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PubMedDate not supplied

Cloning of the breakpoint of an X;21 translocation associated with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder which affects approximately 1 in 3,300 males, making it the most common of the neuromuscular dystrophies. The biochemical basis of the disease is unknown and as yet no effective treatment is available. A small number of females are also affected with the disease, and these have been found to carry X; autosome translocations involving variable autosomal sites but always with a breakpoint within band Xp21 of the X chromosome (implicated by other kinds of genetic evidence as the site of the DMD lesion). In these female patients the normal X chromosome is preferentially inactivated, which it is assumed silences their one normal DMD gene, leading to expression of the disease. In one such affected female the autosomal breakpoint lies in the middle of the short arm of chromosome 21, within a cluster of ribosomal RNA genes. Here we have used rRNA sequences as probes to clone the region spanning the translocation breakpoint. A sequence derived from the X-chromosomal portion of the clone detects a restriction fragment length polymorphism (RFLP) which is closely linked to the DMD gene and uncovers chromosomal deletions in some male DMD patients.

Animals↗
PubMedDate not supplied

Germline mosaicism and Duchenne muscular dystrophy mutations.

Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disease with an incidence of approximately 1 in 3,500 newborn boys. The DMD locus has a high mutation frequency: one third of the cases is thought to result from a new mutation. Linkage studies using probes to detect restriction fragment length polymorphisms and DNA deletion studies have greatly improved DMD carrier detection and prenatal diagnosis. Here we report on two families in which a pERT87 (DXS164) deletion was transmitted to more than one offspring by women who showed no evidence for the mutation in their own somatic (white blood) cells. We also show that the deletion in both siblings in one of the families is identical, indicating that the deletion must have occurred during mitosis in early germline proliferation, leading to a germline mosaicism. This phenomenon may turn out to be a major factor contributing to the induction of DMD mutations, and has important implications for the counselling of DMD families.

Chromosome Deletion↗
PubMedDate not supplied

Preferential deletion of exons in Duchenne and Becker muscular dystrophies.

Duchenne and Becker muscular dystrophy (DMD and BMD) genes are located in Xp21 on the short arm of the X chromosome. DMD patients display a much more severe clinical course than BMD patients, and yet about 10% of cases of each have been reported to have deletions for parts of the gene. Using a complementary DNA subclone of the DMD gene we have screened 66 DMD and BMD patients who had not previously shown deletions with the probes then available. Fifteen patients have a deletion of this part of the gene, indicating a higher deletion frequency in this region (22%). Exons were deleted in five severely affected DMD patients and in ten BMD patients. Significantly, most of these deletions begin in the same region of the cDNA, which implies that there is a common mechanism for the generation of many of these mutations. An apparently identical deletion in one family gave classical BMD in two brothers (presenting in their teens) and only very mild muscle weakness in their 86-year-old great-great-uncle. Taking these data together with data using the probes previously published, we are able to detect deletions directly in 40% of our families requiring antenatal diagnosis or carrier detection.

Adolescent↗
PubMed1983

Multiple-dose doxepin kinetics in depressed patients.

Doxepin (DOX) and desmethyldoxepin (DMD) kinetics were examined in seven depressed patients receiving single daily doses of 150 mg DOX for 1 to 3 wk. Blood samples were collected at 0, 4, 12, 15, 18, and 24 hr after the first dose, at bedtime before doses 7, 14, and 21, and at 4, 12, 15, 18, and 24 hr after the last dose. Plasma concentrations of DOX and DMD were analyzed by high-pressure liquid chromatography. Clinical response to DOX treatment was evaluated by the Zung self-rating depression scale and the Hamilton rating scale for depression. Mean DOX t1/2 after the first dose was 17.7 hr, and it rose to 21.8 hr after the last dose. Mean DMD t1/2 was not significantly affected by multiple dosing (34.2 hr after first dose and 37.1 hr after last dose). Mean values for plasma clearance, volume of distribution, and first-pass metabolism were 0.87 l/hr/kg, 23.8 l/kg, and 69.5%. In depressed patients kinetics were in the normal range. Steady-state concentrations of DOX and DMD were reached within 2 wk of beginning DOX dosing. The concentration-response curve indicated strong correlation between total DOX concentration (DOX + DMD) and antidepressant effect (r2 = 0.76).

