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PubMed2002

Analysis of sequence upstream of the endogenous H19 gene reveals elements both essential and dispensable for imprinting.

Imprinting of the linked and oppositely expressed mouse H19 and Igf2 genes requires a 2-kb differentially methylated domain (DMD) that is located 2 kb upstream of H19. This element is postulated to function as a methylation-sensitive insulator. Here we test whether an additional sequence 5' of H19 is required for H19 and Igf2 imprinting. Because repetitive elements have been suggested to be important for genomic imprinting, the requirement of a G-rich repetitive element that is located immediately 3' to the DMD was first tested in two targeted deletions: a 2.9-kb deletion (Delta D MD Delta G) that removes the DMD and G-rich repeat and a 1.3-kb deletion (Delta G) removing only the latter. There are also four 21-bp GC-rich repetitive elements within the DMD that bind the insulator-associated CTCF (CCCTC-binding factor) protein and are implicated in mediating methylation-sensitive insulator activity. As three of the four repeats of the 2-kb DMD were deleted in the initial 1.6-kb Delta DMD allele, we analyzed a 3.8-kb targeted allele (Delta 3.8kb-5'H19), which deletes the entire DMD, to test the function of the fourth repeat. Comparative analysis of the 5' deletion alleles reveals that (i) the G-rich repeat element is dispensable for imprinting, (ii) the Delta DMD and Delta DMD Delta G alleles exhibit slightly more methylation upon paternal transmission, (iii) removal of the 5' CTCF site does not further perturb H19 and Igf2 imprinting, suggesting that one CTCF-binding site is insufficient to generate insulator activity in vivo, (iv) the DMD sequence is required for full activation of H19 and Igf2, and (v) deletion of the DMD disrupts H19 and Igf2 expression in a tissue-specific manner.

Alleles↗
PubMed2002

Reduced aquaporin 4 expression in the muscle plasma membrane of patients with Duchenne muscular dystrophy.

BACKGROUND: In Duchenne muscular dystrophy (DMD), previous freeze-fracture electron microscopic studies demonstrated that muscle plasma membrane contained markedly decreased numbers of orthogonal arrays. Recent investigations showed that orthogonal arrays were composed of aquaporin 4 (AQP4) molecules, a member of the water channel protein family. OBJECTIVES: To study whether the immunostainability of anti-AQP4 antibody is reduced in muscles of patients with DMD and whether, if it is reduced, the problem is at the genomic DNA, messenger RNA (mRNA), or posttranscriptional level. PATIENTS AND METHODS: We analyzed the muscle and blood samples from 6 boys with DMD, 6 normal control subjects, and 12 patients with neuromuscular diseases at the protein, genomic DNA, and mRNA levels. At the protein level, immunohistochemical staining and immunoblot analysis were performed. At the genomic DNA and mRNA levels, the polymerase chain reaction and reverse transcription polymerase chain reaction, respectively, were used to screen for mutations in the AQP4 gene. RESULTS: At the protein level, immunohistochemical staining of our originally generated rabbit anti-AQP4 antibody in DMD muscles was markedly reduced. Most of the DMD myofibers showed negative staining with sporadic partially positive fibers at their myofiber surface, whereas the control muscles displayed continuous myofiber surface staining. Immunoblot analysis showed that the content of AQP4 in DMD muscles was remarkably decreased. Amplification of leukocyte genomic DNA by polymerase chain reaction showed that the patients with DMD had genomic DNA of the AQP4 molecule. Quantitative reverse transcription polymerase chain reaction demonstrated that DMD skeletal muscles contained markedly decreased AQP4 mRNA compared with controls. CONCLUSION: The reduction in AQP4 in DMD muscles results from decreased levels of AQP4 mRNA in DMD myofibers.

Aquaporin 4↗
PubMed1998

Brain biochemistry in Duchenne muscular dystrophy: a 1H magnetic resonance and neuropsychological study.

