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PubMed1992

[Early differentiation between Duchenne and Becker muscular dystrophy: clinical, laboratory, electrophysiology, histochemical, and immunohistochemical study of 138 cases].

194 clinical, laboratory, electrophysiologic, histological, histochemical and immunohistochemical parameters were studied through statistical analysis in 112 cases of Duchenne muscular dystrophy (DMD) and in 26 cases of Becker muscular dystrophy (BMD). It was found a significant statistical difference (p < 0.05) between the two groups concerning the age of evaluation, beginning of symptoms, difficulty in walking, running, climbing and going downstairs, frequent falling down, support to walk, localized muscle pain, stopping climb stairs, and inability to walk. Muscle biopsy showed statistically significant (p < 0.05) differences between the two groups regarding the intensity of connective tissue and focal adipose tissue proliferation, presence of diffuse rounded atrophic and angulated fibers, diffuse hypertrophic and splitting fibers. There were also differences regarding excessive internal fibers nuclei, hypertrophic types 1 and 2 fibers, angulated atrophic fibers and focal increasing in the NADH-TR, angulated atrophic fibers in non-specific esterase, and accumulated NBT in the periphery of fibers in succinic dehidrogenase. Isolatedly muscle biopsy gave the correct diagnosis in 52.7% of DMD cases and in 69.2% of BMD cases. Dystrophin detection by immunofluorescence (60 cases) showed: absence in 87.0% of fibers in DMD cases, and sarcolemmal membrane discontinuites in all BMD cases. The muscle biopsy diagnosis had an agreement with the dystrophin results in 82.6% of DMD cases and 71.4% of BMD cases.

Biopsy↗
PubMed2001

Focusing on dissociated motor development in Brazilian children.

Dissociated motor development (DMD) is considered when the baby starts independent walking late, with normality of the other fields of development. There is evidence that babies with DMD present an atypical crawling pattern and hypotonia. To investigate the frequency and characteristics of DMD, neurological examination was performed monthly in 177 healthy full-term babies from 6 months age, in urban and rural zone samples in Brazil. Among 20 children with atypical crawling, none presented hypotonia neither did they start independent walking late. The means of the ages at the beginning of atypical crawling and independent walking acquisitions, 7.40 mo (SD 1.4) and 12.76 mo (SD 2.5) respectively, did not differ from the group with crossed crawling pattern. Thus, in this sample of Brazilian healthy children we did not find cases with DMD.

Brazil↗
PubMed2001

Gene therapy for muscular dystrophies: current status and future prospects.

Since the identification in 1987 of the gene for Duchenne muscular dystrophy (DMD), research on the molecular pathogenesis of muscular dystrophy has progressed extensively. In particular, discovery of the DMD gene product, dystrophin, led to the identification of dystrophin-associated proteins and, subsequently, the recognition of other types of muscular dystrophy caused by the defects in each of the sarcoglycan genes. On the other hand, effective therapy for DMD has not yet been established. Some of the viral vectors, such as adeno-associated virus vectors or lentiviral vector, have been proven to enable the long-term expression of the exogenous gene without overt host immune reactions. However, dystrophin cDNAs are too large (14kb) to be accommodated in these viral vectors. To solve this problem, we and other research groups succeeded in truncating full-length dystrophin cDNA to small dystrophin cDNA (4 to 5kb), the products of which protect dystrophin-deficient mdx muscle from contraction-induced membrane damage when introduced by viral vectors or as a transgene into mdx mice. The usefulness of these truncated dystrophin cDNAs should be confirmed using other animal models such as dystrophic dogs. To develop successful treatment of DMD, the authors believe that several different approaches should be used, such as cell transfer therapy, drug design to up-regulate utrophin, or a strategy to repair the mutation in vivo.

Animals↗
PubMed1996

Distribution of dystrophin and dystrophin-associated protein 43DAG (beta-dystroglycan) in the central nervous system of normal controls and patients with Duchenne muscular dystrophy.

