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PubMed1993

Topographic pattern of the rearrangement of the dystrophin gene in Japanese Duchenne muscular dystrophy.

To compare the frequency and distribution of rearrangements in the dystrophin gene in Duchenne muscular dystrophy (DMD) between Japanese DMD patients and those in North America and Europe, Southern blot analyses of the dystrophin gene were carried out in 88 probands classified as DMD. Gene rearrangements were found in 61 (69%) subjects, and they were composed of partial gene deletions in 53 (60%) probands and partial duplications in 7 (8%) probands. A total deletion of the gene was found in 1 (1%) patient. Among 53 patients with deletions, 34 (64%) had breakpoints between introns 44 and 52 and 7 (13%) had breakpoints between introns 2 and 11. Both the frequency and the distribution of gene rearrangements found in this study were similar to those reported in North America and Europe. These data suggest that there are no ethnic or racial differences in the frequency and distribution of rearrangements thought to be caused by similar mechanisms in the dystrophin gene in all human racial groupings.

Adolescent↗
PubMed1995

Importance of lower limb surgery in Duchenne muscular dystrophy.

A total of 123 patients with Duchenne muscular dystrophy (DMD) was surgically treated during two different periods of their course by hip and knee release, aponeurectomy of the iliotibial band and z-shaped Achilles' tendon lengthening. In 57 patients (group I) this was carried out prophylactically as retractions of the lower limb joints were just beginning at the age of 6.4 +/- 1.43 years and in 66 patients (group II) as mild contractures of the joints at the end of walking ability were already manifest with an average age of 9.27 +/- 1.86 years. The average follow-up was 3.7 +/- 1.2 years in both groups. To be able to assess the interindividual course of both groups, we defined "joint and motor quotients", which allowed a complex assessment of joint function and motoric capacity. In addition, both groups were compared with a control group (natural history) consisting of 100 non-operated DMD patients. In both groups a significant release of the contractures could be obtained primarily. Patients in group I showed a much better long-term effect than those in group II. The motor quotient in group I was significantly better over the whole follow-up period (P < 0.001) than in group II or the control group. The prolongation of walking ability by about 2 years compared with the natural history is in our opinion not the central goal of this surgical treatment concept of lower limbs in DMD, but rather the additionally achieved prolongation of an assisted standing ability with the lower limbs free from contractures and deformities.(ABSTRACT TRUNCATED AT 250 WORDS)

Child↗
PubMed1989

Effect of feeding some plant foods as source of dietary fibre on biological utilisation of diet in rats.

Isoproteinous diets containing 1% cholesterol and 10% fibre derived from plant foods namely, peepalbanti (Ficus religiosa), barbanti (Ficus bengalensis), gullar (Ficus glomerata), teent (Capparis decidua) and khejri beans (Prsopsis cineria) or pure cellulose, were fed to rats for 40 days. Effect of incorporation of these whole plant parts on feed intake, weight gain, feed efficiency ratio (FER), dry matter digestibility (DMD) and true protein digestibility (TPD) in weanling rats was studied. Their inclusion did not affect the weight gain significantly whereas all other parameters were influenced to a varying extent. Foods rich in lignin had relatively lower FER, DMD and TPD whereas cellulose and pectin rich foods had higher DMD and TPD.

Animals↗
PubMedDate not supplied

Neurophysiological mechanisms of the attention disturbance in children with learning difficulties.

The features of orientation reaction (OR) and the background EEG were investigated with the purpose of studying the neurophysiological mechanisms of the disturbance of voluntary attention in children aged 6.5-9 years with learning difficulties caused by delayed mental development (DMD). A decrease in the expressivity of components of the OR as compared with the norm, discovered in a situation of involuntary attention against a background of insufficiently developed cortical rhythmicity in the alpha range, was compensated for given an increase in the significance of the stimuli. These facts support the hypothesis of a deficit in regulatory corticofugal influences in children with DMD. The inadequacy of the engagement of central regions of the cortex characteristic of children with DMD in the realization of OR in a situation of directed attention can be regarded as a reflection of disturbances of the integrative activity of the brain.

Attention↗
PubMed1996

Allele frequencies of intragenic, and 5' and 3' markers of the dystrophin gene in Japanese families afflicted with Duchenne or Becker muscular dystrophy.

