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PubMed1996

Brain metabolism is abnormal in the mdx model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder primarily affecting young boys, often causing mental retardation in addition to the well-known progressive muscular weakness. Normal dystrophin expression is lacking in skeletal muscle and the CNS of both DMD children and the mdx mouse model. To date, 31P-magnetic resonance spectroscopy (MRS) has shown in vivo several abnormalities within skeletal muscle of mdx mice and DMD boys. In this study, we determined whether similar abnormalities occur in mdx brain in vivo by using 31P-MRS in addition to metabolite and enzyme analysis to study cerebral metabolism. An increased inorganic phosphate (P(i))/phosphocreatine (PCr) and pH was found in vivo for mdx brain compared with controls, and biochemical analysis showed a reduction in total creatine, an increased extracellular and decreased intracellular volume in mdx brain. No differences were found in any glycolytic or mitochondrial maximal enzyme activities. These changes are discussed with respect to the biochemical changes found in muscle from DMD patients and mdx mice. It is proposed that these biochemical changes may be a factor in the reduced cognitive capacity of mdx mice and some DMD children.

Animals↗
PubMed1997

Enhancement by indole-3-carbinol of liver and thyroid gland neoplastic development in a rat medium-term multiorgan carcinogenesis model.

The modification potential of indole-3-carbinol (I3C), a naturally occurring compound found in cruciferous vegetables, on neoplastic development was assessed using a rat medium-term multiorgan carcinogenesis model. One-hundred male Sprague-Dawley (SD) rats were randomly divided into three groups and sequentially treated with diethylnitrosamine (DEN; 100 mg/kg b.w., a single i.p.), N-methyl-N-nitrosourea (MNU; 20 mg/kg b.w., four times i.p., at days 5, 8, 11 and 14), and dihydroxy-di-N-propyl-nitrosamine (DHPN; 0.1% in the drinking water during weeks 1 and 3) (DMD treatment; groups 1 and 2) or the vehicles alone (group 3) in the first 3-week initiation period. Animals of groups 1 and 3 were then given diet containing 0.25% I3C from week 4 until week 24, followed by a return to basal diet for 28 weeks, and subgroups were killed at weeks 24 and 52. I3C caused significant increases in both number (no./cm2) and area (mm2/cm2) of glutathione S-transferase placental form (GST-P)-positive liver cell foci assessed at week 24 of the experiment (P<0.01, 0.001). The incidence of hepatocellular adenomas in the DMD and I3C group at week 52 showed a tendency for elevation as compared to the DMD alone group, but this was not statistically significant. The thyroid gland tumour incidences in the DMD and I3C groups were significantly increased compared with the DMD alone group values at week 52 (P<0.01). In conclusion, I3C enhanced liver and thyroid gland neoplastic development when given during the promotion stage in the present rat medium-term multiorgan carcinogenesis model.

Adenocarcinoma↗
PubMed1993

Discrepancy between systolic and diastolic dysfunction of the left ventricle in patients with Duchenne muscular dystrophy.

To assess the systolic and diastolic dysfunction of the left ventricle (LV) in relation to age and the severity of impairment in Duchenne muscular dystrophy (DMD), we performed M-mode, two-dimensional and pulsed-wave Doppler echocardiography in 45 male subjects with DMD aged 8 to 25 years and in 40 age-matched healthy controls. Systolic dysfunction started in the first decade of life, with some patients showing severe systolic dysfunction in their early teens. This dysfunction, however, did not always depend on the severity of the skeletal muscle disease. No patients with DMD showed an increase in peak atrial velocity and time-velocity integrals of the atrial contraction velocity curve, findings frequently reported to precede the abnormalities in many cardiac diseases; it was thought therefore that these patients had no increase in left atrial compensation. Diastolic dysfunction may not routinely precede or accompany the systolic dysfunction in DMD, in contrast with what is reported in patients with ischaemic or hypertensive heart disease. DMD patients usually show a predominant systolic dysfunction.

Adolescent↗
PubMed2002

A chronic inflammatory response dominates the skeletal muscle molecular signature in dystrophin-deficient mdx mice.