Duchenne muscular dystrophy (DMD) is a progressive muscle disorder associated with an intellectual deficit which is non-progressive. We obtained localised 1H magnetic resonance spectra from the left frontal lobe and left cerebellum of 15 boys with DMD (mean age 106 months+/-32) and 15 similarly aged control boys (mean age 115 months+/-31); all boys underwent a battery of neuropsychological tests. We found a significant (P<0.01) increase in the ratio of choline-containing compounds to N-acetylaspartate (Cho/NA) in the left cerebellum in boys with DMD compared with control boys. There was no change in the creatine/NA ratio and a significant increase (P=0.03) in the Cho/creatine ratio, suggesting that the change in Cho/NA ratio was due to an increase in choline-containing compounds; this increase has been previously observed in the brain of the murine model of DMD, the mdx mouse. No significant changes were observed in spectra obtained from left frontal lobe in DMD compared to controls. We also observed a significant association between Cho/NA in the left cerebellum, and the performance of DMD boys on the Matrix Analogies Test (MAT). The MAT is a test of visuo-spatial ability and non-verbal reasoning which requires neither manual dexterity nor a verbal response for an adequate performance. A comparison of DMD boys whose cerebellar Cho/NA fell within 2 standard deviations of the control norm (0.56+/-0.24) with DMD boys whose cerebellar Cho/NA was outside this range (i.e. >0.80) revealed a significant difference in ability on the MAT (P<0.05). DMD boys whose Cho/NA ratio is more than two standard deviations higher than controls perform significantly better on the MAT than DMD boys whose Cho/NA ratio is within the normal range. This finding suggests that the observed elevation in Cho/NA and Cho/creatine is not associated with intellectual deficit (as sampled by the MAT), and may represent a compensatory mechanism. The possible interpretations of these metabolic changes are discussed.

Age Factors↗
PubMed2002

Brain function in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is the second most commonly occurring genetically inherited disease in humans. It is an X-linked condition that affects approximately one in 3300 live male births. It is caused by the absence or disruption of the protein dystrophin, which is found in a variety of tissues, most notably skeletal muscle and neurones in particular regions of the CNS. Clinically DMD is characterized by a severe pathology of the skeletal musculature that results in the premature death of the individual. An important aspect of DMD that has received less attention is the role played by the absence or disruption of dystrophin on CNS function. In this review we concentrate on insights into this role gained from investigation of boys with DMD and the genetically most relevant animal model of DMD, the dystrophin-deficient mdx mouse. Behavioural studies have shown that DMD boys have a cognitive impairment and a lower IQ (average 85), whilst the mdx mice display an impairment in passive avoidance reflex and in short-term memory. In DMD boys, there is evidence of disordered CNS architecture, abnormalities in dendrites and loss of neurones, all associated with neurones that normally express dystrophin. In the mdx mouse, there have been reports of a 50% decrease in neurone number and neural shrinkage in regions of the cerebral cortex and brainstem. Histological evidence shows that the density of GABA(A) channel clusters is reduced in mdx Purkinje cells and hippocampal CA1 neurones. At the biochemical level, in DMD boys the bioenergetics of the CNS is abnormal and there is an increase in the levels of choline-containing compounds, indicative of CNS pathology. The mdx mice also display abnormal bioenergetics, with an increased level of inorganic phosphate and increased levels of choline-containing compounds. Functionally, DMD boys have EEG abnormalities and there is some preliminary evidence that synaptic function is affected adversely by the absence of dystrophin. Electrophysiological studies of mdx mice have shown that hippocampal neurones have an increased susceptibility to hypoxia. These recent findings on the role of dystrophin in the CNS have implications for the clinical management of boys with DMD.

Adult↗
PubMed1996

Identification of a transcriptional enhancer within muscle intron 1 of the human dystrophin gene.

