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PubMed2006

Current treatment of adult Duchenne muscular dystrophy.

Patients with Duchenne muscular dystrophy (DMD) are living longer into adulthood due to a variety of improvements in health care practices. This growing patient population presents new therapeutic challenges. In this article, we review the literature on current treatment of adult DMD as well as our own experience as a multidisciplinary team actively caring for 23 men ages 19-38 years of age. Approximately one quarter of our adult DMD patients have remained on moderate dose corticosteroids. Daily stretching exercises are recommended, particularly of the distal upper extremities. Cardiomyopathy is anticipated, detected, and treated early with afterload reduction. Oxygen saturation monitoring, noninvasive positive pressure ventilation and cough assist devices are routinely used. Other medical issues such as osteoporosis, gastrointestinal and urinary symptoms are addressed. Current and future therapies directed at prolonging the lifespan of those with DMD will result in further increases in this adult population with special needs and concerns. These needs are best addressed in a multidisciplinary clinic.

Adult↗
PubMed2005

Contribution of Doppler tissue imaging and myocardial performance index to assessment of left ventricular function in patients with Duchenne's muscular dystrophy.

Doppler tissue velocities (DTV) are abnormal in a variety of cardiac conditions when standard measures of ventricular function are normal. Detection of left ventricular dysfunction in Duchenne's muscular dystrophy (DMD) has relied on 2-dimensional imaging yet often these images are suboptimal. This study was undertaken to determine if DTV and the myocardial performance index (MPI) could provide additional diagnostic information in DMD. We determined in 31 patients and 13 age-matched control subjects the prevalence of both abnormal DTV of the mitral annulus and abnormal MPI. Mean values for early diastolic DTV were significantly lower for patients compared with control subjects (P < .001) and were abnormally low in 86% of patients. The MPI was abnormal in 79% of patients. All but one patient with DMD had either abnormal DTV or abnormal MPI yet 19% had normal fractional shortening. DTV and MPI are important additions to the echocardiographic evaluation of patients with DMD.

Adolescent↗
PubMed2005

Functional ability and muscle force in healthy children and ambulant Duchenne muscular dystrophy patients.

Neuromuscular disorders are characterised by progressive muscle weakness, which in time causes functional impairment. To quantify the extent of disease progression, muscle force and functional ability can be measured. Which of these parameters changes most depends on the disease stage. In a previous study, we reported normal values for muscle force obtained by hand-held dynamometry in healthy children aged 4-16 years. In the present study, we report normal values for timed functional tests in healthy children aged 4-11 years. These normal values were compared with values obtained in 16 ambulant patients with Duchenne muscular dystrophy (DMD) aged 5-8 years to study the extent of functional impairment. In ambulant patients with DMD, we found that muscle function assessed by timed functional tests (running 9 m and rising up from the floor) and muscle force assessed by hand-held dynamometry were severely impaired. However, a small reduction of muscle force was accompanied by a large reduction in functional ability. Therefore, in our group of ambulant patients with DMD, timed functional testing was the most sensitive parameter to determine the extent of disease progression. Timed functional testing may therefore be considered as an additional outcome measure in drug trials to evaluate the effects of therapy in ambulant patients with DMD and possibly in other neuromuscular disorders.

Aging↗
PubMed2005

A comparison of gait in spinal muscular atrophy, type II and Duchenne muscular dystrophy.

This study investigated and compared the gait of two patients with spinal muscular atrophy, type II (SMA II) and two patients with Duchenne muscular dystrophy (DMD). These diseases cause a progressive and proximal to distal muscular weakness resulting in the loss of ambulation. The DMD cases had comparable muscle weakness with the SMA II cases on manual muscle testing and patients were assessed using kinematics, kinetics, electromyography and video analysis. SMA II and DMD patients employed different gait strategies for forward movement. SMA II patients used pelvic rotation initiated by the upper body to propel the leg forward and produce the necessary step-length whereas the DMD patients tended to use hip flexion and plantar flexion. Management of SMA II patients would include preservation of hip abductor and flexor strength to maintain mobility.

Biomechanical Phenomena↗
PubMed2005

Mutant viral polymerase in the transition of virus to error catastrophe identifies a critical site for RNA binding.

