Joint contractures are a common complication of several neuromuscular disorders, but in some they are an early feature and specific joints are commonly affected. In particular, disorders known as Emery–Dreifuss muscular dystrophies are characterized by elbow contractures and often associated with a rigid spine and cardiac defects. In this chapter we focus on the Emery–Dreifuss syndromes, in particular those related to defects associated with proteins of the nuclear envelope.
Both X-linked and autosomal dominant forms of Emery–Dreifuss muscular dystrophy (X-EDMD and AD-EDMD) have been identified, and most are caused by defects in nuclear envelope proteins ( , ). In the Online Mendelian Inheritance in Man (OMIM) database, seven disorders and eight entries are listed as EDMD caused by defects in six genes (EDMD1–7; Table 13.1 ). It has been questioned whether they should all be classified as separate entities or whether some are merely part of the clinical spectrum associated with disorders caused by the same gene. For example, limb-girdle muscular dystrophy 1B is caused by mutations in the gene encoding lamin A/C, and the gene encoding FHL1 does not encode for a nuclear protein but also causes reducing body myopathy and scapuloperoneal disorders, and there are pathological similarities to myofibrillar myopathies (see Ch. 16 ). Recently, however, the FHL1B isoform has been shown to interact with lamin A/C and emerin, components of the nuclear envelope, suggesting a link with nuclear membrane defects ( ; see below). In addition, other genes of the nuclear membrane, nuclear lamina and matrix are either considered as genetic modifiers or cause a variety of clinical syndromes, some of which involve skeletal and/or cardiac muscle. These include SUN1 and SUN2, MAN1, LBR, LMNB1 and LMNB2, LAP2a, LAP1B, LAP1C, BANF1 and ZMPSTE24 ( ). The products of several of these genes interact with or are components of the linker of nucleoskeleton and cytoskeleton (LINC) complex. The LINC complex is important in maintaining the integrity of the nuclear envelope, nuclear positioning and movement and signalling across the nuclear envelope ( ).
|Dominant, de novo dominant (rare recessive/homozygous cases)||LMNA||1q21.23||Lamin A/C|
|Dominant (rare recessive/homozygous cases)||SYNE1||6q25||Nesprin-1|
|X-linked dominant ∗∗||FHL1||Xq26.3||FHL1|
∗∗ This disorder is similar to a form of myofibrillar myopathy (see text and Ch. 16 ).
Emery–Dreifuss muscular dystrophy has been recognized as a separate entity from Duchenne and Becker muscular dystrophy for many years and the first description can be attributed to Cestan and Lejonne in 1902 ( ). Following reassessment of a large Virginian family first described by Dreifuss and Hogan in 1961 ( ), Alan Emery published a seminal description of the X-linked form, now commonly referred to as Emery–Dreifuss muscular dystrophy ( ). When the defective protein responsible for the X-linked form was identified, it was named ‘emerin’ in recognition of Alan Emery’s contribution to the description of the disease. Description of autosomal dominant cases followed later ( ) and once the underlying pathogenesis relating to nuclear membrane proteins was identified, and the similarity in clinical features recognized, they became linked under the same title of ‘Emery–Dreifuss muscular dystrophy’. Emery appreciated the wide variability of the disorders and introduced the term ‘Emery–Dreifuss syndromes’ ( ); the term ‘Emery–Dreifuss-like syndromes’ has also been used ( ).
The clinical features of the X-linked and autosomal forms are similar but often more severe in the latter ( Table 13.2 ). They both present with muscle weakness and early contractures of the elbow, the Achilles tendons and the spinal extensor muscles. These usually precede the appearance of cardiac abnormalities, which begin with conduction defects and lead to complete heart block. Most cases show conduction defects before the third decade of life and cardiac problems are frequently more severe in the most common autosomal form associated with defects in lamin A/C. The contractures are progressive and lumbar lordosis and rigidity of the spine often become marked. Contractures of the wrists and finger flexors can also occur. Arthrogryposis, adducted thumbs and club feet have been noted as features associated with defects in SYNE1 encoding nesprin-1 in the few early-onset cases identified ( ).
|Onset in childhood, adolescence or adult life|
|Mild muscle weakness (can be severe in early-onset cases)|
|Wasting of upper arms and lower legs|
|Rigidity of spine|
|Tightness of Achilles tendon|
|Cardiac arrhythmia, also in carriers of the X-linked form|
|Ambulation||Usually maintained in X-linked form|
|Lost in first decade in several dominant cases|
|Creatine Kinase||Normal, or slight to moderate elevation|
|Pathology||Mild to moderate myopathic changes|
|Variation in fibre size|
|Atrophic type 1 fibres|
|Absence of emerin from all nuclei in X-linked form |
Absence of nesprin in recessive/homozygous cases with SYNE1 mutations
|Normal localization of lamins to nuclear envelope in muscle biopsies|
|Reduced sarcolemmal laminin β1|
Muscle weakness and wasting has a distinct pattern. In the X-linked form it is humero-peroneal, and in the autosomal form, scapulohumero-peroneal. Striking wasting of the upper arms and lower legs is often apparent in both. A particular pattern of muscle involvement is apparent with muscle magnetic resonance imaging (MRI) in each form and can be helpful in differential diagnosis ( ). There are also patients who present with a more limb-girdle muscular dystrophy phenotype ( ).