Adult↗
PubMed1993

A missense mutation in the dystrophin gene in a Duchenne muscular dystrophy patient.

About two thirds of Duchenne muscular dystrophy (DMD) patients have either gene deletions or duplications. The other DMD cases are most likely the result of point mutations that cannot be easily identified by current strategies. Utilizing a heteroduplex technique and direct sequencing of amplified products, we screened our nondeletion/duplication DMD population for point mutations. We now describe what we believe to be the first dystrophin missense mutation in a DMD patient. The mutation results in the substitution of an evolutionarily conserved leucine to arginine in the actin-binding domain. The patient makes a dystrophin protein which is properly localized and is present at a higher level than is observed in DMD patients. This suggests that an intact actin-binding domain is necessary for protein stability and essential for function.

Amino Acid Sequence↗
PubMed2004

Restoration of dystrophin expression in mdx mice by intravascular injection of naked DNA containing full-length dystrophin cDNA.

Duchenne muscular dystrophy (DMD) is a lethal, X-linked, recessive disease caused by a defect in the dystrophin gene. No effective therapy is available. Dystrophin gene transfer to skeletal muscle has been proposed as a treatment for DMD. However, successful treatment for DMD requires restoration of dystrophin in the affected muscle fibers to at least 20% of the normal level. Current gene transfer methods such as intramuscular injection of viral vector or naked DNA can only transfect a small area of muscle, and therefore is of little clinical utility. We have developed a semisystemic method for gene transfer into skeletal muscle of mdx mice, an animal model for DMD. Naked DNA was injected through the tail artery or vein of mice, in which the aorta and the vena cava were clamped at the location just below the kidneys. The DNA solution was thus forced into the blood vessels of both legs. Luciferase gene expression was detected in all muscle groups in both legs. The effects of injection speed, injection volume, and ischemia time on gene expression were also optimized. LacZ staining was used to check the spread of gene expression in muscle. Although the percentage of transfected fibers was modest (approximately 10%), beta-galactosidase was found in all muscle groups of both legs. Finally, plasmid DNA encoding full-length dystrophin gene was injected into mdx mice and widespread restoration of dystrophin protein was observed in all muscles of both hind limbs. In conclusion, these results demonstrate that the semisystemic delivery of naked DNA is a potential approach towards the long-term goal of gene therapy for DMD.

Animals↗
PubMed1995

Inhibition of proliferation in 8-week-old mdx mouse muscle fibroblasts in vitro.

Our purpose is to understand why mdx muscle does not show the progressive degeneration observed in human Duchenne muscular dystrophy (DMD) muscle. In the mouse, the regenerative process compensates for the necrosis of the muscle fibers, particularly during the acute phase of the disease (5-9 weeks). In DMD muscle, there is a gradual failure of the regenerative process and the muscle fibers are replaced by connective and fatty tissue. We propose that distinct properties of mdx and DMD muscle fibroblasts could be one of the reasons for the differences between the mdx and DMD phenotypes. We found that fibroblasts taken from human DMD and control muscle had similar in vitro proliferative capacities. The proliferation rate of mouse muscle fibroblasts decreased during the acute phase of the disease, and inhibition was complete in fibroblasts from 8-week-old mdx mice. Moreover, the medium conditioned by these cells inhibited fibroblast proliferation. The effect was specific for fibroblasts, since this conditioned medium stimulated myoblast proliferation, as did control fibroblast-conditioned medium. These results suggest that 8-week-old mdx mouse muscle fibroblasts produce an inhibitor of their own proliferation and a growth factor specific for myoblasts in vitro. If these factors are secreted in vivo, the growth inhibitory factory may stop fibroblast proliferation whereas the mitogenic activity could stimulate satellite cell proliferation, thus favouring muscle regeneration.

Adolescent↗
PubMedDate not supplied

Duchenne muscular dystrophy: a model for studying the contribution of muscle to energy and protein metabolism.

