Emery-Dreifuss Muscular Dystrophy: Nuclear Envelopathies

Introduction

Emery-Dreifuss muscular dystrophy (EDMD) is a rare inherited disorder presenting in childhood or adolescence with relatively benign neuromuscular features and potentially fatal cardiac involvement. It is characterized by the triad of (1) early contractures of the Achilles tendons, elbows, and posterior cervical muscles; (2) slowly progressive muscle weakness and wasting, with humeroperoneal distribution in the early stages; and (3) cardiomyopathy with conduction defects. The disease is transmitted usually as an X-linked recessive trait, rarely as an autosomal dominant (AD) trait, and exceptionally as an autosomal recessive (AR) or X-linked dominant trait. First clinically defined almost half a century ago, the progress made in the last 20 years, with several genes discovered to be associated with the EDMD phenotype, has provided tremendous insight into its pathogenesis. Strikingly, all these genes encode nuclear envelope proteins, so that it may be appropriate to classify EDMD under the rubric “nuclear envelopathies.”

Historical Background

In the early 1900s, Cestan and LeJonne and later Schenk and Mathias reported patients with muscular dystrophy and early contractures. In 1961, Dreifuss and Hogan described a large family from Virginia with “an unusual type of benign X-linked muscular dystrophy.” Contractures and cardiac abnormalities were not noted at the time, and the authors proposed that the slowly and rapidly progressive muscular dystrophies be grouped under an all-embracing term such as X-chromosomal or Duchenne-type muscular dystrophy. A reassessment of the same family a few years later by Emery and Dreifuss made it clear that they were facing a unique nosological entity. In particular, they drew attention to the presence of contractures and the absence of pseudohypertrophy as being different from Becker muscular dystrophy. Cardiac involvement was considered an essential part of the clinical picture. Thus, the symptoms of EDMD had been delineated. The report of Emery and Dreifuss was followed by a period of confusion, when cases with similar phenotypes were published under different designations. Rowland and coworkers suggested the use of the eponym Emery-Dreifuss muscular dystrophy for all these cases, based on the remarkably constant features of the clinical phenotype.

Several linkage studies pointed the localization of the gene to the long arm of the X chromosome. The gene responsible for X chromosome-linked EDMD (X-EDMD), STA or EMD , and the gene product, emerin, were identified in 1994. While the X-linked form was clinically well established in the literature, several reports of families showing male-to-male inheritance made it clear that an autosomal dominant form (AD-EDMD) with essentially the same clinical features also existed. The gene for the AD and AR forms, LMNA on 1q21, encoding lamin A/C, was identified in 1999.

About 50% of EDMD patients do not carry mutations in EMD or LMNA , suggesting the existence of other causative genes. Recently, mutations in SYNE1 and SYNE2 , encoding nesprin 1 and nesprin 2 proteins, were also found to be associated with the AD form of EDMD. The latest additions to the genes causing EDMD were FHL1 encoding four-and-a-half-LIM protein 1 (FHL1) and TMEM43 encoding LUMA.

Molecular Biology

X-linked EDMD

Mutations in EMD result in X-linked recessive EDMD (EDMD 1). The gene is located on the long arm of the X chromosome at Xq28 and contains 6 exons. The product of EMD , emerin, is a 254-amino acid conserved nuclear envelope (NE) protein.

Recently, mutations in FHL1 encoding FHL1 protein were found to be associated with X-linked dominant EDMD phenotype myopathy with hypertrophic cardiomyopathy (EDMD 6). FHL1 is highly expressed in skeletal and cardiac muscles. Mutations in FHL1 also cause X-linked dominant scapuloperoneal myopathy, X-linked myopathy with postural muscle atrophy, and reducing body myopathy.

See Case Example 35.1 for an example of X-linked recessive EDMD.

Case Example 35.1

X-linked Recessive Emery-Dreifuss Muscular Dystrophy

The propositus, a 54-year-old man, was one of a pair of monozygotic twins. He was admitted to the hospital because of chest pain and was found to have atrial arrest, for which a pacemaker was inserted. Elbow contractures had been noted before age 3 years, and he had been toe-walking since early childhood. Mild weakness, which showed very little progression over the years, had been noticed around 10 years of age. He had had a cerebrovascular accident with left hemiparesis at age 31, at which time a slow heart rate (40 beats/minute) was noted. He had been on anticoagulation since then.

