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PubMed1996

Skeletal muscle of patients with Duchenne's muscular dystrophy: evidence of a mitochondrial proteolytic factor responsible for calmitine deficiency.

We studied the effect of mitochondrial extracts of skeletal muscle obtained from patients with Duchenne's muscular dystrophy (DMD) on calmitine of the mitochondrial matrix isolated from skeletal muscle of control mice. Our results in vitro clearly show that calmitine of the mitochondrial matrix of control muscle was degraded in the presence of mitochondrial extracts of muscle from DMD patients. The diseased muscle apparently contains an abnormal calmitine-specific proteolytic factor responsible for the calmitine deficiency previously observed in this tissue. As calmitine binds calcium and probably plays a role in regulating the balance of bound and free calcium within mitochondria, a calmitine deficiency could result in an overload of mitochondrial free calcium. Certain enzymes involved in ATP synthesis would be inhibited, resulting in the muscular degeneration characteristic of this myopathy. Our results suggest the cause of mitochondrial calcium overload and the events leading to muscular degeneration in this disease model. Abnormal protease activity could be the factor triggering all of these processes in the DMD patient. These findings suggest that it may now feasible to search for an efficient pharmacologic treatment for DMD.

Animals↗

PubMed1997

Targeted disruption of exon 52 in the mouse dystrophin gene induced muscle degeneration similar to that observed in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a degenerative disorder of the skeletal muscle in human and is caused by mutations in the dystrophin gene. The mdx mouse is a spontaneous mutant and an animal model for DMD. It has a point mutation in exon 23 of the dystrophin gene that eliminates the expression of dystrophin. However, this mutation does not disrupt the expression of four other shorter isoforms that are also expressed from the dystrophin gene through differential promoter usage. We generated another mutant mouse by gene targeting. Exon 52 of the dystrophin gene was disrupted, because the deletion of this exon is known to result in the DMD phenotype in human. In this mouse (mdx52), Dp140 and Dp260, shorter dystrophin isoforms, were absent in addition to dystrophin. The skeletal muscles were hypertrophic and the histology exhibited variations in the fiber size with a necrotic and regenerating process. This mouse is thus considered to represent another model for DMD.

Animals↗

PubMed2001

Differential distribution of the members of the dystrophin glycoprotein complex in mouse retina: effect of the mdx(3Cv) mutation.

Dystrophin glycoprotein complex (DGC) assembly and function require mediation by dystrophin in skeletal muscle. The existence of such complexes and the correlation with DMD phenotypes are not yet established in the central nervous system. Here we have studied the expression of DMD gene mRNAs and proteins in retina from C57BL/6 and mdx(3Cv) mouse strains. Then we have comparatively investigated the localization of dystrophin and dystrophin-associated proteins (DAPs) in both strains to analyze the repercussion of the mdx(3Cv) mutation on the retinal distributions of alpha/beta-dystroglycan, alpha1-syntrophin, alpha-dystrobrevin, and delta/gamma-sarcoglycan. Results showed that DMD gene product deficiency affects the expression of dystroglycan assembly exclusively at the outer plexiform layer without an apparent effect on the other DAPs. We conclude that the localization of members of the DGC could be independent of the presence of the DMD gene products and/or utrophin.

Animals↗

PubMed1993

Heterozygotic gene expression in endomyocardial biopsies: a new diagnostic tool confirms the Duchenne carrier status.

Identification of the defective gene and the absent gene product dystrophin can substantiate the clinical evidence for manifesting X-linked Duchenne type muscular dystrophy (DMD). It is not always possible, however, to rule out definitely a clinically asymptomatic carrier status in question, since even in the proven carrier DNA analysis is often inconclusive, and multinucleated skeletal muscle fibers express a basically normal membrane dystrophin. To substantiate the value of endomyocardial biopsy as a new tool for detection of the DMD carrier status we examined an endomyocardial biopsy of a volunteer who met the clinical criteria of a DMD carrier. Dystrophin immunohistochemistry and western blot of her skeletal muscle biopsy were inconclusive, and polymerase chain reaction and cDNA analysis failed to locate directly the X-chromosomal defect. We observed a clearcut mosaic of dystrophin-positive and -negative mononucleated cardiac muscle cells, reflecting a heterozygote carrier status in her endomyocardial biopsy, whereas 20 controls were uniformely positive. The incidence of DMD (1:3000 males) and especially the 30% spontaneous mutation rate, still the major pitfall in DNA analysis, show the need for an additional diagnostic tool.