Duchenne muscular dystrophy (DMD) is associated with a dramatic muscle mass loss. We hypothesized that DMD would be associated with significant changes in both energy and protein metabolism. We studied the resting energy expenditure (REE) in DMD and control children using indirect calorimetry, and their protein metabolism using an intravenous infusion of leucine and glutamine labeled with stable isotopes. In spite of a 75% muscle mass loss in the DMD children, the REE only decreased by 10%. DMD was associated with increased leucine oxidation but neither protein degradation nor protein synthesis were different from that of the controls. In contrast, whole body turnover of glutamine, an amino acid mainly synthesized in the muscle, was significantly decreased. These studies emphasized the quantitatively poor contribution of muscle to energy and protein metabolism in children. The qualitative impact of muscle mass loss on amino acid metabolism (glutamine) offers a fascinating field of research for the next few years and has therapeutic potential.

Basal Metabolism↗
PubMed2001

Serum phospholipid fatty acid composition and insulin action in type 2 diabetic patients.

Relationships have been demonstrated between insulin sensitivity and the fatty acid (FA) composition of serum and tissue lipids in adult humans. The present study aimed to investigate the above relationships in different groups of type 2 diabetic patients (DM2). The FA composition of serum phospholipids (S-PL) measured by gas liquid chromatography and insulin action during a 2-step hyperinsulinemic isoglycemic clamp (1 and 10 mU/kg. min) were determined in 21 newly diagnosed DM2 subjects (DMN), in groups of long-term DM2 patients treated with hypoglycemic agents (DMH; n = 21) or diet alone (DMD; n = 11), and in 24 healthy subjects (HS). In diabetics, the metabolic clearance rates of glucose at both insulin levels (MCR(glu)submax and MCR(glu)max) were significantly reduced compared with HS (MCR(glu)submax DMN, 5.35 +/- 2.7 mL x kg(-1) x min(-1), DMH, 5.38 +/- 2.17 mL x kg(-1) x min(-1); DMD, 5.48 +/- 2.35 mL x kg(-1) x min(-1) v HS, 10.9 +/- 3.3 mL x kg(-1) x min(-1); P <.01; MCR(glu)max DMN, 13.3 +/- 3.3 mL x kg(-1) x min(-1); DMH, 12.5 +/- 3.0 mL x kg(-1) x min(-1); DMD, 13.3 +/- 3.0 mL x kg(-1) x min(-1) v HS, 17.4 +/- 3.8 mL x kg(-1) x min(-1); P <.05). Increased contents of highly unsaturated n-6 family FA (P <.01), arachidonic acid in particular (DMN, 10.98% +/- 1.79%; DMD, 10.78% +/- 1.64%; DMH, 10.97% +/- 1.7% v HS, 8.51% +/- 1.53%; P <.001), were found in all groups of diabetics compared with HS, while lower levels of linoleic acid were seen in DMN (P <.001) and DMH (P <.05). The contents of saturated FA and monounsaturated FA were comparable in HS, DMN, and DMD. While in HS there were significant negative correlations between MCR(glu) and the contents of saturated FA and a positive association between insulin action and proportions of linoleic and arachidonic acids, no significant relationships were found in diabetic subjects. Different groups of DM2 patients show an altered FA pattern of S-PL, which is not related to insulin action. The above data support the hypothesis that changes in FA composition may play a role in modulating insulin action in peripheral tissues, but cannot explain the insulin resistance (IR) in DM2 patients.

Adult↗
PubMed2001

Cause of progression in Duchenne muscular dystrophy: impaired differentiation more probable than replicative aging.

Replicative aging of myogenic cells (satellite cells) owing to enhanced myofiber turnover is a common explanation of the progression of Duchenne muscular dystrophy (DMD). This hypothesis has been reexamined recently by telomere length measurements in dystrophic tissue. We evaluate the controversial results of these studies. We also review a large body of in vitro, animal (mdx), and patient data which indicate that impaired differentiation, but not replicative aging, is the leading cause of progression in DMD. We recommend in vivo investigations of cell kinetics in DMD muscle, as well as telomere length and telomerase analyses of DMD satellite cells in vitro for a definite judgement of the replicative aging hypothesis. Analogous investigations were helpful in AIDS research where replicative aging was embraced as a simple explanation of the paradigmatic CD4 lymphocyte decline but had to be rejected in favour of more complex models of disturbed lymphocyte homeostasis and regeneration. The question of replicative aging versus impaired differentiation is relevant for the understanding of therapeutic failures and the design of new strategies. Impaired differentiation is compatible with the failure of myoblast transfer in DMD and calls for further studies on the myofiber environment. Replicative aging, on the other hand, could possibly be treated by telomerase gene delivery.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

[Characteristics in the treatment of scoliosis in muscular diseases].