The 14 kb muscle isoform of the Duchenne muscular dystrophy (DMD) gene is expressed primarily in skeletal and cardiac muscle. Transcription of the muscle isoform is induced as myoblasts differentiate into multinucleated myotubes and transcript levels are increased a further 10-fold in mature skeletal muscle. In previous studies we have demonstrated that the core muscle promoter of the human DMD gene contains sequences that regulate the induction of DMD gene expression with myoblast differentiation. However, direct injection studies have indicated that the activity of the core muscle promoter in mature skeletal muscle is 30-fold lower than in immature myotubes. This discrepancy between endogenous transcript levels and core promoter activity suggested that additional transcriptional elements are involved in the regulation of DMD gene expression in muscle. In this report we present evidence for the existence of a muscle-specific enhancer within intron 1 of the human DMD gene. Functional analysis of Hindill fragments from within a 36 kb region surrounding muscle exon 1 of the human DMD gene resulted in the identification of a 5.0 kb fragment within muscle intron 1 that consistently provided high levels of reporter gene expression in both immature and mature skeletal muscle. Sequences within this 5 kb fragment were shown to be functionally independent of position and orientation and to be inactive in fibroblasts, properties that are consistent with the definition of a muscle-specific enhancer. Although this enhancer provided a 30-fold increase in transcription from a SV40 viral promoter in mature skeletal muscle, only a 3-fold increase was observed from the DMD core muscle promoter. Intron 1 enhancer activity alone is therefore insufficient to account for the discrepancy between endogenous transcript levels and core muscle promoter activity in immature and mature skeletal muscle and points to the existence of additional enhancer elements in other regions of the DMD gene. This report provides the first evidence for the involvement of a transcriptional enhancer in DMD gene regulation in muscle and impacts on our understanding of the functional consequences of mutations at the 5'-end of gene. In this regard, deletions in this region in X-linked dilated cardiomyopathy patients provides indirect evidence for a role for this enhancer in regulating DMD gene expression in cardiac muscle.

Dystrophin↗
PubMed2006

The effects of glucocorticoid therapy on the inflammatory and dendritic cells in muscular dystrophies.

Various clinical trials have documented the therapeutic benefit of glucocorticoids (GCs) in enhancing muscle strength and slowing disease progression of Duchenne and Becker muscular dystrophies (DMD/BMD). We hypothesized that GCs may have relevance to the differential anti-inflammatory effect on mononuclear inflammatory cells (MICs) and Dendritic cells (DCs) infiltrating the dystrophic muscles. In this prospective study, two muscle biopsies were obtained (before and after 6-month prednisone therapy) from 30 patients with dystrophies (DMD = 18; BMD = 6; and limb girdle muscular dystrophies (LGMD) = 6). MICs and DCs infiltrating the muscles were examined using mouse monoclonal antibodies and immunoperoxidase staining methods. Muscle strength was evaluated monthly by manual testing, motor ability and timed tests. Prednisone therapy was associated with: (i) functional improvement of overall motor disability, in upper limbs of DMD (P < 0.001) and BMD (P < 0.01) and lower limbs of DMD (P < 0.001) and BMD (P < 0.05); (ii) histological improvement such as fibre size variation (DMD, P < 0.01; BMD, P < 0.05), internalization of nuclei (DMD, P < 0.05), degeneration and necrosis (DMD and BMD, P < 0.01), regeneration (DMD, P < 0.001; BMD, P < 0.01) and endomysial connective tissue proliferation (DMD, P < 0.01; BMD, P < 0.05) and (iii) reduction of total MICs (P < 0.01) and DCs (P < 0.01). There was a positive correlation between the degree of improvement in overall motor disability and reduction of DCs numbers (In upper limbs; r = 0.638, P < 0.01 for DMD and r = 0.725, P < 0.01 for BMD, in Lower limbs; r = 0.547, P < 0.05 for DMD and r = 0.576, P < 0.05 for BMD). Such improvements and changes of MICs/DCs were absent in LGMD. In DMD/BMD, prednisone therapeutic effect was associated with reduced MICs and DCs numbers. Whether this therapeutic effect reflects targeting of the deleterious immune response produced by these cells mandates further investigations.

Adolescent↗
PubMed2001

Calcium currents and transients in co-cultured contracting normal and Duchenne muscular dystrophy human myotubes.

