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PubMed1991

Carbonic anhydrase III in serum in muscular dystrophy and other neurological disorders: relationship with creatine kinase.

We measured with a radioimmunoassay the concentrations of carbonic anhydrase III (CA-III, EC 4.2.1.1) in sera from 68 patients with muscular dystrophy, 10 carriers of Duchenne muscular dystrophy (DMD), and 63 patients with other neurological disorders. The values obtained were compared with those for creatine kinase (CK, EC 2.7.3.2). Serum CA-III was strikingly increased in patients with DMD (mean, 274.4 micrograms/L) and congenital (Fukuyama-type) (182.8 micrograms/L) and limb-girdle (203.7 micrograms/L) dystrophies and positively correlated with the activities of CK in patients with DMD. CA-III concentration decreased with the subjects' age and the severity of the disease, similar to the tendency observed between age or severity and the concentration of CK. We found moderately increased CA-III in patients with polymyositis, myotonic dystrophy, amyotrophic lateral sclerosis, spinal progressive muscular atrophy, or Kugelberg-Welander disease and in carriers of DMD.

Adolescent↗
PubMed1990

Pharmacokinetics of diltiazem in patients with liver cirrhosis.

The pharmacokinetics of diltiazem (DTZ) was investigated in seven control subjects with normal liver function and in seven patients with liver cirrhosis. After long-term oral administration of diltiazem, 30 or 60 mg thrice daily, serum levels of DTZ and its active metabolites, deacetyl DTZ (DAD) and N-demethyl DTZ (DMD), were determined by high performance liquid chromatography. The mean peak serum concentrations (nmol/L) in control patients were 280 for DTZ, 58 for DAD and 101 for DMD. In cirrhotic patients, the serum DTZ tended to increase and the DAD increased (p less than 0.05), while the DMD decreased (p less than 0.05) compared with that of the control (335 for DTZ, 133 for DAD and 77 for DMD, nmol/L). Pharmacokinetic analysis using a one-compartment model revealed no change in the absorption, but a decrease in the elimination for cirrhotic patients (t 1/2; 5.3 to 7.2 h, p less than 0.1). The elimination rate constant correlated with some biochemical indices for hepatocyte function. These results may be explained by the impaired oxidative metabolism of diltiazem in liver cirrhosis.

Adult↗
PubMed1990

[Molecular pathology of Duchenne and Becker muscular dystrophy].

The gene for Duchenne (DMD) and Becker (BMD) types of muscular dystrophy has been isolated by Kunkel's and Worton's groups and shown to be the largest one over known in human, spanning more than 65 exons distributed over 2,500 kb in P21 region of X-chromosome. Fourteen kb cDNA encodes 427 kD cytoskeletal protein "dystrophin", supposed to form an anti-parallel homodimer like alpha-actinin and spectrin. The polyclonal antibodies against the synthetic peptides or fusion proteins predicted from dystrophin cDNA disclosed the complete absence of dystrophin at the surface membrane of both skeletal and cardiac muscles of DMD in marked contrast with the continuous and uniform staining in normal muscles. In manifested carriers, the mosaic expression of dystrophin was observed at the surface membrane of the skeletal muscle. BMD, which is thought to be allelic to DMD, revealed a faint or patchy immunostaining along with the abnormal and/or lower amount of dystrophin. In BMD, there is an intimate connection between the amount of dystrophin and the severity of the clinical course. It should be noted that 5 out of 39 patients with clinical diagnosis of limb-girdle (L-G) muscular dystrophy showed a patchy staining pattern, suggesting BMD not L-G. On the basis of dystrophin discovery, a possible therapeutic trial of DMD is discussed.

Cloning, Molecular↗
PubMed1990

[Clinical significance of serum cardiac myosin light chain I in patients with muscular dystrophy].

We examined serum cardiac myosin light chain I (LCI), serum creatine kinase (CK) levels and left ventricular function in patients with muscular dystrophy and secondary cardiac involvement. LCI levels were determined by a two-site immunoradiometric assay method in 25 patients with muscular dystrophy and 10 normal subjects. This study included 15 patients with Duchenne muscular dystrophy (DMD), 8 patients with Fukuyama type congenital muscular dystrophy (FCMD) and 2 sisters with non-Fukuyama type congenital muscular dystrophy (nFCMD). We measured the value of left ventricular fractional shortening (FS) using echocardiography. All patients with DMD and FCMD showed moderate or severe skeletal muscle weakness. The mean values of LCI were significantly higher in patients with DMD (11.0 +/- 8.3 ng/ml, p less than 0.01) and in patients with FCMD (1.6 +/- 1.4 ng/ml, p less than 0.05) than in normal subjects (0.3 +/- 0.2 ng/ml). In patients with DMD, LCI level correlated closely with CK level (r = 0.81, p less than 0.01) but not with FS (r = 0.35, n.s.). In patients with FCMD, LCI level correlated significantly with CK level (r = 0.75, p less than 0.05) but not with FS (r = 0.44, n.s.). Close correlation between LCI and CK levels was thought to result from the cross reaction between cardiac LCI and myosin light chains of skeletal muscle in the assay method we used. Two siblings with nFCMD showed mild skeletal muscle weakness. A 22-year-old sister with mild left ventricular dysfunction (FS = 0.41) showed high level of CK (4794/U/L) and mild elevation of LCI (7.3 ngml).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1979

