Emery-Dreifuss muscular dystrophy.

A man had weakness of humeroperoneal distribution associated with limited range of motion of the cervical spine and elbows. At age 25 he developed permanent atrial paralysis, and a cardiac pacemaker was inserted. Although this case was sporadic, most others have been transmitted as an X-linked recessive trait. Mixed patterns in electromyography and muscle histology have caused nosological confusion, but the unique clinical signs seem to define a distinct form of muscular dystrophy, warranting the designation "emery-Dreifuss" type.     

Emery-Dreifuss muscular dystrophy

Emery-Dreifuss muscular dystrophy (EDMD) is the third most common X-linked muscular dystrophy. This disorder is characterized by childhood onset of early contractures, humeroperoneal muscle atrophy, and cardiac conduction abnormalities. Weakness is slowly progressive, but there is a broad spectrum of clinical severity. Patients and carriers are at risk of sudden death. Regular cardiac evaluation is mandatory to assess the risk of cardiac arrhythmias. Unique atrial pathology is seen at autopsy. The mutated gene in EDMD is localized to the long arm of the X chromosome. Mutations in the gene lead to abolished synthesis of the gene product, emerin. Emerin is localized to the nuclear membrane of skeletal, cardiac, and smooth muscle. The term Emery-Dreifuss syndrome describes patients who have the EDMD phenotype without X-linked inheritance. There is no treatment for the underlying disease, but early placement of pacemakers may be lifesaving.     

Emery-Dreifuss muscular dystrophy

Emery-Dreifuss muscular dystrophy (EDMD) is inherited in an X-linked or autosomal manner. X-linked EDMD is caused by mutations in EMD, which encodes an integral protein of the nuclear envelope inner membrane called emerin. Autosomally inherited EDMD is caused by mutations in LMNA, which encodes A-type nuclear lamins, intermediate filament proteins associated with inner nuclear membrane. Although the causative mutations have been described and mouse models have been created, the pathogenic processes by which mutations in genes encoding nuclear envelope proteins cause striated muscle abnormalities in EDMD remain obscure. Working hypotheses include effects on nuclear structural integrity, increased cellular susceptibility to mechanical stress damage, alterations in gene expression in response to nuclear envelope changes, and effects on cell proliferation and differentiation.     

Emery-Dreifuss muscular dystrophy

Emery-Dreifuss muscular dystrophy (EDMD) is a rare muscular dystrophy, but is particularly important to diagnose due to frequent life-threatening cardiac complications. EDMD classically presents with muscle weakness, early contractures, cardiac conduction abnormalities and cardiomyopathy, although the presence and severity of these manifestations vary by subtype and individual. Associated genes include EMD, LMNA, SYNE1, SYNE2, FHL1, TMEM43, SUN1, SUN2, and TTN, encoding emerin, lamin A/C, nesprin-1, nesprin-2, FHL1, LUMA, SUN1, SUN2, and titin, respectively. The Online Mendelian Inheritance in Man database recognizes subtypes 1 through 7, which captures most but not all of the associated genes. Genetic diagnosis is essential whenever available, but traditional diagnostic tools can help steer the evaluation toward EDMD and assist with interpretation of equivocal genetic test results. Management is primarily supportive, but it is important to monitor patients closely, especially for potential cardiac complications. There is a high potential for progress in the treatment of EDMD in the coming years.     

Emery-Dreifuss muscular dystrophy. An autopsy case

We reported the autopsy findings in a 50-year-old man with typical clinical features of Emery-Dreifuss muscular dystrophy. Special attention was directed to the spinal cord and ventral spinal roots to determine whether cause of the muscle wasting was denervation or myopathy. Neuropathological studies disclosed no abnormality of the spinal cord, and the ventral spinal roots were intact. The skeletal muscles showed dystrophic changes of varying degrees, and marked cardiomyopathy was evident. We consider that muscle wasting in this man was due to muscular dystrophy.     

Mutation analysis in Emery-Dreifuss muscular dystrophy.