In skeletal muscles of patients with Duchenne muscular dystrophy (DMD), the absence of dystrophin was thought to lead to the large reduction in all of the dystrophin-associated proteins (DAPs). Of the seven types of DAPs identified in skeletal muscle, only the 43-kDa glycoprotein (beta-dystroglycan) has recently been found in the monkey brain. To clarify the distribution and characterization of dystrophin and beta-dystroglycan in the brain of humans, we carried out immunostaining and immunoblotting studies on tissues from three DMD patients with intellectual disturbances (ages 17,22, and 26 years) and in five controls (age range, 42-74 years). An antidystrophin antibody revealed dystrophin to be localized in neuronal cells and in the vascular wall in control brains, but it was absent from these tissues in DMD patients. In contrast, beta-dystroglycan was distributed throughout neuronal cells and in the vascular wall of control brains, and was well preserved in the brain of patients with DMD.

Adolescent↗
PubMedDate not supplied

Dystrophin analysis in the diagnosis of childhood muscular dystrophy: an immunohistochemical study of 75 cases.

Seventy-five consecutive pediatric muscular dystrophy (MD) cases were analyzed by dystrophin immunohistochemistry (75/75), Western blot analysis (26/75), DNA analysis (30/75), and immune electron microscopy (8/75). The patients included 64 males and 11 females and the clinical diagnoses were Duchenne MD (DMD) (41), Becker MD (BMD) (8), intermediate/outlier MD (4), female DMD (3), limb girdle or Becker (1), congenital MD (CMD) (10), Fukuyama CMD (1), facioscapulohumeral MD (FSH) (3), limb girdle MD (2), and other uncharacterized dystrophies (2). Dystrophin analysis was performed on all cases using the N- and C-terminal antidystrophin antibodies. Dystrophin analysis helped to exclude an Xp21 dystrophy in four patients. Except for two patients who showed normal staining with the N-terminal and abnormal staining with the C-terminal antibody, all DMD cases showed absent staining except for the immunoreactive revertant fibers, which were generally under 5%. A variety of staining patterns was seen in BMD, ranging from normal to abnormal (variable intensity of staining, partially stained/unstained fibers). Abnormalities were observed with the C-terminal antibody in one case of CMD and Fukuyama CMD, and normal staining was present in the other dystrophies. Immune electron microscopy confirmed absence of staining in DMD and normal membrane staining in other dystrophies. Our study underscores the importance of using antibodies with specificities to different regions of the dystrophin molecule for accurate diagnosis. As abnormal staining may be encountered in non-Xp21 dystrophies such as CMD, dystrophin staining should not be used in isolation to make a diagnosis of a dystrophinopathy.

Adolescent↗
PubMed2025

Proteomics of Duchenne Muscular Dystrophy Patient iPSC-Derived Skeletal Muscle Cells Reveal Differential Expression of Cytoskeletal and Extracellular Matrix Proteins.

Proteomics of dystrophic muscle samples is limited by the amount of protein that can be extracted from patient biopsies. Cells and tissues derived from patient-derived induced pluripotent stem cells (iPSCs) can be an expandable alternative source. We have patterned iPSCs from three Duchenne muscular dystrophy (DMD) patient lines into skeletal muscle cells using a two-dimensional as well as our three-dimensional organoid differentiation system. Probes with sufficient protein amounts could be extracted and prepared for mass spectrometry. In total, 3007 proteins in 2D and 2709 proteins in 3D were detected in DMD patient probes. A total of 83 proteins in 2D and 338 proteins in 3D can be described as differentially expressed between DMD and control patient probes in a post hoc test. We have identified and we propose Myosin-9, Collagen 18A, Tropomyosin 1, BASP1, RUVBL1, and NCAM1 as proteins specifically altered in their expression in DMD for further investigation. Proteomics of skeletal muscle organoids resulted in greater consistency of results between cell lines in comparison to the two-dimensional myogenic differentiation protocol.

Humans↗
PubMed1989

[Sequential changes of the cardiomyopathy in Duchenne muscular dystrophy by 201Tl myocardial SPECT].