1. The goal of the present study was to investigate differences in calcium movements between normal and Duchenne muscular dystrophy (DMD) human contracting myotubes co-cultured with explants of rat spinal cord with attached dorsal root ganglia. Membrane potential, variations of intracellular calcium concentration and T- and L-type calcium currents were recorded. Further, a descriptive and quantitative study by electron microscopy of the ultrastructure of the co-cultures was carried out. 2. The resting membrane potential was slightly less negative in DMD (-61.4 +/- 1.1 mV) than in normal myotubes (-65.5 +/- 0.9 mV). Both types of myotube displayed spontaneous action potentials (mean firing frequency, 0.42 and 0.16 Hz, respectively), which triggered spontaneous calcium transients measured with Indo-1. 3. The time integral under the spontaneous Ca(2+) transients was significantly greater in DMD myotubes (97 +/- 8 nM s) than in normal myotubes (67 +/- 13 nM s). 4. The L- and T-type current densities estimated from patch-clamp recordings were smaller in DMD cells (2.0 +/- 0.5 and 0.90 +/- 0.19 pA pF(-1), respectively) than in normal cells (3.9 +/- 0.7 and 1.39 +/- 0.30 pA pF(-1), respectively). 5. The voltage-dependent inactivation relationships revealed a shift in the conditioning potential at which inactivation is half-maximal (V(h,0.5)) of the T- and L-type currents towards less negative potentials, from -72.1 +/- 0.7 and -53.7 +/- 1.5 mV in normal cells to -61.9 +/- 1.4 and -29.2 +/- 1.4 mV in DMD cells, respectively. 6. Both descriptive and quantitative studies by electron microscopy suggested a more advanced development of DMD myotubes as compared to normal ones. This conclusion was supported by the significantly larger capacitance of the DMD myotubes (408 +/- 45 pF) than of the normal myotubes (299 +/- 34 pF) of the same apparent size. 7. Taken together, these results show that differences in T- and L-type calcium currents between normal and DMD myotubes cannot simply explain all observed alterations in calcium homeostasis in DMD myotubes, thus suggesting that other transmembrane calcium transport mechanisms must also be altered in DMD myotubes compared with normal myotubes.

Animals↗
PubMed1997

Turn/amplitude-analysis in subclinical myogenic lesions.

OBJECTIVES: To investigate the accuracy of the turn/amplitude-analysis (TAA) in the detection of subclinical myogenic lesions, for which Duchenne (DMD) carriers were taken as a model. MATERIALS AND METHODS: Conventional EMG (MUAP analysis) and the TAA with/without force monitoring were applied to the right brachial biceps and femoral rectus muscles of 26 healthy subjects, 11 possible DMD carriers and 5 obligate DMD carriers. RESULTS: Conventional EMG was unspecifically abnormal in 4 possible and 2 obligate DMD carriers, neurogenic in 1 possible DMD carrier and myogenic in none of the DMD carriers. Mean turns/s (T/S), amplitude/turn (A/T) and the ratio (T/S:A/T) were not significantly different between controls and possible or between controls and obligate DMD carriers. With force monitoring, the ratio (T/S:A/T) was myogenic in 1 obligate DMD carrier at 20% of maximum (brachial biceps). One possible DMD carrier showed a neurogenic distribution of the single T/S-A/T pairs around the normal cloud at 60% of maximum (brachial biceps). Without force monitoring, the TAA was normal in all DMD carriers. CONCLUSIONS: TAA is of limited help in demonstrating subclinical myopathy, irrespective of whether it is carried out with or without force monitoring.

Adult↗
PubMed1981

Abnormal growth kinetics and 5'-nucleotidase activities in cultured skin fibroblasts from patients with Duchenne muscular dystrophy.

The experiments reported herein compare growth kinetics and biochemical properties of cultured skin fibroblasts from patients with Duchenne muscular dystrophy (DMD) and matched normal controls. On day 7 after plating (6000 cells/cm2) cell number and DNA per dish are significantly reduced (P less than 0.0001) in the cultures from DMD patients (n = 14), compared to those from controls (n = 10). Moreover DMD cells contain less lipids and proteins per dish but more per cell than normal fibroblasts (not significant). Variations of media (McCoy's medium instead of Eagle's minimum essential medium) resulted in the same differences between DMD and control cells. Cell kinetic experiments (plating density: 2000 cells/cm2) show increased doubling times of DMD fibroblasts (P less than 0.001; nDMD = 5; ncontrols = 4) whereas plating efficiency is equal for both DMD and controls. On day 7 activity of the membrane bound enzyme 5'-nucleotidase either per mg protein or per microgram DNA is significantly elevated in cells from DMD patients (P less than 0.0005; nDMD = 8; ncontrols = 9) independent of cell density. Thus all findings in cultured DMD fibroblasts: increased doubling time, tendency to more voluminous cells, and elevated 5'-nucleotidase activity per cell suggest, that the DMD cells behave similar to prematurely aging cells. Until now we were not able to check whether any alterations of the plasma membrane are inducing early senescence or, reversely, premature aging is the cause of the postulated membrane alterations. If these findings were to be confirmed in cultured amniotic cells from DMD fetuses, thay could serve as a potential prenatal diagnosis of the disease.