Erythrocyte membrane enzyme abnormalities in two hereditary disorders of muscle.

Enzymatic properties of erythrocyte membranes in Duchenne muscular dystrophy (DMD) and malignant hyperthermia (MH), two genetically determined abnormalities of skeletal muscle, were examined. Acetylcholinesterase (AChE) and ATPase activities were chosen for investigation since alterations in these enzymes have been demonstrated in animal models of dystrophy. A significant decrease in Na+,K+-ATPase activity was noted in DMD patients and a number of possible DMD carriers, suggesting that this enzyme may provide a useful marker of the carrier state in carriers not exhibiting an elevation in plasma creatine phosphokinase activity. No abnormalities in AChE were demonstrable in any of our DMD patients, indicating that human dystrophy is biochemically distinct from certain animal models of dystrophy (e.g., dystrophic mice) where erythrocyte AChE is decreased. In contrast, evidence was found in two known MH carriers, who had normal erythrocyte ATPase activities, for the presence of an altered membrane AChE characterized by an increase in substrate affinity and a large decrease in maximal hydrolytic rate. While the exact relevance of this membrane defect, if any, to the pathogenesis of MH remains to be seen, the presence of this modified enzyme may serve to identify those individuals in a family where a positive history of MH exists who are at risk of developing a hyperthermic crisis during anesthesia.

4-Nitrophenylphosphatase↗
PubMed1989

[A study of superoxide dismutase in erythrocytes in Duchenne muscular dystrophy].

In orders to search for possible events in the pathogenesis of Duchenne muscular dystrophy (DMD), the activity of erythrocyte superoxide dismutase has been determined in thirty-seven patients and fifteen carriers of DMD, comparison to fourty-five age-matched normal controls, seventeen cases of infantile, Kugelberg-Welander type spinal muscle atrophy. The results showed that superoxide dismutase activity were elevated especially in early periods of disease in DMD but not in other groups of patients. These findings suggest that alterations of SOD do not constitute the primary mechanism of inducing membrane damage. A considerable increased SOD activity in DMD patients may be a compensatory phenomenon secondary to muscle degeneration.

Adult↗
PubMed1989

Molecular genetics of Duchenne and Becker muscular dystrophy: emphasis on improved diagnosis.

Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disorder affecting 1 in 3500 males. A less severe and less common form is Becker muscular dystrophy (BMD). Only recently has the basic defect in DMD and BMD been recognized: a region on the human X chromosome is disrupted by mutation. The primary transcript of the region was detected, and cDNA clones were isolated that encompassed the entire transcript. The sequence of the encoded protein was predicted from cDNA nucleotide sequence, portions of the protein were overexpressed in bacterial cells, and these peptides were used to generate immunoreagents against the DMD gene protein, dystrophin. The molecular genetic identification of this protein via analysis of mutations found in patients' material has led to a means of improved diagnosis of DMD/BMD in affected individuals and their family members. The severely affected DMD patients have little or no detectable dystrophin in their muscle, whereas BMD patients have nearly normal concentrations of an altered form of dystrophin; patients with all other neuromuscular diseases have normal dystrophin.

Chromosome Mapping↗
PubMed1989

[Ultrasound imaging of muscles in Duchenne muscular dystrophy].

The ultrasound imaging of quadriceps, gastrocnemius and soleus muscles was performed in 30 patients with Duchenne muscular dystrophy (DMD) and 16 control subjects. In controls, the skeletal muscle itself was scarcely echogenic. However, bone surface and fascia were clearly echogenic. The transverse scan of muscle in all DMD patients showed an increased echogenicity, which made the echo from bone or fascia less intense. The abnormal muscle echo was graded according to Heckmatt et al. From the quantitative aspect, there was a significant correlation between disability scale of DMD patients and abnormal echogenicity of the quadriceps muscle. A similar correlation was also observed between results of manual muscle testing the ultrasound imaging. The soleus muscle was usually less abnormal than the gastrocnemius in the ultrasound imaging. Thus, the ultrasound imaging seemed to provide an important information for the clinical assessment of DMD patients.