A foot-and-mouth disease virus (FMDV) polymerase (3D) with amino acid replacements G118D, V239M and G373D (triple DMD mutant) was obtained from a molecular clone derived from a virus population treated with ribavirin, in the transition to error catastrophe (virus extinction through lethal mutagenesis). DMD 3D was expressed in Escherichia coli, purified, and its activity compared with that of wild-type enzyme and mutant enzymes with either replacement G118D, G118A or D338A (the latter affecting the catalytic motif YGDD), generated by site-directed mutagenesis. No differences among the enzymes were noted in their interaction with monoclonal antibodies specific for the FMDV polymerase. Mutant enzymes with G118D or G118A showed a 100-fold decrease in polymerization activity relative to wild-type 3D, using poly(A)/oligo(dT)15 and poly(A)/VPg as template-primers, under several reaction conditions. As expected, the activity of 3D with D338A was undetectable (<0.01 times the value for wild-type 3D). DMD and the G118 mutants showed impaired binding to template-primer RNA whereas the D338A mutant showed a binding similar to wild-type 3D. Transfection of cells with FMDV RNA encoding DMD 3D resulted in selection of revertant viruses that maintained only substitutions V239M and G373D. Consistently, when infectious transcripts encoded 3D with either G118D, G118A or D338A, viruses with reversions to the wild-type sequence were isolated. The implication of G118 in template-primer binding is supported by the location of this residue in the template-binding groove of the FMDV polymerase. In addition to identifying an amino acid residue that is critical for the binding of polymerase to RNA, the results document the presence of defective genomes in the transition of virus to error catastrophe.

Binding Sites↗
PubMed2006

Utrophin upregulation for treating Duchenne or Becker muscular dystrophy: how close are we?

Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disorder for which there is currently no effective treatment. This disorder is caused by mutations or deletions in the gene encoding dystrophin that prevent expression of dystrophin at the sarcolemma. A promising pharmacological treatment for DMD aims to increase levels of utrophin, a homolog of dystrophin, in muscle fibers of affected patients to compensate for the absence of dystrophin. Here, we review recent developments in our understanding of the regulatory pathways that govern utrophin expression, and highlight studies that have used activators of these pathways to alleviate the dystrophic symptoms in DMD animal models. The results of these preclinical studies are promising and bring us closer to implementing appropriate utrophin-based drug therapies for DMD patients.

Animals↗
PubMed2004

A possible role of tryptase in angiogenesis in the brain of mdx mouse, a model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and affects the CNS. Dystrophin is absent in muscle and CNS of both DMD patients and mdx mouse, a model of DMD. While the involvement of vascular compartment in DMD was poorly investigated, some studies suggested a role for mast cells (MC). Tryptase, contained in the MC granules, stimulates angiogenesis in vitro and in vivo. We demonstrated for the first time a correlation between the extent of angiogenesis and the number of tryptase-positive neurons and microvessels and suggest that the tryptase contained in the neurons and in the endothelial cells of the mdx mouse brain may be involved in the regulation of angiogenesis taking place in mdx mouse.

Animals↗
PubMed2002

Prognostic value of electrocardiograms, ventricular late potentials, ventricular arrhythmias, and left ventricular systolic dysfunction in patients with Duchenne muscular dystrophy.

Myocardial involvement is a common finding in patients with Duchenne-type muscular dystrophy (DMD). Nevertheless, the prognostic values of standard electrocardiogram (ECG), ventricular arrhythmias, ventricular late potentials (LPs), and left ventricular (LV) systolic dysfunction have not been extensively investigated. Eighty-four patients with DMD (aged 18.6 +/- 4.8 years) underwent standard and signal-averaged electrocardiography, 24-hour Holter monitoring, and echocardiography. The prevalence of electrocardiographic abnormalities, frequent ventricular premature complexes, LPs, and LV systolic dysfunction was 71%, 32%, 28%, and 35%, respectively. Median follow-up was 76 months (range 5 to 106). The mortality rate in the follow-up period was 27%. The typical DMD electrocardiographic alterations, ventricular arrhythmic pattern, and LPs were not predictors of mortality. In contrast, the presence of LV systolic dysfunction detected on echocardiography was a powerful predictor of mortality in the follow-up period (p = 0.013, hazard ratio 3.14, 95% confidence interval 1.27 to 7.79). Thus, echocardiographic assessment of LV systolic dysfunction provides prognostic information in patients with DMD. Electrocardiographic alterations, ventricular arrhythmias, and LPs have no prognostic value in predicting mortality in these patients.