Neurologic examination showed a left hemiparesis with mild left facial weakness. The right side was taken into consideration in reporting the muscle weakness. Moderate weakness of scapulohumeroperoneal muscles and mild weakness of the proximal lower extremity muscles were noted. Contractures were present at the elbows, wrists, knees, and ankles. The neck could not be fully flexed. Deep tendon reflexes were absent. A left Babinski sign was present.

Serum creatine kinase (CK) was mildly elevated. EMG was predominantly myopathic, combined with neurogenic features. Muscle biopsy showed minimal changes, consisting of fiber size variation and increased perimysial connective tissue. Cardiac evaluation revealed atrial paralysis.

His twin brother had a similar neuromuscular picture. He had had a cerebrovascular accident with aphasia and right hemiparesis at age 41. Cardiac evaluation revealed atrial paralysis, for which a pacemaker was inserted. Of the two affected maternal nephews, the elder, aged 32, had neck, elbow, wrist, and ankle contractures and mild humeral weakness. He also had atrial paralysis. The younger nephew, aged 13 years, had a similar examination, except that he lacked neck contractures and cardiac involvement.

In this family with X-linked recessive inheritance, limitation of elbow extension was noted in very early childhood, followed by toe-walking in all the patients. Of note was the fact that the youngest patient had not yet developed the full phenotype at age 13 years; he had no neck contractures and no cardiac involvement. The mutation in this family was a splice donor mutation 421 G>A in intron 2 of EMD .

AD and AR EDMD

The gene for AD-EDMD (EDMD 2) and AR-EDMD (AR-EDMD, EDMD 3) is LMNA on chromosome 1q11–q23. LMNA is composed of 12 exons encoding lamin A and lamin C, two A-type lamins produced as a result of alternative RNA splicing.

LMNA mutations were found to be associated with a great variety of conditions that affect striated muscle, adipose tissue, peripheral nerves, or multiple systems with signs of accelerated aging. They are collectively called “laminopathies” and include limb girdle muscular dystrophy 1B, congenital muscular dystrophy, Charcot-Marie-Tooth neuropathy 2, dilated cardiomyopathy 1 A, Dunnigan type partial lypodystrophy, mandibuloacral dysplasia, Hutchinson-Gilford progeria syndrome, atypical Werner syndrome, lipoatrophy with diabetes, hepatic steatosis, hypertrophic cardiomyopathy, leukomelanodermic papules syndrome, and tight skin contracture syndrome.

Additional genes encoding NE proteins such as SYNE1 (EDMD 4) encoding nesprin 1 and SYNE2 (EDMD 5) encoding nesprin 2 have also been found to cause the AD form of EDMD. More recently, another NE protein, LUMA, encoded by TMEM43 , was implicated in an AD-EDMD like phenotype (EDMD 7).

Case Example 35.2 gives an example of autosomal EDMD.

Case Example 35.2

Autosomal Emery-Dreifuss Muscular Dystrophy

The proband is an 11-year-old girl. She walked at 1 year of age and developed symptoms of muscle weakness and an awkward gait at 3 years. By age 6 years, she had bilateral elbow contractures (10 degrees), a stiff gait, a positive Gowers’ sign, and mild right knee and ankle contractures. Lower extremity involvement was asymmetrical. At age 8 years, right heel cord lengthening and right hamstring lengthening at the knee were performed for the 20-degree equinus and flexion contractures, respectively. These procedures were subsequently done to relieve left-sided contractures. At age 11 years, elbow contractures had increased to 30 degrees. Her neck still had a full range of forward flexion, but early thoracolumbar paraspinal muscle tightness developed, limiting forward spinal flexion. Cardiac evaluations, which included physical examination, electrocardiogram (ECG), and two-dimensional echocardiogram, were normal at 9 and 11 years of age. Head and spinal cord magnetic resonance imaging was normal. Serial serum CK levels were consistently elevated (280 IU/L; normal, 4–150 IU/L). Three quadriceps muscle biopsies done at 5, 8, and 11 years of age showed progressive worsening of myocyte degeneration with fibrofatty infiltrates.

The proband’s parents and an older female sibling were evaluated by physical examination, 12-lead ECG, and echocardiogram. In each, these evaluations were normal. A serum CK level in her father was normal (153 IU/L; normal, 41–500 IU/L).

