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PubMed1982

Decreased A23187-induced chemiluminescence in Duchenne muscular dystrophy granulocytes.

A number of recent reports suggest that intracellular calcium concentration is increased in skeletal muscle in duchenne muscular dystrophy (DMD). Leucocyte chemiluminescent responses are dependent on calcium ions and can be induced by the calcium ionophore A23187. Chemiluminescence may therefore reflect intracellular calcium levels. In order to determine whether non-muscle cells in DMD share the calcium abnormality, we have examined A23187-induced chemiluminescence in DMD leucocytes. Peak calcium dependent chemiluminescence occurred at 0.25-0.75 mM added calcium chloride. Peak chemiluminescent responses in the 13-paired samples were reduced in DMD leucocytes (P less than 0.01) using a paired t-test. These result suggest that there is an abnormality of calcium dependent A23187-induced chemiluminescence in DMD leucocytes and that there may be a generalised abnormality of calcium metabolism in DMD.

Anti-Bacterial Agents↗
PubMed1984

Erythrocyte (Ca2+ + Mg2+)-ATPase activity and calcium homeostasis in Duchenne muscular dystrophy.

Because the erythrocyte (RBC) in Duchenne's muscular dystrophy (DMD) is thought to be a suitable experimental paradigm for the sarcolemma, the RBC membrane-bound enzyme (Ca2+ + Mg2+)-ATPase has been investigated as to its relevance to abnormalities of calcium metabolism in DMD muscle. In this study, RBC (Ca2+ + Mg2+)-ATPase activity, intracellular calcium and potassium contents and complete hemogram were examined in 10 DMD patients and 16 age-matched controls. (Ca2+ + Mg2+)-ATPase activity was found elevated in the DMD RBC, consistent with reports from previous studies, but no abnormalities in intracellular calcium, potassium or hemograms were detected. It seems that although the (Ca2+ + Mg2+)-ATPase activity is changed, it bears no relevance to calcium homeostasis in DMD RBC. It is inferred that the increase in intramuscular calcium in DMD muscle, which is also found in other neuromuscular diseases, may be a non-specific finding in the diseased muscle and part of the final common pathway leading toward cellular degeneration and death.

Adolescent↗
PubMed1987

Duchenne muscular dystrophy: do both parents contribute genetically to the disease?

By observing the effect of 0.08 and 0.02 mg/ml linoleic acid (LA on the electrophoretic mobility of fresh red blood cells derived from the parents of a subject with DMD, it has been shown that all of 16 fathers as well as 15 mothers, consistently differ from normal. In normal subjects, whilst 0.08 mg/ml LA causes increased mobility, 0.02 mg/ml causes reduced mobility (P less than 0.001). In both parents this reversal is abolished and 0.02 mg/ml LA gives the same increased electrophoretic mobility of the RBC as does 0.08 mg/ml. This indicates that there is qualitative alteration of the RBC membrane in both, apparently genetically determined. Only when such an abnormal male mates with an abnormal female can DMD occur in a male offspring; other children appear either normal or showing the same abnormality as do the parents, thus continuing the production of DMD parents, the chance mating of whom produces further DMD. The evidence supports the hypothesis that in DMD there is a widespread membrane disturbance. Other relatives have also been explored. It would appear that the common DMD of children is of autosomal recessive origin with strong limitation to the male.

Adolescent↗
PubMed1991

Preservation of the C-terminus of dystrophin molecule in the skeletal muscle from Becker muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disorder of muscle in children. The DMD gene product, "dystrophin", is absent from DMD, while the allelic disease, Becker muscular dystrophy (BMD), exhibits dystrophin of abnormal size and/or quantity. But we are still uncertain about the scenario that internally deleted (or duplicated) dystrophin in BMD possesses its carboxy (C)-terminal region, and severely truncated dystrophin in DMD does not. Here we use a new monoclonal antibody directed against an peptide in the C-terminal end of the dystrophin molecule to show that the C-terminus is preserved in 30 BMD and 24 control skeletal muscles but not in 21 DMD specimens. This result, taken together with data on deletions of the dystrophin gene, emphasizes both the diagnostic and biological importance of the C-terminal domain which is required for proper function and stability of dystrophin, and substantiates the validity of the reading frame hypothesis for DMD versus BMD deletions on a biochemical level.

Amino Acid Sequence↗
PubMed1987

Dystrophin: the protein product of the Duchenne muscular dystrophy locus.