Adolescent↗
PubMed2003

Proteasome inhibitor (MG-132) treatment of mdx mice rescues the expression and membrane localization of dystrophin and dystrophin-associated proteins.

Dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene, is absent in the skeletal muscle of DMD patients and mdx mice. At the plasma membrane of skeletal muscle fibers, dystrophin associates with a multimeric protein complex, termed the dystrophin-glycoprotein complex (DGC). Protein members of this complex are normally absent or greatly reduced in dystrophin-deficient skeletal muscle fibers, and are thought to undergo degradation through an unknown pathway. As such, we reasoned that inhibition of the proteasomal degradation pathway might rescue the expression and subcellular localization of dystrophin-associated proteins. To test this hypothesis, we treated mdx mice with the well-characterized proteasomal inhibitor MG-132. First, we locally injected MG-132 into the gastrocnemius muscle, and observed the outcome after 24 hours. Next, we performed systemic treatment using an osmotic pump that allowed us to deliver different concentrations of the proteasomal inhibitor, over an 8-day period. By immunofluorescence and Western blot analysis, we show that administration of the proteasomal inhibitor MG-132 effectively rescues the expression levels and plasma membrane localization of dystrophin, beta-dystroglycan, alpha-dystroglycan, and alpha-sarcoglycan in skeletal muscle fibers from mdx mice. Furthermore, we show that systemic treatment with the proteasomal inhibitor 1) reduces muscle membrane damage, as revealed by vital staining (with Evans blue dye) of the diaphragm and gastrocnemius muscle isolated from treated mdx mice, and 2) ameliorates the histopathological signs of muscular dystrophy, as judged by hematoxylin and eosin staining of muscle biopsies taken from treated mdx mice. Thus, the current study opens new and important avenues in our understanding of the pathogenesis of DMD. Most importantly, these new findings may have clinical implications for the pharmacological treatment of patients with DMD.

Animals↗
PubMed2004

Cloning of cDNA encoding a regeneration-associated muscle protease whose expression is attenuated in cell lines derived from Duchenne muscular dystrophy patients.

In the dystrophin-mutant mdx mouse, an animal model for Duchenne muscular dystrophy (DMD), damaged skeletal muscles are efficiently regenerated and thus the animals thrive. The phenotypic differences between DMD patients and the mdx mice suggest the existence of factors that modulate the muscle wasting in the mdx mice. To identify these factors, we searched for mRNAs affected by the mdx mutation by using cDNA microarrays with newly established skeletal muscle cell lines from mdx and normal mice. We found that in the mdx muscle cell line, 12 genes, including L-arginine:glycine amidinotransferase and thymosin beta4, are up-regulated, whereas 7 genes, including selenoprotein P and a novel regeneration-associated muscle protease (RAMP), are down-regulated. Northern blot analysis and in situ hybridization revealed that RAMP mRNA is predominantly expressed in normal skeletal muscle and brain, and its production is enhanced in the regenerating area of injured skeletal muscle in mice. RAMP expression was much lower in individual muscle cell lines derived from biopsies of six DMD patients compared to a normal muscle cell line. These results suggest that RAMP may play a role in the regeneration of skeletal muscle and that its down-regulation could be involved in the progression of DMD in humans.

Amino Acid Sequence↗
PubMedDate not supplied

Carrier detection and prenatal molecular diagnosis in a Duchenne muscular dystrophy family without any affected relative available.

In this paper we report a family where the affected DMD patients were not available for study and a molecular strategy was used for female carriers detection and for prenatal diagnosis. Linkage analysis was performed with two markers within the DMD gene, in all family members screened. DMD markers used (pERT87.8/Taq1 and pERT87.15/Xmn1) seemed not to be informative because the propositas mother (II-2) was homozygous for the minor allele at each marker (T2 and X2), however, the proposita and one sister carried only the major allele, which was inherited from the father. These results suggested that a deletion involving both markers could be present, and was inherited from the mother to both daughters. Quantitative multiplex PCR confirmed the deletion in female carriers, involving at least exons 12 to 17. DNA studies of cultured amniotic fluid cells at 14 weeks gestation, by amplification of specific Y-chromosome sequences, followed by multiplex PCR, lead to the diagnosis of a male fetus affected by DMD.

