Emery-Dreifuss muscular dystrophy with major conduction disorders and cardiac excitability

The case of a 53-year-old patient with scapulo-humero-peroneal wasting, early flexion contractures of the elbows and ankles, abnormal cardiac conduction and probable X-related heredity is reported. Histology was suggestive of a primary and very slowly progressive muscular disorder. CT scan revealed fatty muscle degeneration which was more extensive than suggested by clinical findings. Electrophysiological studies revealed right atrial paralysis, left atrial tachycardia and supra and, above all, infra-His block. Sustained episodes of ventricular tachycardia, an anomaly described only rarely in pathology of this type, occurred some time after the fitting of a permanent pacemaker. The originality of this case of Emery-Dreifuss progressive muscular dystrophy lies in the usefulness of muscle CT scan and the existence of life-threatening arrhythmias.     

Heart-specific localization of emerin: new insights into Emery-Dreifuss muscular dystrophy

Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked inherited disease characterized by early contracture of the elbows, Achilles tendons and post-cervical muscles, slow progressive muscle wasting and weakness and cardiomyopathy presenting with arrhythmia and atrial paralysis: heart block can eventually lead to sudden death. The EDMD geneencodes a novel ubiquitous protein, emerin, which decorates the nuclear rim of many cell types. Amino acid sequence homology and cellular localization suggested that emerin is a member of the nuclear lamina-associated protein family. These findings did not explain the role of emerin nor account for the skeletal muscle- and heart-specific clinical manifestations associated with the disorder. Now we report that emerin localizes to the inner nuclear membrane, via its hydrophobic C-terminal domain, but that in heart and cultured cardiomyocytes it is also associated with the intercalated discs. We propose a general role for emerin in membrane anchorage to the cytoskeleton. In the nuclear envelope emerin plays a ubiquitous and dispensable role in association of the nuclear membrane with the lamina. In heart its specific localization to desmosomes and fasciae adherentes could account for the characteristic conduction defects described in patients.     

Miyoshi distal muscular dystrophy

Miyoshi distal muscular dystrophy (MDMD) is a young-adult-onset, autosomal recessive inherited dystrophy initially affecting the plantar flexers. We analysed 12 MDMD families, five with consanguineous marriage, for chromosomal linkage using polymorphic microsatellite DNA markers to map MDMD gene. A significant lod score was obtained with the 2p13 locus D2S291 (Zmax = 15.3 at theta = 0). A gene for autosomal recessive limb-girdle muscular dystrophy 2B (LGMD2B) was also mapped 2p13. The onset was in the late teens with weakness and wasting of the pelvic girdle muscles. Now we cannot exclude the possibility that the cause of these diseases are allelic variants in the same gene. YAC contig of the region was constructed. Scleening for muscle genes in the MDMD region is under way.     

Cardiomyopathy of limb-girdle muscular dystrophy

OBJECTIVES: This study sought to find an association between dilated cardiomyopathy and limb-girdle muscular dystrophy. BACKGROUND: Cardiomyopathy has been seen in various neuromuscular disorders, but it has not been recognized to be associated with limb-girdle muscular dystrophy. METHODS: We investigated three sisters with well documented limb-girdle dystrophy and congestive heart failure by the 3rd decade of life. All underwent noninvasive evaluation of left ventricular systolic function by both echocardiography and radionuclide scanning, and one also had cardiac catheterization. Deoxyribonucleic acid (DNA) linkage analysis was performed in these affected subjects and in the unaffected family members, and DNA was extracted from mononuclear cells with primer sequences for three chromosome 13q microsatellite markers. RESULTS: The parents had no evidence of clinical disease, but all three sisters had echocardiographic evidence of dilated cardiomyopathy. The sister with additional evidence of left ventricular dysfunction of cardiac catheterization had no coronary artery disease. The affected subjects had the same paternal allele for three potential markers of limb-girdle muscular dystrophy but different maternal alleles. The very small family size did not permit statistical confirmation or refutation of linkage for chromosome 13q markers. CONCLUSIONS: Demonstrable cardiomyopathy accompanying limb-girdle muscular dystrophy and its probable genetic associations require continued investigation by anticipating the cardiomyopathy in limb-girdle muscular dystrophy.     