Using the polymerase chain reaction method (PCR), we examined the allele frequencies and heterozygosities of 7 polymorphic sites (pERT87, and CA polymorphisms in the 5' and 3' regions) of the dystrophin gene in 20 Japanese Duchenne muscular dystrophy and Becker muscular dystrophy (DMD or BMD) families consisting of 36 males, including 23 cases of DMD and BMD, and 28 females. The allele frequencies of three primer and enzyme sets in the pERT87 locus were well comparable to those in the previously reported Japanese female cases but different from in other countries. The frequencies of 5' markers of the dystrophin gene in Japanes were different from the reported Caucasian frequencies. As for 5'DYS-I and 5'DYS-II, the numbers of alleles in our cases were less than in Caucasians, and the heterozygosities of all three markers (5'DYS-I, II and III) were lower than in Caucasians. However, the 3'CA polymorphisms showed almost the same frequencies and heterozygosities as in Caucasians. All of our females showed a heterozygous pattern for at least one locus, with the combination of the seven markers. The usefulness of linkage analysis involving PCR methods with these intragenic, and 5' and 3' markers of the dystrophin gene in the carrier and prenatal diagnosis of DMD and BMD was confirmed by the successful prenatal diagnoses in 15 fetuses, the exception being one case considered to have a new mutation.

Alleles↗
PubMed1993

Detection of partial deletion and partial duplication of dystrophin gene in Japanese patients with Duchenne or Becker muscular dystrophy.

The dystrophin gene was analyzed in 59 Japanese patients with Duchenne muscular dystrophy (DMD) from 48 unrelated families, including 11 pairs of siblings, and three patients with Becker muscular dystrophy (BMD) from two unrelated families, including one pair of siblings. The relationship between the type of gene abnormality and clinical symptoms was examined. Twenty-seven of 50 (54.0%) unrelated DMD or BMD patients were found to have partial deletions, and five (10%) appeared to have partial duplications in the dystrophin gene. Nine DMD patients, including three pairs of siblings, showed mental retardation, the existence of which was coincident in each pair of siblings, but deletion of an identical exon was not always related to mental retardation in unrelated patients.

Adolescent↗
PubMed1990

Plasma thyroxine levels in Duchenne muscular dystrophy.

Some young Duchenne muscular dystrophy (DMD) patients (3-7 years) had total thyroxine (T4) levels and T4 to thyroxine binding globulin (TBG) ratios above the normal range and significantly increased free thyroxine indices (fT4I) which, however, remained within the normal range. Older DMD patients (7-11 years) had T4 and TBG levels and fT4I similar to normal. In both DMD groups the thyroxine binding index (TBI) values were in the normal range.

Age Factors↗
PubMed1992

Somatic mosaicism for a deletion of the dystrophin gene in a carrier of Becker muscular dystrophy.

Duchenne muscular dystrophy (DMD) and the allelic milder form of Becker muscular dystrophy (BMD) are caused by mutations of the dystrophin gene on the short arm of the X chromosome. One third of affected individuals are expected to result from de novo mutations. Genetic counselling of families with sporadic cases is complicated by the potential meiotic origin of the mutation in the mother resulting in germline mosaicism. Here we present direct evidence for combined somatic and germline mosaicism for a deletion of the dystrophin gene, thereby proving the mitotic origin of this deletion and pinpointing a further potential pitfall for genetic counselling. The mother of a BMD son and a BMD carrier daughter, both carrying a deletion of dystrophin cDNA 7 (0.5 kb Hind III fragment) and cDNA 8, was herself clinically healthy and had normal creatine kinase levels. A muscle specimen of the mother showed mild overall pathology as well as focal dystrophin deficiency. In contrast chromosomal in situ suppression (CISS) hybridization of metaphase chromosomes using a cosmid clone of the corresponding cDNA deleted in her son revealed no evidence of somatic mosaicism in their lymphocytes. These results emphasize the value of an approach correlating genetic and immunological data for the definition of a carrier state in BMD or DMD. The possibility of somatic mosaicism should be considered when genetic counselling of a family with a sporadic case of BMD or DMD is performed.

Blotting, Southern↗
PubMed1983

Radioimmunoassayable myoglobinaemia and Duchenne carrier detection.

