopathy. In contrast, muscle biopsies of patients with EDMD6 do not show reducing bodies, but the expression of FHL1A protein is moderately to severely decreased [10].

Autosomal dominant and recessive forms — Both an autosomal dominant (EDMD2) and a rare autosomal recessive (EDMD3) form are linked to mutations of the LMNA gene on chromosome 1q21.2 that encodes for lamin A and lamin C, two A-type lamins found in the nuclear envelope [14-16].

Other EDMD-like phenotypes with autosomal dominant inheritance are linked to mutations of SYNE1 (EDMD4) and SYNE2 (EDMD5), both of which encode for nuclear envelope proteins [3,17]. However, the number of reported cases is small and thus the muscle phenotype remains to be defined.

Mutations in the TMEM43 gene, which encodes another nuclear envelope protein called LUMA, are also associated with an autosomal dominant EDMD-like phenotype (EDMD7) [18]. Such mutations were found in 2 of 41 patients with EDMD-related myopathy. As with SYNE1 and SYNE2, additional data are needed to further delineate the phenotype of TMEM43-related myopathy [19].

Laminopathies — In addition to EDMD2 and EDMD3, a number of other laminopathies (ie, disorders caused by LMNA gene mutations) have been identified [20]:

●Limb-girdle muscular dystrophy with atrioventricular conduction defects (LGMD1B) (see "Limb-girdle muscular dystrophy")

●Autosomal dominant dilated cardiomyopathy with conduction defects (CMD1A or DCM-CD) [21,22]

●Autosomal dominant dilated cardiomyopathy with apical left ventricular aneurysm [23]

●Autosomal dominant quadriceps myopathy with dilated cardiomyopathy and associated conduction defects [24]

●A relatively severe form of congenital muscular dystrophy classified as LMNA-related congenital muscular dystrophy [25-27]

●Charcot-Marie-Tooth type 2B1 [28]

●Familial partial lipodystrophy type 2 (see "Lipodystrophic syndromes", section on 'FPLD type 2')

●Mandibuloacral dysplasia (see "Lipodystrophic syndromes", section on 'Mandibuloacral dysplasia')

●Hutchinson-Gilford progeria syndrome [29]

●Dilated cardiomyopathy and hypergonadotropic hypogonadism (atypical Werner syndrome) [30]

●Restrictive dermopathy (also known as tight skin contracture syndrome), a lethal neonatal laminopathy [31]

Several reports have found patients harboring mutations in both EMD and LMNA genes [32,33]. The clinical presentations included severe EDMD, a combination of Charcot-Marie-Tooth type 2 and EDMD, and isolated cardiomyopathy.

Mutations in both emerin and desmin genes were found in a patient with cardioskeletal myopathy [32].

CLINICAL MANIFESTATIONS — The major features of EDMD are early contractures, slowly progressive humeroperoneal muscle weakness/wasting, and cardiac disease with conduction defects, arrhythmias, and cardiomyopathy [3,5,34]. The different forms of EDMD have generally similar symptoms, which usually begin in the first or second decade of life. However, the disease exhibits significant inter- and intra-familial variability with regard to age at onset, severity, and progression of the major manifestations [35]. Cases of adult onset with slow progression have been observed.

Symptoms and signs — Contractures at the elbows are noted early and are commonly the first manifestations of EDMD. Contractures of the posterior aspect of the neck, the entire spine, and the Achilles tendons also occur. Achilles tendon contractures are frequently associated with toe walking. Severe spine and leg contractures eventually may lead to loss of ambulation.

Muscle weakness and wasting has a humeroperoneal distribution; it typically begins in the arms, involving both the biceps and triceps, with relative preservation of the deltoid muscles. Subsequently, distal leg weakness with atrophy of the peroneal muscles is noted. In some cases, mild facial weakness may also be observed. The myopathy tends to be slowly progressive during the first three decades of life, but more rapid thereafter.

A dilated cardiomyopathy is seen in most patients with EDMD. It is typically associated with atrioventricular conduction abnormalities such as first-degree atrioventricular block, but also with sinus bradycardia or supraventricular tachycardia, which may be early signs of cardiac involvement [36]. Other findings include atrial paralysis, atrial fibrillation, and atrial flutter; these are most common in EDMD1. Symptoms of hypoperfusion (syncope or near syncope) often result from infranodal or atrioventricular conduction block with the development of slow junctional rhythms, requiring pacemaker insertion [37-39]. The onset of cardiac abnormalities is usually in the third decade of life but earlier onset has been observed [22]. Sudden death may develop in patients not previously diagnosed because they have little or no skeletal myopathy [39]. There is no correlation between the degree of neuromuscular involvement and the severity of cardiac abnormalities [40]. (See "Definition and classification of the cardiomyopathies".)