Adolescent↗
PubMed1989

A membrane fluidizing factor in sera from Duchenne muscular dystrophy patients: effect on lymphocyte membranes of incubation in patient and control lipoproteins.

Sera from Duchenne muscular dystrophy (DMD) patients showed a membrane fluidizing effect on DMD and control lymphocytes. To look for the cause of this membrane fluidizing effect, human lymphocytes from healthy subjects were incubated in sera and in different serum fractions from DMD patients and healthy control subjects, and membrane fluidity was determined by steady state fluorescence polarization of the probe diphenyl hexatriene. DMD sera and total DMD lipoproteins showed a similar membrane fluidizing effect (p less than 0.02) after incubation, whereas lipoprotein deficient serum did not show any effect on membrane fluidity. Control and DMD HDL showed a membrane fluidizing effect, the fluidizing effect of DMD HDL being slightly higher as compared to control HDL. Control LDL and DMD LDL showed a membrane rigidifying effect, the rigidifying effect of DMD LDL being significantly lower as compared to control LDL (p less than 0.02). These data demonstrate that the membrane fluidizing effect of DMD serum is lipoprotein associated, LDL being the most important mediator of this effect.

Adolescent↗
PubMed2005

Training-related factors associated with dorsometacarpal disease in young Thoroughbred racehorses in the UK.

REASONS FOR PERFORMING STUDY: Dorsometacarpal disease (DMD) is common in young Thoroughbred (TB) racehorses, often interfering with their training programme. No reports exist on incidence rate or associated risk factors in the UK. OBJECTIVES: To estimate the incidence rate of DMD in TB horses in training for flat racing in the UK and identify associated risk factors, particularly in relation to training regimens. METHODS: Data were drawn from a large prospective study in which TB horses in 13 training yards were monitored for a period of up to 2 years, recording daily training information and details of musculoskeletal injury, including DMD. The incidence of DMD was calculated and survival analysis performed to determine features of the training regimen related to the risk of disease. RESULTS: A total of 335 horses provided 4235 months at risk of DMD. Seventy-nine first episodes were recorded, resulting in an incidence rate of 1.87/100 horse months (95% confidence interval 1.50-2.33). Increasing exercise distances at canter and high speed in short periods (up to 1 month) were associated with an increasing risk of DMD. However, increasing cumulative exercise distances since entering training were associated with a decreasing risk of the disease. CONCLUSIONS: The risk of DMD in young TBs decreases with accumulation of distances exercised at canter and high speed; this reflects the adaptive response of the third metacarpal bone to the loads placed upon it. However, increasing exercise distances in short periods (up to 1 month) increases the risk of DMD, probably as a consequence of microdamage and its associated remodelling response, and should therefore be avoided. POTENTIAL RELEVANCE: Training regimens for young TBs can be adjusted to prevent the occurrence of DMD. Early but gradual introduction of small amounts of high-speed exercise may be beneficial. Canter exercise should be kept minimal on high-speed work days and large amounts of both cantering and high-speed work per week, 2 weeks or per month should be avoided, particularly during the early stages of training, in order to minimise the risk of DMD.

Animals↗
PubMed1992

Protein and energy metabolism in patients with progressive muscular dystrophy.