Mutations in dystrophin cause Duchenne muscular dystrophy (DMD), but absent dystrophin does not invariably cause necrosis in all muscles, life stages and species. Using DNA microarray, we established a molecular signature of dystrophinopathy in the mdx mouse, with evidence that secondary mechanisms are key contributors to pathogenesis. We used variability controls, adequate replicates and stringent analytic tools, including significance analysis of microarrays to estimate and manage false positive rates. In leg muscle, we identified 242 differentially expressed genes, >75% of which have not been previously reported as altered in human or animal dystrophies. Data provide evidence for coordinated activity of numerous components of a chronic inflammatory response, including cytokine and chemokine signaling, leukocyte adhesion and diapedesis, invasive cell type-specific markers, and complement system activation. Selective chemokine upregulation was confirmed by RT-PCR and immunoblot, and may be a key determinant of the nature of the inflammatory response in dystrophic muscle. Up-regulation of secreted phosphoprotein 1 (minopontin, osteopontin) mRNA and protein in dystrophic muscle identified a novel linkage between inflammatory cells and repair processes. Extracellular matrix genes were up-regulated in mdx to levels similar to those in DMD. Since, unlike DMD, mdx exhibits little fibrosis, data suggest that collagen regulation at post-transcriptional stages mediates extensive fibrosis in DMD. Taken together, these data identify a relatively neglected aspect of DMD, suggest new treatment avenues, and highlight the value of genome-wide profiling in study of complex disease processes.

Animals↗
PubMed1993

Characterization of translational frame exception patients in Duchenne/Becker muscular dystrophy.

The clinical progression of Duchenne muscular dystrophy (DMD) patients with deletions can be predicted in 93% of cases by whether the deletion maintains or disrupts the translational reading frame (frameshift hypothesis). We have identified and studied a number of patients who have deletions that do not conform to the translational frame hypothesis. The most common exception to the frameshift hypothesis is the deletion of exons 3 to 7 which disrupts the translational reading frame. We identified a Becker muscular dystrophy (BMD) patient, an intermediate, and a DMD patient with this deletion. In all three cases, dystrophin was detected and localized to the membrane. One DMD patient with an inframe deletion of exons 4-18 produced no dystrophin. One patient with a mild intermediate phenotype and a deletion of exon 45, which shifts the reading frame, produced no dystrophin. Two patients with large inframe deletions had discordant phenotypes (exons 3-41, DMD; exons 13-48, BMD), but both produced dystrophin that localized to the sarcolemma. The DMD patient, 113, indicates that dystrophin with an intact carboxy terminus can be produced in Duchenne patients at levels equivalent to some Beckers. The dystrophin analysis from these patients, together with patients reported in the literature, indicate that more than one domain can localize dystrophin to the sarcolemma. Lastly, the data shows that although most patients show correlation of clinical severity to molecular data, there are rare patients which do not conform.

Adolescent↗
PubMed2003

Developmentally regulated functions of the H19 differentially methylated domain.

Igf2 and H19 are physically linked imprinted genes. In embryonic liver, their reciprocal expression (paternal for Igf2 and maternal for H19) is controlled by a paternally methylated region (H19 DMD) located 5' of H19. This region contains a methylation-sensitive insulator that prevents the Igf2 promoters being activated by downstream enhancers on the maternal chromosome. In adult liver, Igf2 is normally not expressed but is reactivated upon tumour formation. By analysing three deletions of the H19 locus, we investigated the mechanism regulating the imprinted expression of the Igf2 gene in the course of liver tumourigenesis. We observed that the role of the H19 DMD in the control of Igf2 expression changes during tumourigenesis. The H19 DMD is required on the paternal chromosome for Igf2 activation in the early stages while its maternal allele is necessary for maintaining Igf2 imprinting only in the late stages. A positive regulatory function of the paternal H19 DMD is also evident in normal neonatal liver, but its relevance for Igf2 expression becomes higher in the second post-natal week. Our results support a model in which both methylated and non-methylated parental copies of the H19 DMD have active roles in the regulation of Igf2 expression in the liver and these activities are under developmental control.

Animals↗
PubMed2005

Human mesenchymal stem cells ectopically expressing full-length dystrophin can complement Duchenne muscular dystrophy myotubes by cell fusion.

Duchenne muscular dystrophy (DMD) is the most prevalent inheritable muscle disease. It is caused by mutations in the approximately 2.5-megabase dystrophin (Dys) encoding gene. Therapeutic attempts at DMD have relied on injection of allogeneic Dys-positive myoblasts. The immune rejection of these cells and their limited availability have prompted the search for alternative therapies and sources of myogenic cells. Stem cell-based gene therapy aims to restore tissue function by the transplantation of gene-corrected autologous cells. It depends on (i) the capacity of stem cells to participate in tissue regeneration and (ii) the efficient genetic correction of defective autologous stem cells. We explored the potential of bone marrow-derived human mesenchymal stem cells (hMSCs) genetically modified with the full-length Dys-coding sequence to engage in myogenesis. By tagging hMSCs with enhanced green fluorescent protein (EGFP) or the membrane dye PKH26, we demonstrated that they could participate in myotube formation when cultured together with differentiating human myoblasts. Experiments performed with EGFP-marked hMSCs and DsRed-labeled DMD myoblasts revealed that the EGFP-positive DMD myotubes were also DsRed-positive indicating that hMSCs participate in human myogenesis through cellular fusion. Finally, we showed that hMSCs transduced with a tropism-modified high-capacity hybrid viral vector encoding full-length Dys could complement the genetic defect of DMD myotubes.