201Tl myocardial SPECT was performed to evaluate cardiomyopathy in Duchenne type of progressive muscular dystrophy (DMD). Follow up SPECT images of the same patients were also obtained about 1 year after the first scan. Cases subjected to study were 10 DMD. At the first study the hypoperfusion area of the left ventricular muscle was observed in 6 cases (60%) out of 10. At the second study the hypoperfusion areas became wider and lower in 4 out of 6 cases (66.7%). The new hypoperfusion area which was not demonstrated at the first study was observed at the second study in one case of these cases. These results suggested that the positive rate of cardiomyopathy in DMD by 201Tl myocardial SPECT was high, and 201Tl myocardial SPECT is a useful examination to detect the change of myocardial damage in DMD.

Adolescent↗
PubMed1999

ERG phenotype of a dystrophin mutation in heterozygous female carriers of Duchenne muscular dystrophy.

PURPOSE: Mutations in the dystrophin gene result in Duchenne muscular dystrophy (DMD). DMD is associated with an abnormal electroretinogram (ERG) if the mutation disrupts the translation of retinal dystrophin (Dp260). Our aim was to determine if incomplete ERG abnormalities would be associated with heterozygous carriers of dystrophin gene mutations. METHODS: Ganzfeld ERGs were obtained under scotopic and photopic testing conditions from a family which includes the heterozygous maternal grandmother, the heterozygous mother, and her children, two affected boys and dizygotic twin sibs, an unaffected male and heterozygous female. Southern blot analyses were done to characterise the dystrophin mutation. RESULTS: The dystrophin gene was found to contain a deletion encompassing exon 50. The ERGs in the two affected boys were abnormal, consistent with the DMD ERG phenotype. Serial ERGs of the heterozygous females were abnormal; however, they were less severely affected than the DMD boys. The ERG of the female sib showed a greater abnormality than her mother and maternal grandmother. The unaffected twin had a normal ERG. CONCLUSIONS: The ERG shows abnormalities associated with carrier status in this family with a single exon deletion. A large study of confirmed obligate carriers is planned to clarify further the value of the ERG in detecting female heterozygous carriers of dystrophin gene mutations.

Adult↗
PubMed1999

Haemostatic abnormalities, cardiac involvement and serum tumor necrosis factor levels in X-linked dystrophic patients.

Left ventricular thrombosis and systemic emboli have been demonstrated to complicate cardiomyopathy in Duchenne and Becker muscular dystrophy (DMD, BMD). We investigated plasma levels of prothrombin fragment 1+2 (F1+2). thrombin-antithrombin III complex (TAT) and circulating levels of tumor necrosis factor-alpha (TNF-alpha), a procoagulant cytokine that has been shown to be elevated in patients with depressed cardiac function, in 20 patients with DMD and 12 patients with BMD as compared with 30 age-matched control subjects. Significantly elevated levels of F1+2 (DMD: 1.4+/-0.8 nmol/l; BMD: 1.8+/-0.8 nmol/l vs. controls: 0.7+/-0.2 nmol/l, p <0.01 and p <0.001, respectively), TAT complexes (DMD: 4.7+/-2.7 microg/l, BMD: 5+/-2.3 microg/l vs. controls: 1.6+/-0.5 microg/l, p <0.001) and TNF-alpha (54+/-9 vs. 25+/-7 pg/ml, p <0.001) were observed in patients with the dystrophic disease compared to control subjects. A significantly negative correlation was also found between F1+2 and TAT complexes and left ventricular ejection fraction (r = -0.65, p <0.0001; r = -0.80, p < 0.0001, respectively) and a positive correlation between F1+2 and TAT complexes and serum TNF-alpha levels (r = 0.67, p <0.0001; r = 0.70, p <0.0001, respectively). Our results indicate a hypercoagulable state in X-linked dystrophic patients. A possible relationship between haemostatic activation, left ventricular dysfunction and TNF-alpha system upregulation may be suggested.

Adolescent↗
PubMed1999

[Analysis of deletions in the dystrophin gene in patients with Duchenne muscular dystrophy in the Bashkir Republic].