INTRODUCTION: Patients suffering from the most frequent muscle disorders Duchenne muscular dystrophy (DMD) and spinal muscular atrophies (SMA), who ceased walking respectively are confined from the outset to the wheel-chair, are developing commonly a progressive scoliosis (collapsing spine) due to an increasing muscle weakness. Basing on the pelvic obliquity these scolioses are leading first of all to problems in sitting as well as difficulties in trunk and head control. Along with the increasing weakness of respiratory muscles these phenomena entail a restrictive respiratory insufficiency. CONSERVATIVE TREATMENT: An effective conservative treatment is not available for these scolioses. The use of a corset, however, can only be taken into consideration as a compromise, either for very young patients or those who refused an operation respectively who have reached an inoperable stage. The exclusive use of so-called "anatomic sitting supports" in the wheel-chair in order to treat or prevent a progressive scoliosis in DMD or SMA is absolutely to be rejected. They should only be applied for very young patients with SMA type II as a transitional solution until a corset or better an surgical stabilisation of the spine will be effected, or as a palliative measure in late stages. SURGICAL TREATMENT: Only the early as possible performed surgical stabilisation of the spine using adequate instrumentation (Luque, CD or modifications), enabling an early mobilization without corset or cast, is the most effective treatment of these scoliosis. Patients with DMD or SMA type III should be stabilized after loss of walking ability and definitive confinement to wheel-chair, if the curve is more than 20 degrees-30 degrees Cobb and progressive and forced vital capacity (FVC) is > 35%. The instrumentation should be applied between D3 or D4 and sacrum. The bony fusion mass should include the lumbar and lumbosacral region. The unfused instrumentation with the telescope-rod after Naumann is a good solution for patients with SMA type II and progressive curves already in the early childhood from ca. 5 years of age. First of all surgical spinal stabilisation improves the sitting comfort. Over and above this the improved cosmetic appearance should not be underestimated for the psychological condition of these patients. Additionally it is proved, that surgical stabilisation of the spine prolongs the life expectancy of patients with DMD. Furthermore stabilization of lung function can be achieved for both DMD and SMA patients in comparison to the natural history of these diseases. Altogether a decisive improvement of quality of life can be reached for all these patients.

Adolescent↗
PubMed2001

Impairment of cardiac autonomic function in patients with Duchenne muscular dystrophy: relationship to myocardial and respiratory function.

BACKGROUND: Previous studies reported an impairment of nervous autonomic activity in patients with Duchenne muscular dystrophy (DMD). However, the relationship of the autonomic dysfunction to the impairment of cardiac mechanical function and of respiratory failure is not completely understood. METHODS: We evaluated cardiac autonomic function by time- and frequency-domain heart rate variability (HRV) analysis on 24-hour Holter recordings in 60 patients with DMD (16.8 +/- 4.8 years) and 28 healthy control patients (15.2 +/- 4.6 years, P = not significant). The circadian rhythm of R-R interval, low frequency, high frequency, and low-frequency/high-frequency ratio was also assessed. In all patients, left ventricular ejection fraction was measured by 2D echocardiography; respiratory function was assessed by spirometry. RESULTS: All HRV parameters were lower in patients with DMD than in control subjects, with the percentage of differences between adjacent R-R intervals >50 ms (11.6% +/- 8.5% vs 27.3% +/- 14.1%, P =.00001) and high frequency (23.9 +/- 10.3 ms vs 36.1 +/- 12.2 ms, P =.0001) showing the strongest differences. A significant circadian rhythm of HRV variables was present in both groups, but it was considerably flattened in patients with DMD. There was no correlation between left ventricular ejection fraction and HRV indexes except for a weak correlation with high frequency (r = 0.30, P =.02) and with low-frequency to high-frequency ratio (r = -0.29, P <.03). Similarly modest correlations were found between forced vital capacity and high frequency (r = 0.4, P =.007) and low-frequency/high-frequency ratio (r = -0.32, P =.026). Multiple regression analysis did not show any independent predictive variable for the autonomic impairment. CONCLUSIONS: Our data show a marked impairment of cardiac autonomic function in patients with DMD, which appears to mainly involve the parasympathetic branch and appears to have a multifactorial origin.

