Emery-Dreifuss muscular dystrophy …

Howard J Worman MD

Neuromuscular Disorders

Updated 03.25.2023
Released 12.19.1994
Expires For CME 03.25.2026

Emery-Dreifuss muscular dystrophy

Author: Howard J Worman MD

See Contributor Disclosures

Editor: Aravindhan Veerapandiyan MD

Emery-Dreifuss muscular dystrophy

In This Article

Quick Link

Introduction

Overview

Emery-Dreifuss muscular dystrophy is a syndrome classically characterized by (1) slowly progressive muscle weakness and wasting in a scapulo-humeroperoneal distribution, (2) early contractures of the elbows, ankles, and posterior neck, and (3) dilated cardiomyopathy with conduction defects. Originally described as an X-linked disorder, Emery-Dreifuss muscular dystrophy–like phenotypes can arise from mutations in both autosomal and X chromosome genes, including those encoding emerin and A-type lamins, as well as in less frequent cases those encoding nesprin1, nesprin2, SUN1, SUN2, four-and-a-half-LIM protein 1, LUMA, and lamina-associated polypeptide 1. Although the skeletal muscle involvement can vary as a result of mutations in these genes, dilated cardiomyopathy is the most prevalent and potentially life-threatening feature.

Key points

	• Emery-Dreifuss muscular dystrophy can be inherited in an X-lined or autosomal manner and result from mutations in several different genes.
	• Variations in the classical Emery-Dreifuss phenotype can occur as a result of mutations in the causative genes.
	• Emery-Dreifuss muscular dystrophy should be considered in patients with muscular dystrophy and cardiac disease.
	• Cardiomyopathy and conduction defects may require early intervention, and cardiologists should evaluate affected patients.

Historical note and terminology

Céstan and LeJonne at l'Hôpital de la Salpêtrière in Paris published what may have been the first case reports of Emery-Dreifuss muscular dystrophy at the beginning of the twentieth century (22). Emery and Dreifuss were the first to fully describe the X-linked form of the disease in a kindred from Virginia (43). Rowland and colleagues at Columbia University in New York reported an additional case in 1979 and applied the term "Emery-Dreifuss type” muscular dystrophy (114). Cases of autosomal inheritance were subsequently reported in the mid-1980s, showing this phenotype to derive from different genetic mutations (90; 125).

Toniolo and colleagues identified EMD (formerly called STA) as the gene on chromosome Xq28 mutated in X-linked Emery-Dreifuss muscular dystrophy (14). In 1999, Ketty Schwartz and collaborators demonstrated that mutations in LMNA on chromosome 1q21.3 cause autosomal dominant cases of Emery-Dreifuss muscular dystrophy (16). The protein products of these genes are localized to the nuclear envelope of virtually all somatic cells. Case reports have further implicated mutations in genes encoding other nuclear envelope proteins as causing Emery-Dreifuss-like phenotypes: mutations in SYNE1 and SYNE2 respectively encoding nesprin1 and nesprin2 (140; 29; 142), TMEM43 encoding LUMA (71), and TOR1AIP1 encoding lamina-associated polypeptide 1 (61), SUN1 and SUN2 (82). Hence, although historically considered a specific disease, more recent advances in genetics have shown that Emery-Dreifuss muscular dystrophy is best considered a syndrome that can result from alterations in several different genes encoding nuclear envelope proteins.

Mutations in FHL1 encoding four-and-a-half-LIM protein 1, a protein localized to the sarcolemma, sarcomere, and nucleus of muscle cells, cause a scapuloperoneal myopathy (110). Some investigators have considered this to be Emery-Dreifuss muscular dystrophy (57). However, the associated cardiomyopathy is hypertrophic rather than dilated (57; 51). Although the distribution of affected skeletal muscle may therefore be similar, this is a distinction from Emery-Dreifuss muscular dystrophy and related phenotypes caused by mutations in genes encoding nuclear envelope proteins.

Clinical manifestations

Presentation and course

This classical presentation of Emery-Dreifuss muscular dystrophy, both X-linked and autosomal, was well described in the earlier clinical literature prior to the identification of the causative genetic mutations. Classically, skeletal involvement in Emery-Dreifuss muscular dystrophy is characterized clinically by slowly progressive muscle weakness and wasting in a scapulo-humeroperoneal distribution and early contractures of the elbows, ankles, and posterior neck (43; 41; 42). Contractures are usually the first clinical sign of the disease occurring in the first decade of life. During the second decade of life, the slowly progressive muscle weakness and wasting typically begin. Severity of the contractures and skeletal muscle wasting and weakness are variable from patient to patient; they can in some cases significantly limit activity but are not life threatening. Usually sometime after the second decade, patients develop evidence of cardiomyopathy (43; 135; 41; 42; 09; 128).

Sudden death from cardiac arrhythmia and heart failure are the potentially lethal clinical manifestations of Emery-Dreifuss muscular dystrophy. The first problem is usually atrioventricular block that can progress to complete heart block. This is classically thought to occur prior to chamber enlargement. Other levels of the conduction system can also be affected, manifesting as sick sinus syndrome, bundle branch blocks, or atrial fibrillation. Arrhythmias, including atrial ectopy, atrial fibrillation, non-sustained ventricular tachycardia, and other ventricular arrhythmias, can also occur prior to or independent of chamber dilatation. Chamber enlargement and systolic dysfunction of one or both ventricles generally occur later, which can lead to worsening ventricular arrhythmias and eventually heart failure.

Cardiomyopathy has best been clinically described in individuals with LMNA mutations (74). Cardiac disease penetrance is age-dependent and almost complete by 70 years of age (130). The course is aggressive, often leading to premature death or cardiac transplantation (09; 126; 128; 104; 64). By 60 years of age, 55% of patients with LMNA mutation and cardiomyopathy die of cardiovascular death or receive a heart transplant, compared with 11% of patients with other inherited cardiomyopathies (126). In a retrospective meta-analysis, sudden cardiac death occurred in 46% and death from heart failure in 12% of patients (128). Male mutation carriers appear to have a worse prognosis than female carriers, with a higher prevalence of malignant ventricular arrhythmias and advanced heart failure (130).

Since the genetic causes of Emery-Dreifuss muscular dystrophy have been deciphered, we realize that the clinical manifestations can vary significantly in patients with the same genetic mutations. The same mutations in LMNA that cause Emery-Dreifuss muscular dystrophy can cause cardiomyopathy with different skeletal muscles affected, including a limb-girdle muscular dystrophy (93), or minimal to no skeletal muscle involvement (44). In fact, the same mutations can cause any of these or overlapping phenotypes even within the same family (17; 19). The same holds true for mutations in EMD (100; 07; 127). Mutations in FHL1 can also lead to muscular dystrophy phenotypes that differ from classical Emery-Dreifuss muscular dystrophy (110; 137) and mutations in TMEM43 arrhythmogenic right ventricular cardiomyopathy (87). From a genetic perspective, Emery-Dreifuss muscular dystrophy is a specific clinically defined phenotype that can occur among a group of diseases caused by mutations in different genes.

Depending on the degree of skeletal muscle versus cardiac involvement and the age of onset of either, patients may be initially evaluated by neurologists or cardiologists. In “classical” cases of Emery-Dreifuss muscular dystrophy with relatively early onset of muscular dystrophy, the typical distribution of weakness with the combination of contractures, the slow progression of symptoms, and the characteristic cardiac conduction abnormalities makes Emery-Dreifuss muscular dystrophy an almost unique condition. These findings, along with a family history, strongly suggest the diagnosis. However, given that the Emery-Dreifuss muscular dystrophy phenotype is only one among a range of variable myopathic phenotypes that can occur in patients with EMD, LMNA, or other gene mutations, the differential diagnosis is often more complicated. Patients with LMNA mutations, and some with EMD mutations, have minimal skeletal muscle involvement and may first present as adults to cardiologists with arrhythmias or signs of heart failure. Early heart block in a patient with a family history of cardiomyopathy would suggest an LMNA mutation. In a study of patients with familial dilated cardiomyopathy and conduction block, 33% had LMNA mutations (05). In patients presenting with a primary dilated cardiomyopathy, whole exome sequencing, whole genome sequencing, or targeted, simultaneous evaluation of candidate genes linked to the disease should be strongly considered to make a genetic diagnosis (81).

