Emery-Dreifuss muscular dystrophy is a degenerative myopathy characterized by weakness and atrophy of muscle without involvement of the nervous system. Flexion deformities of the elbows dating from early childhood, mild pectus excavatum, signs of cardiac involvement and absence ... Emery-Dreifuss muscular dystrophy is a degenerative myopathy characterized by weakness and atrophy of muscle without involvement of the nervous system. Flexion deformities of the elbows dating from early childhood, mild pectus excavatum, signs of cardiac involvement and absence of muscle pseudohypertrophy, involvement of the forearm muscles, and mental retardation distinguish the Emery-Dreifuss form (EDMD1) from the Becker form (300376). - Genetic Heterogeneity of Emery-Dreifuss Muscular Dystrophy An autosomal dominant form of Emery-Dreifuss muscular dystrophy, EDMD2 (181350), is caused by mutation in the lamin A/C gene (LMNA; 150330); a possible autosomal recessive form of the disorder that lacks cardiac features (EDMD3; see 181350) may be caused by mutation in the LMNA gene (150330.0014). Additional autosomal dominant forms include EDMD4 (612998), caused by mutation in the SYNE1 gene (608441), EDMD5 (612999), caused by mutation in the SYNE2 gene (608442), and EDMD7 (614302), caused by mutation in the TMEM43 gene (612048). A second X-linked form (EDMD6; see 300696) is caused by mutation in the FHL1 gene (300163).
Dreifuss and Hogan (1961) and Emery and Dreifuss (1966) studied a Virginia kindred in which there were 8 affected males in 3 generations in a typical X-linked pedigree pattern. Onset of muscle weakness, first affecting the lower extremities ... Dreifuss and Hogan (1961) and Emery and Dreifuss (1966) studied a Virginia kindred in which there were 8 affected males in 3 generations in a typical X-linked pedigree pattern. Onset of muscle weakness, first affecting the lower extremities with a tendency to walk on the toes, was noted around the age of 4 or 5 years. By the early teens, waddling gait with increased lumbar lordosis was marked and weakness of the shoulder girdle musculature appeared later. Slow progression with continued gainful employment is the rule. - Cardiac The cardiac conduction defect in EDMD patients is the most serious and life-threatening clinical manifestation of the disease. Cardiac defects have been described in female carriers (Emery, 1989) in the absence of any skeletal muscle abnormality, suggesting a prominent role in cardiac conduction for emerin. Becker (1972) republished illustrations of typical cases reported by Cestan and LeJonne (1902). Dickey et al. (1984) reported a large kindred in which adults, both male hemizygotes and female heterozygotes, had lethal cardiac disease characterized especially by atrial arrhythmias. Skinner and Emery (1974) pointed out that the serum creatine kinase of carriers is elevated mainly in young women and gave a 'normal' curve for carrier and noncarrier women. After a period of 25 years, Emery (1987) reinvestigated the original Virginia family. He confirmed that cardiomyopathy, presenting most often as atrioventricular block, is a significant feature of the disease, which is characterized by the triad of (1) slowly progressive muscle wasting and weakness with humeroperoneal distribution in the early stages; (2) early contractures of the elbows, Achilles tendons, and postcervical muscles; and (3) cardiomyopathy. Takahashi (1971) reported the same disorder as Mawatari and Katayama (1973) in 2 brothers. Wright and Elsas (1980) provided genetic studies of the kindred discussed by Waters et al. (1975). The onset was in the teens, with total disability by the third decade and death by age 50. Type I muscle fibers were affected, resulting in an unusual distribution of atrophy in the proximal upper and distal lower limbs. Cardiac conduction defects often preceded overt muscle atrophy. Cardiac signs began with small P waves and prolonged PR intervals, and progressed to complete AV heart block with bradycardiac idioventricular rhythms and atrial paralysis requiring pacemaker implantation. Cardiac signs were detected as early as age 12. The earliest pacemaker insertion was in a 20-year-old male who could still do heavy