Cell Fusion↗
PubMed2006

Smooth muscle-specific dystrophin expression improves aberrant vasoregulation in mdx mice.

Duchenne muscular dystrophy (DMD) is a fatal X-linked muscle-wasting disease caused by mutations of the gene encoding the cytoskeletal protein dystrophin. Therapeutic options for DMD are limited because the pathogenetic mechanism by which dystrophin deficiency produces the clinical phenotype remains obscure. Recent reports of abnormal alpha-adrenergic vasoregulation in the exercising muscles of DMD patients and in the mdx mouse, an animal model of DMD, prompted us to hypothesize that the dystrophin-deficient smooth muscle contributes to the vascular and dystrophic phenotypes of DMD. To test this, we generated transgenic mdx mice that express dystrophin only in smooth muscle (SMTg/mdx). We found that alpha-adrenergic vasoconstriction was markedly attenuated in the contracting hindlimbs of C57BL/10 wild-type mice, an effect that was mediated by nitric oxide (NO) and was severely impaired in the mdx mice. SMTg/mdx mice showed an intermediate phenotype, with partial restoration of the NO-dependent modulation of alpha-adrenergic vasoconstriction in active muscle. In addition, the elevated serum creatine kinase levels observed in mdx mice were significantly reduced in SMTg/mdx mice. This is the first report of a functional role of dystrophin in vascular smooth muscle.

Animals↗
PubMedDate not supplied

Cystic fibrosis, Duchenne muscular dystrophy and preimplantation genetic diagnosis.

Cystic fibrosis (CF) is the most common genetic disease among Caucasians. Duchenne muscular dystrophy (DMD) is one of the most common X-linked genetic disorders. The CF and DMD genes were discovered a few years ago, which provided the possibility for prenatal diagnosis and preimplantation diagnosis of CF and DMD by using specific DNA analysis. In this article, CF, DMD, the process of the identification of the genes of CF and DMD and preimplantation genetic diagnosis are briefly described.

Blastocyst↗
PubMed1985

Human X chromosome markers and Duchenne muscular dystrophy.

Two DNA markers, a random DNA fragment 754 and the cDNA sequence encoding the gene for ornithine transcarbamylase (OTC) have been studied in kindreds segregating for Duchenne muscular dystrophy. 754 and OTC are located close physically to the mutation in the region Xp21 below the breakpoints in two Duchenne females. The genetic distance was found to be approximately 10cM between 754 and DMD (two crossovers in 26 meioses) and to be approximately 10cM between OTC and DMD (two crossovers in 26 meioses). Physical data suggest the order DMD-754-OTC. The frequency of recombination compared to physical distance between these markers and DMD suggests that there may be a hot spot of recombination. The relevance of these observations for the isolation of the DMD mutation and clinical use of these probes is discussed.

Chromosome Mapping↗
PubMed2005

Human muscle gene expression responses to endurance training provide a novel perspective on Duchenne muscular dystrophy.

Global gene expression profiling is used to generate novel insight into a variety of disease states. Such studies yield a bewildering number of data points, making it a challenge to validate which genes specifically contribute to a disease phenotype. Aerobic exercise training represents a plausible model for identification of molecular mechanisms that cause metabolic-related changes in human skeletal muscle. We carried out the first transcriptome-wide characterization of human skeletal muscle responses to 6 wk of supervised aerobic exercise training in 8 sedentary volunteers. Biopsy samples before and after training allowed us to identify approximately 470 differentially regulated genes using the Affymetrix U95 platform (80 individual hybridization steps). Gene ontology analysis indicated that extracellular matrix and calcium binding gene families were most up-regulated after training. An electronic reanalysis of a Duchenne muscular dystrophy (DMD) transcript expression dataset allowed us to identify approximately 90 genes modulated in a nearly identical fashion to that observed in the endurance exercise dataset. Trophoblast noncoding RNA, an interfering RNA species, was the singular exception-being up-regulated by exercise and down-regulated in DMD. The common overlap between gene expression datasets may be explained by enhanced alpha7beta1 integrin signaling, and specific genes in this signaling pathway were up-regulated in both datasets. In contrast to these common features, OXPHOS gene expression is subdued in DMD yet elevated by exercise, indicating that more than one major mechanism must exist in human skeletal muscle to sense activity and therefore regulate gene expression. Exercise training modulated diabetes-related genes, suggesting our dataset may contain additional and novel gene expression changes relevant for the anti-diabetic properties of exercise. In conclusion, gene expression profiling after endurance exercise training identified a range of processes responsible for the physiological remodeling of human skeletal muscle tissue, many of which were similarly regulated in DMD. Furthermore, our analysis demonstrates that numerous genes previously suggested as being important for the DMD disease phenotype may principally reflect compensatory integrin signaling.