Prognosis and complications

Skeletal involvement in Emery-Dreifuss muscular dystrophy is considered a relatively benign disorder, and most affected individuals remain ambulant for life with only some resultant limitations of physical activity. Cardiomyopathy is a major cause of death or debilitating heart failure, especially with LMNA mutations. With LMNA mutations, heart disease penetrance is almost complete by 70 years of age, with more than half of the patients having heart failure by age 60 years (130). Sudden cardiac death may occur in half of patients with LMNA mutations, based on retrospective data from before implantable cardioverter-defibrillator placement was less common (128). In other series, about 60% of patients with LMNA mutations had placement of implantable cardioverter-defibrillators (64). Death from heart failure occurs in 12% to 13% of patients with LMNA mutations (128; 64).

Clinical vignette

A 10-year-old girl was brought in for neurology consultation because of recent onset of mild exercise intolerance and tendency to walk on tip toes. She could run but more slowly than her peers. The early motor milestones were normal. Her father also had a tendency to walk on tiptoes and was never physically active. He developed atrial fibrillation, left bundle branch block, and nonsustained ventricular tachycardia in his early 40s, and sick sinus syndrome required implantation of a dual chamber pacemaker at 49 years of age.

On physical examination, the girl showed generalized muscle thinning, mild scapular winging, and a posture characterized by standing on tip toes because of contractures of both Achilles tendons. Manual muscle testing showed mild weakness in a scapuloperoneal distribution and flexion contractures of the elbows and ankles. There was mild rigidity of the lumbar spine. She got up from the floor with some mild difficulties more related to her contractures than to weakness. Tendon reflexes were elicited.

Laboratory examination revealed a serum creatine kinase activity three times the upper limits of normal. Electrocardiogram and echocardiogram were normal. Her forced vital capacity was normal. A muscle biopsy showed a myopathic picture, with variability in fiber size, an increase in internal nuclei, and occasional basophilic fibers, suggesting regeneration. Emerin expression was normal, as was the expression of all sarcolemmal and extracellular matrix proteins associated with congenital and limb-girdle forms of muscular dystrophy. Genetic analysis of LMNA revealed a mutation in exon 6 generating an amino acid substitution in the protein. This dominant mutation was probably inherited from her father. She was referred for genetic counseling and to a cardiologist.

A program of stretching exercises for the ankles and elbows was started. At last follow-up, the patient was 22 years of age and had been followed up regularly in the neurology and cardiology clinics. Her muscle power had not changed significantly. Her contractures had progressed in her elbows, and the spine rigidity also got worse. She complained of lightheadedness and palpitations; an electrocardiogram showed first-degree heart block, and a Holter monitor documented short runs of supraventricular tachycardia. Echocardiogram revealed a normal ejection fraction of 65% without chamber thickening or dilatation. Her primary cardiologist referred her to a cardiac electrophysiologist to determine if a primary prevention intracardiac cardioverter defibrillator was indicated.

Biological basis

Etiology and pathogenesis

Mutations in nine different genes have been reported to cause Emery-Dreifuss muscular dystrophy or related phenotypes: EMD encoding emerin, LMNA encoding A-type lamins, SYNE1 encoding nesprin1, SYNE2 encoding nesprin2, SUN1 encoding Sun1, SUN2 encoding Sun2, FHL1 encoding four-and-a-half-LIM protein 1, TMEM43 encoding LUMA, and TOR1AIP1 encoding lamina-associated polypeptide 1. The connection of mutations in EDM and LMNA to Emery-Dreifuss muscular dystrophy is extremely strong. Causative mutations that segregate with disease have been reported in numerous families. EDM mutations that cause Emery-Dreifuss muscular dystrophy generally lead to loss of expression of the encoded protein. In the case of LMNA, several genetically modified mouse models have been generated that recapitulate the human disease (123; 06; 92; 12). However, emerin-deficient mice surprisingly show little pathology (83; 102). Even heterozygous deletion of Lmna in emerin-deficient mice does not lead to significant pathology (134). Only a few cases with Emery-Dreifuss muscular dystrophy-like phenotypes have been linked to mutations in SYNE1, SYNE2, SUN1, SUN2, TMEM43, and TOR1AIP1. FHL1 mutations are linked to myopathies; however, affected individuals have hypertrophic rather than dilated cardiomyopathy. One study of gene expression in myotubes differentiated from myoblasts of patients, albeit with extremely small sample sizes, suggested that EMD, LMNA, SUN1, SYNE1, and FHL1 mutations may lead to some common downstream alterations in cellular metabolic and other pathways (35). OMIM classifies Emery-Dreifuss muscular dystrophy as types 1 through 7 depending on the genetic etiology.

Emery-Dreifuss muscular dystrophy 1 (EDMD1). This is transmitted as an X-linked recessive trait. The responsible gene on chromosome Xq28 was identified by Toniolo and colleagues and originally given the symbol STA and now EMD (14). It encodes a type II integral membrane protein of 254 amino acids, with a 219-amino acid amino-terminal domain followed by a 21-amino acid transmembrane segment 11 residue from the carboxyl terminus. Emerin was subsequently localized to the inner nuclear membrane (77; 101). Emerin is expressed in most terminally differentiated somatic cells but absent in almost all patients with EDMD1.

In addition to classical Emery-Dreifuss muscular dystrophy, phenotypic variants have been reported in patients with EMD mutations (100; 07; 127). Bione and colleagues and Nagano and colleagues invariably found lack of emerin in cardiac and skeletal muscles in patients with EDMD1, demonstrating that absence of protein on muscle biopsy can be diagnostic (15; 101). As emerin is also expressed in other tissues, its absence from skin cells and in buccal smear cells can also be used for diagnostic purposes, including carrier detection (78).

Emery-Dreifuss muscular dystrophy 2 (EDMD2). EDMD2 is inherited in an autosomal dominant manner. Bonne and colleagues originally identified mutations in LMNA on chromosome 1q21 affected individuals in six families with autosomal dominant Emery-Dreifuss muscular dystrophy (16). LMNA encodes A-type nuclear lamins, the major somatic cell isoforms being lamin A and lamin C, which arise by alternative splicing of RNA from this gene (72). Lamin A and lamin C are intermediate filament proteins that are components of the nuclear lamina, a protein meshwork localized to the inner aspect of the inner nuclear membrane (01; 48; 53; 80). These proteins are expressed in virtually all differentiated somatic cells. Lamins interact with chromatin as well as integral protein of the inner nuclear membrane, including emerin (136).

Although classical autosomal dominant Emery-Dreifuss muscular dystrophy was the first phenotype attributed to LMNA mutations, it is now apparent that the same mutations in these genes can cause dilated cardiomyopathy with much more variable skeletal muscle involvement (16; 17; 44; 19; 93; 74). The variable skeletal muscle presentation includes classical Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy in between phenotypes such as a limb-girdle distribution with early contractures or no obvious skeletal muscle disease at all. LMNA mutations have also been reported to cause early onset and severe cases resembling congenital muscular dystrophy in patients as young as 5 months of age (85; 86; 84; 18; 60; 109; 76; 106).

The LMNA mutations that cause these cardiomyopathy/muscular dystrophies are mostly missense or small in-frame deletions, which lead to expression of variant proteins, or to splice site, truncation, or promoter mutations that result in decreased levels of A-type lamins. Loss of function of A-type lamins may indeed be responsible for striated muscle disease as Lmna null mice develop cardiac and skeletal muscle disease (123). In humans, loss of A-type lamin function may result from some type of “dominant interference” as stable variants are often expressed; cardiac transgenic expression of a lamin A variant associated with Emery-Dreifuss muscular dystrophy in humans leads to severe heart damage in transgenic mice (133). Because proteins are expressed from one or both LMNA alleles in humans, immunohistochemical analysis of muscle or other tissue is not diagnostic. Definitive diagnosis relies on genetic testing.

Intriguingly, more than a dozen differently named clinical conditions have been linked to mutations in LMNA. These diseases are often referred to as “laminopathies.” Laminopathies can be grouped into disorders selectively affecting striated muscle (such as autosomal dominant Emery-Dreifuss muscular dystrophy), adipose tissue (Dunnigan-type familial partial lipodystrophy), peripheral nerves (Charcot-Marie-Tooth disease type 2B1), or multiple systems. Among the disorders affecting multiple systems are Hutchinson-Gilford progeria syndrome and mandibuloacral dysplasia, which have features of accelerated aging. Hence, the laminopathies raise a fascinating question: how do mutations in a single gene cause such varied pathological phenotypes?

Emery-Dreifuss muscular dystrophy (EDMD3). EDMD3 has been attributed to an autosomal recessively inherited LMNA mutation (111). Only one patient has been described who had early onset contractures and subsequent diffuse muscle wasting. There was no reported heart disease by 40 years of age. Both parents were heterozygous for the mutation and had no evidence of skeletal muscle disease.

