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PubMed1990

Cultural differences in family communication about Duchenne muscular dystrophy.

This study compared the patterns of communication and use of professional support systems of Irish and American families with sons with Duchenne muscular dystrophy (DMD). Structured interviews were used with the parents of 34 Irish boys and 21 American boys attending the muscular dystrophy services of Central Remedial Clinic, Dublin, and Children's Hospital, Boston. A matched control group was interviewed in each culture to compare use of professional support systems. Difficulties in communicating about DMD with their spouses and with their affected sons were reported by significantly more Irish parents than by their American counterparts. More Irish parents had never spoken about DMD with their affected sons. American DMD families reported significantly more contact with professional support systems than did the Irish families. Factors which may contribute to these cultural differences are discussed.

Adaptation, Psychological↗
PubMed1977

Fibroblast cultures in Duchenne muscular dystrophy. Alterations in synthesis and secretion of collagen and noncollagen proteins.

Primary skin fibroblast cultures were grown from forearm pinch skin biopsies obtained from 24 patients with Duchenne muscular dystrophy (DMD) and ten normal controls matched for sex and age. The first subcultures were grown for 7 days and incubated with L-(3H)-proline for 24 hours. Intracellular collagen incorporation was significantly decreased (2.2 X) and extracellular collagen incorporation significantly increased (1.8 X) in fibroblast cultures from patients with DMD by both collagenase assay and polyacrylamide gel electrophoresis. The synthesis of noncollagen proteins showed low values from the DMD fibroblast cultures. The alterations in synthesis and secretion of collagen and noncollagen proteins were characteristic only for the log phase of DMD fibroblasts.

Cells, Cultured↗
PubMed1982

Significance of serum myoglobin in neuromuscular diseases and in carrier detection of Duchenne muscular dystrophy.

In a retrospective study, the serum myoglobin concentration (S-myoglobin) was determined in patients with neuromuscular diseases and in carriers of Duchenne muscular dystrophy (DMD). Myoglobin was quantified by a sensitive radioimmunoassay. Serum creatine kinase (CK, EC 2.7.3.2) activity (S-CK) and serum creatine kinase B-subunit activity (S-CKB) were determined for comparison. Sera from 70 patients with various neuromuscular diseases and from 17 female relatives of patients with DMD were analysed. Increased levels of S-myoglobin were found both in dystrophic and in spinal myopathies. Because of a marked overlap of the range of values between the different dystrophic myopathies and even between the dystrophic and the spinal myopathies, S-myoglobin is of little value in the final diagnosis of neuromuscular diseases. In the detection of carriers of DMD, simultaneous determination of S-myoglobin and S-CK gave a higher detection rate compared to the detection rate with S-CK. S-CKB was normal in all carriers and only elevated in some of the patients with DMD and limb girdle muscular dystrophy.

Adult↗
PubMed1992

Dystrophin or a "related protein" in Duchenne muscular dystrophy?

Previously we have shown low levels of dystrophin immunoreactivity in muscle from patients with DMD. According to the "frame-shift hypothesis" DMD muscle should not synthesize any dystrophin through to the C-terminus and it has been suggested that the protein detected is not dystrophin, but a related autosomal homologue. We have labelled serial sections of DMD muscle with specific monoclonal antibodies to the amino, rod and C-terminal domains of dystrophin and find labelling on the same individual fibres, allowing us to conclude that the protein detected is Xp21-encoded dystrophin. This has an impact on the interpretation of myoblast transfer experiments. The abundance (on blots) of "C-terminal dystrophin" appears lower than "rod dystrophin" in both BMD and DMD.

Antibodies, Monoclonal↗
PubMed1987

Conservation of the Duchenne muscular dystrophy gene in mice and humans.

A portion of the Duchenne muscular dystrophy (DMD) gene transcript from human fetal skeletal muscle and mouse adult heart was sequenced, representing approximately 25 percent of the total, 14-kb DMD transcript. The nucleic acid and predicted amino acid sequences from the two species are nearly 90 percent homologous. The amino acid sequence that is predicted from this portion of the DMD gene indicates that the protein product might serve a structural role in muscle, but the abundance and tissue distribution of the messenger RNA suggests that the DMD protein is not nebulin.