The deletion spectrum and distribution of deletion breakpoints (DBs) in 36 patients with Duchenne muscular dystrophy (DMD) from 33 families and in three patients with Becker muscular dystrophy (BMD) from one family from Bashkortostan were studied by amplifying 20 exons of the dystrophin gene by multiplex polymerase chain reaction (mPCR). Eight out of 34 unrelated DMD (BMD) patients (23.2%) were shown to carry a deletion varying in size from one to seven exons. Most DBs (15 out of 16, 93.7%) were in the distal region of the gene, commonly between exons 44-45, 45-47, and 50-52. Thus, high-polymorphic intergenic markers located in introns 44 (STR 44), 45 (STR 45), 49 (STR 49), and 50 (STR 50) can be used for indirect or direct carrier detection among women closely related to DMD patients that carry a deletion with DB located between exons 44-45, 45-47, and 50-52. Prenatal diagnosis of DMD is also possible in these families.

Adolescent↗
PubMed2000

[Pathogenesis of pulmonary thrombosis in Duchenne muscular dystrophy; a consideration from changes in serum CK and LDH levels].

We assessed the hypercoagulative state in patients with Duchenne muscular dystrophy (DMD) by measuring peripheral blood creatine kinase (CK) and lactate dehydrogenase (LDH) levels. In 76 patients with DMD who had no complications during examination, the CK and LDH levels were examined in a total of 173 times. Both enzyme levels were elevated and highly correlated (R = 0.93). We examined the temporal alteration of serum CK and LDH levels during episodes of pulmonary thrombosis experienced in 7 DMD patients who fulfilled the following diagnostic criteria: 1. sudden onset of dyspnea, chest pain, and hypoxia; 2. abnormal coagulation profile or abnormal chest CT findings, such as peripheral wedged shaped shadow and; 3. pneumothorax ruled out from X-ray findings. Throughout the episode of pulmonary thrombosis, CK and LDH levels changed within the range of those from DMD patients who had no complications, however, the CK level was significantly elevated from the basal level (2.12 times, p = 0.0075) on the first day of the episode. The LDH level rose for several days, and subsequently both CK and LDH returned to the basal level. In patients with compartment syndrome, CK levels were reportedly elevated due to muscle fiber necrosis which lead a hypercoagulative state. Therefore, we propose that muscle fiber necrosis is one of causal factors in pulmonary thrombosis. In addition, elevated CK may be helpful in predicting pulmonary thrombosis.

Adolescent↗
PubMed2000

[Improvement of obstructive sleep apnea by uvulopalatopharyngoplasty and tonsillectomy in a case of Duchenne muscular dystrophy].

A 10-year-old boy with Duchenne muscular dystrophy (DMD) underwent uvulopalatopharyngoplasty and tonsillectomy for obstructive sleep apnea (OSA). He has snored loudly during nocturnal sleep since infancy, and OSA developed one and a half years after he was wheel chair-bound at 8 years. Magnetic resonance imaging (MRI), conventional spirometry and overnight polysomnography were performed before and after the surgery. MRI before surgery revealed moderate tonsillar hypertrophy and a long uvula which narrowed the upper airway. After the surgery, his vital capacity (VC) was not changed (% VC; from 77 to 78%), but forced expiratory volume (FEV) was improved (FEV 1.0%; from 75 to 86%). A preoperative apnea index of 32.8/hour decreased to 0.8/hour postoperatively. REM-related falls in HbSaO2 improved remarkably. The present case suggests that subjects with DMD with tonsillar hypertrophy and a redundant uvula tend to develop noctrurnal OSA earlier than DMD cases with a normal tonsil and uvula. Assessment of respiratory function, particularly FEV 1.0%, is important for determining surgical indication of OSA in patients with DMD.

Child↗
PubMed2001

[Non-invasive prenatal diagnosis of Duchenne muscular dystrophy].