Biopsy↗
PubMed1996

Oxidative damage to muscle protein in Duchenne muscular dystrophy.

The hypothesis that reactive free radical species (ROS) may contribute to the pathogenesis of Duchenne muscular dystrophy (DMD) has been suggested previously, but experimental data obtained in support of the above have to date proved inconclusive. The recent discovery that nitric oxide synthase (required for muscle relaxation) is associated with the sarcolemmal protein dystrophin normally and that both proteins are absent in DMD has heightened interest in the potential role of ROS in this disorder. We therefore investigated oxidative damage to proteins in the quadriceps femoris muscle by quantifying protein carbonyl levels in six patients with DMD and six normal controls. In DMD, the mean protein carbonyl level in the quadriceps femoris muscle was increased by 211% (p < 0.005) compared with the normal control subjects. The data thus support the hypothesis for the role of ROS induced protein oxidation of muscle cell damage in DMD.

Adolescent↗
PubMed2001

Relating familial stress to the psychosocial adjustment of adolescents with Duchenne muscular dystrophy.

Adolescence is a time that offers significant challenges to families dealing with Duchenne muscular dystrophy (DMD). A major developmental task in the adjustment process for the adolescent is the achievement of a sense of self-identity. Mastering stress in families of adolescents with DMD has also been shown to be a major task in the adjustment process for the family. In this study, the relationships between familial stress and psychosocial adjustment in adolescents with DMD were investigated. The study participants (36 caregivers and 32 adolescents) were all registered with the Muscular Dystrophy Association of Canada and all resided in the province of Ontario. The Offer Self-Image Questionnaire for Adolescents (Offer et al., 1982, 1989) was used to measure psychosocial adjustment of adolescents with DMD. Family stress was measured by the Questionnaire on Resources and Stress (Holroyd, 1987). All but a few of the participants were interviewed and completed self-report instruments in their own homes. The other families were interviewed in other settings (e.g., clinic, adolescent's school). The results indicate that, overall and in several specific areas, the adolescents demonstrate lower levels of psychosocial adjustment than their normal reference group. The results also indicate that familial stress is not related to sociodemographic variables, but is associated with psychosocial adjustment in the adolescent (P = 0.0004), and with intellectual function of the adolescent (P = 0.001). In fact, the results of a regression analysis show that the level of stress experienced by the family predicts the degree of psychosocial adjustment of the adolescent with DMD (R2 = 0.38, P = 0.0003). These findings underscore the importance of a holistic approach with these families. Limitations of the study, and implications of the results, are discussed in terms of clinical practice and future research.

Adaptation, Psychological↗
PubMed1999

Clinical evidence for dystrophin dysfunction as a cause of hearing loss in locus DFN4.

OBJECTIVE: Locus DFN4 is an X-linked nonsyndromic hearing loss locus originally mapped to Xp21.2. Recently, we have mapped deafness in a second family from Turkey to the same region, refining the location to within the Duchenne muscular dystrophy (DMD) locus. The objective of this study was to characterize the clinical phenotype of the Turkish family with comprehensive audiovestibular testing and high-resolution temporal bone computerized tomography. METHODS: Fourteen members of a three-generation family were studied in detail including two deaf affected males. Members of the family underwent general physical and otologic examination, vestibular testing, pure-tone audiometry, otoacoustic emissions, and immitance testing. An affected male underwent high-resolution computerized tomography of the temporal bone, electroretinogram (ERG), electromyography, electroneurography, and determination of serum creatinine phosphokinase level. RESULTS: Affected males were congenitally deaf with normal vestibular function. Carrier females showed a mild sensorineural hearing loss affecting all frequencies and absent otoacoustic emissions. Otoacoustic emissions in a younger, 3-year-old carrier girl were normal. In an affected male, ERG demonstrated subnormal scotopic b-wave typically seen in DMD. Computerized tomography of the temporal bone was normal. With the exception of the ERG finding, there was no clinical or laboratory evidence of DMD or Becker muscular dystrophy (BMD). CONCLUSION: The abnormal ERG in the Turkish family in conjunction with mapping of the DFN4 locus to within DMD strongly suggests that a defect in dystrophin is responsible for the hearing loss in this family. Patients with DMD and BMD should be screened systematically for sensorineural hearing loss. This family provides additional evidence for the critical role of cytoskeletal proteins in normal hearing.