physical labor. In the absence of gross muscle atrophy, he had markedly elevated creatine phosphokinase (CPK) levels. In some, contractures at the elbows were evident as early as age 13. Contractures also developed in the neck and Achilles tendons. Buckley et al. (1999) investigated the cardiac status in 3 patients with EDMD. The effect on the heart became apparent in the teenage years and was characterized by cardiac conduction defects and infiltration of the myocardium by fibrous and adipose tissue. It first affected the atria, which resulted in atrial paralysis; treatment with ventricular pacing was usually needed. The authors found that female carriers can develop heart problems and are at risk of sudden death. - Skeletal Dubowitz (1973) gave the name rigid spine syndrome to the disorder in a 17-year-old boy with a myopathy and stiffness of the back and neck from an early age and progressive scoliosis in his teens. For several years he had had difficulty in extending his elbows. Creatine phosphokinase was moderately elevated. Dubowitz (1973) made reference to 3 other similar cases he had seen. Wettstein et al. (1983) suggested that this may be an X-linked disorder and may be related to the Emery-Dreifuss muscular dystrophy with contractures. Rigid spine syndrome (602771) is distinguished from Emery-Dreifuss muscular dystrophy by lack of cardiac involvement and autosomal recessive inheritance. - Scapuloperoneal Syndrome Although Davidenkow (1939) of Leningrad considered X-linked scapuloperoneal syndrome to be a distinct disorder, many kindreds reported to have an X-linked scapuloperoneal syndrome, or humeroperoneal neuromuscular disease, have been determined to have Emery-Dreifuss muscular dystrophy. Under the designation scapuloperoneal syndrome, Thomas et al. (1972) described a kindred with typical X-linked inheritance of a myopathy manifesting as muscular weakness and wasting, affecting predominantly the proximal muscles of the legs. Accompanying features were contractures of the elbows, pes cavus, and, in adulthood, cardiomyopathy. Pseudohypertrophy was absent. Close linkage with deutan colorblindness (303800) was found. The authors pointed out similarities to the Emery benign type of muscular dystrophy with contractures but thought that the distribution of muscular involvement distinguished the two. They later revised their opinion and concluded that the disorder is in fact EDMD (Thomas and Petty, 1985). Many studies reached the conclusion that X-linked scapuloperoneal syndrome was the same condition as Emery-Dreifuss muscular dystrophy (Rotthauwe et al., 1972; Mawatari and Katayama, 1973; Rowland et al., 1979; Sulaiman et al., 1981; Thomas and Petty, 1985; Merlini et al., 1986). Goldblatt et al. (1989) presented clinical and molecular genetic evidence that the Emery-Dreifuss syndrome and X-linked muscular dystrophy with contractures are genetically homogeneous. Emery (1989) insisted that the designation scapuloperoneal syndrome should be reserved for an autosomal dominant disorder that can be either myopathic (181430) or more often neuropathic (181400), has later onset (in adulthood) with late development of contractures, and does not show cardiac conduction defects. - Limb-Girdle Presentation Ura et al. (2007) reported 2 unrelated males with EDMD confirmed by genetic analysis who presented with limb-girdle muscular dystrophy. The first patient was a 9-year-old boy who developed proximal muscle weakness and atrophy of the lower limbs, waddling gait, and lordotic posture by age 6. He had showed unsteady gait at age 4. Serum creatine kinase was increased and muscle biopsy showed moderate fiber size variation, internalized nuclei, and absence of emerin staining. Electrocardiogram revealed transient sinus arrhythmia. The second patient was a 50-year-old man who noted progressive proximal muscle weakness in the lower limbs beginning at age 35. He had waddling gait, Gowers sign, and minimal joint contractures. Cardiac studies showed valvular insufficiency and atrioventricular block. Ura et al. (2007) noted that LMNA mutations, which can result in EDMD1, also underlie LGMD1B (159001). The findings expanded the phenotypic features associated with X-linked EDMD.