Adolescent↗
PubMed1984

Abnormal collagen metabolism in cultured skin fibroblasts from patients with Duchenne muscular dystrophy.

Total collagen synthesis is decreased by about 29% (P less than 0.01) in skin fibroblasts established in vitro from male patients with Duchenne muscular dystrophy (DMD) as compared with that in normal male skin fibroblasts in vitro. The reduction in collagen synthesis is associated with an approximately 2-fold increase in collagen degradation in DMD fibroblasts. Correlated to these alterations in the metabolism of collagen, DMD fibroblasts express a significantly higher hydroxyproline/proline ratio (DMD: 1.36-1.45; P less than 0.01) than do normal fibroblasts (controls: 0.86-0.89). The increased hydroxylation of proline residues of collagen (composed of type I and type III) could be the cause for the enhanced degradation of collagen in DMD fibroblasts.

Adolescent↗
PubMed1992

Detection of dystrophin in the postsynaptic density of rat brain and deficiency in a mouse model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a common, lethal, chromosome X-linked inherited disease. Moderate cognitive impairment is a feature of DMD, but the underlying mechanisms are unknown. DMD is characterized by a defect in a protein, dystrophin, that is located predominantly in muscle but has been detected in brain. We sought to directly localize dystrophin within the complex synaptic structure of the cerebral cortex by focusing on the postsynaptic density (PSD), which appears to be central to synaptic function. We report that a specific anti-dystrophin antibody (anti 6-10) recognizes three distinct proteins in the purified PSD: the 400-kDa dystrophin and two previously unidentified dystrophin-related proteins of 120 and 110 kDa. These proteins exhibited differential regional expression in PSDs from cerebral cortex, cerebellum, and olfactory bulb. In the cortical PSD, the 400-kDa dystrophin was predominant, whereas the 120-kDa protein was the major species in cerebellum and olfactory bulb PSDs. The three proteins were differentially expressed in the PSD during cortical development: the 400-kDa protein exhibited a selective 9-fold increase during postnatal days 7 to 10, suggesting a normal physiological role in synaptic maturation. The PSD from the mdx mouse, a model of human DMD, contained no detectable 400-kDa dystrophin but expressed the two dystrophin-related proteins. Our results indicate that brain dystrophins are localized to the PSD, potentially as three isoforms, and raise the possibility that cognitive abnormalities in DMD are attributable to synaptic dysfunction associated with deficits in brain dystrophin molecules.

Animals↗
PubMed2002

Electroretinographic findings in Duchenne/Becker muscular dystrophy and correlation with genotype.

PURPOSE: To correlate the electroretinography (ERG) findings in patients with Duchenne/Becker muscular dystrophy (D/BMD) with the genotype and evaluate the ERG findings in DMD carriers. MATERIALS AND METHODS: Fifteen deletion positive patients with DMD, two deletion positive patients with BMD and six DMD carriers in two families having a positive disease history were evaluated with DNA analysis, ophthalmologic and ERG findings. RESULTS: The mean age of the deletion positive D/BMD patients was 11.1 +/- 3.7 (range: 7-20). No abnormality was detected in the ophthalmic examination of the patients. In three out of 17 patients with D/BMD, ERG was normal whereas in 14 patients electronegative ERG was recorded in scotopic conditions. Mutational alterations observed in these three cases with normal ERG were located exceptionally at 5' hot spot; not like the others within central region. In all DMD carriers ERG findings were recorded as normal. CONCLUSION: ERG findings in D/BMD patients may show some correlations with molecular analysis, whereas it is not useful in DMD carriers.

Adolescent↗
PubMed1985

Neuropsychological impairment in Duchenne muscular dystrophy.