OBJECTIVE: This paper was designed to investigate the feasibility of non-invasive prenatal diagnosis of Duchenne muscular dystrophy(DMD). METHODS: The nucleated red blood cells(NRBC) were separated with percoll using a discontinuous density gradient method. The cells were smeared on microscope slides using a cyto-centrifuge and then stained by Wright- Giemsa. NRBCs were detected and individually retrieved into glass capillary pipettes using a micromanipulator under microscopic observation. The whole genome of a single cell was amplified by improved primer extension preamplification(PEP). The procedures for making prenatal diagnosis of DMD and determining the origin of NRBCs proceeded at the same time using sex determination and linkage analysis of several STR loci of dystrophin. Genotypes were analyzed by amplifying the 9 STR fragments using fluorescence-PCR technique and NRBCs origin was further determined. RESULTS: A case of DMD in male fetus was diagnosed. CONCLUSION: With the use of the method reported, the non-invasive prenatal diagnosis of DMD is possible.

Female↗
PubMed2001

iNOS expression in dystrophinopathies can be reduced by somatic gene transfer of dystrophin or utrophin.

BACKGROUND: Nitric oxide (NO) is an inorganic gas produced by a family of NO synthase (NOS) proteins. The presence and the distribution of inducible-NOS (NOS II or iNOS), and NADPH-diaphorase (NADPH-d), a marker for NOS catalytic activity, were determined in muscle sections from control, DMD, and BMD patients. MATERIALS AND METHODS: NADPH-d reactivity, iNOS- and nNOS (NOS I)-immunolocalization were studied in muscles from mdx mice before and after somatic gene transfer of dystrophin or utrophin. RESULTS: In control patients, few fibers (<2%) demonstrated focal accumulation of iNOS in sarcolemma. In DMD patients, a strong iNOS immunoreactivity was observed in some necrotic muscle fibers as well as in some mononuclear cells, and regenerating muscle fibers had diffusely positive iNOS immunoreactivity. In DMD patients, NADPH-d reactivity was increased and mainly localized in regenerating muscle fibers. In mdx mice quadriceps, iNOS expression was mainly observed in regenerating muscle fibers, but not prior to 4 weeks postnatal, and was still present 8 weeks after birth. The expression of dystrophin and the overexpression of utrophin using adenovirus-mediated constructs reduced the number of iNOS-positive fibers in mdx quadriceps muscles. The correction of some pathology in mdx by dystrophin expression or utrophin overexpression was independent of the presence of nNOS. CONCLUSIONS: These results suggest that iNOS could play a role in the physiopathology of DMD and that the abnormal expression of iNOS could be corrected by gene therapy.

Adenoviridae↗
PubMed2001

[Current state and prospects for gene therapy of Duchenne muscular dystrophy in the world and in Russia].

Failure of drug therapy of Duchenne muscular dystrophy (DMD) stimulated intense search for adequate methods of gene therapy (GT) which would ensure effective delivery of the dystrophin (D) gene, its long-term persistence in transfected cells, and its expression in muscle fibers. The main results of the experimental GT of DMD with the use of viral and nonviral delivery of the D gene into muscles of biological models are discussed. Delivery of a mini-gene of D with a specific muscle promoter using a modified adenoassociated virus is currently the most promising method, which will soon be available for clinical trials. The main results of the studies on the DMD GT in Russia are summarized. The results of experiments on genetic transfection of mdx mice with marker genes and various constructions with the D gene are outlined. The genes are delivered into muscles by means of gene gun, electroporation, viral oligopeptides, liposomes, microspheres, lactoferine, and other nonviral vehicles. It is emphasized that consolidation of funds and efforts of all Russian laboratories dealing with gene and cell therapy of DMD are necessary to complete the experiments and start clinical trials.

Animals↗
PubMed2001

[Central nervous system involvements in Duchenne/Becker muscular dystrophy].