Emery-Dreifuss muscular dystrophy 4 (EDMD4). Autosomal dominant mutations in SYNE1 encoding nesprin1 have been reported to cause Emery-Dreifuss muscular dystrophy-like phenotypes (140; 108; 29; 142). Nesprins are transmembrane proteins of the nuclear envelope that contain a KASH (klarsicht, Anc1, and Syne homology) domain. There are several nesprin1 isoforms that arise from alternative RNA splicing; the larger ones are localized to the outer nuclear membrane and smaller ones to the inner nuclear membrane. The outer nuclear membrane isoforms bind within the perinuclear space to SUN proteins in the inner nuclear membrane and in the cytoplasm to cytoskeletal filament networks. As a result of these interactions, nesprin1 and other nesprins function in nuclear positioning (58). The nesprin1alpha isoform, presumably localized at least partially to inner nuclear membrane, also interacts with emerin and A-type lamins (91).

Zhang and colleagues reported two unrelated patients with heterozygous mutations in SYNE1 that lead to amino acid substitutions in nesprin1alpha (140). One of these patients had only asymptomatic increased serum creatine kinase activity; the other had weakness and atrophy of the neck and shoulder muscle with contractures starting at age 11 years, leading to his requiring a wheelchair for mobility by age 26 years of age. A heterozygous SYNE1 mutation leading to an amino acid substitution in nepsrin1alplha has also been reported in an individual who developed dilated cardiomyopathy requiring cardiac transplantation (108). Zhou and colleagues identified three different SYNE1 missense mutations in seven patients with sporadic dilated cardiomyopathy (142). Chen and colleagues described a family with three patients—a proband, his elder sister, and his mother—with progressive muscular dystrophy and joint contractures without significant cardiac involvement (at least at the ages examined) who had a heterozygous missense mutation in SYNE1 (29).

Recessively inherited mutations in SYNE1 have more clearly been linked to cerebellar ataxia (56). These subjects frequently have additional extra-cerebellar neurologic and nonneurologic dysfunctions (124). Recessive SYNE1 mutations have also been reported in a family with arthrogryposis multiplex congenita, which is characterized by congenital joint contractures, reduced fetal movements, clubfoot, delay in motor milestones, and progressive motor decline after the first decade (08).

Emery-Dreifuss muscular dystrophy 5 (EDMD5). SYNE2 encodes nesprin2, which like nesprin1 is a KASH domain protein with several isoforms, the larger ones localized to the outer nuclear membrane and connecting the nucleus to the cytoskeleton (58). Some nesprin2 isoforms, presumably smaller ones localized in part to the inner nuclear membrane, also bind to emerin and A-type lamins (141). Zhang and colleagues identified two families with muscular dystrophy and mutations in SYNE2 (140). In one family with a heterozygous mutation leading to an amino acid substitution in nesprin2, one affected woman carrying the mutation had a history of muscle weakness and died at 30 years of age from cardiomyopathy (140). Her son who inherited the mutant allele suffered from muscle weakness starting in early childhood, heart rhythm disturbances at the age of 17 years, and subsequent cardiomyopathy necessitating heart transplantation at age 26 years. This son and his unaffected father were also heterozygous for an SYNE1 variant that was likely non-pathogenic. In a second family with the same SYNE2 mutation, a father, his son, and his daughter all carried the mutation and suffered from skeletal or heart muscle defects or both. A father and son with a SYNE2 missense have also been described to have an Emery-Dreifuss-like skeletal muscle phenotype of progressive muscular dystrophy and joint contractures, but without apparent heart involvement (70).

Emery-Dreifuss muscular dystrophy 6 (EDMD6). After identification of EMD as a causative mutation of X-linked Emery-Dreifuss muscular dystrophy, several families with an X-linked inheritance pattern were found not to have mutations in this gene. Gueneau and colleagues studied six unrelated families and an isolated individual with joint contractures, neck stiffness, muscle weakness, and cardiomyopathy that had mutations in FHL1 on chromosome Xq26.3 (57). Knoblauch and coworker extended this to another large family with Emery-Dreifuss muscular dystrophy-like phenotypes (63). A significant difference between these Emery-Dreifuss muscular dystrophy cases and those with mutations in EMD or LMNA is the presence of hypertrophic versus dilated cardiomyopathy. The left ventricular hypertrophy caused by FHL1 mutations has been highlighted in an additional published case (51; 55). Prior to being associated with the Emery-Dreifuss muscular dystrophy phenotype, FHL1 mutations had been linked to muscular dystrophies that had been classified as reducing body myopathy (116), X-linked myopathy with postural muscle atrophy (137), and X-linked scapuloperoneal myopathy (110).

FHL1 encodes four-and-a-half-LIM protein 1, which is expressed in cardiac and skeletal muscle. It contains LIM domains, which are tandem zinc-finger motifs. There appear to be three isoforms of four-and-a-half-LIM protein 1, and these isoforms have multiple functions either in the cytoplasm or nucleus (119). All of the other genes implicated so far in Emery-Dreifuss muscular dystrophy encode proteins uniquely localized to the nuclear envelope. Given the different subcellular localizations of four-and-a-half-LIM protein 1 and the hypertrophic rather than dilated cardiomyopathy linked to FHL1 mutations, perhaps the clinical disease caused by these mutations should be classified as something other than Emery-Dreifuss muscular dystrophy.

Emery-Dreifuss muscular dystrophy 7 (EDMD7). LUMA is an integral protein of the inner nuclear membrane (38). Mutations in TMEM43 encoding LUMA were originally identified in families with arrhythmogenic right ventricular cardiomyopathy (87). Heterozygous mutations in TMEM43 have also been identified in two sporadic patients with an Emery-Dreifuss muscular dystrophy phenotype, including a cardiac conduction disease (71). The same heterozygous TMEM43 mutation was described in a father and son with Emery-Dreifuss muscular dystrophy-like phenotypes (99).

Emery-Dreifuss muscular dystrophy-like myopathy caused by TOR1AIP1 mutation. TOR1AIP1 encodes lamina-associated polypeptide 1, an integral protein of the inner nuclear membrane associated with lamins in the nucleus and the AAA+ ATPase torsinA in the perinuclear space (117; 54). Lamina-associated polypeptide 1 was shown to bind to emerin, and its depletion from skeletal muscle and the heart causes muscular dystrophy and cardiac dysfunction in mice (122; 121). Kayman-Kurekci and colleagues have described a consanguineous family with three affected individuals with variable proximal and distal skeletal muscle weakness and atrophy, rigid spine, contractures of the proximal and distal interphalangeal hand joints, and cardiomyopathy (61). The affected individuals had a homozygous frameshift mutation in TOR1AIP1 that resulted in a premature stop codon and lack of expression of the 1B isoform of lamina-associated protein 1 in muscle. A single patient has also been reported with a homozygous TOR1AIP1 missense mutation causing dystonia and cerebellar atrophy, and the patient also had cardiomyopathy and severe contractors of the Achilles tendons (37). Ghaoui and colleagues identified compound heterozygous mutations in TOR1AIP1 leading to reduced protein expression in two siblings who presented with muscular dystrophy and heart failure, which required cardiac transplantation (52). Additional cases have since been described (46; 73). TOR1AIP1 mutations causing combined loss of both the LAP1B and LAP1C isoforms cause severe multisystem disease and early death (47).

Emery-Dreifuss muscular dystrophy-like myopathy caused by SUN1 and SUN2 mutations. Emery-Dreifuss muscular dystrophy-like myopathy has been reportedly caused by SUN1 and SUN2 mutations. Meinke and colleagues identified nonsynonymous SUN1 and SUN2 mutations in three individuals who had Emery-Dreifuss muscular dystrophy-like phenotypes (82). One sporadic patient had a heterozygous amino acid substitution in a region of Sun1 with a high degree of evolutionary conservation. Another patient was compound heterozygous for amino acid substitutions in Sun1 with one variant inherited from each unaffected parent. Another sporadic patient carried heterozygous amino acid substitutions in both Sun1 and Sun2 in evolutionarily conserved parts of the proteins. No segregation of the variants among affected and unaffected family members was reported.

Pathophysiology. The pathogenesis and pathophysiology of Emery-Dreifuss muscular dystrophy and the related myopathic phenotypes caused by mutations in the same genes remains an area of active research. A common connection between emerin, A-type lamins, nesprin1, nesprin2, Sun1, Sun2, lamina-associated polypeptide 1, and LUMA is that they are all localized to the nuclear envelope. Indeed, emerin, nesprins, Sun1, Sun2, lamina-associated polypeptide 1, and lamins all interact at the nuclear envelope. A major enigma in genetic and cell biological research is how mutations in genes encoding nuclear envelope proteins expressed in all or most differentiated somatic cells cause tissue-selective diseases (34; 138).