Challenges in Duchenne muscular dystrophy

The last seven years has witnessed an explosion in our understanding of the muscular dystrophies. In the early 1980s, prenatal diagnosis of Duchenne muscular dystrophy was developed. The cloning of the gene, in 1996, resulted in a better understanding of the disease process and led to the identification of a novel complex at the membrane. This information led to the cloning of other genes responsible for the autosomally inherited dystrophies. As we approach the millenium, the challenge is shifting to the development of therapy of these diseases. This review, in honour of Professor Alan Emery, explains how these advances have an impact in the clinical management of patients and head the promise the progress holds for the future.     

Cardiac involvement in Becker muscular dystrophy

OBJECTIVES: The purpose of this study was to assess the incidence of myocardial involvement and the relation of cardiac disease to the molecular defect at the deoxyribonucleic acid (DNA) or protein level in Becker muscular dystrophy. BACKGROUND: Dystrophin gene mutations produce clinical manifestations of disease in the heart and skeletal muscle of patients with Becker muscular dystrophy. METHODS: Thirty-one patients underwent electrocardiographic and echocardiographic examination and 24-h Holter monitoring. The diagnosis was established by neurologic examination, dystrophin immunohistochemical assays or Western blot on muscle biopsy, or both, and DNA analysis. RESULTS: Electrocardiographic and echocardiographic findings were abnormal in 68% and 62% of the patients, respectively. Right ventricular involvement was detected in 52%. Left ventricular impairment was observed either as an isolated phenomenon (10%) or in association with right ventricular dysfunction (29%). Right ventricular disease was manifested in the teenagers, and an impairment of the left ventricle was observed in older patients. Right ventricular end-diastolic volumes were significantly increased compared with those in a control group. The left ventricular ejection fraction was significantly lower in older patients than in control subjects or younger patients. Life-threatening ventricular arrhythmias were detected in four patients. No correlations were found between skeletal muscle disease, cardiac involvement and dystrophin abnormalities. In our patients, exon 49 deletion was invariably associated with cardiac involvement. Exon 48 deletion was associated with cardiac disease in all but two patients. CONCLUSIONS: The cardiac manifestation of Becker muscular dystrophy is characterized by early right ventricular involvement associated or not with left ventricular impairment. Exon 49 deletion is associated with cardiac disease.     

Microsatellite analysis of Duchenne muscular dystrophy

Duchenne muscular dystrophy is X-linked recessive neuromuscular disorders caused by mutations in the dystrophin gene. Prenatal diagnosis and carrier detection are usually performed using diallelic RFLP-markers which are not always informative. Now 30 of microsatellite marker have reported, these microsatellite polymorphism can easily be amplified using PCR technique. If mutations are known to localize in this region of the dystrophin gene or if routine RFLP-analysis is uninformative, the analysis of microsatellite markers is the preferable technique in prenatal diagnosis and carrier detection.     

Urinary dysfunction in Duchenne muscular dystrophy

In Duchenne muscular dystrophy (DMD), sphincter muscles tend to be clinically spared. However, urinary incontinence is occasionally reported, usually late in the course of the disease. We wished to determine the etiology of urinary dysfunction in patients with DMD. Seven boys with DMD and urinary dysfunction were examined by a neurologist and a urologist followed by urodynamic and electrophysiological assessment. Based on the results of these evaluations, patients were defined as having an upper motor neuron (UMN), lower motor neuron (LMN), or myopathic lesion. Five of the patients had UMN abnormalities consisting of either uninhibited contractions or bladder/sphincter dyssynergy. One patient had a LMN lesion with prolonged duration and high-amplitude motor units. No patient demonstrated myopathic motor units. Five boys had undergone spinal fusion for scoliosis. We conclude that urinary incontinence in DMD is most often due to UMN dysfunction and not due to a severe myopathy of the detrusor or external sphincter. The most likely causes of the UMN abnormalities are severe scoliosis or a complication of spinal fusion surgery.     