Duchenne/Becker muscular dystrophy (DMD/BMD) are the most common inherited muscular diseases caused by mutations in the dystrophin gene. The identification of novel dystrophins in the brain has recently implicated its absence or malfunction etiologically in mental retardation (MR). We therefore examined the relationship between molecular abnormalities and clinical phenotypes. Deletions of the dystrophin gene were analyzed in a total of 137 DMD/BMD patients (DMD 94, BMD 43) to determine central nervous system (CNS) symptoms. The mental capacity was assessed and patients with IQs below 70 were defined as mentally retarded. Thirty-nine percent of DMD boys and 12% of BMD patients were classified as mentally retarded. Eight DMD and 2 BMD patients were diagnosed as having autism. Forty-four percent of DMD and 79% of BMD patients had deletions in the dystrophin gene. All the DMD/BMD patients with deletions upstream of the 5' end of the gene were mentally normal. All of DMD/BMD patients with MR and/or autism had deletions containing the 3' end, although some patients with similar deletions were mentally normal. Our data suggest that Dp140, Dp71 and/or Dp116, the C-terminal translational products of dystrophin, may be related to MR and/or autism in DMD/BMD. However, there was an exception in our series. Three of eight sibling pairs in our cases had different phenotypes, although they had the same mutations in the dystrophin gene. Thus the CNS phenotypes were not determined by the mutations of dystrophin gene alone, and the interaction of dystrophin with other nuclear genes may play important roles.

Adolescent↗
PubMed1975

Effect of pretreatment with prednisolone on enzyme efflux from isolated skeletal and heart muscle.

In a previous study, the efflux of creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) which takes place from isolated mouse skeletal muscle was shown to be significantly reduced by pretreatment of the intact animal with diethylstilbestrol (DES). This compound is known to reduce the high serum enzymes present in patients with Duchenne's muscular dystrophy (DMD). Glucocorticoids also reduce the serum enzymes in DMD. The purpose of this study was to determine if pretreatment with the glucocorticoid, prednisolone, also lowered the efflux from isolated mouse skeletal and cardiac muscle. The results of these studies show that prednisolone pretreatment lowers the enzyme efflux from isolated skeletal muscle, but not from heart. There is an optimal dose which produces this reduction, which if exceeded, augments the efflux. Thus two agents are now known which lower the efflux of CPK and LDH from isolated skeletal muscle. These same two agents lower the high serum enzymes in DMD. This suggests, but does not prove, that the mechanism by which these agents lower the serum enzymes in DMD is by reducing enzyme efflux from skeletal muscle.

Animals↗
PubMedDate not supplied

[Muscular dystrophy due to a deficit of gamma-sarcoglycan. A report of three patients with the Delta-521t mutation].

INTRODUCTION: gamma-sarcoglicanopathies, also classified as limb girdle muscular dystrophy type 2C (LGMD2C) are a group of autosomal recessive muscular dystrophies due to mutations in 13q12 and subsequent g sarcoglican deficiency. The protein is one of the components of the dystrophin associated glycoprotein complex and is thought to impart structural integrity to the myofibre. The clinical course of the disease may be heterogeneous, ranging from severe forms with onset in the first decade and rapid progression resembling Progressive Duchenne muscular dystrophy (DMD) to milder forms with later onset and slower course. Cases hitherto reported in Spain corresponds to gypsie patients, homozygous for C283Y missense mutation. CASE REPORTS: Here, we report three new galician (Northwest Spain) patients (one male and one female sibling cases) with a severe DMD like muscular dystrophy homozygous for D 521T. In the first male familial case, initial diagnosis of DMD was made. On reevaluation fourteen years later, inmunohistochemical and molecular studies allowed for a definitive g sarcoglicanopathy diagnosis. CONCLUSIONS: Patients with a primary sarcoglycanopathy may be clinically indistinguishable from those with the primary dystrophinopathies. Probably, the diagnosis of LGMD are underestimated and a number of male patients diagnosed as DMD really corresponds to a recessive form o muscular dystrophy. Consequently, a definitive diagnosis rests on appropriate inmunohistochemical and molecular analysis, specially in those patients showing a normal pattern of dystrophin and/or suggestive for an autosomal recessive mode of inheritance.

Adolescent↗