1 case of Duchenne Muscular Dystrophy (DMD) definite carrier, 3 probable and 17 possible (all analytically positive: "possible +") carriers were classed as Group A, 23 DMD possible carriers (all analytically negative "possible") as Group B and 26 normal subjects as Controls. The three groups were subjected to serum myoglobin (MGB) radioimmunoassay. Since the differences between MGB levels of Group A vs. Controls and Group A vs. Group B were statistically significant, it is suggested that the determination of MGB should be included among the tests for DMD carrier detection.

Adolescent↗
PubMed1988

Cardiomyopathy of Duchenne muscular dystrophy.

A total of 18 male patients with Duchenne muscular dystrophy (DMD), aged 8-29 years (mean, 15.7 years), were prospectively studied to assess the cardiomyopathy associated with DMD, using clinical parameters and noninvasive cardiovascular investigations: electrocardiogram (ECG), Holter monitoring, and echocardiography. In addition, five clinical tests of cardiovascular autonomic function were used to assess the role of the autonomic nervous system in the pathogenesis of dysrhythmias. The majority of subjects were asymptomatic, but four had abnormal physical findings. All had abnormal ECG, the commonest abnormality (in 16) being tall R waves or increased R/S ratios in the right precordial leads; 14 had abnormal findings on echocardiography, including three with poor left ventricular function and five with mitral valve prolapse (MVP). Labile abrupt sinus tachycardia was present in 11, and four had high-grade ventricular ectopy. None had definite clinical evidence of autonomic dysfunction. The cardiomyopathy of DMD appears to be unrelated to disease severity. However, abnormal Q waves or Q/R ratios in ECG leads I, aVL9 and V5-V6 are significantly related to young age (p less than 0.05), and high-grade ventricular ectopy occurred significantly more frequently (p less than 0.05) in older subjects (greater than 15 years). Dysrhythmias were not related to the presence of MVP, poor left ventricular function, or autonomic dysfunction.

Adolescent↗
PubMed1990

Deletion screening and prenatal diagnosis of Duchenne muscular dystrophy using cDNA probes Cf 23a and Cf 56a.

We have screened patients of 14 families at risk for Duchenne muscular dystrophy (DMD) from the northern part of the German Democratic Republic using the cDNA clones Cf 23a and CF 56a. Of the 14 unrelated DMD families, 7 (50%) showed different deletions with these cDNA probes. A prenatal diagnosis by chorionic villi sampling was performed in a DMD family with patients showing a deletion of the 5.4 kb Pst I band detected by the cDNA probe Cf 56a. This band corresponds to a 10 kb exon region of the cDNA probe 8 of Koenig et al. The patient's mother was informative only for the flanking marker 99.6. The male fetus showed the same haplotype and the same deletion as the two patients.

Chromosome Deletion↗
PubMed1995

Influence of dystrophin-gene mutation on mdx mouse behavior. I. Retention deficits at long delays in spontaneous alternation and bar-pressing tasks.

X-linked Duchenne muscular dystrophy (DMD) is frequently associated with a nonprogressive, cognitive defect attributed to the absence of dystrophin in the brain of DMD patients. The mutant mdx mouse, lacking in 427-kDa dystrophin in both muscle and brain tissues, is considered to be a valuable model of human DMD. In the present study, we compared mdx and C57BL/10 control mice and showed that mdx mice had impaired retention in a T-maze, delayed spontaneous alternation task 24 h, but not 6 h, after acquisition. mdx mice were not impaired in acquisition of a bar-pressing task on 4 consecutive days but showed poor retention 22 days after the last training session. Mutants and controls showed similar behavioral responses in free exploration and light/dark choice situations and did not differ in spontaneous locomotor activity or motor coordination. Retention impairments at long delays in mdx mice suggest a role of dystrophin in long-term consolidation processes.

Animals↗
PubMedDate not supplied

Suitable analyzed signal duration and criteria for abnormal signal-averaged electrocardiogram on frequency-domain analysis in patients with Duchenne's muscular dystrophy.