Adult↗

PubMed1992

Point mutations and polymorphisms in the human dystrophin gene identified in genomic DNA sequences amplified by multiplex PCR.

About one third of Duchenne muscular dystrophy (DMD) patients have no gross DNA rearrangements in the dystrophin gene detectable by Southern blot analysis or multiplex exon amplification. Presumably, in these cases, the deficiency is caused by minor structural lesions of the dystrophin gene. However, to date, only a single human DMD case has been described where a point mutation, producing a stop codon, accounts for the DMD phenotype. To screen for microheterogeneities in the dystrophin gene, we applied analysis by chemical mismatch cleavage to thirteen exons amplified in multiplex sets by the polymerase chain reaction. This analysis covers approximately 20% of the dystrophin-coding sequence. Sixty DMD patients without detectable deletions or duplications were investigated, leading to the identification of two point mutations and four polymorphisms with a frequency higher than 5%. Both point mutations are frameshift mutations in exons 12 and 48, respectively, and are closely followed by stop codons, thus explaining the functional deficiency of the dystrophin gene products in both patients.

Base Sequence↗

PubMed1987

Population data on benign and severe forms of X-linked muscular dystrophy.

Epidemiological data on Becker muscular dystrophy (BMD) and Duchenne muscular dystrophy (DMD) from a large sample of the Italian population are reported. For BMD the incidence rate was found to be 5.5 X 10(-5) live-born males (lbm) and the prevalence rate, 13.1 X 10(-6); the mutation rate was estimated to be about 6.0 X 10(-6). For DMD the incidence and prevalence rates were found to be respectively 26 X 10(-5) lbm and 31.6 X 10(-6). The DMD mutation rate obtained by the Haldane formula was 86.6 X 10(-6) and by the semi-direct method, 65.6 X 10(-6). The results are discussed in the light of possible allelism of BMD and DMD.

Adult↗

PubMed1987

DNA deletions in mild and severe Becker muscular dystrophy.

The DNA of 33 patients diagnosed as suffering from Becker muscular dystrophy (BMD) has been probed with cloned DNA sequences from Xp21, known to reveal DNA deletions in patients suffering from the more severe Duchenne muscular dystrophy (DMD). Two BMD cases showed clear deletions. A third case gave aberrant band sizes, which further analysis showed to be caused by a small deletion. This suggests that deletions in DXS164 occur approximately as frequently in BMD as they do in DMD. Of the two cases showing large deletions, one is at the severe end of the Becker clinical spectrum, whilst the other is a classical Becker-type dystrophy. The fact that loci defined by probes commonly deleted in classical DMD patients are also deleted in BMD patients of varying severity is strong additional evidence that these disorders are allelic, and further justifies the use of probes with defined linkage relationships to DMD also being used for counselling in BMD families.

Adolescent↗

PubMed1987

Familial deletion of Xp21.2 with glycerol kinase deficiency and congenital adrenal hypoplasia.

Congenital adrenal hypoplasia (CAH) and glycerol kinase deficiency (GKD) were diagnosed in a male during the neonatal period. On prometaphase chromosomes there was an interstitial deletion involving Xp21.2 and possibly Xp21.3 in the propositus and his mother. Duchenne muscular dystrophy (DMD) was excluded on the basis of normal serum creatine kinase and a muscle biopsy. Molecular hybridization of DNA from the propositus with 11 probes covering Xp21, including the DMD locus, was normal. In situ hybridization with the probe pERT87.15 showed a normal signal at the expected site indicating that the DMD locus was preserved and not translocated. This suggests that the DMD locus is located at the most proximal part of the sub-band Xp21.2 or in Xp21.1, and that the DXS68 (probe L1) is far from it on the distal flanking DNA.