The protein product of the human Duchenne muscular dystrophy locus (DMD) and its mouse homolog (mDMD) have been identified by using polyclonal antibodies directed against fusion proteins containing two distinct regions of the mDMD cDNA. The DMD protein is shown to be approximately 400 kd and to represent approximately 0.002% of total striated muscle protein. This protein is also detected in smooth muscle (stomach). Muscle tissue isolated from both DMD-affected boys and mdx mice contained no detectable DMD protein, suggesting that these genetic disorders are homologous. Since mdx mice present no obvious clinical abnormalities, the identification of the mdx mouse as an animal model for DMD has important implications with regard to the etiology of the lethal DMD phenotype. We have named the protein dystrophin because of its identification via the isolation of the Duchenne muscular dystrophy locus.

Animals↗
PubMed1990

Effect of chronic administration of verapamil in Duchenne muscular dystrophy.

1. In DMD patients the effect of chronic treatment with verapamil was investigated in the p-nitrophenylphosphatase from erythrocytes, the CK and LDH in serum and the functional activity of the muscle. 2. A different behaviour in the p-nitrophenylphosphatase from untreated compared to treated DMD patients and controls is supported by the following findings: (a) values of "n" altered in F- inhibition of the enzyme with Hill coefficients -1.43, -2.18 and -2.19; (b) Arrhenius plots between 16 and 40 degrees C with inflection points for the enzyme from treated DMD patients and controls and not from untreated DMD patients. 3. Although CK and LDH in serum and the muscular evaluation showed no statistical difference between both groups, evidence is presented that in treated DMD patients the interaction membrane-enzyme is different from untreated DMD patients.

4-Nitrophenylphosphatase↗
PubMed1996

Skeletal, cardiac, and smooth muscle failure in Duchenne muscular dystrophy.

The goals of this study were to describe the clinical course of skeletal, cardiac, and gastrointestinal muscle manifestations and trends in age at diagnosis and survival of Duchenne muscular dystrophy (DMD) patients. A retrospective cohort of 33 male patients with DMD, born between 1953 and 1983 and followed at the Mayo Clinic during their second decade of life, was studied. The mean age at DMD diagnosis was 4.6 years. Skeletal muscle weakness present in all patients at diagnosis progressed to wheelchair dependency in 32 patients (97%) by the age of 13 years (median age 10 years). Cardiac muscle failure developed in 5 patients (15%) (median age 21.5 years). Smooth muscle manifestations related to the digestive and urinary tracts occurred in 7 (21%) and 2 (6%) patients (median age 15 years), respectively. The gastrointestinal dilatations were primary in 2 patients or secondary to surgery or acute respiratory illness in 5 patients. By the end of the study period, 17 deaths had occurred (median age 17 years). Over time, there was a decrease in the time to DMD diagnosis (P = .05) but no significant change in survival (P = .44). Cardiac and smooth muscle manifestations occur late in the course of DMD. Clinical gastrointestinal symptoms related to smooth muscle function most often were secondary to surgery or a respiratory illness. In recent years, the diagnosis of DMD has been made at a younger age, but survival has not changed.

Adolescent↗
PubMed1988

Further studies of gene deletions that cause Duchenne and Becker muscular dystrophies.

Fetal muscle cDNA clones covering at least 11.4 kb of the Duchenne muscular dystrophy (DMD) gene sequence were used to identify a deletion-prone region in DNA from DMD and Becker muscular dystrophy (BMD) patients. Of 36 BMD cases, 17 (47%) had deletions and all of the deletions began in the same intron of the gene. Of 107 DMD patients, 27 (25%) were deleted for this region, and 19 deletions originate in the same intron. Using a cDNA probe for an adjacent region of the gene, 32 new deletions were detected in DMD patients (total 44%). No new BMD deletions were detected. The DMD deletions were very heterogeneous. Thus two cDNA probes covering 2.4 kb could detect 53% of these deletions. Considering the whole locus, DMD and BMD are caused by a deletion of the gene sequence in at least 67% of cases.

Chromosome Deletion↗
PubMed1992

A yeast artificial chromosome contig containing the complete Duchenne muscular dystrophy gene.

A contig of 36 overlapping yeast artificial chromosome (YAC) clones has been constructed for the complete Duchenne muscular dystrophy (DMD) gene in Xp21. The YACs were isolated from a human 48,XXXX YAC library using the DMD cDNA and brain promoter fragments as hybridization probes. The YAC clones were characterized for exon content using HindIII or EcoRI digests, hybridization of individual DMD cDNA probes, and polymerase chain reaction (PCR) amplification of specific exons near the 5' end of the gene. For comparison to the known long-range restriction map of the DMD gene, YAC clones were digested with SfiI and hybridized with DMD cDNA probes. The combined analysis of the exon content and the SfiI map allowed an approximately 3.2-Mb YAC contig to be constructed. The complete 2.4-Mb DMD gene could be represented in a minimum set of 7 overlapping YAC clones.