Amino Acid Sequence↗
PubMed2023

Assessment of systemic AAV-microdystrophin gene therapy in the GRMD model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by the absence of dystrophin, a membrane-stabilizing protein encoded by the DMD gene. Although mouse models of DMD provide insight into the potential of a corrective therapy, data from genetically homologous large animals, such as the dystrophin-deficient golden retriever muscular dystrophy (GRMD) model, may more readily translate to humans. To evaluate the clinical translatability of an adeno-associated virus serotype 9 vector (AAV9)-microdystrophin (μDys5) construct, we performed a blinded, placebo-controlled study in which 12 GRMD dogs were divided among four dose groups [control, 1 × 1013 vector genomes per kilogram (vg/kg), 1 × 1014 vg/kg, and 2 × 1014 vg/kg; n = 3 each], treated intravenously at 3 months of age with a canine codon-optimized microdystrophin construct, rAAV9-CK8e-c-μDys5, and followed for 90 days after dosing. All dogs received prednisone (1 milligram/kilogram) for a total of 5 weeks from day -7 through day 28. We observed dose-dependent increases in tissue vector genome copy numbers; μDys5 protein in multiple appendicular muscles, the diaphragm, and heart; limb and respiratory muscle functional improvement; and reduction of histopathologic lesions. As expected, given that a truncated dystrophin protein was generated, phenotypic test results and histopathologic lesions did not fully normalize. All administrations were well tolerated, and adverse events were not seen. These data suggest that systemically administered AAV-microdystrophin may be dosed safely and could provide therapeutic benefit for patients with DMD.

Animals↗
PubMed2005

Transfer of the full-length dystrophin-coding sequence into muscle cells by a dual high-capacity hybrid viral vector with site-specific integration ability.

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, making it a potential target for gene therapy. There is, however, a scarcity of vectors that can accommodate the 14-kb DMD cDNA and permanently genetically correct muscle tissue in vivo or proliferating myogenic progenitors in vitro for use in autologous transplantation. Here, a dual high-capacity adenovirus-adeno-associated virus (hcAd/AAV) vector with two full-length human dystrophin-coding sequences flanked by AAV integration-enhancing elements is presented. These vectors are generated from input linear monomeric DNA molecules consisting of the Ad origin of replication and packaging signal followed by the recently identified AAV DNA integration efficiency element (p5IEE), the transgene(s) of interest, and the AAV inverted terminal repeat (ITR). After infection of producer cells with a helper Ad vector, the Ad DNA replication machinery, in concert with the AAV ITR-dependent dimerization, leads to the assembly of vector genomes with a tail-to-tail configuration that are efficiently amplified and packaged into Ad capsids. These dual hcAd/AAV hybrid vectors were used to express the dystrophin-coding sequence in rat cardiomyocytes in vitro and to restore dystrophin synthesis in the muscle tissues of mdx mice in vivo. Introduction into human cells of chimeric genomes, which contain a structure reminiscent of AAV proviral DNA, resulted in AAV Rep-dependent targeted DNA integration into the AAVS1 locus on chromosome 19. Dual hcAd/AAV hybrid vectors may thus be particularly useful to develop safe treatment modalities for diseases such as DMD that rely on efficient transfer and stable expression of large genes.

Adenoviridae↗
PubMed1990

Molecular and functional analysis of the muscle-specific promoter region of the Duchenne muscular dystrophy gene.