Autosomal dominant EDMD associated with lamin A/C defects is more common than the X-linked form caused by defects in emerin and generally more severe, with earlier onset, even in very early childhood. Ambulation is lost in a significant number of affected patients in the first decade.
Serum creatine kinase (CK) levels are usually normal or mildly elevated, up to 10 times the normal level, but never in the high range of Duchenne or Becker muscular dystrophy.
The typical X-linked form is caused by a mutation in the EMD gene on chromosome Xq28 and encodes a protein named emerin ( ). Emerin is a 34 kDa protein which has a hydrophobic C-terminus anchored in the inner nuclear membrane and an N-terminal tail projecting into the nucleoplasm ( ). The EMD gene has six exons and mutations have been found throughout the gene, with no ‘hot spots’. Most are nonsense or frameshift mutations or occur at splice sites. A list of identified mutations can be found at the Emery–Dreifuss website ( www.lovd.nl/EMD ). The majority of mutations result in an absence of protein expression, which can be demonstrated with antibodies ( ; see below), although rare cases have been reported in which emerin expression is only reduced ( ).
Females carrying mutations in the gene encoding emerin rarely manifest with muscle weakness but are at risk of cardiac involvement. The absence of emerin in a proportion of nuclei can be detected in these carriers (see below).
The most prevalent form of autosomal dominant Emery–Dreifuss muscular dystrophy is caused by mutations in the LMNA gene on chromosome 1q21.2, which encodes an alternatively spliced protein, lamin A/C, localized to the nuclear lamina ( ). The gene has 12 exons and alternative splicing produces at least four different RNAs encoding closely related proteins (lamin A, lamin A δ10, lamin C and lamin C2). Lamin A and C are the predominant forms and result from alternative splicing of exon 10; a large part of the protein is therefore common to both ( ). Lamin A is longer and uses the C-terminal exons 11 and 12, while splicing at exon 10 results in the shorter lamin C. Lamin A is synthesized as a precursor, prelamin A, which is then processed to form the mature protein. Prelamin A has a role in premature ageing ( ). Many mutations have been found and are of all types and occur in all exons; but most occur in the common α-helical rod domain of exons 1–10, with a mutation (R453W) in exon 7 being one of the most frequent.
The majority of mutations are dominantly inherited, with a striking frequency of de novo dominant mutations. These usually result in no detectable alteration in lamin A/C protein localization using immunohistochemistry ( ; see below). Rare cases with recessive mutations on both alleles inherited from unaffected parents have been documented ( ), and germline mosaicism can mimic recessive inheritance ( ). Mutations in the LMNA gene are relatively common within the population, many of them de novo, and as the phenotype is wide this gene is often worth considering in the differential diagnosis of a patient. In addition, digenic causes of disease should sometimes be considered, particularly in cases with an atypical or more severe phenotype. There are examples of cases with mutations affecting both lamin A/C and emerin, and lamin A/C and desmin ( ).
There is considerable clinical variability, both between and within families, with mutations in the LMNA gene. The phenotypes attributed to it include not only the autosomal dominant form of Emery–Dreifuss muscular dystrophy and the allelic limb-girdle muscular dystrophy 1B but also familial partial lipodystrophy, an axonal neuropathy (Charcot–Marie–Tooth type 2B1), mandibuloacral disease, premature ageing disorders and restrictive dermopathy ( ). These are now often referred to as ‘laminopathies’. Although familial partial lipodystrophy has a distinct phenotype, muscle MRI of autosomal cases of typical EDMD may show a significant reduction of subcutaneous fat ( ). Similarly, some patients with lipodystrophy may have a rigid spine, cardiac abnormalities and muscle involvement ( ), and there is clinical overlap with patients with mutations in the gene encoding cavin-1 ( PTRF ) (see Ch. 11 ). Some severely affected infants with axial weakness have also been found to have de novo mutations in the gene encoding lamin A/C, and it is often worth considering this gene in a severely affected infant or neonate in whom the muscle biopsy shows non-specific myopathic changes ( ). These cases are considered to overlap with congenital muscular dystrophies (see Ch. 12 ), and some have been described as having a ‘dropped head’ syndrome ( ).
Additional autosomal genes encoding proteins of the nuclear envelope are also associated with a dominant EDMD phenotype, although there are also reports of homozygous patients, but relatively few cases have been identified (see Table 13.1 ). Identification of the genes that encode nesprin-1 and nesprin-2 ( SYNE1 and SYNE2 ) and a protein known as transmembrane protein 43 (TMEM43; previously known as LUMA) ( ) emphasizes the importance of the nuclear envelope and the complex of proteins that interact with emerin and lamins ( ). Defects in nesprin are also responsible for a recessive disorder with homozygous mutations that presents with arthrogryposis ( ). Defects in several additional genes are associated with a variety of other clinical phenotypes, and variants in SUN1 and SUN2 in patients with EDMD are thought to be genetic modifiers ( ).