Chromosomes, Fungal↗
PubMed2006

Myocardial strain changes in Duchenne muscular dystrophy without overt cardiomyopathy.

BACKGROUND: Patients with Duchenne muscular dystrophy (DMD) are at risk of the development of dilated cardiomyopathy and heart failure, thus making early identification of high-risk patients necessary. Myocardial strain imaging (MSI) can be used for quantitative analysis of wall motion of the left ventricle (LV). The aim of this study was to determine whether MSI could detect early changes in myocardial properties in presymptomatic DMD patients with normal LV function. METHODS AND RESULTS: Two-dimensional echocardiographic and tissue Doppler examinations were performed in 13 DMD patients (age range, 11 to 20 years) with normal LV function and in 10 healthy controls. MSI was obtained from tissue Doppler information. In control subjects, strain values in both inner and outer layers of the myocardium were positive at the short-axis image showing the radial systolic thickening. In 10 of the 13 DMD patients, however, myocardial strain showed a negative strain value in systole in the outer layer of the posterolateral wall at the parasternal short-axis image for each cardiac cycle. In 5 of these 10 patients, the timing of the peak systolic velocity at the inferoposterior wall was delayed more than 60 ms than that at the posterolateral wall (mean 80.0+/-17.5 ms). CONCLUSIONS: In some DMD patients with normal LV function, myocardial strain profiles at the posterolateral wall of the LV were different from those in healthy controls, suggesting abnormal myocardial contraction. MSI appears to detect early changes in myocardial features in DMD patients before the onset of overt cardiomyopathy.

Adolescent↗
PubMed1998

Sequential changes in cardiac structure and function in patients with Duchenne type muscular dystrophy: a two-dimensional echocardiographic study.

BACKGROUND: Most patients with progressive muscular dystrophy of the Duchenne type (DMD) die of respiratory failure at approximately 20 years of age. However, some patients with DMD die of heart failure in relatively short periods of time. We investigated the long-term progression of cardiac impairment in patients with DMD by two-dimensional echocardiography. METHODS: We monitored 74 patients for 4 years with two-dimensional echocardiography. Patients were classified into four groups according to the 8-grade Swinyard-Dever system. We also evaluated the echocardiographic features of 22 other patients with DMD with studies performed within 1 year before their deaths. RESULTS: During the 4-year follow-up the left ventricle expanded, and regional left ventricular wall motion abnormalities developed in the posterior wall and apex. Almost all patients had myocardial dysfunction that progressed in parallel with their Swinyard-Dever stage. However, in a few patients who died of congestive heart failure, left ventricular dilation and circumferential left ventricular wall motion were severely impaired. CONCLUSIONS: Myocardial impairment is accelerated in patients with DMD who died of heart failure. Two-dimensional echocardiography is a useful tool for the early diagnosis of left ventricular dysfunction and provides useful information for the treatment of patients with DMD.

Adult↗
PubMed1995

Circadian rhythm and variability of heart rate in Duchenne-type progressive muscular dystrophy.

Using 24-hour Holter monitoring and time domain and power spectral measurements, we evaluated the variability of the heart rate and its circadian rhythm in 55 male patients with Duchenne-type progressive muscular dystrophy (DMD) to characterize their autonomic function versus findings in 20 normal controls. Comparisons were also made in patients with mild, moderate, and severe stages of DMD. The percent difference between successive RR intervals that exceeded 50 ms, a measure of parasympathetic tone, was significantly lower even in patients with early stage of DMD than in controls (p < 0.01). This trend became marked with disease progression. Power in the high-frequency (HF) range (0.15 to 0.40 Hz), a measure of parasympathetic tone, was lower (p < 0.01), and the ratio of the power in the low-frequency (LF) range (0.04 to 0.15 Hz) and that of HF range (LF/HF ratio), a measure of sympathetic tone, was higher in DMD patients versus controls (p < 0.01). This trend was also marked with disease progression. Patients with mild or moderate disease had a slight circadian alteration in HF and LF/HF ratio. Patients with severe disease had virtually no circadian rhythm in HF. Their LF/HF ratio was higher at night (p < 0.01), lower in the morning (p < 0.01), and still lower during the day (p < 0.01), the opposite of control findings. The autonomic abnormalities in DMD were thus characterized by a significant increase in sympathetic activity and a significant decrease in parasympathetic activity. Thus, heart rate variability and circadian rhythm were useful in assessing autonomic dysfunction in DMD.