Adrenal Insufficiency↗

PubMed1994

Dystrophin and dystrophin-related protein in the central nervous system of normal controls and Duchenne muscular dystrophy.

To clarify the localization and characterization of dystrophin and dystrophin-related protein (DRP) in the human central nervous system (CNS), we carried out immunoblotting and immunostaining studies using three region-specific anti-dystrophin and one anti-DRP antibodies. With immunostaining, punctuate immuno-reactivity of dystrophin was seen along the cell bodies and dendrites of the cerebral cortical neurons and cerebellar Purkinje cells in the normal controls autopsied. By contrast, dystrophin was not detected at all in the CNS of Duchenne muscular dystrophy (DMD) patients with intellectual disturbance. Immunoreactivity of DRP was observed in the vascular walls of both normal and DMD brains, but not in the neuronal cells. Compensatory increase of DRP was not noted in DMD brains. This study suggests that in DMD the brain-type dystrophin originally present in neurons is absent and may be related to the intellectual disturbance.

Adolescent↗

PubMed1982

Twenty years-Iowa muscle clinic: reminiscences and prospects.

The activities of the last twenty years of the Iowa clinic for neuromuscular diseases are briefly reviewed. Main emphasis in this paper is on management and guidance of the patient with Duchenne muscular dystrophy (DMD) by the families, the school and the public at large. Guidance and treatment given to our patients is briefly described. It is well known that chronic debilitating disease affects not only the patient but the whole family; management of DMD should therefore include the parents and siblings of the patient. Preventability of DMD is illustrated by the experiences in our clinic. The importance of early carrier detection and genetic counseling is stressed. Possible future developments in DMD research are briefly mentioned.

Family↗

PubMed1988

Ultrastructure of the skeletal muscle in the X chromosome-linked dystrophic (mdx) mouse. Comparison with Duchenne muscular dystrophy.

Ultrastructurally there are some clear differences in the pathology of muscle in X chromosome-linked muscular dystrophy of the mouse (mdx) and Duchenne muscular dystrophy (DMD). In particular the mouse muscle does not become infiltrated by large aggregations of connective tissue. It has been proposed that the differences are due to secondary biochemical changes consequent on the absence of dystrophin in both conditions. If this is the case, attention should be directed to the earliest ultrastructural changes held in common by both disorders. The most conspicuous of these, preceding myofibril breakdown, is dilation of the sarcoplasmic reticulum. Any physiological link between this and the absence of dystrophin remains to be determined. We suggest that in the mdx mouse, the widespread myofibre necrosis occurring at 3-4 weeks is triggered by increased mechanical demands causing the lack of dystrophin to become critical at this time. Subsequent regeneration of the myofibres appears to be almost completely successful. The ultimate failure of regeneration in DMD, in contrast, may be due to an additional factors acting in DMD exacerbating the lack of dystrophin. This additional factor may be associated with the plasma membrane lesions (not seen in mdx). Alternatively there may be factors present in the mouse that compensate for the lack of dystrophin. It is pointed out that to understand better the different processes occurring in mdx and DMD we need to learn more about the factors which control the balance between the growth of muscle and the growth of connective tissue in both normal and pathological human and mouse muscle.

Animals↗

PubMed1991

Gene-deletion and carrier detections, and prenatal diagnosis of Duchenne muscular dystrophy by analysis of the dystrophin gene amplified by polymerase chain reaction.

Polymerase chain reaction (PCR)-based diagnosis was carried out in 62 patients (57 probands) with Duchenne or Becker muscular dystrophy (DMD or BMD) and 226 members in 57 families. The PCR studies were also performed for carrier detection in 57 mothers and 58 sisters, and prenatal diagnosis of 4 fetuses at risk of DMD. The PCR with 7 sets of primers, which amplify 7 different exon-sequences of the dystrophin gene, detected gene deletion of at least one exon in 49% of the probands. The PCR with the other 4 primer sets, which amplify 3 intragenic loci, and subsequent endonuclease digestion detected in 84% of the mothers a heterozygous pattern in at least one such locus/segment. Using the same primer sets, carrier detection was successful in 5 sisters of familial DMD cases, while recombination between the ERT87 and the 3' end intragenic loci was observed in 11% of family members studied. Prenatal diagnosis was made in all the 4 fetuses; two males were affected, one male fetus non-affected, and the remaining one female fetus a carrier. Thus, the PCR study and the primers used in the present study are useful and convincing for rapid diagnosis of DMD and/or BMD.