Studies were made on whether body weight loss in patients with muscular dystrophy is due to reduced intake and/or abnormal expenditure of energy. For this, food intakes and various physiological variables were surveyed in totals of 310 patients with Duchenne muscular dystrophy (DMD) of 11 to 29 years old and 28 patients with limb-girdle muscular dystrophy (LGMD) of 30 to 47 years old. Energy and protein intakes, expressed on a unit body weight basis, in DMD patients were comparable to, or higher than the allowances for age-matched healthy controls, whereas those in LGMD patients were 92 and 94% respectively of these allowances. The basal metabolic rate (BMR), expressed as kcal/kg/day, of DMD patients of all ages was higher than that of controls, the difference increasing with age, and being about 20 to 30% higher than that of controls in older patients with DMD. The BMR of LGMD patients was nearly normal. The maintenance requirements of conventional dietary protein in DMD and LGMD patients were 1.26 and 0.84 g/kg/day, respectively. These values were about 68 and 12% higher than the normal adult value (0.75 g/kg/day), indicating decreased protein utilization and increased protein catabolism. Daily excretion of urinary 3-methylhistidine (3MH) per unit muscle mass (micrograms/mg creatinine) by MD patients was significantly higher than that by controls, indicating increased degradation of muscle protein. The BMR, maintenance protein requirement and 3MH excretion of DMD patients suggest that DMD is a hypercatabolic disease. Comparison of the energy and protein intakes with the allowances estimated in consideration of increased requirements showed deficiencies of energy and protein in DMD patients. Thus, we conclude that the underweight of the DMD patients resulted from nutrient deficiencies due to hypercatabolism, despite their considerably high intakes of energy and protein, expressed as per kg body weight. These deficiencies were confirmed by demonstrating decreased concentrations of free essential amino acids, particularly branched chain amino acids, in their serum. The values of variables of LGMD patients were intermediate between those of DMD patients and control subjects.

Adolescent↗
PubMed2003

Relationship between utrophin and regenerating muscle fibers in duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a dystrophinopathy, and its associated gene is located on Xp21. Moreover, utrophin, a recently identified structural homologue of dystrophin is reported to be up-regulated in DMD. In order to investigate the association between utrophin and muscle regeneration in DMD, an immunohistochemical study using antibodies to utrophin, dystrophin, vimentin and desmin was carried out in 17 cases of DMD, 3 cases of polymyositis and 1 case of dermatomyositis. Dystrophin was negative in almost all cases of DMD, but positive in all cases of inflammatory myopathy (IM). Utrophin was positive in 94.0% of DMD and in 75.0% of IM. 36.4% of the myofibers were positive in DMD, as compared to 10.5% in IM (p=0.001). In both groups, utrophin positivity was present most commonly in small regenerating fibers (p=0.001, 0.013). Vimentin and desmin were intensely positive in regenerating fibers in all cases of DMD and IM. 34.4% and 35.4% of myofibers were positive for vimentin and desmin in DMD, as compared to 21.8% and 20.9% in IM (p=0.001, 0.001). In both groups, vimentin and desmin positivity were present most commonly in small regenerating fibers (p=0.001, 0.001). The staining intensities of utrophin, vimentin and desmin were also higher in small regenerating fibers. These results show that utrophin up-regulation is regeneration-associated, and that it is proportional to the quantity of regenerating myofibers, but is not specific for DMD.

Adolescent↗
PubMed2005

[Therapy of Duchenne muscular dystrophy with umbilical cord blood stem cell transplantation].