Based on the proband’s clinical diagnosis—probable autosomal EDMD—direct sequencing of LMNA was undertaken. DNA samples from the proband revealed a G>A transition at nucleotide 1072 in exon 6, which replaces the normal glutamic acid residue at position 358 (GAG) with lysine (AAG) (designated Glu358Lys). No sample derived from other family members or 200 normal control samples contained this G>A transition.

A second sequence variant was identified in exon 11 of the proband’s DNA. A C>A transition was present at nucleotide 1871 that replaces arginine 624 (CGC) with histidine (CAC) (designated Arg624His). Analyses of DNA from the proband’s father also demonstrated the adenosine nucleotide at position 1871. DNA from the proband’s sister, mother, and 200 normal control samples did not exhibit this transition.

It seems that the compound heterozygous mutations account for the particularly severe phenotype in the proband, and it has been hypothesized that the Arg624His amino acid change may exert a synergistic or modifier effect on disease expression. The absence of pathology in the father suggests that Arg624His functions either as a dominant mutation with incomplete penetrance or as a recessive allele.

Pathogenesis

The proteins that play a key role in the pathogenesis of EDMD are located in the nucleus, in contrast to the proteins involved in most other muscular dystrophies that are associated with the sarcolemma.

A definition of the NE and a brief summary of the localization and interrelationships of the nuclear proteins involved in the pathogenesis of EDMD are necessary to have some idea of the complex. The NE acts as a barrier separating the nucleus from the cytoplasm and is essential for the maintenance of the nuclear shape and its integrity. It consists of two membranes (inner and outer) and a dense network of nuclear intermediate filaments formed by A-type and B-type lamins. Lamins A and C are the major isoforms of A-type lamins.

The NE contains over 100 different proteins, the functions of most of which still remain unexplored. Three groups of NE proteins relevant to the pathogenesis of EDMD are LEM-domain proteins (emerin and others), SUN-domain proteins (SUN1 and SUN2), and KASH-domain proteins (nesprins 1, 2, 3, and others). Emerin is an integral membrane protein localizing to the inner membrane. It binds to lamins (most importantly to the A-type lamins) and to BAF (barrier-to-autointegration factor), which is a highly conserved protein essential for chromosome segregation, cell cycle progression, and postmitotic nuclear assembly. This trio (emerin-lamins-BAF) forms a major component of the NE-associated nucleoskeletal structure known as “nuclear lamina.” In addition to their role in maintaining the mechanical stability of the NE throughout the phases of the cell cycle, emerin and lamins interact with many proteins that regulate DNA synthesis, chromatin organization, gene transcription, and cell differentiation.

Emerin also binds directly to SUN-domain and KASH-domain proteins. SUN-domain proteins, which span the inner nuclear membrane, bridge to KASH-domain proteins, which span the outer nuclear membrane. SUN- and KASH-domain proteins form the LINC-complex (linker of nucleoskeleton and cytoskeleton), which is proposed to form a mechanical link between the nucleoskeleton and cytoskeleton.

As can be seen, the proteins causing EDMD, emerin, lamin A/C, nesprin 1, and nesprin 2, interact with each other. LUMA is also a binding partner of emerin. The interactions of FHL-1 with NE proteins are not yet known. FHL1 is localized to the sarcomere, the sarcolemma, and the nucleus, and has important roles in maintaining the stability of the sarcolemma, myofibrillar assembly, and transcriptional regulation. Absence or reduced level of FHL1 protein may cause delayed myotube formation.

Disrupted function of these proteins is the key pathophysiological mechanism in EDMD. Accumulating data suggest that EDMD might be caused by the uncoupling of the nucleoskeleton and cytoskeleton because of damaged emerin-nesprin-lamin interactions. However, how the mutations cause disease is still far from being elucidated. It is particularly puzzling that these ubiquitous proteins lead to tissue-specific disorders. Proposed hypotheses on pathogenesis include NE defects affecting nuclear stiffness and increased susceptibility to mechanical stress, NE defects as determinants of altered nucleocytoplasmic interplay, altered cell cycle control, alterations of the nuclear morphology affecting chromatin rearrangements, disruption of the process of skeletal muscle regeneration, altered DNA repair due to oxidative stress, and increased susceptibility to apoptosis.

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