Adolescent↗
PubMed1995

Brain abnormalities in Duchenne muscular dystrophy: phosphorus-31 magnetic resonance spectroscopy and neuropsychological study.

Duchenne muscular dystrophy (DMD) is one of a range of muscular dystrophies caused by abnormalities of the short arm of the X chromosome (Xp21), which often cause mental retardation in addition to progressive muscular weakness. Normal dystrophin expression is lacking in both skeletal muscle and brain of affected subjects. Phosphorus-31 magnetic resonance spectroscopy has shown several abnormalities in skeletal muscle in DMD. We looked for similar abnormalities in brain in patients with DMD and related the findings to neuropsychological test results. We studied by magnetic resonance spectroscopy 19 boys (aged 76-167 months) diagnosed as having DMD and 19 control boys of similar age (87-135 months). Intelligence quotient (IQ) was assessed with the Wechsler Intelligence Scale for children. The DMD patients had significantly higher values than the controls in the brain ratios of inorganic phosphate to adenosine triphosphate (mean 0.53 [SD 0.21] vs 0.36 [0.09], p = 0.003), to phosphomonoesters (0.40 [0.07] vs 0.29 [0.07], p = 0.0001), and to phosphocreatine (0.44 [0.10] vs 0.37 [0.08], p = 0.02). There were significant differences between the DMD patients and the controls in full-scale IQ (76 [16] vs 101 [16], p = 0.0001), performance IQ (78 [17] vs 94 [14], p = 0.003), and verbal IQ (78 [17] vs 106 [17], p = 0.0001). These altered metabolite ratios parallel the findings in dystrophic muscle and suggest bioenergetic similarities in tissues that lack dystrophin.

Adenosine Triphosphate↗
PubMed1999

Signs and symptoms of Duchenne muscular dystrophy and Becker muscular dystrophy among carriers in The Netherlands: a cohort study.

BACKGROUND: Carriers of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) may show muscle weakness or dilated cardiomyopathy. Studies focusing on skeletal-muscle involvement were done before DNA analysis was possible. We undertook a cross-sectional study in a population of definite carriers to estimate the proportion and to assess the clinical profile of carriers with symptoms. We also assessed a possible correlation between genotype and phenotype. METHODS: Carriers of DMD and BMD, aged 18-60 years, were traced through the files of the central register kept at the Department of Human Genetics in Leiden, Netherlands. For each carrier who agreed to participate a medical history was taken, and muscle-strength assessment by hand-held dynamometry and manual muscle testing and cardiological assessment were done. FINDINGS: 129 carriers of muscular dystrophy (85 DMD, 44 BMD) participated in the study. In 90 women from 52 (70%) families, 37 different mutations were found. 28 (22%) women had symptoms. 22 (17%) had muscle weakness, varying from mild to moderately severe. Muscle weakness was found in carriers of DMD and BMD, but dilated cardiomyopathy was found only in seven (8%) carriers of DMD, of whom one had concomitant muscle weakness. There was an unexpectedly high proportion of left-ventricle dilation (18%). No genotype-phenotype correlation was found. INTERPRETATION: Clinical manifestation of muscle weakness, dilated cardiomyopathy, or both can be found in about a fifth of carriers of DMD and BMD. If left-ventricle dilation is taken into account, the proportion of carriers with symptoms is even higher, amounting to 40%.

Adolescent↗
PubMed1999

Is glutamine a 'conditionally essential' amino acid in Duchenne muscular dystrophy?

To determine whether whole body protein kinetics are altered in Duchenne muscular dystrophy (DMD), six 9 +/- 1-year-old children with DMD and five weight and height matched controls, received intravenous infusion of L-[1-(13)C]leucine and L-[2-(15)N]glutamine in the post-absorptive state. Glutamine rate of appearance was approximatly 24% lower in DMD boys than in controls (321 +/- 22 vs 425 +/- 37 micromol kg(-1)h(-1), P< 0.05) resulting from a 32% decrease in glutamine de novo synthesis (230 +/- 21 vs 340 +/- 34 micromol kg(-1)h(-1), P< 0.05). Whereas there was no difference between groups in estimates of protein degradation and synthesis, leucine oxidation rate was 44% higher in DMD boys than in controls (23 +/- 2 vs 16 +/- 2 micromol kg(-1)h(-1), P< 0.05). The data suggest that the dramatic mucle mass loss observed in DMD boys is associated with a) significant protein wasting, since increased leucine oxidation reflects a more negative whole body leucine balance, and b) a significant decrease in glutamine availability in the postabsorptive state. Glutamine might therefore be a 'conditionally essential' amino-acid in DMD.