Research has provided an emerging view of the nuclear envelope as a critical signaling node in development and disease (34). In heart and skeletal muscle of genetically modified mice carrying a LMNA mutation orthologous to one that causes Emery-Dreifuss muscular dystrophy in humans, there is abnormally enhanced activation of mitogen-activated protein kinase cascade (96; 94). At least in cardiac muscle, activation of the extracellular signal-regulated kinase 1/2 branch of this cascade occurs early, prior to the onset of clinical cardiomyopathy (96; 31). Studies have shown that treatment of these mice with drugs that block activation of extracellular signal-regulated kinase 1/2 leads to partial improvement in cardiac and skeletal muscle function (98; 97; 94; 139). In cellular and small animal models of cardiomyopathy caused by LMNA mutation, extracellular signal-regulated kinase 1/2 catalyzes the phosphorylation/activation of cofilin-1, which in turn disassembles actin filaments (26). Further research has shown that phosphorylated cofilin-1 binds to myocardin-related transcription factor A in the cytoplasm, thus, preventing the stimulation of serum response factor in the nucleus and leading to decreased alpha-tubulin acetylation by reducing expression of the gene encoding alpha-tubulin acetyltransferase 1 (68). Increasing alpha-tubulin acetylation levels in Lmna mutant mice with tubastatin A improves cardiac function. Extracellular signal-regulated kinase 1/2 also catalyzes the phosphorylation of formin homology domain proteins, inhibiting their actin bundling activity and leading to abnormal nuclear positioning in cardiomyocytes (04). Although mice lacking emerin do not develop significant disease, there is also evidence of abnormally enhanced extracellular signal-regulated kinase 1/2 in their hearts (95).

Abnormally increased AKT-mTOR signaling that blocks autophagy has also been implicated in the pathogenesis of cardiomyopathy and skeletal myopathy in mouse models of Emery-Dreifuss muscular dystrophy caused by LMNA mutations, and rapamycin and its analogues have beneficial effects (30; 112). Enhanced transforming growth factor-beta signaling may contribute to the cardiac fibrosis, skeletal muscle fibrosis, and tendon contractures (06; 25; 10). Platelet-derived growth factor signaling pathways are also activated in cardiomyocytes derived from induced pluripotent stem cells of patients with cardiomyopathy caused by LMNA mutations (69). Dysregulation of mitogen-activated protein kinase, ATK-mTOR, and potentially other signaling pathways may, therefore, result from alteration in the nuclear envelope caused by mutations that cause Emery-Dreifuss muscular dystrophy and contribute to striated muscle disease. In addition, abnormal cellular calcium homeostasis contributes to pathology, as ryanodine receptors are post-translationally remodeled to generate a calcium “leak” in hearts of humans with LMNA mutations as well as cardiac and skeletal muscle of mouse models (39).

It is unclear how defects in nuclear envelope proteins that occur in Emery-Dreifuss muscular dystrophy lead to abnormalities in signal transduction pathways. Deficiency of both A-type lamins and emerin from cells lead to defects in nuclear mechanics and mechanotransduction (20; 67; 66). LMNA mutations causing muscular dystrophy reduce nuclear stability and cause transient rupture of the nuclear envelope in skeletal muscle cells, resulting in DNA damage and DNA damage response activation (40). DNA damage with activation of the DNA damage response pathway also occurs in the hearts of mice with conditional deletion of Lmna from cardiomyocytes (27). Expression of lamin A variants associated with Emery-Dreifuss muscular dystrophy also block the normal actin-dependent rearward movement of nuclei in migrating fibroblasts, which is also blocked by depletion of a giant isoform of nesprin2 (75; 50). Lack of emerin and Sun protein variants found in patients with Emery-Dreifuss muscular dystrophy-like phenotypes also block this rearward nuclear movement (24; 82). Actin-dependent rearward nuclear movement has been shown to occur in migrating myoblasts, suggesting it may play a role in striated muscle differentiation (23). Defects in nuclear envelope proteins linked to Emery-Dreifuss muscular dystrophy may, therefore, interfere with myoblast migration and overall cellular mechanics and stability, making cells, especially those in contractile muscle, more responsive to mechanical stress. As a result, stress-activated signaling pathways may be more readily activated, leading to cross activation of other pathways and detrimental responses. This hypothesis requires further testing.

Another line of investigation has focused on changes in chromatin in Emery-Dreifuss muscular dystrophy. In human hearts from patients with dilated cardiomyopathy caused by LMNA mutations, lamin-associated chromatin domain are redistributed in association with altered CpG methylation and gene expression (28). However, another study has reported that human-induced pluripotent stem cell-derived cardiomyocytes with a haploinsufficient LMNA mutation have only limited differences in chromatin compartmentalization (11). End-stage dilated human hearts and cardiomyocytes derived from induced pluripotent stem cells may be expected to have differences in chromatin organization and gene expression. Loss of A-type lamins in mice leads to deregulated defective repression of transcription by polycomb group protein epigenetic regulators in in muscle satellite stem cells (13). More research is necessary to determine the specificity and reproducibility of chromatin alterations in Emery-Dreifuss muscular dystrophy and their contribution to disease pathogenesis.

Management

There is no specific therapy for Emery-Dreifuss muscular dystrophy. The skeletal muscle weakness and joint contractures could possibly benefit from physical therapy. In some cases, orthopedic surgery to lengthen the Achilles tendon may be beneficial (118). Potential surgical treatment of severe upper extremity contractures has also been described in case reports (49).

Cardiologists should follow all patients diagnosed with Emery-Dreifuss muscular dystrophy, as heart involvement is invariant. Guidelines on the management of cardiac complications have been proposed but have not been firmly established (21). A scientific statement from the American Heart Association has recommended: (1) individuals with Emery-Dreifuss muscular dystrophy, regardless of genotype, should be referred for cardiology assessment at the time of diagnosis, even if asymptomatic; (2) at least annual evaluation with echocardiogram, electrocardiogram, and ambulatory electrocardiogram is reasonable for patients with autosomal dominant and X-linked Emery-Dreifuss muscular dystrophy; and (3) annual electrocardiogram and ambulatory electrocardiography are reasonable for autosomal recessive Emery-Dreifuss muscular dystrophy (45). Some data suggest that atrial arrhythmias occur earlier in patients with Emery Dreifuss muscular dystrophy mutations and that ventricular arrhythmias are much more common in those with LMNA mutations (79). Early recognition of cardiac conduction block may prevent sudden death by placement of a pacemaker. Because of the associated ventricular tachyarrhythmias that are particularly common with LMNA mutations, an implantable cardioverter-defibrillator ought to be considered in this condition (09; 128; 88; 65).

A study of 269 LMNA mutation carriers identified potential risk factors for malignant ventricular arrhythmias that may indicate cardioverter-defibrillator placement (129). Based on its findings, American and European cardiological societies have recommended that for patients with LMNA mutations, cardioverter-defibrillator placement should be considered if greater than or equal to two of the following criteria are present: male sex, nonmissense mutations, nonsustained ventricular tachycardia, and a left ventricular ejection fraction less than 45% (107; 03). Wahbi and colleagues have since developed a risk prediction model called the LMNA-risk VTA calculator for life-threatening ventricular tachyarrhythmia in patients with dilated cardiomyopathy caused by LMNA mutations that improves on these previous criteria (132). An independent validation of the LMNA-risk VTA calculator in 118 patients showed a high sensitivity for subsequent ventricular tachyarrhythmia but overestimated arrhythmic risk in some patients with relatively mild to moderate phenotypes (113). As recommendations for timing intervention with an implantable cardioverter-defibrillator may change with further research, a cardiac electrophysiologist with experience in genetic cardiomyopathies should ideally follow patients with Emery-Dreifuss muscular dystrophy, even when they are asymptomatic. Progressive heart failure should be treated with standard methods. For end-stage heart failure, evaluation for cardiac transplantation would be indicated (105; 36; 131).

Outcomes

There is little information on treatment outcomes in Emery-Dreifuss muscular dystrophy caused by any known genetic mutation. Early implantable cardioverter-defibrillator placement may prevent sudden death in patients with LMNA mutations, but there are currently no published prospective data. The same is true for patients with other inherited forms of the disease. Two studies suggest that radiofrequency catheter ablation of ventricular tachycardia in patients with LMNA mutations and cardiomyopathy may not be beneficial and even lead to poor outcomes (65; 59).