A protein in the nuclear matrix, matrin 3, is responsible for a dominant distal myopathy with vocal cord and pharyngeal weakness ( ; see Ch. 16 ) and is also associated with amyotrophic lateral sclerosis (ALS) ( ). Matrin 3 is an RNA-binding protein that binds to several proteins, for example TDP-43 in cultured cells, and studies in mice suggest it interacts with PABPN1, which is associated with oculopharyngeal muscular dystrophy (see Ch. 14 ; ).
Lamins are intermediate filament proteins and are a major component of the nuclear envelope that separates the nucleoplasm from the rest of the cell. The nuclear envelope is composed of an inner and outer nuclear membrane, joined at nuclear pores, and the nuclear lamina (see Ch. 5 ). The outer membrane is continuous with the rough endoplasmic reticulum, while the inner membrane contains a number of proteins that bind to lamins and chromatin. Lamins are components of the nuclear lamina and among their proposed functions are maintenance of the structural integrity of the nuclear envelope, organization of interphase chromatin and reassembly of the nuclear membrane during mitosis ( ). Nuclei contain a number of other proteins, including isoforms of actin, isoforms of titin and spectrin ( ).
There are two main types of nuclear lamins, A and B, which have sequence homology to type V intermediate filaments. Lamin A and C are the two main forms produced by splicing from the LMNA gene, while lamin B1 and B2 are encoded by separate genes. A-type lamins, in contrast to ubiquitously expressed B lamins, are believed to be developmentally regulated and are not expressed in embryonic stem cells, early embryonic cells, stem cells in the immune and haematopoietic systems nor cells in the neuroendocrine system ( ). Lamin A/C interacts with several proteins, including LAP2, emerin and MAN1. These proteins share a LAP2-emerin-MAN1 (LEM) domain, which binds the barrier-to-autointegration factor (BAF), a protein thought to have an important role in chromatin organization, transcription and efficient retroviral DNA integration ( ).
Nesprins also interact with emerin and lamins, forming the linker of the nucleoskeleton to the cytoskeleton (LINC) complex that links the nuclear membrane to the actin cytoskeleton ( ). There is a family of four nesprins with different functions. Nesprins-1 and nesprin-2, which are affected in EDMD, link directly to the actin cytoskeleton; nesprin 3 links the nuclear envelope to the cytoskeletal protein, plectin; and nesprin 4 associates indirectly with microtubules but is only expressed in secretory epithelial cells and cochlear hair cells ( ). Lamin B proteins are often studied in parallel with emerin and lamin A/C (see below) and there is considerable interest in other nuclear envelope proteins as candidates for disorders with clinical similarity to the Emery–Dreifuss muscular dystrophies, as several patients are molecularly unresolved.
The main histological and histochemical features of both X-linked and lamin A/C-related autosomal dominant EDMD are similar, and the degree of change varies with the involvement of the muscle sampled. In quadriceps biopsies, the abnormal variation in fibre size is not usually marked ( Fig. 13.1 ). Occasional atrophic fibres are common, and some fibres may be hypertrophic. Measurement of fibre diameters may be necessary to appreciate this. Internal nuclei may be occasional or numerous, with more than one per fibre (see Fig. 13.1 ). Inflammation is not usually seen in EDMD but may occur, especially in some early-onset cases ( ).
Necrotic fibres are rare and there is usually only a mild increase in adipose or connective tissue (see Fig. 13.1 ). There are exceptions, however, such as a severely affected boy we assessed prior to the appearance of the characteristic contractures and thought to have a form of limb-girdle muscular dystrophy ( ). The pathology resembled a severe limb-girdle type of muscular dystrophy with a wide variation in fibre size, a pronounced increase in connective tissue and necrosis ( Fig. 13.2 ). He was eventually found to have a digenic problem, with lack of emerin in a muscle biopsy (see below) caused by a mutation in the EMD gene, and to also have an LMNA mutation which is presumed to have contributed to his severe phenotype ( ). We have also noted the presence of a few small basophilic fibres that may be slightly granular in appearance and show aggregation of NADH-TR stain ( Fig. 13.3 ). These fibres may be regenerating fibres, as they show fetal myosin and desmin (see Fig. 13.3 ). A two-fibre type pattern is usually maintained with oxidative enzyme stains and ATPase, with a tendency for the type 1 fibres to be smaller, but not usually to the degree seen in congenital myopathies ( Fig. 13.4 ; see Ch. 15 ). A predominance of type 1 fibres may also occur. Structural changes such as cores and unevenness of staining for oxidative enzymes can occur, and they were a pronounced feature together with indistinct fibre typing in a girl with an LMNA mutation that we have observed ( Fig. 13.5 ). A mutation in an additional gene has not been excluded in this child. Occasional rimmed vacuoles have also been reported ( ). In a detailed study of 16 patients with a matrin-3-related myopathy, pathological features of muscle biopsies included variation in fibre size, an increase in internal nuclei, variable degrees of fibrosis and rimmed vacuoles ( ).