The purpose of this study was to search for STA gene defects in three families with clinically typical Emery-Dreifuss muscular dystrophy. Emery-Dreifuss is an X-linked muscular dystrophy with humeroperoneal weakness and life-threatening, but treatable, cardiac abnormalities in male patients and in female carriers. The defect is in the gene coding for emerin, a 254 amino acid protein of unknown function. Complementary and genomic DNA from T lymphocytes from the reported patients and their family members were amplified, cloned, and sequenced. A novel mutation, a 26 base-pair deletion in three brothers and a carrier mother, was detected in one family. A splicing mutation with one base pair insertion and a five base-pair deletion, which have been described previously, were found in the second and third families, respectively. The additional novel mutation detected and the findings of three different mutations in these three families support the idea of genetic heterogeneity of Emery-Dreifuss muscular dystrophy with different mutations in different families.     

Emery-Dreifuss muscular dystrophy with unusual features

Two families with Emery-Dreifuss muscular dystrophy (EMD) are described. Several unusual features for EMD are emphasized. One of the patients had severe neuromuscular disability with inability to walk during early childhood. This patient also had mild bifacial paresis. His brothers had the typical slow progression of EMD. In some of the patients, muscle weakness distribution was more widespread than has usually been reported, with prominent involvement of finger extensors. It is suggested that there is a wide phenotypic spectrum in EMD. In both families, the disease segregated with markers spanning the EMD locus in Xq28. © 1993 John Wiley & Sons, Inc.     

Severe clinical expression in X-linked Emery-Dreifuss muscular dystrophy.

X-linked Emery-Dreifuss muscular dystrophy (EDMD) is a relatively rare benign neuromuscular disorder which can vary remarkably in onset, course and severity. In the present study, a TCTAC deletion spanning the nucleotides 631-635 of the emerin gene caused an unusually severe disease phenotype including loss of ambulation and severe muscle wasting in two affected brothers. The same mutation has been reported previously in an unrelated family showing a significantly milder phenotype. The interfamilial heterogeneity in distribution and in severity of the features in the two families point to environmental or genetic modification as the cause of clinical variability in Emery-Dreifuss muscular dystrophy.     

Emerin and cardiomyopathy in Emery-Dreifuss muscular dystrophy

Emery-Dreifuss muscular dystrophy (EDMD) is an inherited disorder characterized by the clinical triad of life-threatening progressive cardiomyopathy with conduction defect, early onset joint contractures and slow progressive muscle weakness in scapulo-humero-peroneal distribution. Cardiomyopathy in EDMD is usually noticed after the second to third decade of life, and becomes worse with age. Permanent auricular paralysis occurs frequently and is considered a hallmark of EDMD cardiomyopathy. Cardiac involvement may also occur in female carriers. In autopsy cases, enlargement of the atria with remarkable thinning have been observed. Identification of the gene responsible for X-linked EDMD (X-EDMD) and the protein product, emerin, provided a diagnostic clue for EDMD. Since the emerin gene is rather small, the entire sequence can easily be surveyed. Western blot and immunohistochemistry show an absence of emerin in muscle and skin tissues and oral exfoliating cells in male patients with X-EDMD, and a reduction of the protein content with a mosaic expression pattern in female carriers. Emerin anchors at the inner nuclear membrane of cardiac, skeletal and smooth muscles, and interacts with lamins and nucleoplasm, thereby possibly maintaining the mechanical stability of the nuclear membrane of muscle cells that shows rigorous contraction/relaxation. More recently, positive emerin staining at the cardiac demosomes and fasciae adherentes was noticed in addition to the specific localization at the inner nuclear membrane. This localization implies a physiological role for the protein in cardiac conduction.     

Cardiac transplantation in female Emery-Dreifuss muscular dystrophy

Summary A young woman with humeroperoneal muscular dystrophy and contractures received a heart transplant for a severe dilated cardiomyopathy. Cardiac histopathology consisted of myocyte hypertrophy, interstitial fibrosis, and nuclear hyperchromaticity without mitochondrial abnormalities. Myopathy and heart disease were not clinically evident in her family, although three relatives had unexplained shortened Achilles tendons without weakness. Tendon contractures may be a partial expression of this myopathic disorder, suggesting an autosomal dominant inheritance with variable penetrance. A muscular dystrophy clinically similar to that of the Emery-Dreifuss (EDMD) type can thus occur in women. Rather than the cardiac arrhythmias typical of EDMD, a dilated cardiomyopathy may occur and present with severe congestive heart failure. This is the first report of cardiac transplantation in such a case.     