References

01: Aebi U, Cohn J, Buhle L, Gerace L. The nuclear lamina is a meshwork of intermediate-type filaments. Nature 1986;323:560-4. PMID 3762708
02: Aldwinckle RJ, Carr AS. The anesthetic management of a patient with Emery-Dreifuss muscular dystrophy for orthopedic surgery. Can J Anaesth 2002;49(5):467-70. PMID 11983660
03: Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018;72(14):1677-749. PMID 29097294
04: Antoku S, Wu W, Joseph LC, et al. ERK1/2 Phosphorylation of FHOD connects signaling and nuclear positioning alternations in cardiac laminopathy. Dev Cell 2019;51(5):602‐16. PMID 31794718
05: Arbustini E, Pilotto A, Repetto A, et al. Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease. J Am Coll Cardiol 2002;39:981-90. PMID 11897440
06: Arimura T, Helbling-Leclerc A, Massart C, et al. Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies. Hum Mol Genet 2005;14(1):155-69. PMID 15548545
07: Astejada MN, Goto K, Nagano A, et al. Emerinopathy and laminopathy clinical, pathological and molecular features of muscular dystrophy with nuclear envelopathy in Japan. Acta Myol 2007;26:159-64. PMID 18646565
08: Attali R, Warwar N, Israel A, et al. Mutation of SYNE-1, encoding an essential component of the nuclear lamina, is responsible for autosomal recessive arthrogryposis. Hum Mol Genet 2009;18(18):3462-9. PMID 19542096
09: Bécane HM, Bonne G, Varnous S, et al. High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation. Pacing Clin Electrophysiol 2000;23(11 Pt 1):1661-6. PMID 11138304
10: Bernasconi P, Carboni N, Ricci G, et al. Elevated TGF β2 serum levels in Emery-Dreifuss muscular dystrophy: Implications for myocyte and tenocyte differentiation and fibrogenic processes. Nucleus 2018;9(1):292-304. PMID 29693488
11: Bertero A, Fields PA, Smith AST, et al. Chromatin compartment dynamics in a haploinsufficient model of cardiac laminopathy. J Cell Biol 2019;218(9):2919-44. PMID 31395619
12: Bertrand AT, Renou L, Papadopoulos A, et al. DelK32-lamin A/C has abnormal location and induces incomplete tissue maturation and severe metabolic defects leading to premature death. Hum Mol Genet 2012;21(5):1037-48. PMID 22090424
13: Bianchi A, Mozzetta C, Pegoli G, et al. Dysfunctional polycomb transcriptional repression contributes to lamin A/C-dependent muscular dystrophy. J Clin Invest 2020;130(5):2408‐21. PMID 31999646
14: Bione S, Maestrini E, Rivella S, et al. Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy. Nat Genet 1994;8:323-7. PMID 7894480
15: Bione S, Small K, Aksmanovic VM, et al. Identification of new mutations in the Emery-Dreifuss muscular dystrophy gene and evidence for genetic heterogeneity of the disease. Hum Mol Genet 1995;4:1859-63. PMID 8595407
16: Bonne G, Di Barletta MR, Varnous S, et al. Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nat Genet 1999;21(3):285-8. PMID 10080180
17: Bonne G, Mercuri E, Muchir A, et al. Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamins A/C gene. Ann Neurol 2000;48(2):170-80. PMID 10939567
18: Bonne G, Yaou RB, Beroud C, et al. 108th ENMC International Workshop, 3rd Workshop of the MYO-CLUSTER project: EUROMEN, 7th International Emery-Dreifuss Muscular Dystrophy (EDMD) Workshop, 13-15 September 2002, Naarden, The Netherlands. Neuromuscul Disord 2003;13(6):508-15. PMID 12899879
19: Brodsky GL, Muntoni F, Miocic S, et al. Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement. Circulation 2000;101:473-6. PMID 10662742
20: Broers JL, Peeters EA, Kujpers HJ, et al. Decreased mechanical stiffness in LMNA-/- cells is caused by defective nucleo-cytoskeletal integrity: implications for the development of laminopathies. Hum Mol Gen 2004;13:2567-80. PMID 15367494
21: Bushby K, Muntoni F, Bourke JP. 107th ENMC International Workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003;13:166-72. PMID 12565916
22: Céstan R, LeJonne P. Une myopathie avec retractions familiales. Nouv Iconogr Salpetr 1902;15:38-52.
23: Chang W, Antoku S, Östlund C, Worman HJ, Gundersen GG. Linker of nucleoskeleton and cytoskeleton (LINC) complex-mediated actin-dependent nuclear positioning orients centrosomes in migrating myoblasts. Nucleus 2015;6(1):77-88. PMID 25587885
24: Chang W, Folker ES, Worman HJ, Gundersen GG. Emerin organizes actin flow for nuclear movement and centrosome orientation in migrating fibroblasts. Mol Biol Cell 2013;24(24):3869-80. PMID 24152738
25: Chatzifrangkeskou M, Le Dour C, Wu W, et al. ERK1/2 directly acts on CTGF/CCN2 expression to mediate myocardial fibrosis in cardiomyopathy caused by mutations in the lamin A/C gene. Hum Mol Genet 2016;25(11):2220-33. PMID 27131347
26: Chatzifrangkeskou M, Yadin D, Marais T, et al. Cofilin-1 phosphorylation catalyzed by ERK1/2 alters cardiac actin dynamics in dilated cardiomyopathy caused by lamin A/C gene mutation. Hum Mol Genet 2018;27(17):3060-78. PMID 29878125
27: Cheedipudi SM, Asghar S, Marian AJ. Genetic ablation of the DNA damage response pathway attenuates lamin-associated dilated cardiomyopathy in mice. JACC Basic Transl Sci 2022;7(12):1232-45. PMID 36644279
28: Cheedipudi SM, Matkovich SJ, Coarfa C, et al. Genomic reorganization of lamin-associated domains in cardiac myocytes is associated with differential gene expression and dna methylation in human dilated cardiomyopathy. Circ Res 2019;124(8):1198‐213. PMID 30739589
29: Chen Z, Ren Z, Mei W, et al. A novel SYNE1 gene mutation in a Chinese family of Emery-Dreifuss muscular dystrophy-like. BMC Med Genet 2017;18(1):63. PMID 28583108
30: Choi JC, Muchir A, Wu W, et al. Temsirolimus activates autophagy and ameliorates cardiomyopathy caused by lamin A/C gene mutation. Sci Transl Med 2012a;4(144):144ra102. PMID 22837537
31: Choi JC, Wu W, Muchir A, Iwata S, Homma S, Worman HJ. Dual specificity phosphatase 4 mediates cardiomyopathy caused by lamin A/C (LMNA) gene mutation. J Biol Chem 2012b;287(48):40513-24. PMID 23048029
32: Choudhry DK, Mackenzie WG. Anesthetic issues with a hyperextended cervical spine in a child with Emery-Dreifuss syndrome. Anesth Analg 2006;103(6):1611-3. PMID 17122279
33: Codd MB, Sugrue DD, Gersh BJ, et al. Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy: a population-based study in Olmsted County, Minnesota, 1975-1984. Circulation 1989;80:564-72. PMID 2766509
34: Dauer WT, Worman HJ. The nuclear envelope as a signaling node in development and disease. Dev Cell 2009;17(5):626-38. PMID 19922868
35: de Las Heras JI, Todorow V, Krečinić-Balić L, et al. Metabolic, fibrotic and splicing pathways are all altered in Emery-Dreifuss muscular dystrophy spectrum patients to differing degrees. Hum Mol Genet 2023;32(6):1010-31. PMID 36282542
36: Dell'Amore A, Botta L, Martin Suarez S, et al. Heart transplantation in patients with Emery-Dreifuss muscular dystrophy: case reports. Transplant Proc 2007;39(10):3538-40. PMID 18089432
37: Dorboz I, Coutelier M, Bertrand AT, et al. Severe dystonia, cerebellar atrophy, and cardiomyopathy likely caused by a missense mutation in TOR1AIP1. Orphanet J Rare Dis 2014;9:174. PMID 25425325
38: Dreger M, Bengtsson L, Schoneberg T, Otto H, Hucho F. Nuclear envelope proteomics: novel integral membrane proteins of the inner nuclear membrane. Proc Natl Acad Sci U S A 2001;98(21):11943-8. PMID 11593002
39: Dridi H, Wu W, Reiken SR, et al. Ryanodine receptor remodeling in cardiomyopathy and muscular dystrophy caused by lamin A/C gene mutation. Hum Mol Genet 2021;29(24):3919-34. PMID 33388782
40: Earle AJ, Kirby TJ, Fedorchak GR, et al. Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells. Nat Mater 2020;19(4):464‐73. PMID 31844279
41: Emery AE. X-linked muscular dystrophy with early contractures and cardiomyopathy (Emery-Dreifuss type). Clin Genet 1987;32(5):360-7. PMID 3319295
42: Emery AE. Emery-Dreifuss muscular dystrophy- a 40 years retrospective. Neuromuscul Disord 2000;10:228-32. PMID 10838246
43: Emery AE, Dreifuss FE. Unusual type of benign X-linked muscular dystrophy. J Neurol Neurosurg Psychiatry 1966;29:338-42. PMID 5969090
44: Fatkin D, MacRae C, Sasaki T, et al. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med 1999;341:1715-24. PMID 10580070
45: Feingold B, Mahle WT, Auerbach S, et al. Management of cardiac involvement associated with neuromuscular diseases: a scientific statement from the American Heart Association. Circulation 2017;136(13):e200-31. PMID 28838934
46: Feng X, Wu J, Xian W, et al. Muscular involvement and tendon contracture in limb-girdle muscular dystrophy 2Y: a mild adult phenotype and literature review. BMC Musculoskelet Disord 2020;21(1):588. PMID 32873274
47: Fichtman B, Zagairy F, Biran N, et al. Combined loss of LAP1B and LAP1C results in an early onset multisystemic nuclear envelopathy. Nat Commun 2019;10(1):605. PMID 30723199