Duchenne muscular dystrophy (DMD) gene transcripts are most abundant in normal skeletal and cardiac muscle and accumulate as normal myoblasts differentiate into multinucleated myotubes. In this report we describe our initial studies aimed at defining the cis-acting sequences and trans-acting factors involved in the myogenic regulation of DMD gene transcription. A cosmid clone containing the first exon of the DMD gene has been isolated, and sequences lying upstream of exon 1 were analyzed for homologies to other muscle-specific gene promoters and for their ability to direct muscle-specific transcription of chimeric chloramphenicol acetyltransferase (CAT) gene constructs. The results indicate that the transcriptional start site for this gene lies 37 base pairs (bp) upstream of the 5' end of the published cDNA sequence and that 850 bp of upstream sequence can direct CAT gene expression in a muscle-specific manner. Sequence analysis indicates that in addition to an ATA and GC box, this region contains domains that have been implicated in the regulation of other muscle-specific genes: a CArG box at -91 bp; myocyte-specific enhancer-binding nuclear factor 1 binding site homologies at -58, -535, and -583 bp; and a muscle-CAAT consensus sequence at -394 bp relative to the cap site. Our observation that only 149 bp of upstream sequence is required for muscle-specific expression of a chimeric CAT gene construct further implicates the CArG and myocyte-specific enhancer-binding nuclear factor 1 binding homologies as important domains in the regulation of this gene. On the other hand, the unique profile of myogenic cell line-specific induction displayed by our DMD promoter-CAT gene constructs suggests that other as yet undefined cis-acting sequences and/or trans-acting factors may also be involved.

Base Sequence↗
PubMed2005

Rasgrf1 imprinting is regulated by a CTCF-dependent methylation-sensitive enhancer blocker.

Imprinted methylation of the paternal Rasgrf1 allele in mice occurs at a differentially methylated domain (DMD) 30 kbp 5' of the promoter. A repeated sequence 3' of the DMD regulates imprinted methylation, which is required for imprinted expression. Here we identify the mechanism by which methylation controls imprinting. The DMD is an enhancer blocker that binds CTCF in a methylation-sensitive manner. CTCF bound to the unmethylated maternal allele silences expression. CTCF binding to the paternal allele is prevented by repeat-mediated methylation, allowing expression. Optimal in vitro enhancer-blocking activity requires CTCF binding sites. The enhancer blocker can be bypassed in vivo and imprinting abolished by placing an extra enhancer proximal to the promoter. Together, the repeats and the DMD constitute a binary switch that regulates Rasgrf1 imprinting.

Animals↗
PubMed1983

The genetic status of mothers of isolated cases of Duchenne muscular dystrophy.

Classical genetic theory, based on assumed equal mutation rates in males and females, predicts that one-third of all cases of Duchenne muscular dystrophy (DMD) in a generation are born as new mutants to non-carrier mothers. Furthermore, less than half the mothers of apparently isolated cases appear to be carriers on the basis of raised serum creatine kinase levels. We have analysed the pedigrees of 61 families of DMD boys seen in the Duke Neuromuscular Research Clinic and 45 DMD families followed at the University of Virginia. The frequency of affected boys among the next born male sibs of 37 initially isolated DMD cases in two clinic populations was significantly greater than predicted by Haldane's theory (p = 0.029) and the estimated proportion of new mutant cases in the combined clinic population of 106 families was 0.127 (SE 0.111). The absence of affected males in earlier generations in families of isolated cases may be explained in part by a high ratio of male to female stillbirths and infant deaths, which was more than three times that of the normal population in this study. These data suggest that new mutant cases are less common than expected and current predictions may underestimate genetic risks in mothers of isolated cases.

Adult↗
PubMed1986

Duchenne muscular dystrophy with adrenal insufficiency and glycerol kinase deficiency: high resolution cytogenetic analysis with molecular, biochemical, and clinical studies.

A syndrome of Duchenne muscular dystrophy (DMD), adrenal hypoplasia, glycerol kinase deficiency, and mental retardation has been recognised. We report a further case ascertained from a history of DMD, severe mental retardation, and an Addison-like disorder. Cytogenetic analysis of the proband revealed an interstitial deletion of the short arm of the X chromosome. from Xp21.1 to Xp22.11, comprising about 9% of the length of the normal X chromosome. His mother was heterozygous for the deletion, but his maternal grandmother and sister both had two normal X chromosomes. DNA probe analysis confirmed the existence of a deletion in the affected boy, as probes 754, C7, XJ1-1, and pERT87 consistently failed to hybridize to his DNA. His sister was heterozygous for the RFLP associated with 754, thus confirming that she had two normal X chromosomes. There was no evidence of chronic granulomatous disease, other immunological defect, or retinitis pigmentosa in this case. Biochemical studies revealed gross glyceroluria and hyperglycerolaemia, indicating glycerol kinase deficiency which has been confirmed enzymatically. We have subsequently screened 21 other boys with DMD for glyceroluria and found one other case. Cytogenetic analysis has also been performed in nine other families, where a boy with DMD has been shown to have a deletion of DNA sequences localised to the region Xp21. None of these cases demonstrated any cytogenetic abnormality, nor has their clinical course been unusual.