Base Sequence↗

PubMed1992

A case of atypical Duchenne type muscular dystrophy with fragile X.

The patient was a 9-year-old boy. He began to walk at the age 1 year and 8 months and began to speak at the age of 2 years, suggesting retarded mental and motor development. A diagnosis of DMD was made when he was 7 years old. On admission, the patient exhibited a peculiar thin and long face, large auricles, narrow palate, malalignment of the teeth, epicanthus, saddle nose, and simian lines in addition to symptoms consistent with DMD. Chromosome analysis showed fragile X at Xq27 at a frequency of 20%. His mother also showed fragile X at the same position. Since the atypical features of this DMD patient are all explained as fragile X syndrome, this case was considered to be a very rare instance of DMD whose clinical pictures were modified by fragile X syndrome.

Child↗

PubMed2004

The relationship between clinical stage, prognosis and myocardial damage in patients with Duchenne-type muscular dystrophy: five-year follow-up study.

UNLABELLED: The evaluation of myocardial damage by [123I] 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) imaging, which represents free fatty acid metabolism, has not been reported in patients with Duchenne-type muscular dystrophy (DMD). To date, the relationship between clinical stage, prognosis and myocardial damage has not been evaluated by radionuclear cardiac imaging. The main goal of this study was to elucidate the relationship of quantitative indices of myocardial damage obtained by radionuclear cardiac imaging ([201Tl] and [123I] BMIPP) to clinical stage and incidence of severe cardiac events in patients with Duchenne-type muscular dystrophy (DMD). METHODS: The study population consisted of 28 male patients with DMD. The average age at the beginning of observation was 19.1 +/- 7.4 yrs. Nuclear tomographic imaging was performed using [201Tl] and [123I] BMIPP. The mid-ventricular short axial slices were classified into four anatomical regions, and the normalized count data in these areas (TL, BM) were obtained. The endpoint was the occurrence of heart failure during the follow up period. RESULTS: Thirteen cases of heart failure occurred during the 5-year follow-up period, including three cases with cardiac death due to congestive heart failure. Clinical staging correlated directly with TL (p = 0.0118) and BM (p = 0.0401) in the whole left ventricle. In regional TL analysis, an association was observed only in the septum (p = 0.0151), and in the anterior (p = 0.0361) region. The only discrepancy between the tracer parameters (TL - BM) in the septum was observed with the radionuclear cardiac values, which exhibited a relationship with cardiac events (p = 0.0124). This discordance, TL < BM, was contrary to that usually observed in patients with ischemic heart disease. CONCLUSION: The septum is the critical area of significance for cardiac events and outcome in patients with DMD. The uptake of [201Tl] in this area was representative of the clinical stage, and TL-BM correlated well with the prognosis.

Adult↗

PubMed2006

Nitric oxide synthase in muscular dystrophies: a re-evaluation.

Duchenne and Becker muscular dystrophies (DMD and BMD) are associated with decreased total nitric oxide (NO). However, mechanisms leading to NO deficiency with consequent muscle-cell degeneration remain unknown. To address this issue, we examined skeletal muscles of DMD and BMD patients for co-expression of NO synthase (NOS) with nitrotyrosine and transcription factor CREB, as well as with enzymes engaged in NO signaling. Employing immunocytochemical labeling, Western blotting and RT-PCR, we found that, in contrast to the most commonly accepted view, neuronal NOS was not restricted to the sarcolemma and that muscles of DMD and BMD patients retained all three NOS isoforms with an up-regulation of the inducible NOS isoform, CREB and nitrotyrosine. We suggest that enhanced nitrotyrosine immunostaining in muscle fibers as well as in the vasculature of DMD and BMD specimens reflects massive oxidative stress, resulting in withdrawal of NO from its regular physiological course via the scavenging actions of superoxides.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2026

Improving survival in Duchenne muscular dystrophy across eras: a systematic review and cumulative meta-analysis.