Ellis et al. (1999) stated that more than 70 different mutations causing EDMD had been identified in the emerin gene. They described 2 missense mutations involving proline-183 (300384.0008-300384.0009). Biochemical analyses had demonstrated that the mobility and expression levels ... Ellis et al. (1999) stated that more than 70 different mutations causing EDMD had been identified in the emerin gene. They described 2 missense mutations involving proline-183 (300384.0008-300384.0009). Biochemical analyses had demonstrated that the mobility and expression levels of the mutant forms of emerin are indistinguishable from those of wildtype emerin, but that they have weakened interactions with nuclear lamina components. In comparison with the usual EDMD phenotype, patients with P183 missense mutations had a later age at onset of first symptoms, elbow contractures, ankle contractures, and upper and lower limb weakness, but there was no difference for the age at onset of cardiac involvement. In 2 brothers with EDMD, Hoeltzenbein et al. (1999) identified a TCTAC deletion spanning nucleotides 631-635 of the emerin gene (310300.0010). Both showed an unusually severe disease phenotype. The same mutation had been found in 2 brothers with a significantly milder phenotype from an unrelated family (Manilal et al., 1998). The interfamilial heterogeneity in the 2 families was thought to be due to environmental or genetic modification of the disease. Ben Yaou et al. (2007) reported a large consanguineous Algerian family with digenic inheritance of mutations in the EMD and LMNA genes. Of 9 living affected family members, 6 (3 males and 3 females) had isolated atrial cardiac disease with conduction abnormalities, 1 female had isolated Charcot-Marie-Tooth axonal sensory neuropathy (CMT2B1; 605588), and 2 males had severe Emery-Dreifuss muscular dystrophy, cardiac disease, and CMT. Transmission of the atrial cardiac disease in this family was consistent with X-linked inheritance, and all 6 patients with isolated atrial cardiac disease had a deletion in the EMD gene. All 3 patients with CMT2B1 had a homozygous LMNA mutation (R298C; 150330.0020). The 2 male patients with all 3 phenotypes had both the homozygous LMNA mutation and the EMD deletion. Heterozygous carriers of the LMNA mutation had no associated phenotype. Three affected males carrying the hemizygous EMD deletion, including 1 without and 2 with a heterozygous LMNA mutation, did not have features of muscular dystrophy. A fourth male patient carrying the EMD deletion and without the LMNA mutation was asymptomatic; however, the 3 males with isolated atrial cardiac disease were all over 40 years of age, and the fourth male was 32 years of age. Ben Yaou et al. (2007) concluded that the EMD deletion acted in a dominant fashion and could alone cause isolated atrial cardiac disease in both men and women, but not a complete EDMD phenotype in men. Coexistence of the homozygous LMNA mutation and the hemizygous EMD deletion in men both worsened the cardiac impairment and caused axonal neuropathy and muscular dystrophy, suggesting a synergistic effect of the 2 mutations.
Among the many genes located in the distal part of Xq28, Bione et al. (1994) selected 8 transcripts expressed at high levels in skeletal muscle, heart, and/or brain as the best candidates for the site of the mutation ... Among the many genes located in the distal part of Xq28, Bione et al. (1994) selected 8 transcripts expressed at high levels in skeletal muscle, heart, and/or brain as the best candidates for the site of the mutation causing EDMD. On further study, they found that each of the 5 patients investigated had a unique mutation in one of the genes, previously symbolized STA; see 300384.0001-300384.0005. These mutations resulted in the loss of all or part of the protein. Wulff et al. (1997) designed a set of primers optimized to amplify and sequence each of the 6 EMD exons. With a heteroduplex analysis of emerin gene exons in 30 unrelated EDMD patients, abnormal patterns of single exons were found in 7 patients. Direct sequencing of the respective exons revealed 6 novel mutations distributed in the promoter region and exons 3-6. This study identified the first mutations in the promoter region and in exon 5. With the mutations here described, a total of 25 mutations were then known. All of the mutations abolished the synthesis of functional emerin.