EDMD6 is associated with hypertrophic cardiomyopathy [10,11]. (See 'X-linked forms' above.)

Arrhythmogenic dilated cardiomyopathy, cardiac failure, and ventricular tachyarrhythmias are more common and more severe in autosomal dominant EDMD2 (due to LMNA mutations) [41,42] but also occur in X-linked EDMD1 (caused by EMD mutations) [43]. (See "Determining the etiology and severity of heart failure or cardiomyopathy" and "Definition and classification of the cardiomyopathies".)

Laboratory studies — EDMD is associated with abnormalities in serum creatine kinase (CK), electrocardiography (ECG), electromyography (EMG), muscle imaging, and muscle biopsy:

●A modest elevation of serum CK concentration, rarely higher than a few hundred units/L, is typical. Increases up to 20 times the upper limit of normal sometimes occur, but may be seen more often in the early stages of the disease. CK levels are not useful in the identification of carriers because, even in obligate carriers, they tend to be normal [44].

●The ECG may show varying degrees of atrioventricular block, small T waves, and atrial arrhythmias.

●The EMG usually displays myopathic features and may also reveal evidence of denervation.

●The muscle biopsy typically shows mild myopathic changes characterized by internal nuclei, variation in fiber size, focal connective tissue proliferation, and occasional necrotic fibers. Inflammatory changes have been noted in the muscle biopsies of some children (≤2 years of age) with infantile LMNA myopathy [27].

●Muscle immunohistochemistry will reveal absence of nuclear staining for emerin in approximately 95 percent of patients with X-linked EDMD [45]. No EMD gene mutations have been detected in patients who were emerin-positive, which underscores the diagnostic value of muscle immunohistochemistry [42]. Emerin can also be detected by immunofluorescence and/or western blot testing in muscle and other tissues including skin, exfoliative buccal cells, lymphocytes, and lymphoblastoid cell lines [46,47].

●In patients with EDMD, leg muscle imaging reveals more severe changes in posterior calf muscles with selective involvement of the soleus in EDMD1 and of the medial gastrocnemius muscle in EDMD2; the magnetic resonance imaging (MRI) abnormalities are mild or moderate in other leg muscles [48]. The pattern is similar in asymptomatic carriers and in patients with various phenotypes caused by LMNA gene mutations [49]. The rectus femoris muscle is spared [49].

EVALUATION AND DIAGNOSIS

Establishing the diagnosis — The clinical diagnosis of EDMD can be made for patients with the cardinal features:

●Early contractures of elbow flexors, ankle plantar flexors, and spine

●Childhood onset of humeroperoneal weakness and wasting

●Cardiac disease with conduction defects, arrhythmias, and cardiomyopathy, which may present later in life

The diagnosis of EDMD is established in a patient with a compatible clinical phenotype by genetic testing that identifies a hemizygous pathogenic variant in EMD or FHL1, a heterozygous pathogenic variant in LMNA, or rarely biallelic pathogenic variants in LMNA [19].

Genetic testing should be ordered as the first diagnostic study in patients with a phenotype suggestive of EDMD (algorithm 1); muscle biopsy is an invasive and less informative procedure [40]. Electromyography and muscle biopsy may be useful in atypical cases, such as patients without a classic phenotype or those lacking a family history.

Genetic testing — The approaches to genetic testing differ according to phenotype and mode of inheritance.

EDMD phenotype — In patients with a phenotype suggestive of EDMD, single gene testing or multigene panel testing is used to establish the genetic diagnosis [19].

●Single gene testing – Single gene testing is appropriate for the following situations:

•In a male with a family history suggesting X-linked inheritance or those with no or unknown family history, testing for EMD pathogenic variants should be performed first, followed by genetic testing for the FHL1 gene if no EMD mutation is found. The proportion of cases with an EDMD phenotype and an X-linked inheritance pattern attributed to EMD gene mutations is approximately 60 percent, whereas the proportion attributed to FHL1 mutations is approximately 10 percent [10,19].

•In cases with a family history suggesting autosomal dominant or recessive inheritance, LMNA-related disease is most likely. In patients with autosomal dominant EDMD, gene sequence analysis or mutation scanning will detect LMNA sequence variants in about 45 percent of patients [19]. For those without LMNA mutations, testing can proceed to evaluate for autosomal dominant pathogenic variants in SYNE1, SYNE2, and TMEM43 genes (algorithm 1).