BACKGROUND: Duchenne muscular dystrophy (DMD) was historically associated with death in the late teens or early twenties, mainly from respiratory failure. Survival has improved substantially with home mechanical ventilation (HMV) and multidisciplinary care, although variability remains. This study evaluated temporal trends in survival in DMD and the impact of HMV. METHODS: A study-level cumulative meta-analysis (PROSPERO CRD420251163011) of studies reporting survival outcomes in patients with DMD was conducted (PubMed 1977 to 13 October 2025). Pooled estimates of median survival were calculated, and random-effects meta-analyses with predefined subgroups (HMV and study period) were performed, alongside meta-regressions. Risk of bias was assessed using the Newcastle-Ottawa Scale. RESULTS: 53 studies (median follow-up 8 years), comprising more than 13,000 patients, of whom 60% received HMV, were included. Median survival differed substantially between ventilated (29 years, 95%CI 27 to 31) and non-ventilated (19 years, 95%CI 18 to 20) patients. Survival improved progressively over time in both groups. Glucocorticoid therapy was not associated with improved survival (p=0.45), whereas treatment with heart failure medications, including renin-angiotensin system inhibitors (p=0.002) and β-blockers (p=0.02), was associated with longer survival. The predominance of mortality shifted from respiratory to cardiac causes, while enhanced cardiac management was associated with a growing contribution of other causes of death. CONCLUSION: Survival in DMD has increased substantially over time, with median survival now approaching the third decade of life among ventilated patients. The growing contribution of cardiac and other non-respiratory causes of death highlights the importance of long-term multidisciplinary and early cardioprotective intervention. STUDY REGISTRATION: The meta-analysis and systematic review have been registered on PROSPERO (CRD420251163011).

Humans↗

PubMed2006

Co-occurrence of mutations in both dystrophin- and androgen-receptor genes is a novel cause of female Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder. Here, we report a novel mechanism for the occurrence of DMD in females. In a Vietnamese DMD girl, conventional PCR amplification analysis disclosed a deletion of exons 12-19 of the dystrophin gene on Xp21.2, with a karyotype of 46, XY. Furthermore, a novel mutation in the androgen-receptor gene on Xq11.2-q12 was identified in this girl, which led to male pseudohermaphroditism. Co-occurrence of mutations of these two genes constitutes a novel mechanism underlying female DMD.

Adolescent↗

PubMed1991

Late potentials in progressive muscular dystrophy of the Duchenne type.

This study describes the late potentials (LPs) obtained by signal-averaged electrocardiography (SAECG) in 66 patients with Duchenne's progressive muscular dystrophy (DMD). It also assesses the possible relationships between LPs and the severity of DMD, and the findings of two-dimensional echocardiography, as well as ventricular arrhythmias examined with the Holter system. SAECGs were performed with a Marquette MAC-1 unit. Based on Swinyard-Deaver's system of stages, ranging from the mildest, S1, to the most severe, S8, one patient each could be assigned to S2 and S4, 6 to S5, 20 to S6, 21 to S7, and 17 to S8. LPs were observed in 21 of the 66 patients (32%), including 3 of the 20 assigned to S6 (15%), 10 of the 21 in S7 (48%), and 8 of the 17 in S8 (47%). The total wall motion index evaluated by the method of Hegar was significantly greater in the patients with LPs (8.4 +/- 4.4) than in those without LPs (5.8 +/- 3.1) (p less than 0.05). The incidence of LPs was found to be higher in the dilated cardiomyopathy (DCM) type (8 of 12;67%) than in the normal type (9 of 41;22%) (p less than 0.01). The incidence of ventricular premature complexes (VPCs) was significantly higher in patients with LPs (13 of 21;62%) than in those without LPs (13 of 45;29%) (p less than 0.05). No sustained ventricular tachycardia (VT) was observed, although nonsustained VT was noted in three patients with LPs. The LPs in patients with DMD were thus associated with left ventricular dysfunction, and the presence of LPs might be correlated with the extent of myocardial derangement in DMD.

Adolescent↗