Background
Although it was probably first described in the early 1900s, Emery-Dreifuss muscular dystrophy (EDMD) was not clearly delineated as a separate disease until the 1960s. In 1961, Dreifuss and Hogan described a large family with an X-linked form of muscular dystrophy that they considered to be a benign form of Duchenne muscular dystrophy. Subsequent evaluation of this family by Emery and Dreifuss in 1966 led to distinguishing this type of X-linked dystrophy from the more severe Duchenne and Becker muscular dystrophies. An autosomal dominant form of EDMD was described by several authors in the early 1980s. The genetic defects in both the X-linked recessive form and the autosomal dominant form of EDMD have been determined.
Pathophysiology
In 5 of 6 gene mutations that have been shown to cause EDMD, the affected protein is present in the LINC (linker of nucleoskeleton and cytoskeleton) complex. This complex includes nuclear membrane integral and associated proteins including emerin, lamin A/C, SUN1, SUN2, nesprin-1, and nesprin-2 that are proposed to form a mechanical link between the nucleoskeleton and cytoskeleton. [1] Even though these proteins are ubiquitously expressed, disease manifestations are tissue specific for as yet unclear reasons. EDMD1 is caused by mutations in the EMD gene on the X chromosome that codes for the nuclear envelope protein emerin. Mutations occur throughout the gene and almost always result in complete absence of emerin from muscle or mislocalization of emerin. On rare occasions, a decreased amount of a modified form of emerin is produced in muscle. Emerin is a ubiquitous inner nuclear membraneprotein, presentin nearly all cell types, although its highest expression is in skeletal and cardiacmuscle.Emerin binds to many nuclear proteins, including several gene-regulatory proteins (eg, barrier-to-autointegration factor, germ cell-less, Btf), nesprins (proteins that act as molecular scaffolds), F-actin, and lamins.
EDMD2/EDMD3 is due to mutations (autosomal dominant and autosomal recessive, respectively) in the LMNA gene that codes for lamins A and C. Mutations in LMNA occur throughout the gene and can cause several different phenotypes (see Causes). Lamins are intermediate filaments found in the inner nuclear membrane and nucleoplasm of almost all cells and have multiple functions including providing mechanical strength to the nucleus, helping to determine nuclear shape, and anchoring and spacing nuclear pore complexes; they are also essential for DNA replication and mRNA transcription. They bind to structural components (emerin, nesprin), chromatin components (histone), signal transduction molecules (protein kinase C), and several gene regulatory molecules.
New mutations have been found in the synaptic nuclear envelope protein 1 (SYNE1) gene and in the synaptic nuclear envelope protein 2 (SYNE2) gene in a few families, also termed Nesprin-1 and Nesprin-2, respectively. [2] Inheritance was autosomal dominant or sporadic. Phenotypes ranged from asymptomatic to limb girdle or in one case, scapular weakness with progression to a wheelchair by age 26 years. Cardiac involvement and contractures were present in some, but not all patients.
Lastly, mutations in the transmembrane protein 43 (TMEM43), also termed LUMA, which binds to emerin and SUN2, has also been reported to cause an EDMD phenotype in a few families.
How mutations in EMD, LMNA, SYNE1, SYNE2, and TMEM43 cause EDMD is unknown. Two main hypotheses have been suggested. The first suggests that disruption of the inner nuclear membrane and the nuclear lamina causes disorganization of nuclear chromatin and gene expression, while the second proposes that the mechanical strength of the cell nucleus is disrupted when the nuclear lamina is weakened leading to structural and signaling defects in mechanically stressed tissue such as muscle and heart. Mutations in all of these genes have been shown to result in defects in the nucleoskeleton and related structures that could cause the above pathologic abnormalities.
Whatever the true mechanism, the discovery of mutations in several different nuclear membrane proteins that cause similar diseases will likely eventually lead to a better understanding of nuclear membrane physiology and the pathophysiology of diseases caused by mutations in these proteins.
Epidemiology
Frequency
No good data exist concerning the frequency of EMD1 or EMD2, but more than 70 different mutations have been reported in the EMD gene and more than 100 in LMNA. Sporadic cases with a mutation in the EMD gene are uncommon but are becoming increasingly more recognized in LMNA. A European collaborative study found LMNA mutations in 18 families and 39 sporadic cases with an EMD2 phenotype. A Japanese study found that laminopathy was slightly more common than emerinopathy. [3] The combined prevalence of X-linked and autosomal EDMD has been estimated at about 1-2 cases per 100,000 people.
Only about 50% of patients with EDMD have a mutation in one of the known nuclear envelope genes, with about 20% each being caused by mutations in EMD and LMNA. This suggests that unknown genes also likely related to the nuclear envelope are involved in EDMD pathogenesis. [1]
Mortality/Morbidity
The major cause of mortality and morbidity in EDMD is cardiac disease, which is consistently present.
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The most common disturbances are a result of atrial conduction defects (eg, bradycardia, atrial arrhythmias, atrioventricular [AV] block, atrial paralysis).
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Cardiomyopathy may be present as well, and it may be severe with only a mild myopathy. This phenotype is more common with EMD2.
In some studies, as many as 40% of patients with EDMD had sudden cardiac death. The timely insertion of a pacemaker can be lifesaving. [4]
Early onset of contractures (often before weakness has developed) is common in EDMD.
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This can lead to even greater functional disability than that caused by weakness.
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Early referral for physical therapy, bracing, or orthopedic surgery can help prevent the formation or lessen the severity of contractures.
Demographics
Males are affected in X-linked EDMD.
About 10-20% of female carriers have cardiac conduction defects, weakness, or both, and they can die from sudden cardiac death.
In autosomal dominant EDMD, males and females are affected in equal numbers.
In X-linked EDMD, contractures and weakness can occur at any time from the neonatal period to the third decade. The mean age of onset is in the teenaged years.
Cardiac symptoms usually occur after weakness has developed (in teenaged persons to those aged 40 y) but occasionally present before the onset of weakness.
The onset of symptoms in autosomal dominant EDMD is similar to that in the X-linked form.
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Left: The photomicrograph is a muscle biopsy with normal emerin immunostaining. Right: The micrograph is from a patient with X-linked Emery-Dreifuss muscular dystrophy. Note the absence of nuclear staining as well as the hypertrophied and atrophied muscle fibers.