•In cases without a clear inheritance pattern, LMNA-related disease is most likely, followed by EMD- and then FHL1-related disease [19].

•In a female who represents a single occurrence in a family, the LMNA gene should be screened first as LMNA-related disease is more likely than an X-linked EDMD [19,40]. Carrier females only rarely manifest symptoms of X-linked EDMD. (See 'Autosomal dominant and recessive forms' above.)

●Multigene panel testing – A multigene panel is an alternative to single gene testing for all patients suspected of EDMD based upon phenotype. The panel should include EMD, FHL1, LMNA, SYNE1, SYNE2, and TMEM43, as well as other genes of interest (see 'Differential diagnosis' below) [19]. This approach is considered most likely to disclose the pathogenic variant causing the condition in a cost-effective manner [19].

Gene panels are widely available, but the clinician has to make sure that deletion/duplication analysis is included in the testing as well.

Atypical phenotype — In atypical cases where the clinical diagnosis of EDMD or other specific myopathies is not evident, the best approach is comprehensive genomic testing using next generation sequencing techniques (which does not require the clinician to determine which candidate genes are likely involved). Exome sequencing is most commonly used; genomic sequencing is an alternative.

Exome microarray to detect single-exon deletions or duplications may be ordered (where available) if exome sequencing is not diagnostic. However, the incidence of deletions/duplications in the three main EDMD genes (EMD, FHL1, LMNA) is very low.

In very atypical cases, some clinicians obtain a muscle biopsy and/or electromyography before proceeding with genetic testing. However, this is not the most cost-effective approach, given that the exome sequencing is now significantly less expensive than when it was first available.

Differential diagnosis — Other than the different inherited muscular dystrophies and myopathies, the differential diagnosis of EDMD includes the rigid spine syndrome (RSS). This disorder is usually associated with limited flexion of the spine, a relatively mild and slowly progressive myopathy, and elbow and ankle contractures [50]. Some patients with RSS develop cor pulmonale with right heart involvement due to restrictive chest wall movement and respiratory muscle weakness [51]. Early and severe scoliosis in the first decade is in favor of RSS. Severe respiratory involvement is usually present in RSS but is unusual in EDMD [40]. Mutations in the selenoprotein N1 gene (SEPN1) have been identified in a subset of patients with RSS (RSMD1). (See "Congenital myopathies", section on 'Multiminicore disease'.)

An Emery-Dreifuss-like phenotype with limb-girdle weakness and early onset of joint contractures, but without cardiomyopathy, is caused by mutations of the TTN gene [52].

MANAGEMENT — There is no disease modifying therapy for EDMD. Management is mainly supportive [5]. Cardiomyopathy and conduction system defects are major problems, as discussed in the following section. (See 'Cardiac issues' below.)

Physical therapy should focus on stretching exercises to prevent the early development of contractures [19]. Other interventions include orthopedic procedures to release contractures, spinal fusion for severe scoliosis, walking aids (eg, canes walkers, orthoses, wheelchairs) to facilitate mobility, and, rarely, respiratory aids in the late stages of the disease.

Cardiac issues — The principal concern in the patient with EDMD is death resulting from cardiac involvement. The cardiac status of the patient should therefore be investigated, even in asymptomatic patients, with a referral for cardiology assessment at the time of diagnosis [53]. Patients with autosomal dominant EDMD and X-linked recessive forms of EDMD should have annual follow-up with electrocardiography (ECG), echocardiography, and ambulatory ECG; patients with autosomal recessive EDMD should have annual ECG and ambulatory ECG. (See 'Prognosis' below and "Determining the etiology and severity of heart failure or cardiomyopathy".)

Cardiac intervention is required to treat arrhythmias, heart failure, and conduction defects [19]. Placement of a cardiac pacemaker alone is insufficient to prevent sudden cardiac death [54]. An implantable cardioverter defibrillator can be lifesaving in patients with evidence of atrioventricular block [55]. Therefore, patients with EDMD and cardiac involvement require primary placement of combined pacemaker with an implantable cardiac defibrillator [54]. (See "Permanent cardiac pacing: Overview of devices and indications" and "Implantable cardioverter-defibrillators: Overview of indications, components, and functions" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Overview of the management of heart failure with reduced ejection fraction in adults" and "Hypertrophic cardiomyopathy: Management of patients without outflow tract obstruction" and "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk".)

Cardiac transplantation may be an option in selected patients with EDMD [56]. (See "Heart transplantation in adults: Indications and contraindications".)