48: Fisher DZ, Chaudhary N, Blobel G. cDNA sequencing of nuclear lamins A and C reveals primary and secondary structural homology to intermediate filament proteins. Proc Natl Acad Sci USA 1986;83:6450-4. PMID 3462705
49: Fishman FG, Goldstein EM, Peljovich AE. Surgical treatment of upper extremity contractures in Emery-Dreifuss muscular dystrophy. J Pediatr Orthop B 2017;26(1):32-5. PMID 26588837
50: Folker ES, Östlund C, Luxton GW, et al. Lamin A variants that cause striated muscle disease are defective in anchoring transmembrane actin-associated nuclear lines for nuclear movement. Proc Natl Acad Sci U S A 2011;108(1):131-6. PMID 21173262
51: Friedrich FW, Wilding BR, Reischmann S, et al. Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy. Hum Mol Genet 2012;21(14):3237-54. PMID 22523091
52: Ghaoui R, Benavides T, Lek M, et al. TOR1AIP1 as a cause of cardiac failure and recessive limb-girdle muscular dystrophy. Neuromuscul Disord 2016;26(8):500-3. PMID 27342937
53: Goldman AE, Maul G, Steinert PM, et al. Keratin-like proteins that coisolate with intermediate filaments of BHK-21 cells are nuclear lamins. Proc Natl Acad Sci USA 1986;83:3839-43. PMID 2424013
54: Goodchild RE, Dauer WT. The AAA+ protein torsinA interacts with a conserved domain present in LAP1 and a novel ER protein. J Cell Biol 2005;168(6):855-62. PMID 15767459
55: Gossios TD, Lopes LR, Elliott PM. Left ventricular hypertrophy caused by a novel nonsense mutation in FHL1. Eur J Med Genet 2013;56(5):251-5. PMID 23500067
56: Gros-Louis F, Dupré N, Dion P, et al. Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia. Nat Genet 2007;39(1):80-5. PMID 17159980
57: Gueneau L, Bertrand AT, Jais JP, et al. Mutations of the FHL1 gene cause Emery-Dreifuss muscular dystrophy. Am J Hum Genet 2009;85:338-53. PMID 19716112
58: Gundersen GG, Worman HJ. Nuclear positioning. Cell 2013;152(6):1376-89. PMID 23498944
59: Hasebe Y, Fukuda K, Nakano M, et al. Characteristics of ventricular tachycardia and long-term treatment outcome in patients with dilated cardiomyopathy complicated by lamin A/C gene mutations. J Cardiol 2019;74(5):451-9. PMID 31060954
60: Higuchi Y, Hongou M, Ozawa K, et al. A family of Emery-Dreifuss muscular dystrophy with extreme difference in severity. Pediatr Neurol 2005;32:358-60. PMID 15866440
61: Kayman-Kurekci G, Talim B, Korkusuz P, et al. Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: a novel gene related to nuclear envelopathies. Neuromuscul Disord 2014;24(7):624-33. PMID 24856141
62: Kim OM, Elliott D. Elective caesarean section for a woman with Emery-Dreifuss muscular dystrophy. Anaesth Intensive Care 2010;38(4):744-7. PMID 20715741
63: Knoblauch H, Geier C, Adams S, et al. Contractures and hypertrophic cardiomyopathy in a novel FHL1 mutation. Ann Neurol 2010;67:136-40. PMID 20186852
64: Kumar S, Androulakis AF, Sellal JM, et al. Multicenter experience with catheter ablation for ventricular tachycardia in lamin A/C cardiomyopathy. Circ Arrhythm Electrophysiol 2016a;9(8):e004357. PMID 27506821
65: Kumar S, Baldinger SH, Gandjbakhch E, et al. Long-term arrhythmic and nonarrhythmic outcomes of lamin A/C mutation carriers. J Am Coll Cardiol 2016b;68(21):2299-307. PMID 27884249
66: Lammerding J, Hsiao J, Schulze PC, Kozlov S, Stewart CL, Lee RT. Abnormal nuclear shape and impaired mechanotransduction in emerin-deficient cells. J Cell Biol 2005;170(5):781-91. PMID 16115958
67: Lammerding J, Schulze PC, Takahashi T, et al. Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction. J Clin Invest 2004;113(3):370-8. PMID 14755334
68: Le Dour C, Chatzifrangkeskou M, Macquart C, et al. Actin-microtubule cytoskeletal interplay mediated by MRTF-A/SRF signaling promotes dilated cardiomyopathy caused by LMNA mutations. Nat Commun 2022;13(1):7886. PMID 36550158
69: Lee J, Termglinchan V, Diecke S, et al. Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy. Nature 2019;572(7769):335‐40. PMID 31316208
70: Lee SJ, Lee S, Choi E, et al. A novel SYNE2 mutation identified by whole exome sequencing in a Korean family with Emery-Dreifuss muscular dystrophy. Clin Chim Acta 2020;506:50‐4. PMID 32184094
71: Liang WC, Mitsuhashi H, Keduka E, et al. TMEM43 mutations in Emery-Dreifuss muscular dystrophy-related myopathy. Ann Neurol 2011;69(6):1005-13. PMID 21391237
72: Lin F, Worman HJ. Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C. J Biol Chem 1993;268(22):16321-6. PMID 8344919
73: Lornage X, Mallaret M, Silva-Rojas R, et al. Selective loss of a LAP1 isoform causes a muscle-specific nuclear envelopathy. Neurogenetics 2021;22(1):33-41. PMID 33405017
74: Lu JT, Muchir A, Nagy PL, et al. LMNA cardiomyopathy: cell biology and genetics meet clinical medicine. Dis Model Mech 2011;4(5):562-8. PMID 21810905
75: Luxton GW, Gomes ER, Folker ES, Vintinner E, Gundersen GG. Linear arrays of nuclear envelope proteins harness retrograde actin flow for nuclear movement. Science 2010;329(5994):956-9. PMID 20724637
76: Makri S, Clarke NF, Richard P, et al. Germinal mosaicism for LMNA mimics autosomal recessive congenital muscular dystrophy. Neuromuscul Disord 2009;19(1):26-8. PMID 19084400
77: Manilal S, Nguyen TM, Sewry CA. The Emery-Dreifuss muscular dystrophy protein, emerin, is a nuclear membrane protein. Hum Mol Genet 1996;5:801-8. PMID 8776595
78: Manilal S, Sewry CA, Man N, Muntoni F, Morris GE. Diagnosis of X-linked Emery-Dreifuss muscular dystrophy by protein analysis of leucocytes and skin with monoclonal antibodies. Neuromuscul Disord 1997;7(1):63-6. PMID 9132142
79: Marchel M, Madej-Pilarczyk A, Tymińska A, et al. Arrhythmias in muscular dystrophies associated with emerinopathy and laminopathy: a cohort study. J Clin Med 2021;10(4):732. PMID 33673224
80: McKeon FD, Kirschner MW, Caput D. Homologies in both primary and secondary structure between nuclear envelope and intermediate filament proteins. Nature 1986;319:463-8. PMID 3453101
81: McNally EM, Golbus JR, Puckelwartz MJ. Genetic mutations and mechanisms in dilated cardiomyopathy. J Clin Invest 2013;123(1):19-26. PMID 23281406
82: Meinke P, Mattioli E, Haque F, et al. Muscular dystrophy-associated SUN1 and SUN2 variants disrupt nuclear-cytoskeletal connections and myonuclear organization. PLoS Genet 2014;10(9):e1004605. PMID 25210889
83: Melcon G, Kozlov S, Cutler DA, et al. Loss of emerin at the nuclear envelope disrupts the Rb1/E2F and MyoD pathways during muscle regeneration. Hum Mol Genet 2006;15(4):637-51. PMID 16403804
84: Mercuri E, Brown SC, Nihoyannopoulos P, et al. Extreme variability of skeletal and cardiac muscle involvement in patients with mutations in exon 11 of the lamin A/C gene. Muscle Nerve 2005;31(5):602-9. PMID 15770669
85: Mercuri E, Manzur AY, Jungbluth H, et al. Early and severe presentation of autosomal dominant Emery-Dreifuss muscular dystrophy (EMD2). Neurology 2000;54(8):1704-5. PMID 10762524
86: Mercuri E, Poppe M, Quinlivan R, et al. Extreme variability of phenotype in patients with an identical missense mutation in the lamin A/C gene: from congenital onset with severe phenotype to milder classic Emery-Dreifuss variant. Arch Neurol 2004;61(5):690-4. PMID 15148145
87: Merner ND, Hodgkinson KA, Haywood AF, et al. Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am J Hum Genet 2008;82(4):809-21. PMID 18313022
88: Meune C, Van Berlo JH, Anselme F, Bonne G, Pinto YM, Duboc D. Primary prevention of sudden death in patients with lamin A/C gene mutations. N Engl J Med 2006;12;354(2):209-10. PMID 16407522
89: Millat G, Bouvagnet P, Chevalier P, et al. Clinical and mutational spectrum in a cohort of 105 unrelated patients with dilated cardiomyopathy. Eur J Med Genet 2011;54(6):e570-5. PMID 21846512
90: Miller RG, Layzer RB, Mellenthin MA, Golabi M, Francoz RA, Mall JC. Emery-Dreifuss muscular dystrophy with autosomal dominant transmission. Neurology 1985;35:1230-3. PMID 4022362
91: Mislow JM, Holaska JM, Kim MS, et al. Nesprin-1alpha self-associates and binds directly to emerin and lamin A in vitro. FEBS Lett 2002;525:135-40. PMID 12163176
92: Mounkes LC, Kozlov SV, Rottman JN, Stewart CL. Expression of an LMNA-N195K variant of A-type lamins results in cardiac conduction defects and death in mice. Hum Mol Genet 2005;14(15):2167-80. PMID 15972724
93: Muchir A, Bonne G, van der Kooi AJ, et al. Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). Hum Mol Genet 2000;9(9):1453-9. PMID 10814726
94: Muchir A, Kim YJ, Reilly SA, Wu W, Choi JC, Worman HJ. Inhibition of extracellular signal-regulated kinase 1/2 signaling has beneficial effects on skeletal muscle in a mouse model of Emery-Dreifuss muscular dystrophy caused by lamin A/C gene mutation. Skelet Muscle 2013;3(1):17. PMID 23815988
95: Muchir A, Pavlidis P, Bonne G, Hayashi YK, Worman HJ. Activation of MAPK in hearts of EMD null mice: similarities between mouse models of X-linked and autosomal dominant Emery Dreifuss muscular dystrophy. Hum Mol Genet 2007a;16(15):1884-95. PMID 17567779