Adolescent↗
PubMed1999

Cardiac involvement in carriers of Duchenne and Becker muscular dystrophy.

A cross-sectional study in a cohort of DNA proven carriers of Duchenne (DMD) and Becker (BMD) muscular dystrophy was undertaken with the following objectives: (1) to estimate the frequency of electrocardiographic (ECG) and echocardiographic abnormalities; (2) to establish the proportion of carriers with dilated cardiomyopathy and (3) to assess possible associations between dilated cardiomyopathy and genotype. One hundred and twenty nine DMD and BMD carriers, aged 18-60 years, were traced through the files of the central register kept at the department of Human Genetics in Leiden. Investigations included full medical history, physical examination, ECG and two-dimensional and M-mode echocardiographic examination. Forty-seven percent had ECG changes. Thirty-six percent (DMD 41%, BMD 27%) had at least one abnormality as is usually found in the male patients. Echocardiographic examination was abnormal in 36% (DMD 38%, BMD 34%). Dilated cardiomyopathy was found in seven DMD carriers (8%), and in none of BMD carriers. In addition, 18% had left ventricle dilatation (DMD 19%, BMD 16%). Only 38% had a completely normal investigation of the heart. We found no association between genotype and cardiac manifestations. Our study underlines that cardiac involvement is part of the dystrophinopathies. Carriers should be told about the increased risk of this complication when asking genetic advice. It also implicates that a complete cardiological evaluation should be performed at least once in all carriers. If left ventricle dilatation or dilated cardiomyopathy is present a yearly follow up is needed, in order to start timely therapy.

Adolescent↗
PubMed1988

The Duchenne muscular dystrophy gene product is localized in sarcolemma of human skeletal muscle.

Duchenne muscular dystrophy (DMD) and its milder form, Becker muscular dystrophy (BMD), are allelic X-linked muscle disorders in man. The gene responsible for the disease has been cloned from knowledge of its map location at band Xp21 on the short arm of the X chromosome. The product of the DMD gene, a protein of relative molecular mass 400,000 (Mr 400K) recently named dystrophin, has been reported to co-purify with triads of mouse and rabbit skeletal muscle when assayed using polyclonal antibodies raised against fusion proteins encoded by regions of mouse DMD complementary DNA. Here we show that antibodies directed against synthetic peptides and fusion proteins derived from the N-terminal region of human DMD cDNA strongly react with an antigen present in skeletal muscle sarcolemma on cryostat sections of normal human muscle biopsies. This immunoreactivity is reduced or absent in muscle fibres from DMD patients but appears normal in muscle fibres from patients with other myopathic diseases. The same antibodies specifically react with a 400K protein in sodium dodecyl sulphate (SDS) extracts of normal human muscle subjected to Western blot analysis. We conclude that the product of the DMD gene is associated with the sarcolemma rather than with the triads and speculate that it strengthens the sarcolemma by anchoring elements of the internal cytoskeleton to the surface membrane.

Antibodies↗
PubMed2001

Cell invasion is affected by differential expression of the urokinase plasminogen activator/urokinase plasminogen activator receptor system in muscle satellite cells from normal and dystrophic patients.

The aim of this study was to evaluate the differential expression and the function in cell movement and proliferation of the urokinase plasminogen activator (u-PA) system in muscle satellite cells (MSC) of normal individuals and patients with Duchenne muscular dystrophy (DMD). By immunoenzymatic, zymographic, and radioligand binding methods and by quantitative polymerase chain reaction of the specific mRNA we have shown that both normal and DMD MSC produce u-PA and the plasminogen activator inhibitor-1 and express u-PA receptors (u-PAR). During the proliferation phase of their growth-differentiation program, MSC from DMD patients show more u-PAR than their normal counterpart, produce more plasminogen activator inhibitor-1, and release low amounts of u-PA into the culture medium. By Boyden chamber Matrigel invasion assays we have shown that normal MSC are more prone than DMD cells to spontaneous invasion but, when subjected to a chemotactic gradient of u-PA, DMD MSC sense the ligand much better and to a greater extent than normal MSC. u-PA also stimulates proliferation of MSC, but no difference is observable between normal and DMD patients. Antagonization of u-PA/u-PAR interaction with specific anti-u-PA and anti-u-PAR monoclonal antibodies and with antisense oligonucleotides inhibiting u-PAR expression indicates that u-PA/u-PAR interaction is required in spontaneous and u-PA-induced invasion, as well as in u-PA-induced proliferation.

Base Sequence↗