Dystrophin↗
PubMed2007

A method to evaluate contractures effects during the gait of children with Duchenne dystrophy.

Joint contractures are the second major impairment affecting the locomotor system of children with Duchenne muscular dystrophy (DMD). While the negative influence of joint contractures has been documented, the passive moments produced by joint contractures could benefit the gait of patients with muscle weakness. We describe a biomechanical model that quantifies the mechanical contribution of ankle and hip flexion contractures to the gait of DMD children. Kinematic and kinetic parameters were measured under the same experimental conditions during the gait and passive resistance assessment of two subjects: one healthy child as a control, and one child with DMD. The child with DMD had a plantar flexion contracture and a greater ankle stiffness coefficient than the control child. During gait, the contribution of the ankle passive moment to the net moment was more important for the child with DMD than for the control child. At the hip, passive joint moments and passive moment contribution were more important for the control child but this was not related to the presence of hip flexion contracture. These preliminary results suggest the model might be used to evaluate contractures effect on a larger cohort of subjects.

Ankle Joint↗
PubMed1998

Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2.

Differentially methylated sequences associated with imprinted genes are proposed to control genomic imprinting. A 2-kb region located 5' to the imprinted mouse H19 gene is hypermethylated on the inactive paternal allele throughout development. To determine whether this differentially methylated domain (DMD) is required for imprinted expression at the endogenous locus, we have generated mice harboring a 1.6-kb targeted deletion of the DMD and assayed for allelic expression of H19 and the linked, oppositely imprinted Igf2 gene. H19 is activated and Igf2 expression is reduced when the DMD deletion is paternally inherited; conversely, upon maternal transmission of the mutation, H19 expression is reduced and Igf2 is activated. Consistent with the DMD's hypothesized role of setting up the methylation imprint, the mutation also perturbs allele-specific methylation of the remaining H19 sequences. In conclusion, these experiments show that the H19 hypermethylated 5' flanking sequences are required to silence paternally derived H19. Additionally, these experiments demonstrate a novel role for the DMD on the maternal chromosome where it is required for the maximal expression of H19 and the silencing of Igf2. Thus, the H19 differentially methylated sequences are required for both H19 and Igf2 imprinting.

Alleles↗
PubMed1980

Sporadic occurrence of Duchenne muscular dystrophy: evidence for new mutation.

The mechanism of inheritance of sporadically occurring Duchenne muscular dystrophy has been investigated in 42 families, using carrier detection methods and genetic evaluation. Our studied find that serum CPK detects 72% of female carriers of DMD. Quantitative LDH and/or its isozymes were not found to be a useful means of carrier detection, as reported by Roses et al. (1977). Employing family pedigree data and CPK carrier testing, we determined by Bayesian methods the probability that the mother and maternal grandmother in these families were DMD carriers. These studies revealed 23 families (Category I) with no evidence for DMD carriers, 11 families (Category II) in which the mother was found to be a carrier, and 3 families (Category III) in which both mother and maternal grandmother were found to be carriers. Nineteen of the 42 families have a greater than 83% probability that the sporadic DMD case arose by mutation in a maternal gamete. This finding is in good agreement with the theoretically expected 1/3 of DMD cases arising by new mutation.

Chromosomes↗
PubMed1997

Genetic epidemiology of Duchenne and Becker muscular dystrophy in Slovenia.

Most population studies on Duchenne (DMD) and Becker (BMD) muscular dystrophies predated the discovery of the gene and its product dystrophin. The diagnosis of these conditions and consequent epidemiological estimates were therefore limited to clinical criteria. In our study of the Slovene population the prevalence and cumulative incidence of DMD and BMD were calculated by including additional diagnostic tests: deletion screening in the dystrophin gene as well as dystrophin immunocytochemistry. The minimal prevalence rates, 2.9/100,000 for DMD, 1.2/100,000 for BMD, and the minimal cumulative DMD incidence rate of 13.8/100,000 are in the range of lower estimates compared to studies world-wide. However, we found a high BMD cumulative incidence rate of 5.7/100,000 and a high proportion of BMD versus DMD cumulative incidence rate (41.3%). Our results imply that the epidemiological figures for BMD might have been underestimated in the past.

Adolescent↗