Adolescent↗
PubMed1989

[Changes in myoglobin localization in the skeletal muscle of neuromuscular diseases demonstrated by immunohistochemistry and immunoelectron microscopy].

The changes of myoglobin localization in the skeletal muscle cells in Duchenne muscular dystrophy (DMD), myotonic dystrophy (MyD), and amyotrophic lateral sclerosis (ALS) were studied by immunohistochemistry and immunoelectron microscopy. In normal skeletal muscle cells, myoglobin was found in I band, Z line, mitochondrial outer membrane and inner membrane structures of sarcoplasmic reticulum and T tube. In contrast, the myoglobin staining of the I bands in degenerative muscle-cells of DMD and MyD was found rather diminished, and A bands, intraluminal spaces of the inner membrane system and intermyofibrillar spaces were myoglobin positive. Moreover, the I band of a myofibril which slipped out of other normally arranged myofibrils showed no myoglobin staining, but the distended intermyofibrillar spaces adjacent to the slipped myofibril showed a definite staining. In addition, there were dilated sarcoplasmic reticula showing the staining in their lumina, but the I bands neighboring them revealed a diminished staining. In DMD muscle, no staining was found in opaque fibers and some small sized fibers. In ALS muscle, myoglobin was usually positive in the I bands, but the small angulated fibers showed a variable staining. In the target fibers, central zone was not stained but intermediate zone showed altered myoglobin localization. These data indicate that (1) myoglobin localization in the muscle cells varies depending on the sorts of diseases and the grades of muscle cell degeneration, (2) myoglobin in dystrophic muscles fluxes from the muscle cells to extracellular spaces through the dilated sarcoplasmic reticula, T tubes and intermyofibrillar spaces, and (3) in DMD muscle, myoglobin also fluxes directly through the deteriorated plasma membrane in opaque fibers or through the plasma membrane altered due to dystrophin deficiency.

Adolescent↗
PubMed1989

Downward shift in IQ in persons with Duchenne muscular dystrophy compared to those with spinal muscular atrophy.

Patients with Duchenne progressive muscular dystrophy (DMD) and those with spinal progressive muscular atrophy (SPMA) were compared on the basis of memory and IQ. The DMD group was inferior to the SPMA group in memory tests and Full Scale IQ. The DMD group showed poorer scores, despite the fact that functional disabilities and social environments were similar for the two groups. Results thus support the current view that lower IQ is one of the primary manifestations of DMD.

Adolescent↗
PubMed1989

Similarity of IQs of siblings with Duchenne progressive muscular dystrophy.

The similarity of IQs of siblings with Duchenne progressive muscular dystrophy (DMD) was examined to determine whether the view that downward shift in IQ of patients with DMD is a genetically determined primary manifestation of the disease. The mean IQ difference was smaller and the IQ correlation was higher for siblings with DMD than for siblings without the disease. Moreover, these two indices were closer to those for healthy monozygotic twins reared together. These results suggest that the lowered IQ in patients with DMD has a genetic background.

Adolescent↗
PubMed1989

X-linked Duchenne muscular dystrophy. Motor functions and prognosis.

69 patients with x-linked Duchenne Muscular Dystrophy (DMD) were included in a retrospective investigation from 1975-1986. A mean profile of the decline of the motor functions was made by using the median age at which the patients were unable to perform specific motor functions by request. It was found that 81.2% of the personal profiles followed the pattern shown in the mean profile of the disease and that DMD is progressing in a uniform way, but with a different progression rate in every DMD patient. Good correlation between two motor functions made it possible to predict a personal prognosis of the decline of the motor functions in the DMD patient. No correlation between late walkers (later than 18 months) and rapid progression was found.

Chromosomes↗
PubMed1978

Biochemical relationships between muscle and erythrocyte membrane. Interpretations with respect to Duchenne muscular dystrophy.

Whether Duchenne muscular dystrophy (DMD) is a disease of primary myogenic, secondary neuropathic, vascular or membrane etiology is the subject of some debate. Using the erythrocyte membrane as a biopsy tissue we present biochemical data that support the possibility of a defect in myosin as the genetic defect in DMD. Peptide analysis of hydrolyzed erythrocyte spectrin supports previous data demonstrating an alteration in DMD spectrin. The biochemical and biophysical similarities between spectrin and myosin can be tested with available technology. The hypothesis that a defect in myosin may be responsible for DMD is attractive because it is testable.

Erythrocyte Membrane↗
PubMed1989

Gene deletions in X-linked muscular dystrophy.