To establish the criteria for an abnormal signal-averaged electrocardiogram (SA-ECG) in patients with Duchenne's muscular dystrophy (DMD), we used the technique of fast-Fourier transformation and studied the effects of analyzed signal phase and attenuation of low frequency components by filter processing. Twenty-three patients with DMD and twenty age-matched healthy volunteers were studied. An abnormal SA-ECG was defined as an area ratio of high frequency components/low frequency components over the 97th percentile of normal controls. Frequency domain analysis of the terminal 40 ms of the QRS complex and 80 ms of the initial ST segment was most predictive for distinguishing DMD patients at risk for ventricular tachycardia (VT). Although filter processing reduced the power of low frequency components and increased the area ratios, the sensitivity for the prediction of VT was not significantly enhanced. The area ratios of 40-100 Hz/0-40 Hz were superior to the area ratios of 20-50 Hz/0-20 Hz for predicting patients with VT.

Adolescent↗
PubMed2005

The role of polymorphic short tandem (CA)n repeat loci segregation analysis in the detection of Duchenne muscular dystrophy carriers and prenatal diagnosis.

BACKGROUND: Duchenne and Becker muscular dystrophies (DMD/BMD) are X-linked diseases caused by mutations in the dystrophin gene at Xp21.2; they include gross deletions (60%), duplications (10%), and small mutations (30%). Since there is no cure or effective treatment for progressive muscular dystrophy, prevention of the disease is important and strongly depends on carrier-status information. Two-thirds of DMD/BMD cases are familial; thus, female relatives are candidates for carrier-risk assessment. AIM: Segregation analysis of polymorphic short tandem (CA)n repeats [STR-(CA)n] was used to establish and compare the haplotypes of female relatives of patients with DMD/BMD with those of the patient in order to identify the mutant dystrophin gene and thus determine each female relative's carrier status. METHODS: 248 individuals from 52 families were studied through segregation of up to 11 STR-(CA)n loci. The assay was performed on leukocyte DNA by PCR amplification, polyacrylamide-gel electrophoresis and autoradiography. Haplotypes were established by determination of alleles on the autoradiography. RESULTS: 38 of 51 (75%) female relatives from familial cases were diagnosed as carriers or non-carriers with a 95-100% likelihood, and 18 out of 56 (32%) female relatives from sporadic cases could be excluded from the risk of being a DMD carrier with the same probability. In addition, STR studies detected gross deletions in 13 of the 52 (25%) families in both male and female individuals, four of which were de novo deletions. STR assays were also informative in families without an available DNA sample of an affected male and in two of seven symptomatic females. Determination of carrier status was particularly significant for prediction of DMD risk in prenatal analysis of five male chorionic villi. Other genetic events revealed by STR analysis were: (i) 11 recombinations identified in 6.6% of meiosis in the DMD families; (ii) germinal mosaicism detected in two female carriers; and (iii) changes in STR-(CA)n length during transmission from father to daughters, including three retractions and one elongation at an estimated rate of 0.004. CONCLUSION: The STR assay is an excellent molecular tool for carrier-status identification and the detection of deletions and other genetic changes in families affected by DMD/BMD. Thus, it is useful in genetic counseling for the prevention of this disease.

Base Sequence↗
PubMed2000

Increased activity of calcium leak channels caused by proteolysis near sarcolemmal ruptures.

Dystrophin, a 427 kD membrane-associated structural protein in muscle cells, is thought to confer strength to the myofiber sarcolemma and protect the membrane from rupture during the stresses of contraction. Dystrophin is absent in muscle cells from Duchenne muscular dystrophy (DMD) patients and mdx mice, a DMD model. Dystrophic muscle membranes undergo more frequent transient, nonlethal tears than normal cell membranes, especially during exercise. In addition, the mean open probability of a background ("leak") calcium channel is higher in dystrophic muscle cells, which leads to higher intracellular free calcium levels. Because elevated calcium levels may contribute to the eventual necrosis of muscle cells in DMD, we examined the possibility that the history of sarcolemmal rupture at a specific location on the membrane affects the open probability of nearby calcium leak channels. Membrane ruptures left by the excision of cell-attached patch-clamp electrodes were used to mimic natural tears. Patches made within 5 microns of excision sites contained channels with a fourfold greater mean open probability than channels in patches 50 microm away from ruptures. The increased leak channel activity near ruptures was seen continuously through the duration of the recordings and was not seen if the rupture was made in the presence of the protease inhibitor leupeptin. Calcium background channels proteolytically activated near ruptures, perhaps in a calcium-dependent manner, may thus be the lasting consequence of the weaker dystrophic sarcolemma, leading to chronically raised intracellular free calcium, increased calcium-dependent proteolysis and, eventually, necrosis.