Emery-Dreifuss muscular dystrophy with autosomal dominant transmission

A woman with early-onset, slowly progressive, humeroperoneal muscle weakness had marked restriction of neck flexion with contracture at the elbows. She developed exertional dyspnea at age 25, atrial fibrillation with slow ventricular rate was discovered, and a cardiac pacemaker was implanted. Her father had a similar disorder. There is at least one other report of autosomal dominant transmission of this clinical picture, which had previously only been reported as Emery-Dreifuss muscular dystrophy with X-linked recessive inheritance. Thus, more than one mode of inheritance is possible for this unusual and distinctive form of muscular dystrophy.     

Nuclear alterations in autosomal-dominant Emery-Dreifuss muscular dystrophy

Electron microscopy study of muscle biopsies from patients with autosomal-dominant Emery-Dreifuss muscular dystrophy revealed nuclear alterations in about 10% of the preserved muscle fibers. The major findings consisted of peripheral heterochromatin loss or detachment from the nuclear envelope, and of interchromatin texture alterations. These abnormalities are similar to those reported in an animal model of the disease and to those found in the X-linked form of Emery-Dreifuss muscular dystrophy. These results suggest that an abnormal ultrastructural arrangement of the nuclear periphery is a common feature in the known forms of Emery-Dreifuss muscular dystrophy, and that several proteins of the nuclear scaffold are necessary in muscle cells to maintain the nuclear structural/functional integrity and a normal muscle cell metabolism.     

Emery-Dreifuss型肌营养不良的临床与病理

目的 研究Emery-Dreifuss型肌营养不良的临床与病理特征。方法 对一例19岁男患临床症状进行跟踪随访。死后剖检，对神经系统、肌肉、心脏进行较祥细的组织病理研究。结果 (1)儿童时发病，早期关节挛缩和心脏受累，相继出现对称性肢体肌肉萎缩和无力是EDMD的临床特征；(2)尽管进行性肌肉萎缩和无力十分明显，但CPK仅轻度增高；(3)肌肉的多种病理改变提示该例属EDMD晚期；(4)脊髓前角细胞正常，腓肠神经无改变，有把握除外神经源性肌萎缩。结论 EDMD是独立的肌营养不良类型，认识其特征临床可以诊断。     

Early onset of X-linked Emery-Dreifuss muscular dystrophy in a boy with emerin gene deletion.

A boy developed contractures of the Achilles tendons at 3 years and of the postcervical muscles at 7 years, although neither contractures of the elbows nor cardiac abnormality were recognized by the age of 9 years. Muscle computed tomography scanning revealed changes characteristic of muscle involvement. Emerin was not detected in the biopsied muscle, and RT-PCR and PCR-based genomic DNA analyses of the emerin gene demonstrated no amplification product in the patient. These results confirmed the diagnosis of X-linked Emery-Dreifuss muscular dystrophy (EDMD), and reinforce the necessity of molecular genetic diagnosis of the membrane protein emerin in younger patients with possible EDMD before appearance of the typical symptoms, to avoid sudden cardiac death.     

Nuclear changes in a case of X-linked Emery-Dreifuss muscular dystrophy.

Ultrastructural alterations in the nuclear architecture were found in skeletal muscle and skin cultured cells from a patient affected by X-linked Emery-Dreifuss muscular dystrophy (EMD) carrying a null mutation. The molecular defect of X-linked EMD is the absence of emerin, a nuclear envelope-associated protein which is considered a component of the nuclear lamina. The nuclear changes were present in skeletal muscle and skin cultured cells with a frequency of about 10% and 18%, respectively. The main structures of the nuclear periphery were involved: lamina and nuclear envelope-associated heterochromatin were affected, whereas the cisterna and the pore complexes appeared preserved, and the cytoplasm of the same cells appeared normal. Analogous localized defects were detectable by immunolabeling with antilamin A/C and B2 antibodies, as well as by selective propidium iodide chromatin staining. The lesions we describe could be the result of anomalous nuclear lamina organization in the absence of emerin.     