Fourteen younger (ages 6 to 10 years) and 11 older (ages 11 to 16 years) Duchenne Muscular Dystrophy (DMD) patients were tested with the WISC-R and neuropsychological language, visual-motor, and motor tasks. Older boys had an average IQ; younger boys were in the low average IQ range. Younger DMD boys were inferior to the older DMD group on tasks requiring some language and attentional-organizational skills, but not on visual-motor tasks. Older DMD boys were inferior on motor tasks. Results suggest that the reported low cognitive skills in DMD patients are not fixed or global, but reflect selective deficits in the younger boys. Possible bases for age differences in performance are discussed.

Adolescent↗
PubMed1981

Structural changes in lysosomes from cultured human fibroblasts in Duchenne's muscular dystrophy.

We have previously reported a decreased activity of the lysosomal enzyme dipeptidyl aminopeptidase-I (DAP-I) in cultured fibroblasts from patients with Duchenne's muscular dystrophy (DMD). Here we report that electron microscope examination of these cells reveals the presence of abundant lamellar bodies, a morphologic abnormalities commonly associated with impaired lysosomal function. Morphometric analysis of these cytoplasmic figures in dystrophic cells shows a sevenfold increase relative to normal controls (P less than 0.01). Analysis of lysosomal density profiles by density gradient centrifugation reveals similar patterns in normal and DMD cells. Treatment of lysosomes wit the nonionic detergent Triton X-100 causes an activation of DAP-I. This activation, attributable to structure-linked latency, is markedly diminished in DMD cells which show an optimal activation of only 180% compared to 255% for control fibroblasts (P less than 0.01). These data suggest an alteration in the properties of the lysosomal membrane in DMD fibroblasts. This suggestion is also supported by studies on the release of DAP-I from lysosomes by osmotic shock which show it to be a membrane-associated enzyme with membrane-binding characteristics intermediate between those of tightly bound beta-glucosidase and those of unbound N-acetylgalactosaminidase. The latency characteristics of these other lysosomal enzymes are not altered in the DMD cells, indicating that the effect is specific for DAP-I.

Cathepsins↗
PubMed2006

Estimating body composition in children with Duchenne muscular dystrophy: comparison of bioelectrical impedance analysis and skinfold-thickness measurement.

BACKGROUND: Duchenne muscular dystrophy (DMD) is often associated with obesity, which worsens the handicap early in the course of the disease. Nutritional assessment, however, can be difficult and often misleading in DMD. OBJECTIVE: Two methods of estimating body composition in DMD, skinfold-thickness (ST) measurement and bioelectrical impedance analysis (BIA), were compared with a reference method, labeled water dilution (WD). DESIGN: Body composition was estimated by using ST measurements and BIA (50 kHz, 800 mAmp), as well as the WD method (1 mL H2(18)O/kg) in 11 DMD patients with a mean (+/-SD) age of 10.0 +/- 2.5 y. RESULTS: When compared with the WD method, ST measurement significantly (P < 0.01) overestimated fat-free mass (FFM) (mean +/- SD ST: 24.5 +/- 5.9 kg; mean +/- SD WD: 18.2 +/- 2.5 kg), which led to an underestimation of the percentage of fat mass (%FM) (ST: 23.3 +/- 10.4%; WD: 40.1 +/- 17.1%; P < 0.05). In contrast, estimates obtained with BIA (FFM: 21.5 +/- 4.5 kg; %FM: 31.3 +/- 13.9%) did not differ from those obtained with WD. The difference from the reference method was less for BIA (mean: 3.3 kg; 95% CI: 0.8, 4.9 kg) than for ST (6.3 kg; 2.2, 8.6 kg). WD and BIA defined 73% and 55%, respectively, of the children as obese (%FM associated with body mass index cutoffs for obesity), whereas ST measurements defined 9% as obese (P < 0.01). CONCLUSIONS: Body-composition estimates by BIA are closer to those by WD than are those by ST measurement. Early detection of fat accumulation and longitudinal monitoring of nutritional care are 2 relevant applications of BIA to prevent obesity and hence lessen the burden of DMD.

Body Composition↗