OBJECTIVE: To analyze a Duchenne muscular dystrophy(DMD) patient's muscular regeneration, dystrophin expression and locomotive variation before and after he underwent umbilical cord blood stem cell transplantation in order to assess the therapeutic effect. METHODS: A 12-year-old DMD boy who could not walk for 3 years was confirmed by gene analysis and dystrophin protein immune test on his muscle. He had no other chronic disease. By HLA matching, a piece of umbilical cord blood stem cell with 6 HLA sites matching to the boy was found in Guangdong Umbilical Cord Blood Bank. The number of the nucleated cells of the umbilical cord blood stem cell was 24.08x 10(8). After pretreatment for the DMD boy with busulfan, cyclophosphamide and rabbit anti-human thymocyte globulin, the allergenic cord blood stem cells were transplanted into him by intravenous injection. Cyclosporin A, methylprednisolone, MMF, prostaglandin E1 and ganciclovir were given after the transplantation. At the same time, Gran, the granulocytic cell stimulating factor, and gamma globulin were administered. The biochemistry profile including serum creatine kinase (CK), the reconstruction of blood making, the deletion exon of DMD gene, the regenerating muscles, the dystrophin protein expression, and the locomotive function of the DMD boy were tested regularly. RESULTS: (1) The white blood cells (WBC) of peripheral blood decreased gradually to zero after pretreatment. In a period of 15 days after transplantation, the neutrophil increased to 0.5x 10(9)/L; at 25 days, WBC increased to normal level. Blood platelet was more than 20x 10(9)/L at 22 days. The hemoglobin rose to 85-100 g/L. At 140 days, sternal puncture revealed the rapid growth of neutrophil, blood platelet and hemoglobin. (2)At 140 days, the blood type of the DMD boy transformed from type O to type AB (the donor's blood type being AB). There was no grafe versus host reaction. (3) At 18, 30, 43, 55, 74 and 233 days after transplantation, the PCR-short tandem repeat test of the boy's peripheral blood DNA showed that his genotype was completely the same as the donor's. The results of PCR-short tandem repeat tests of the bone marrow cells DNA by sternal puncture at 140, 183 and 235 days were the same as those of the blood DNA. (4) At 60 days, DMD gene analysis by PCR showed that the defected DMD gene (exon 19 deletion) had been corrected by the umbilical cord stem cells transplantation. (5) At 75 days, the biopsy of calf muscle showed there were myoblast cells and muscular tubes growing. The dystrophin expressions were weak, but a few of them were strong. DNA analysis showed that the donor's gene DNA accounted for 1%-13%. At 126 days, obviously increased dystrophin positive muscular fibers of the boy were found. The donor's fibers rose to 2.5%-25%. (6) The serum CK of the boy declined from 5735 U/L to 274 U/L. (7) At 100 days, physical examination revealed improvement in his arms and legs. CONCLUSION: The therapy of Duchenne muscular dystrophy with allogeneic umbilical cord blood hematopoietic stem cell transplantation may reset up the blood-making function, decrease the serum CK level, restore the dystrophin in muscles, and improve the locomotive function of the DMD boy. These data suggest that the allogeneic umbilical cord blood hematopoietic stem cell transplantation may benefit the DMD boys.

Alprostadil↗
PubMed1989

Molecular-genetic study of Duchenne and Becker muscular dystrophies: deletion analyses of 45 Japanese patients and segregation analyses in their families with RFLPs based on the data from normal Japanese females.

This study consisted of 1) molecular deletion analyses in patients with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) using the entire cDNA for the DMD gene as hybridization probes, 2) RFLP analyses in a large number of Japanese normal women using 11 DMD-linked cloned DNAs as probes, and 3) segregation analyses with these RFLP data in 17 DMD families in which prenatal or carrier diagnosis was required. The deletion study showed that 18 (43%) of 42 male DMD patients had a deletion within the DMD gene, while no detectable deletion was found in 3 BMD patients. These deletions were preferentially observed at the 5' end of the DMD gene, while no deletion was found in the 3' portion of the gene. Of a total of 15 RFLPs detected with the 11 probes, one was a new RFLP (probe/enzyme: P20/MspI). In 6 RFLPs, the allele frequencies in the Japanese were statistically different from those in the Caucasian. Based on the RFLP data combined with the result of the deletion study, an estimated diagnostic rate for prenatal diagnosis and/or carrier detection in the Japanese DMD families was 63%. The real diagnostic rate obtained from the prenatal and carrier diagnoses, which were practically performed in 17 families, corresponded to the estimation. A protocol useful for the diagnosis in Japanese DMD families is presented.

Chromosome Deletion↗
PubMed1990

Dystrophin protein and RFLP analysis for fetal diagnosis and carrier confirmation of Duchenne muscular dystrophy.

