Myoclonus epilepsy with ragged-red fibers
Nov. 06, 2023
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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.
• 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.
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.
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).
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).
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.
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.
Emery-Dreifuss muscular dystrophy is an orphan disease, but precise data on its prevalence and incidence are not available. Given the variable myopathy and cardiomyopathy phenotypes caused by EDM and LMNA mutations, prevalence and incidence calculations are complicated based on whether a clinical or genetic diagnosis was used. In series from referral centers, LMNA mutations have been reported in approximately 8% of patients with dilated cardiomyopathy (126; 103; 89). The prevalence of “idiopathic” dilated cardiomyopathy is estimated to be 1 in 2500 (33), and about 50% of such cases may have a genetic etiology (126). Based on these estimates, the prevalence of dilated cardiomyopathy caused by LMNA mutations would be approximately 4800 in the United States, 8000 in the European Union, and 2000 in Japan. Many of these would have concurrent Emery-Dreifuss muscular dystrophy or EDMD-like myopathic phenotypes. Cases of Emery-Dreifuss muscular dystrophy or related phenotypes caused by SYNE1, SYNE2, TMEM43, SUN1, SUN2, TOR1AIP1, and FHL1 mutations are likely exceptionally rare, as only single case reports or extremely small series of patients have been published.
Prenatal diagnosis of mutations that can cause Emery-Dreifuss muscular dystrophy is possible in families with known carriers. The occurrence of de novo dominant mutations in LMNA needs to be taken into account when counseling apparently sporadic cases. Somatic mosaicism for LMNA mutations has also been reported and may need to be considered when counseling families (76).
Associated disorders include inherited dilated cardiomyopathies with or without skeletal myopathy caused by other genetic mutations.
A careful family history is a key part of the diagnostic evaluation. From a neurologic perspective, laboratory workup includes determination of serum creatine kinase activity, which may be mildly or moderately elevated but is sometimes normal. Electromyography and nerve conduction studies should be performed to confirm primary myopathy versus neurogenic disease. Muscle biopsy may be helpful, and samples from male patients should be processed for immunohistochemistry with antibodies against emerin, which is almost invariably absent in X-linked Emery-Dreifuss muscular dystrophy. Because some A-type lamins are always expressed, immunostaining with antibodies against them is not generally helpful. Cardiac evaluation is also critical. Baseline electrocardiogram and echocardiogram should likely be obtained, even in the absence of overt cardiac symptoms. Long-term Holter monitoring should also be considered as well as referral to an expert in cardiac electrophysiology.
Genetic diagnosis should now be considered standard. Analysis of mutations in EDM and LMNA is routinely available in commercial and academic laboratories. If there is a compelling clinical picture of Emery-Dreifuss muscular dystrophy but genetic testing for EDM and LMNA mutations is negative, analysis of SYNE1, SYNE2, TMEM43, SUN1, SUN2, FHL1, and TOR1AIP1 genes should be considered. More extensive DNA sequencing for possible promoter mutations and whole exome sequencing could also be considered, as well as whole exome sequencing to detect novel gene mutations.
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).
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).
No specific complication clearly related to pregnancy has been reported. There is one published case report of a 36-year-old woman diagnosed with autosomal dominant Emery-Dreifuss muscular dystrophy (LMNA mutation). She was diagnosed during the first trimester of pregnancy and developed acute preeclampsia and subsequent congestive heart failure after cesarean section (115). This suggests that prenatal and postpartum cardiac evaluation and monitoring may be indicated.
A potentially major issue regarding anesthesia in patients with Emery-Dreifuss muscular dystrophy is the possible presence of cardiac disease. Patients with the Emery-Dreifuss muscular dystrophy neuromuscular phenotype should undergo cardiac evaluation prior to general anesthesia, and if heart disease is present, anesthesia should be approached as with any patient with cardiomyopathy. Cardiac arrhythmias and heart failure-associated arrhythmias and heart failure if present could be significant complicating issues for a patient receiving general anesthesia. Anesthetic issues related to neck hyperextension in an Emery-Dreifuss muscular dystrophy case have also been reported (32). The anesthetic management of patients undergoing orthopedic surgery and elective caesarean section has been reported in the literature (02; 120; 62).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
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
Aravindhan Veerapandiyan MD
Dr. Veerapandiyan of University of Arkansas for Medical Sciences has no relevant financial relationships to disclose.See Profile
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