Adult↗
PubMed1996

Acute gastric dilatation in Duchenne muscular dystrophy: a case report and review of the literature.

Duchenne muscular dystrophy (DMD) is the most common neuromuscular disorder of childhood. Its clinical characteristics that derive from skeletal muscle involvement have been well described. Less well known is that visceral smooth muscle is affected in DMD. We report a case of a 19-year-old man with DMD who presented with severe nonradiating epigastric pain. He was initially sent home from the emergency department with a diagnosis of costochondritis. Acute gastric dilation was not considered in the differential diagnosis despite supportive history, physical examination findings, and radiographs. The case illustrates the lack of familiarity by clinicians of the gastrointestinal manifestations of DMD, including gastric dilatation and intestinal pseudoobstruction. Following a case discussion, the literature relevant to acute gastric atony is reviewed.

Acute Disease↗
PubMed1997

Clinical implications of maximal respiratory pressure determinations for individuals with Duchenne muscular dystrophy.

OBJECTIVE: To analyze the relationship between disease progression, pulmonary volumes, respiratory muscle strength (maximum inspiratory [MIP] and expiratory [MEP] pressure), and arterial blood gases for patients with Duchenne muscular dystrophy (DMD). DESIGN: An inception cohort study of pulmonary volumes, MIPs, and MEPs, correlated with age and PaCO2 levels and with each other using linear and nonlinear regression analyses. SETTING: Outpatient clinic. PATIENTS: Fifty-two consecutive DMD patients who presented for regular evaluations at a regional DMD center. RESULTS: Maximum expiratory pressures were 47.7% +/- 10.9% of normal in the 167- to 14-year-old patients and decreased linearly thereafter (MEP% = -2.7 x age +73.8; p < .001). Declines in MEP also correlated linearly with expiratory reserve volume (p < .001) and inversely with residual volume (p < .001). By contrast, MIP was 66.3% +/- 19.0% in the 357- to 14-year-old patients and then declined to 30.2% +/- 19.5% after age 14. No linear relationships were found with age but declines did correlate linearly with inspiratory reserve volume (p < .001) and total lung capacity (p < .001). PaCO2 elevations correlated best with decreases in MIP (p < .0001) and appeared when MIP was below 30cmH2O. CONCLUSIONS: Lung volume changes in DMD patients correlate with respiratory muscle weakness, and although inspiratory muscle dysfunction plays a key role in the development of chronic ventilatory insufficiency, reductions in expiratory muscle strength are the first signs of dysfunction and lead to the first episodes of respiratory failure.

Adolescent↗
PubMed2001

Service system finance: implications for children with depression and manic depression.

An estimated 6.2% of children in the United States satisfy the criteria for a depression diagnosis, but approximately half of this group do not receive necessary treatment. Thus it is important to consider potential barriers to use through service system finance. This article reviews three major types of changes affecting access: parity legislation, managed care, and public contracting. How these developments will affect children with depression and manic depression (DMD) is unclear. To better understand the potential effects on children with DMD, this review uses new data from the Medical Expenditure Panel Survey to describe the service use patterns of this population. These children have higher levels of expenditures, higher rates of inpatient use, and higher rates of Medicaid payment than do other children with mental health diagnoses; they also are overrepresented among the costliest cases of mental illness in children. Children with DMD pay a relatively low out-of-pocket share, suggesting that parity efforts focusing only on copayments and deductibles will have little effect on the absolute out-of-pocket burden for these children. Because children with DMD are overrepresented among high utilizers of health services, health care rationing arrangements or techniques, such as utilization review and capitation, may place this population at particular risk.

Bipolar Disorder↗
PubMed1998

Quantitative ELISA for platelet m-calpain: a phenotypic index for detection of carriers of Duchenne muscular dystrophy.