A pregnant woman with indeterminate Duchenne muscular dystrophy (DMD) carrier status, but with DMD diagnosed in her deceased brother (unavailable for study), presented for prenatal diagnosis, intending to continue the pregnancy only if proven unaffected with DMD with near absolute certainty. Creatine kinase (CK) assays to clarify carrier status were inconclusive. Male sex in the fetus was identified, but DNA restriction fragment length polymorphism (RFLP) analysis was not yet available to this centre to investigate the possible transmission of the DMD gene, and the pregnancy was terminated. Tissue histology and dystrophin protein analysis demonstrated the absence of DMD. In a situation with proven maternal carrier status, future fetal inheritance of the opposite maternal X chromosome would indicate the presence of DMD. However, maternal carrier status remained in doubt through a second pregnancy, even with RFLP studies, and was finally established when dystrophin analysis confirmed the presence of DMD in the second fetus. Histologic findings are presented, contrasting features in the two fetuses. The value of dystrophin analysis for establishing the diagnosis of fetal DMD, in this case proving maternal carrier status in a difficult situation, and for demonstrating DMD gene:RFLP haplotype relationships is illustrated.

Adult↗
PubMed1992

Birth and population prevalence of Duchenne muscular dystrophy in The Netherlands.

Mutations causing Duchenne muscular dystrophy (DMD) have a short survival. Therefore, birth and population prevalence are maintained by new mutations. The present inventory was made to estimate the birth and population prevalence rates of DMD in the Netherlands. Seven methods of case identification were used. Data on 496 definite, probable or possible DMD patients born since 1961, or alive on January 1, 1983, were obtained. Several methods gave an estimated ascertainment of more than 95%. The prevalence rate at birth of DMD was estimated at 23.7 x 10(-5) (1:4215) male live births (MLB) yearly. The prevalence rate in the male population on January 1, 1983 was 5.4 x 10(-5) (1:18496). About 1% of the males in this study may have autosomal recessive Duchenne-like muscular dystrophy. Until now there has been no convincing evidence for geographic differences in DMD prevalence at birth. A list of frequency studies of Duchenne muscular dystrophy is included. The DMD mutation rate calculated by the indirect method is 7.9 x 10(-5) genes per generation. However, this may well be an over-estimate, as this method does not account for germline mosaicism. Using a modified sex ratio method the proportion of sporadic DMD among all cases was estimated to be 0.106 (range 0-0.332). High frequency of germline mosaicism in DMD is a likely cause for the apparent lack of sporadic cases as found in previous studies, if mutation rates in male and female gametes are equal. Therefore, methods for estimating the proportion of new mutants in DMD should take germline mosaicism into account. The modified sex ratio method allows incorporation of data on germline mosaicism if available.

Cohort Studies↗
PubMed1978

Sequence of cardiac changes in Duchenne muscular dystrophy.

Boys with Duchenne muscular dystrophy (DMD) rarely have clinical evidence of myocardial dysfunction during life. Nevertheless, congestive heart failure is a frequent terminal event and autopsy invariably shows dystrophic myocardial involvement. Little is known regarding the progression of heart functional abnormalities in boys with DMD from birth to death. Therefore we have examined the hearts of 18 DMD boys aged 4 to 15 years with the following non-invasive methods: cardiovascular physical examination, electrocardiography, chest x-ray, serum enzymes, and echocardiography. Control subjects were 25 normal boys matched to their DMD counterparts by age and by body surface area. The dystrophic patients were divided into early (N = 9) and late (N = 9) DMD according to manual muscle testing of skeletal muscles. In early DMD, six of 23 cardiac indices differed from control boys; in the late stage, an additional five indices became abnormal. Early DMD was characterized by these abnormalities: tachycardia, large ECG R/S ratio in V1, augmented q wave voltages in Leads I, II, and V5 of the ECG, diminished contractile excursion of the left venticular posterior wall (LVPW) and interventricular septum, and decreased rate of relaxation of the LVPW. In late DMD additional cardiac abnormalities appeared: enlarged heart volume by x-ray, reduced cardiac ejection fraction, diminished change in left ventricular diameter from diastole to systole, reduced maximal systolic endocardial velocity, and decreased rate of circumferential fiber shortening as detected in the echocardiogram. Most of the cardiac abnormalities were revealed only by echocardiography, which is thus shown to be a sensitive method for monitoring the progression of cardiac dystrophy during the life span of the DMD child.

Adolescent↗