Anesthesia — Potential problems related to anesthesia should be anticipated for patients with EDMD undergoing surgery, which may be required to manage orthopedic complications of the disease [19,57].

●Cardiac pacing (temporary or permanent) should be available perioperatively.

●Anesthetic agents with myocardial depressant activity should be avoided in patients with significant cardiomyopathy. (See "Perioperative management of heart failure in patients undergoing noncardiac surgery" and "Intraoperative management for noncardiac surgery in patients with heart failure".)

●Neck flexion may be markedly reduced, causing difficulty with endotracheal intubation.

●Flexion contractures of the cervical and lumbar paravertebral muscles may interfere with spinal and epidural anesthesia.

●Succinylcholine is contraindicated because patients with degenerative or dystrophic neuromuscular disease are at increased risk for the development of severe hyperkalemia.

●Rhabdomyolysis, hyperkalemia, or other catabolic reactions in muscle have not been described in EDMD. However, episodes that mimic malignant hyperthermia have been reported in other muscular dystrophies and neuromuscular disorders, with clinical manifestations that include rhabdomyolysis, hyperkalemia, and sudden cardiac arrest [58-60]. Thus, we recommend avoidance of potential triggering agents such as depolarizing muscle relaxants (eg, succinylcholine) and volatile anesthetic drugs (eg, halothane, isoflurane, desflurane, and sevoflurane). (See "Susceptibility to malignant hyperthermia: Evaluation and management".)

PROGNOSIS — In most cases of EDMD, muscle weakness and atrophy are slowly progressive during the first three decades of life but advance more rapidly thereafter [35]. Most patients remain ambulatory for many years and seldom if ever develop profound motor or respiratory dysfunction [1]. Loss of ambulation is seen more often with autosomal dominant EDMD and is unusual in X-linked EDMD [1].

Patients with EDMD are at risk of death from advanced atrioventricular block and from progressive heart failure. The onset of cardiac abnormalities usually occurs in the third decade in EDMD. Earlier onset of severe involvement is rare [61-63], but may occur; there is a least one reported case of serious ventricular arrhythmia in a young patient with EDMD1 [36]. Cardiac involvement is more aggressive in EDMD2 [64]; ventricular arrhythmias occur earlier and lead to dilated cardiomyopathy [22,41]. Sudden death can occur, more frequently in EDMD2, but also in EDMD1. There is no correlation between the severity of the neuromuscular involvement and the degree of cardiac abnormality [61,65,66]. (See 'Cardiac issues' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Muscular dystrophy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Muscular dystrophy (The Basics)")

●Beyond the Basics topics (see "Patient education: Overview of muscular dystrophies (Beyond the Basics)")

SUMMARY

●Emery-Dreifuss muscular dystrophy (EDMD) is a genetically heterogenous disorder. The most common type is autosomal dominant EDMD caused by a heterozygous LMNA mutation, followed by X-linked EDMD caused by EMD or FHL1 mutations. (See 'Genetics' above.)

●The onset of symptoms from EDMD usually occurs in the first or second decade of life. The cardinal features are early contractures, childhood onset of slowly progressive humeroperoneal muscle weakness/wasting, and cardiac disease with conduction defects, arrhythmias, and cardiomyopathy. (See 'Symptoms and signs' above.)

●Laboratory findings in EDMD include elevation of serum creatine kinase (typically modest but sometimes severe), electrocardiography abnormalities (eg, atrioventricular block, small T waves, atrial arrhythmias), and myopathic features on electromyography (EMG) and muscle biopsy. (See 'Laboratory studies' above.)

●In cases with typical clinical features of EDMD and a supportive family history, single gene testing may confirm the diagnosis (algorithm 1). In cases with early contractures that otherwise lack typical features of EDMD, the presence of myopathic changes on EMG and muscle biopsy is supportive of EDMD. However, multigene panel testing may be more cost-effective and specific for EDMD. (See 'Evaluation and diagnosis' above.)

●There is no disease modifying therapy for EDMD. Management is supportive. Cardiac interventions may be required to treat arrhythmias, heart failure, and conduction defects. (See 'Management' above and 'Cardiac issues' above.)

●Potential problems related to anesthesia should be anticipated for patients with EDMD undergoing surgery. (See 'Anesthesia' above.)

●Most patients with EDMD remain ambulatory for many years and seldom if ever develop profound motor or respiratory dysfunction. However, loss of ambulation can occur and is seen more often with autosomal dominant EDMD than with X-linked EDMD. (See 'Prognosis' above.)