In order to measure the amount of m-calpain in platelets from Duchenne muscular dystrophy (DMD) patients, carriers and controls, an enzyme linked immunosorbent assay (ELISA) has been developed using polyclonal antibodies raised against m-calpain (Calcium dependent neutral protease), purified from human placenta. Compared to controls a nine-fold increase in the level of m-calpain was observed in all 25 DMD patients and eight obligate carrier mothers studied. Serum creatine kinase (SCK) values of four of these obligate carriers were found to be overlapping with that of normal values, limiting its usefulness. Since calpain levels were found to be raised in all DMD patients and obligate carriers, the estimation of calpain in all female relatives of the ones affected with DMD (with or without raised serum CK) would prove a facile index. Population screening for carrier females using this cost and labour effective index may help in assessing the carrier status and counselling the at risk families.

Adolescent↗
PubMed2001

Transcriptional activation of the non-muscle, full-length dystrophin isoforms in Duchenne muscular dystrophy skeletal muscle.

Despite promoter tissue specificity, up-regulation of the brain and Purkinje cell type dystrophin isoforms was described in skeletal muscle of X-linked dilated cardiomyopathy (XLDCM) and BMD affected individuals. An extended population of 11 Duchenne muscular dystrophy (DMD) and 11 Becker muscular dystrophy (BMD) patients was investigated to determine whether ectopic muscle expression of the two full-length non-muscular isoforms is a common event in dystrophinopathies and if it has functional significance. Up-regulation of the two non-muscle-specific isoforms was detected in four DMD patients but in none of the BMD affected individuals or non-dystrophic controls. This is the first report of an expression of these two isoforms in DMD skeletal muscle. Ectopic expression is not confined to regenerating or revertant fibers and does not correlate with age at biopsy, clinical phenotype, cardiac involvement, deletion size or location. We consider that muscle ectopic expression of the brain and Purkinje cell-type isoforms has no favorable prognostic significance in DMD and BMD patients.

Adolescent↗
PubMed1996

Immunohistochemical localization of utrophin and other cytoskeletal proteins in skin smooth muscle in neuromuscular diseases.

We investigated the immunohistochemical distribution of cytoskeletal proteins in smooth muscles of 15 patients with Duchenne muscular dystrophy (DMD), 8 patients with Becker muscular dystrophy (BMD), 28 patients with various neuromuscular diseases, and 2 normal controls, performing skin and muscle biopsies. Dystrophin immunostaining confirmed absent reaction in the arrector pili muscles of DMD patients, faint positive reaction in BMD patients, and strong dystrophin reaction in patients with other neuromuscular diseases and normal controls. Immunostaining of utrophin was positive with variable intensity in the arrector pili muscles in all DMD patients. In BMD patients, utrophin was faintly expressed in the arrector pili muscles in 2 cases, and negative in the other 5 patients. In the other cases of neuromuscular diseases and in normal controls, immunostaining for utrophin was negative in the arrector pili muscles. Staining of the capillary endothelial cells and muscular vessel walls was seen in normal controls, as well as in DMD, BMD, and other neuromuscular diseases. Vinculin, vimentin and desmin were expressed both in arrector pili smooth muscles and in vessel walls of patients with dystrophinopathy and other neuromuscular diseases, as well as in normal controls. Thus utrophin is normally expressed in the smooth muscle of the vessels and its expression does not vary in neuromuscular diseases. On the contrary, in the arrector pili smooth muscle utrophin is not expressed in normal controls but it is in dystrophinopathies, paralleling the findings in striated muscle, which expresses utrophin in a reciprocal manner with respect to dystrophin.

Biopsy↗
PubMed1988

Gene studies in newborn males with Duchenne muscular dystrophy detected by neonatal screening.

18,000 newborn males were screened for Duchenne muscular dystrophy (DMD) by creatine kinase (CK) analysis of filter paper blood spots between Jan 1, 1986, and Dec 31, 1987. 5 affected boys have been identified, and in 3 of 5 probands molecular deletions or duplications have been found. 3 of 5 mothers were judged highly likely to be carriers of DMD because of repeatedly raised CK levels, identified gene rearrangements, or both abnormalities. 1 mother has a very low probability of being a carrier and 1 is at an intermediate risk. The use of DNA analyses in new DMD probands identified by neonatal screening has allowed confirmation of the diagnosis and accurate assignment of carrier status in mothers and female relatives in over half the cases studied, and may help to reduce the population incidence of DMD by avoiding delay before clinical diagnosis.

Creatine Kinase↗