96: Muchir A, Pavlidis P, Decostre V, et al. Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy. J Clin Invest 2007b;117(5):1282-93. PMID 17446932
97: Muchir A, Reilly SA, Wu W, et al. Treatment with selumetinib preserves cardiac function and improves survival in cardiomyopathy caused by mutation in the lamin A/C gene. Cardiovasc Res 2012;93(2):311-9. PMID 22068161
98: Muchir A, Shan J, Bonne G, Lehnart SE, Worman HJ. Inhibition of extracellular signal-regulated kinase signaling to prevent cardiomyopathy caused by mutation in the gene encoding A-type lamins. Hum Mol Genet 2009;18(2):241-7. PMID 18927124
99: Mukai T, Mori-Yoshimura M, Nishikawa A, et al. Emery-Dreifuss muscular dystrophy-related myopathy with TMEM43 mutations. Muscle Nerve 2019;59(2):E5-7. PMID 30311943
100: Muntoni F, Lichtarowicz-Krynska EJ, Sewry CA, et al. Early presentation of X-linked Emery Dreifuss muscular dystrophy resembling limb-girdle muscular dystrophy. Neuromuscul Disord 1998;8:72-6. PMID 9608559
101: Nagano A, Koga R, Ogawa M, et al. Emerin deficiency at the nuclear membrane in patients with Emery-Dreifuss muscular dystrophy. Nat Genet 1996;12:254-9. PMID 8589715
102: Ozawa R, Hayashi YK, Ogawa M, et al. Emerin-lacking mice show minimal motor and cardiac dysfunctions with nuclear-associated vacuoles. Am J Pathol 2006;168(3):907-17. PMID 16507906
103: Parks SB, Kushner JD, Nauman D, et al. Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. Am Heart J 2008;156(1):161-9. PMID 18585512
104: Pasotti M, Klersy C, Pilotto A, et al. Long-term outcome and risk stratification in dilated cardiolaminopathies. J Am Coll Cardiol 2008;52(15):1250-60. PMID 18926329
105: Pethig K, Genschel J, Peters T, et al. LMNA mutations in cardiac transplant recipients. Cardiology 2005;103(2):57-62. PMID 15539782
106: Prigogine C, Richard P, Van den Bergh P, Groswasser J, Deconinck N. Novel LMNA mutation presenting as severe congenital muscular dystrophy. Pediatr Neurol 2010;43(4):283-6. PMID 20837309
107: Priori SG, Blomström-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the Management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 2015;36(41):2793-867. PMID 26320108
108: Puckelwartz MJ, Kessler EJ, Kim G, et al. Nesprin-1 mutations in human and murine cardiomyopathy. J Mol Cell Cardiol 2010;48(4):600-8. PMID 19944109
109: Quijano-Roy S, Mbieleu B, Bönnemann CG, et al. De novo LMNA mutations cause a new form of congenital muscular dystrophy. Ann Neurol 2008;64(2):177-86. PMID 18551513
110: Quinzii CM, Vu TH, Min KC, et al. X-linked dominant scapuloperoneal myopathy is due to a mutation in the gene encoding four-and-a-half-LIM protein 1. Am J Hum Genet 2008;82(1):208-13. PMID 18179901
111: Raffaele Di Barletta RM, Ricci E, Galluzzi G, et al. Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy. Am J Hum Genet 2000;66(4):1407-12. PMID 10739764
112: Ramos FJ, Chen SC, Garelick MG, et al. Rapamycin reverses elevated mTORC1 signaling in lamin A/C-deficient mice, rescues cardiac and skeletal muscle function, and extends survival. Sci Transl Med 2012;4(144):144ra103. PMID 22837538
113: Rootwelt-Norberg C, Christensen AH, Skjølsvik ET, et al. Timing of cardioverter-defibrillator implantation in patients with cardiac laminopathies-external validation of the LMNA-risk ventricular tachyarrhythmia calculator. Heart Rhythm 2023;20(3):423-9. PMID 36494026
114: Rowland LP, Fetell M, Olarte M, Hays A, Singh N, Wanat FE. Emery-Dreifuss muscular dystrophy. Ann Neurol 1979;5:111-7. PMID 426473
115: Sato M, Shirasawa H, Makino K, et al. Perinatal management of pregnancy complicated by autosomal dominant Emery-Dreifuss muscular dystrophy. AJP Rep 2016;6(1):e145-7. PMID 27054045
116: Schessl J, Zou Y, McGrath MJ, et al. Proteomic identification of FHL1 as the protein mutated in human reducing body myopathy. J Clin Invest 2008;118(3):904-12. PMID 18274675
117: Senior A, Gerace L. Integral membrane proteins specific to the inner nuclear membrane and associated with the nuclear lamina. J Cell Biol 1988;107(6 Pt 1):2029-36. PMID 3058715
118: Shapiro F, Specht L. Orthopedic deformities in Emery-Dreifuss muscular dystrophy. J Pediatr Orthop 1991;11(3):336-40. PMID 2056082
119: Shathasivam T, Kislinger T, Gramolini AO. Genes, proteins and complexes: the multifaceted nature of FHL family proteins in diverse tissues. J Cell Mol Med 2010;14(12):2702-20. PMID 20874719
120: Shende D, Agarwal R. Anaesthetic management of a patient with Emery-Dreifuss muscular dystrophy. Anaesth Intensive Care 2002;30(3):372-5. PMID 12075650
121: Shin JY, Le Dour C, Sera F, et al. Depletion of lamina-associated polypeptide 1 from cardiomyocytes causes cardiac dysfunction in mice. Nucleus 2014;5(3):260-459. PMID 24859316
122: Shin JY, Mendez-Lopez I, Wang Y, et al. Lamina-associated polypeptide-1 interacts with the muscular dystrophy protein emerin and is essential for skeletal muscle maintenance. Dev Cell 2013;26(6):591-603. PMID 24055652
123: Sullivan T, Escalante-Alcalde D, Bhatt H, et al. Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy. J Cell Biol 1999;147:913-20. PMID 10579712
124: Synofzik M, Smets K, Mallaret M, et al. SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study. Brain 2016;139(Pt 5):1378-93. PMID 27086870
125: Takamoto K, Hirose K, Uono M, Nonaka I. A genetic variant of Emery-Dreifuss disease. Muscular dystrophy with humeropelvic distribution, early joint contracture, and permanent atrial paralysis. Arch Neurol 1984;41:1292-3. PMID 6497732
126: Taylor MR, Fain PR, Sinagra G, et al. Natural history of dilated cardiomyopathy due to lamin A/C gene mutations. J Am Coll Cardiol 2003;41:771-80. PMID 12628721
127: Ura S, Hayashi YK, Goto K, et al. Limb-girdle muscular dystrophy due to emerin gene mutations. Arch Neurol 2007;64:1038-41. PMID 17620497
128: van Berlo JH, de Voogt WG, van der Kooi AJ, et al. Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of sudden death. J Mol Med 2005;83:79-83. PMID 15551023
129: van Rijsingen IA, Arbustini E, Elliott PM, et al. Risk factors for malignant ventricular arrhythmias in lamin a/c mutation carriers a European cohort study. J Am Coll Cardiol 2012;59:493-500. PMID 22281253
130: van Rijsingen IA, Nannenberg EA, Arbustini E, et al. Gender-specific differences in major cardiac events and mortality in lamin A/C mutation carriers. Eur J Heart Fail 2013;15(4):376-84. PMID 23183350
131: Volpi L, Ricci G, Passino C, et al. Prevalent cardiac phenotype resulting in heart transplantation in a novel LMNA gene duplication. Neuromuscul Disord 2010;20(8):512-6. PMID 20580235
132: Wahbi K, Ben Yaou R, Gandjbakhch E, et al. Development and validation of a new risk prediction score for life-threatening ventricular tachyarrhythmias in laminopathies. Circulation 2019;140(4):293-302. PMID 31155932
133: Wang Y, Herron AJ, Worman HJ. Pathology and nuclear abnormalities in hearts of transgenic mice expressing M371K lamin A encoded by an LMNA mutation causing Emery-Dreifuss muscular dystrophy. Hum Mol Genet 2006;15:2479-89. PMID 16825283
134: Wang Y, Shin JY, Nakanishi K, et al. Postnatal development of mice with combined genetic depletions of lamin A/C, emerin and lamina-associated polypeptide 1. Hum Mol Genet 2019;ddz082. PMID 31009944
135: Waters DD, Nutter DO, Hopkins LD, Dorney ER. Cardiac features of an unusual X-linked humeroperoneal neuromuscular disease. N Engl J Med 1975;293:1017-22. PMID 1178008
136: Wilson KL, Foisner R. Lamin-binding proteins. Cold Spring Harb Perspect Biol 2010;2(4):a000554. PMID 20452940
137: Windpassinger C, Schoser B, Straub V, et al. An X-linked myopathy with postural muscle atrophy and generalized hypertrophy, termed XMPMA, is caused by mutations in FHL1. Am J Hum Genet 2008;82(1):88-99. PMID 18179888
138: Worman HJ, Fong LG, Muchir A, Young SG. Laminopathies and the long strange trip from basic cell biology to therapy. J Clin Invest 2009;119(7):1825-36. PMID 19587457
139: Wu W, Muchir A, Shan J, Bonne G, Worman HJ. Mitogen-activated protein kinase inhibitors improve heart function and prevent fibrosis in cardiomyopathy caused by mutation in lamin A/C gene. Circulation 2011;123(1):53-61. PMID 21173351
140: Zhang Q, Bethmann C, Worth NF, et al. Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity. Hum Mol Gen 2007;16:2816-33. PMID 17761684
141: Zhang Q, Ragnauth CD, Skepper JN, et al. Nesprin-2 is a multi-isomeric protein that binds lamin and emerin at the nuclear envelope and forms a subcellular network in skeletal muscle. J Cell Sci 2005;118:673-87. PMID 15671068
142: Zhou C, Li C, Zhou B, et al. Novel nesprin-1 mutations associated with dilated cardiomyopathy cause nuclear envelope disruption and defects in myogenesis. Hum Mol Genet 2017;26(12):2258-76. PMID 28398466