Emery-Dreifuss muscular dystrophy - a 40 year retrospective

Emery-Dreifuss muscular dystrophy (EDMD) was delineated as a separate form of muscular dystrophy nearly 40 years ago, based on the distinctive clinical features of early contractures and humero-peroneal weakness, and cardiac conduction defects. The gene, STA at Xq28, for the commoner X-linked EDMD encodes a 34 kD nuclear membrane protein designated 'emerin', and in almost all cases on immunostaining is absent in muscle, skin fibroblasts, leucocytes and even exfoliative buccal cells, and a mosaic pattern in female carriers. The gene, LMNA at 1q21, for the autosomal dominant Emery-Dreifuss muscular dystrophy encodes other nuclear membrane proteins, lamins A/C. The diagnosis (at present) depends on mutation analysis rather than protein immunohistochemistry. It is still not at all clear how defects in these nuclear membrane proteins are related to the phenotype, even less clear that LMNA mutations can also be associated with familial dilated cardiomyopathy with no weakness, and even familial partial lipodystrophy with diabetes mellitus and coronary heart disease! What began as clinical studies in a relatively rare form of dystrophy has progressed to detailed research into the functions of nuclear membrane proteins particularly in regard to various forms of heart disease.     

The rigid spine syndrome and Emery-Dreifuss muscular dystrophy

We present five patients, three of whom suffered from a rigid spine syndrome and two from Emery-Dreifuss muscular dystrophy.

One patient with rigid spine syndrome showed a nonprogressive course, normal cardiac rhythm and mild myopathic changes in muscle histology, while in the other two patients there was a rapidly progressive course, sinus tachycardia without cardiac conduction defects and marked fiber necrosis in muscle histology.

The two patients suffering from Emergy-Dreifuss muscular dystrophy showed a very mildly progressing course, myopathic changes in muscle histology, cardiac conduction defects and deviations in electrocardiograms. These findings show that rigid spine syndrome can be distinguished from Emery-Dreifuss muscular dystrophy.     

Desmin immunolocalisation in autosomal dominant Emery-Dreifuss muscular dystrophy

Autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD) is one of a number of allelic disorders caused by mutations in the nuclear lamina proteins, lamins A and C. The disorder is characterised by the early onset of skeletal muscle weakness and joint contractures and later, by dilated cardiomyopathy and cardiac arrythmias. Although the pathophysiology is not understood, one theory suggests that disordered structural organisation at weakened nuclei in contractile cells may underlie the disease. Previous work shows that mice deficient in lamin A/C develop similar skeletal and cardiac muscle signs to patients with AD-EDMD and ultrastructural examination of muscle from these mice shows abnormal localisation of desmin. We hypothesised therefore that desmin localisation may be abnormal in muscle or cells from patients with AD-EDMD and/or in cells expressing mutant lamins. In order to evaluate this, desmin immunolocalisation was determined in skeletal muscle biopsy sections from patients with AD-EDMD and cell lines including MyoD-transfected fibroblast-derived myotubes from AD-EDMD patients and murine embryonic stem cell-derived cardiomyocytes stably transfected with mutant human lamin A. Ultrastructural examination of patient muscle was also performed. Desmin was expressed and localised normally in patient muscle and cell lines and ultrastructural examination was similar to controls. These results fail to provide any evidence that dominant mutations in lamin A/C lead to a disorganisation of the desmin associated cytoskeleton.     

Cardioembolic stroke prompting diagnosis of LMNA-associated Emery-Dreifuss muscular dystrophy

The diagnosis of Emery-Dreifuss muscular dystrophy (EDMD) is suggested by the combination of musculoskeletal weakness and wasting, joint contractures, and cardiac disease. Herein we report a patient in whom an ischemic stroke prompted the diagnosis of EDMD. A mutation in the LMNA gene (c.266G>T, p.Arg89Leu) was found. It had been reported previously exclusively with isolated cardiac disease, thus reinforcing the high phenotypic heterogeneity of laminopathies.