Adolescent↗
PubMed1986

Linkage analysis of polymorphisms within the DNA fragment XJ cloned from the breakpoint of an X;21 translocation associated with X linked muscular dystrophy.

Cloning of a DNA segment including the translocation breakpoint in a female with an X;21 translocation and X linked muscular dystrophy has led to identification of three subclones which detect polymorphic markers. The alleles of these markers, XJ1 X 1, XJ1 X 2, and XJ2 X 2, are in strong linkage disequilibrium. Linkage analysis in 31 families with Duchenne or Becker muscular dystrophy has shown recombination within the XJ segment in one case, and recombination of DMD with both the XJ segment and the pERT87 segment in a second, but has revealed no recombination between the XJ and pERT87 segments. The XJ markers increase the proportion of DMD and BMD families that are informative for carrier detection and prenatal diagnosis, but in view of the risk of recombination they must be used with caution. The site(s) of the DMD mutation(s) relative to the XJ and pERT87 markers, and the detailed molecular structure of the DMD region, remain to be determined.

Alleles↗
PubMed1988

Mild and severe muscular dystrophy associated with deletions in Xp21 of the human X chromosome.

We have analysed over 300 patients suffering from Duchenne or Becker muscular dystrophy (DMD or BMD). Deletions have been characterised which encompass either the pERT87 (DXS164) locus only, the XJ1.1 (DXS206) and HIP25 loci only, or all three loci. These loci have been shown to lie within the DMD region covering several hundred kilobases (kb) of DNA. One mildly affected BMD patient possesses a deletion of at least 110 kb including exons of the DMD gene. Other patients with similar exon deletions, or smaller deletions, show the more severe phenotype typical of DMD. We conclude from these studies that the severity of the clinical phenotype cannot be explained on the basis of the size of the deletion. We discuss this in the context of candidate gene sequences.

Chromosome Deletion↗
PubMed1989

Duchenne muscular dystrophy in Wales: a 15 year study, 1971 to 1986.

A register of families with Duchenne muscular dystrophy (DMD) in Wales was set up in 1973 and has been regularly maintained ever since. All women at significant risk in these families were offered estimation of their carrier status by creatine kinase and pedigree analysis. A total of 225 of the 512 women tested was assigned a risk of carrying the DMD gene of less than 5%. One hundred and twenty live births from this group were notified to the register and only one was an affected male. This was the expected number and shows that the risks given were largely accurate. Women given a risk of 5% or greater were offered fetal sexing with termination of any male. Amniocentesis was of limited value and chorionic villus sampling, introduced in 1984, was acceptable to more women at risk. The incidence of DMD in Wales dropped from one in 3435 at the beginning of the study to one in 4046 by 1982, and the proportion of recurrent cases from 40% to 22%. Common reasons for recurrence were birth of a second affected boy before diagnosis of the first, and failure of families with affected dead members in previous generations to be notified to the register. Maintaining an accurate register of DMD families is an essential tool in their management.

Female↗
PubMed1992

Congenital hydrocephalus secondary to Walker-Warburg syndrome identified on the Manitoba Neonatal Screening Programme for Duchenne muscular dystrophy.

This report describes our first experience with a clinically important true false positive neonatal screening test for Duchenne muscular dystrophy (DMD). Neonatal screening for DMD began as a pilot programme in Manitoba on 1 January 1986 by analysis of creatine kinase (CK) activity in dried filter paper blood spots. To date, all except two males with positive initial and follow up neonatal CK screening tests were subsequently diagnosed as having DMD. Of these two, one was a newborn male with congenital hydrocephalus whose positive DMD screening test led to the identification of an associated congenital myopathy and confirmation of the diagnosis of Walker-Warburg syndrome.