Facioscapulohumeral muscular dystrophy (FSHD)

Facioscapulohumeral muscular dystrophy (FSHD; MIM 158900) is one of the major forms of muscular dystrophy, and is inherited in an autosomal dominant fashion. In most patients with FSHD, deletion of 3.3 kb tandemly repeated units within the EcoRI fragment, as detected by p13E-11 (D4F104S1) on chromosome 4q35, is associated with the disease (FSHD1A or 4q35-FSHD). Rare (< 5%) 4q35-unlinked FSHD (FSHD1B) is also known, and therefore genetic heterogeneity exists among FSHD. Recent studies based on the distinction of 4q35 EcoRI fragments from those of 10q26 improved the reliability of molecular diagnosis of the disease (> 95% accuracy). However, gene for FSHD1A has not been identified yet. Identification of the FSHD gene and characterization of the gene product are waited on tiptoe with expectation.     

Progressive muscular dystrophy in alpha-sarcoglycan-deficient mice

Limb-girdle muscular dystrophy type 2D (LGMD 2D) is an autosomal recessive disorder caused by mutations in the alpha-sarcoglycan gene. To determine how alpha-sarcoglycan deficiency leads to muscle fiber degeneration, we generated and analyzed alpha-sarcoglycan- deficient mice. Sgca-null mice developed progressive muscular dystrophy and, in contrast to other animal models for muscular dystrophy, showed ongoing muscle necrosis with age, a hallmark of the human disease. Sgca-null mice also revealed loss of sarcolemmal integrity, elevated serum levels of muscle enzymes, increased muscle masses, and changes in the generation of absolute force. Molecular analysis of Sgca-null mice demonstrated that the absence of alpha-sarcoglycan resulted in the complete loss of the sarcoglycan complex, sarcospan, and a disruption of alpha-dystroglycan association with membranes. In contrast, no change in the expression of epsilon-sarcoglycan (alpha-sarcoglycan homologue) was observed. Recombinant alpha-sarcoglycan adenovirus injection into Sgca-deficient muscles restored the sarcoglycan complex and sarcospan to the membrane. We propose that the sarcoglycan-sarcospan complex is requisite for stable association of alpha-dystroglycan with the sarcolemma. The Sgca-deficient mice will be a valuable model for elucidating the pathogenesis of sarcoglycan deficient limb-girdle muscular dystrophies and for the development of therapeutic strategies for this disease.     

Congenital muscular dystrophy and cerebellar atrophy

Two siblings and two other unrelated patients had congenital muscular weakness and dystrophic changes but normal immunocytochemical stainings for merosin, dystrophin, and dystrophin-related proteins on muscle biopsy. All had marked ataxia and cerebellar atrophy or hypoplasia. Cerebral white matter and cortical organization appeared normal.     

Apoptotic myonuclei in human Duchenne muscular dystrophy

The current view that apoptosis precedes necrosis in death of dystrophin-deficient muscle fibers of the mdx mouse has been well substantiated. Moreover, apoptotic myonuclei have been reported to increase in dystrophin-deficient mice 2 days after spontaneous exercise. To investigate the role of apoptosis in human muscular dystrophy, muscles from 11 patients of different ages with Duchenne muscular dystrophy were analyzed for apoptosis. The amount of apoptosis was assessed by terminal deoxynucleotidyl transferase assay, and the expression of bcl-2 and bax was examined by immunohistochemistry. Although very rare in normal muscles (less than 0.1%), apoptotic nuclei were detected in dystrophic muscles, particularly at the interstitial level. Nevertheless, few dystrophin-deficient myofibers with centrally located nuclei showed a positive reaction for DNA fragmentation. A mosaic pattern of bcl-2/bax-positive myofibers characterized dystrophic muscles, thus the relative proportion of pro- and antiapoptotic proteins differs among muscle fibers in correlation with the presence of apoptotic myonuclei. In the interstitium, apoptotic cells were identified as macrophages and activated satellite cells. This is the first study to show an apoptotic process in adult muscle fibers of patients with Duchenne muscular dystrophy, thereby shedding new light on muscle damage and its progression in dystrophinopathies.