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Howard J Worman MD

Dr. Worman of Columbia University received contracted research and consulting fees from Sarepta Therapeutics and consulting fees from Johnson and Johnson and Eiger BioPharmaceuticals.
See Profile

Editor

Aravindhan Veerapandiyan MD

Dr. Veerapandiyan of University of Arkansas for Medical Sciences has no relevant financial relationships to disclose.
See Profile

Former Authors

Werner Trojaborg MD PhD (original author) and Francesco Muntoni MD

Patient Profile

Age range of presentation: 1 month to 65+ years
Sex preponderance: Autosomal dominant EDMD: male=female

X-linked EDMD: only male affected
Heredity: X-linked recessive

autosomal dominant

autosomal recessive
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Hereditary progressive muscular dystrophy: 359.1
ICD-10: Muscular dystrophy: G71.0
OMIM: Cardiomyopathy, dilated 1A; CMD1A: #115200

Muscular dystrophy, limb-girdle, type 1B; LGMD1B: #159001

Emery-Dreifuss muscular dystrophy 2, autosomal dominant; EDMD2: #181350

Myopathy, X-linked, with postural muscle atrophy; XMPMA Emery-Dreifuss muscular dystrophy 6, X-linked, included; EDMD6, included: #300696

Emery-Dreifuss muscular dystrophy 1, X-linked; EDMD1: #310300

Emery-Dreifuss muscular dystrophy 4, autosomal dominant; EDMD4: #612998

Emery-Dreifuss muscular dystrophy 5, autosomal dominant; EDMD5: #612999

Muscular dystrophy, congenital, LMNA-related: #613205

Emery-Dreifuss muscular dystrophy 7, autosomal dominant; EDMD7: #614302

Lamin A/C; LMNA prelamin A A, included: *150330

Four-and-a-half LIM domains 1; FHL1 FHL1B, included: *300163

Merin; EMD: *300384

Synaptic nuclear envelope protein 1; SYNE1: *608441

Synaptic nuclear envelope protein 2; SYNE2: *608442

TorsinA interacting protein 1; TOR1AIP1: *614512

Transmembrane protein 43; TMEM43: *612048

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Emery-Dreifuss muscular dystrophy

Associated Disorders

Arthrogryposis multiplex congenital
Dunnigan-type familial partial lipodystrophy
Cerebellar ataxia
Charcot-Marie-Tooth disease type 2B1
Hutchinson-Guilford progeria syndrome
- Limb-girdle muscular dystrophy type 1B
- Restrictive dermopathy
- Mandibuloacral dysplasia

Differential Diagnosis

Other cardiomyopathies
Other types of muscular dystrophy

Also Relevant

Facioscapulohumeral muscular dystrophy
Limb-girdle muscular dystrophies
Molecular diagnosis of neurogenetic disorders

Clinical Categories

Neuromuscular Disorders

Patient Handouts

Muscular dystrophy

Web References

Guidelines

AAN: Neuromuscular guidelines

Emery-Dreifuss muscular dystrophy …

Emery-Dreifuss muscular dystrophy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

ALS-like disorders of the Western Pacific

Paraspinal neuromuscular syndromes

Dementia associated with amyotrophic lateral sclerosis

Collagen VI-related dystrophies: Ullrich congenital muscular dystrophy, Bethlem muscular dystrophy, and intermediate COL6-RD

Sleep and neuromuscular and spinal cord disorders

Periodic paralysis and the nondystrophic myotonias (skeletal muscle channelopathies)

Malignant hyperthermia

Desmin body myofibrillar myopathy

Emery-Dreifuss muscular dystrophy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

ALS-like disorders of the Western Pacific

Paraspinal neuromuscular syndromes

Dementia associated with amyotrophic lateral sclerosis

Collagen VI-related dystrophies: Ullrich congenital muscular dystrophy, Bethlem muscular dystrophy, and intermediate COL6-RD

Sleep and neuromuscular and spinal cord disorders

Periodic paralysis and the nondystrophic myotonias (skeletal muscle channelopathies)

Malignant hyperthermia

Desmin body myofibrillar myopathy

This is an article preview.
Start a Free Account
to access the full version.