Biopsy↗
PubMed2007

New approaches in the therapy of cardiomyopathy in muscular dystrophy.

Cardiomyopathy is a frequent occurrence in muscular dystrophy, and heart disease in muscular dystrophy can contribute to both morbidity and mortality. A number of novel therapies are being developed for muscular dystrophy, and the efficacy of these therapies for heart disease is unknown. The most common X-linked recessive disease is Duchenne muscular dystrophy (DMD), which arises from defects in the dystrophin gene. Therapy specifically aimed at DMD is reviewed in the context of its projected effect on cardiomyopathy associated with DMD. Additionally, novel therapies are being pursued to treat specifically the cardiomyopathy of DMD. There is substantial genetic heterogeneity underlying the muscular dystrophies, and not all muscular dystrophy patients develop cardiomyopathy. A subset of muscular dystrophies may place patients at significantly greater risk of developing cardiomyopathy and cardiac rhythm disturbances. These disorders are discussed, highlighting recent studies and recommendations for therapy.

Cardiomyopathies↗
PubMed2002

Global/temporal gene expression in diaphragm and hindlimb muscles of dystrophin-deficient (mdx) mice.

The mdx mouse is a model for human Duchenne muscular dystrophy (DMD), an X-linked degenerative disease of skeletal muscle tissue characterized by the absence of the dystrophin protein. The mdx mice display a much milder phenotype than DMD patients. After the first week of life when all mdx muscles evolve like muscles of young DMD patients, mdx hindlimb muscles substantially compensate for the lack of dystrophin, whereas mdx diaphragm muscle becomes progressively affected by the disease. We used cDNA microarrays to compare the expression profile of 1,082 genes, previously selected by a subtractive method, in control and mdx hindlimb and diaphragm muscles at 12 time points over the first year of the mouse life. We determined that 1) the dystrophin gene defect induced marked expression remodeling of 112 genes encoding proteins implicated in diverse muscle cell functions and 2) two-thirds of the observed transcriptomal anomalies differed between adult mdx hindlimb and diaphragm muscles. Our results showed that neither mdx diaphram muscle nor mdx hindlimb muscles evolve entirely like the human DMD muscles. This finding should be taken under consideration for the interpretation of future experiments using mdx mice as a model for therapeutic assays.

Aging↗
PubMed2005

Oxandrolone enhances skeletal muscle myosin synthesis and alters global gene expression profile in Duchenne muscular dystrophy.

Earlier studies have shown that the progressive, unrelenting muscle loss associated with Duchenne muscular dystrophy (DMD) involves an imbalance between the rates of synthesis and degradation of muscle proteins. Although previous studies have suggested that oxandrolone may be beneficial in DMD, the mechanism of action of oxandrolone on muscle in DMD remains unclear. To address these issues, we combined stable isotope studies and gene expression analysis to measure the fractional synthesis rate of myosin heavy chain (MHC), the key muscle contractile protein, the transcript levels of the isoforms of MHC, and global gene expression profiles in four children with DMD before and after 3 mo of treatment with oxandrolone. Gastrocnemius muscle biopsies and blood samples were collected during the course of a primed 6-h continuous infusion of l-[U-(13)C]leucine on two separate occasions, before and after the 3-mo treatment with oxandrolone (0.1 mg.kg(-1).day(-1)). Gene expression analysis was done with microarrays and RT-qPCR. In response to the treatment, MHC synthesis rate increased 42%, and this rise was accounted for, at least in part, by an upregulation of the transcript for MHC8 (perinatal MHC). Gene expression data suggested a decrease in muscle regeneration as a consequence of oxandrolone therapy, presumably because of a decrease in muscle degeneration. These findings suggest that 1) oxandrolone has a powerful protein anabolic effect on a key contractile protein and 2) larger and longer-term studies are warranted to determine whether these changes translate into meaningful therapy for these patients.

Adolescent↗