Of the approximately 170 families with X-linked muscular dystrophy of the Duchenne (DMD) and Becker (BMD) type in Finland, we have studied 90 unrelated patients for intragenic deletions by using the cDNA probes described by Koenig et al. Forty-five patients (50%) had molecular deletions of one or several of the 65 exon-containing HindIII fragments. In six deletion cases junction fragments of altered size were seen. Thirty-eight (84%) of the 45 deletions were detected using only two (1-2a and 8) of the six cDNA subclones. Using a wheelchair age of 12 years to distinguish between DMD and BMD, we found that the proportions of patients with deletions were similar. Deletions were equally common in familial and sporadic disease. BMD was more commonly caused by deletions in the 5' end of the gene than was DMD. In at least three instances deletions of similar type resulted in diseases of similar severity. Of 14 patients with mental retardation seven had deletions; six of these comprised exons contained in probe 8. We conclude that cDNA hybridization studies provide a powerful diagnostic tool in DMD and BMD and that they promise to produce better insights into molecular-clinical correlations.

Chromosome Deletion↗
PubMed1988

Immunocytochemical study of dystrophin in muscle cultures from patients with Duchenne muscular dystrophy and unaffected control patients.

Using immunocytochemical methods, the localization of dystrophin, the gene product affected in Duchenne muscular dystrophy (DMD) in aneural, differentiating human muscle cultures, was studied. Dystrophin was not demonstrable in undifferentiated myoblasts from control patients and from two patients with DMD. After myoblast fusion, the protein was found in circumscribed sarcoplasmic patches, in the perinuclear area, and along the surface of all normal multinucleate myotubes, with more mature myotubes showing predominantly sarcolemmal distribution. There was no staining in myotubes from one DMD patient and only faint diffuse fluorescence in myotubes from the second affected boy, however. These data provide further evidence that dystrophin is a sarcolemma-associated protein, that it is developmentally regulated, and that it is absent or greatly reduced in quantity in skeletal muscle cultures from patients with DMD.

Adult↗
PubMed1986

[Female transmitters of Duchenne's myopathy: detection by quantitative ultrasonography combined with blood creatine kinase].

Duchenne muscular dystrophy (DMD) is a disease inherited in an X-linked recessive manner. Nothing is yet known about the gene defect involved. The problem of DMD carrier detection is very important and now without satisfactory solution. Presently the best method, for this detection, is the determination of the serum creatine-kinase (CK) level. However about 30% of DMD children's mothers have normal CK levels. In this study we associated CK determination and a new echographic method. This physical investigation is based on the muscle attenuation measurements through the evolution of the running spectral moments. The parameter expressed is the slope of the ultrasound attenuation signal (in decibels by centimetre and by megahertz; dB . cm-1 . MHz-1). We measured this parameter in vivo on the vastus medialis. The use of the chemical technique and of the physical one improves largely the detection of obligate carriers of Duchenne muscular dystrophy than when one of these methods is employed alone. One such combination recognizes 17 out of the 19 obligate carriers in our series. The difference of the results obtained by these two unrelated methods cannot be yet interpreted, but can reflect genetic heterogeneity in DMD and the inactivation of the X chromosomes.

Creatine Kinase↗
PubMed1988

Cysteine and metalloproteinase activities in serum of Duchenne muscular dystrophic genotypes.

Lysosomal cysteine proteinase (cathepsin B, H, and L) and MMP-7ase muscle metalloproteinase activities were measured in serum from Duchenne muscular dystrophic male patients and their mothers as gene-carriers. The activity of cathepsin H significantly increased in the Duchenne muscular dystrophic (DMD)-hemizygotes group and in the group of DMD heterozygotes. Significant positive correlation was found between the activity of serum creatine kinase (which previously has been proven to be a marker of muscular dystrophy) and of cathepsin L in the DMD-hemizygotes group. Furthermore, correlations were found between the activity of creatine kinase and MMP-7ase or between activity of creatine kinase and cathepsin H in the DMD heterozygotes. The changes in activity of proteolytic enzymes in serum of dystrophic patients can be explained by the elevated proteolytic enzyme activity in dystrophic muscle observed previously.

Adult↗
PubMed1987

Detection and identification of myoglobin in serum by immunoblotting. Effect of exercise on patients with Duchenne muscular dystrophy.

The diurnal changes and the effect of pre- and postexercise on serum myoglobin (Mb) levels and creatine kinase (CK) activity were investigated and compared in 11 male patients with Duchenne muscular dystrophy (DMD) and 11 normal male controls. The Mb levels and the CK activity in patients with DMD were significantly higher (p less than 0.001) than in the controls under both resting and exercise conditions. No correlation was found between serum Mb levels and CK activity in patients with DMD. The results indicate that Mb is also a useful parameter in both the RIA and the immunoblotting technique for diagnosing muscle-fiber degeneration and screening DMD.

Child↗