Animals↗
PubMedDate not supplied

X-chromosomal (p21) muscular dystrophy and left ventricular diastolic and systolic function.

In order to screen for cardiac abnormalities, we prospectively studied 15 patients (age 8-25 years, mean 15.5 years) with Duchenne's (DMD) (n = 9) and Becker's (BMD) (n = 6) muscular dystrophy using the echocardiogram. Data were compared to a control group of 92 healthy individuals (age 7.9-25 years, mean 14.3 years). Left ventricular filling in diastole showed a different pattern when comparing echocardiographic Doppler results in patients and controls: Patients had lower peak velocity of early left ventricular diastolic filling (E-vmax)(P < 0.0001) and smaller time velocity integral of the E-wave (E-tvi)(P < 0.0001). In contrast, the atrial component (A-vmax, A-tvi) of diastolic filling in DMD/ BMD showed no significant difference to controls. The mean area of the mitral valve orifice was significantly larger in patients (P < 0.0001) without presence of mitral regurgitation. Systolic left ventricular function was significantly impaired in the DMD/BMD group; we found lower heart rate corrected fiber shortening velocity VCFc (P < 0.001) and higher peak systolic wall stress (P < 0.001) in DMD/BMD. In 8 of 15 patients, peak systolic wall stress was above 95th percentile of controls. In 6 of 15 patients, VCFc was lower than the 5th percentile of controls. Systolic and diastolic myocardial impairment was found even in young patients and at low stages of disability--equally among patients with DMD or BMD. Diastolic left ventricular impairment predominantly affected the early diastolic filling, but atrial compensation was poor. Peak systolic wall stress measurements were particularly useful in patients with CMP, reflecting the left ventricular afterload.

Adolescent↗
PubMed2004

Compositional analysis of muscle in boys with Duchenne muscular dystrophy using MR imaging.

OBJECTIVE: Boys with Duchenne muscular dystrophy (DMD) present by age 5 years with weakness and, untreated, stop walking unaided by age 10 or 11 years. We used magnetic resonance (MR) imaging to study age-related changes in the composition and distribution of diseased muscles. DESIGN AND PATIENTS: Eleven boys (mean 7.1+/-1.6 years) with DMD underwent clinical and MR examinations. Quantitative muscle strength and timed functional testing was performed. Thigh muscles were scanned at three levels (hip, mid-thigh, and knee) using T1-weighted spin echo and short-tau inversion recovery (STIR) sequences. Outcome measures included intramuscular fatty infiltration, intermuscle fat deposition, edema, and muscle size. RESULTS: Ten boys completed the study. Older boys demonstrated more prominent fatty infiltration of muscles. Fatty infiltration occurred in a characteristic pattern with the gluteus and adductor magnus muscles most commonly involved and the gracilis most commonly spared. Similarly, patchy increases in free water content suggested a pattern of intramuscular edema or inflammation. Atrophy occurred in muscles heavily infiltrated with fat, and true hypertrophy selectively occurred in those that were spared. CONCLUSIONS: While fibrofatty changes have been described in DMD, this study further defines differential involvement and additionally suggests widespread edema or inflammation. Improved imaging techniques to quantify the degree and distribution of these changes may provide a basis for exploring mechanisms of action of medications and perhaps another means for selecting treatment regimens and monitoring their effects.

Adipose Tissue↗
PubMed2002

Quantitative MR evaluation of body composition in patients with Duchenne muscular dystrophy.

The aim of this study was to propose a quantitative MR protocol with very short acquisition time and good reliability in volume construction, for the evaluation of body composition in patients affected by Duchenne muscular dystrophy (DMD). This MR protocol was compared with common anthropometric evaluations of the same patients. Nine boys affected by DMD, ranging in age from 6 to 12 years, were selected to undergo MR examination. Transversal T1-weighted spin-echo sequences (0.5T; TR 300 ms, TE 10 ms, slice thickness 10 mm, slice gap 1 mm) were used for all acquisitions, each consisting of 8 slices and lasting just 54 s. Whole-body examination needed an average of nine acquisitions. Afterwards, images were downloaded to an independent workstation and, through their electronic segmentation with a reference filter, total volume and adipose tissue volumes were calculated manually. This process took up to 2 h for each patient. The MR data were compared with anthropometric evaluations. Affected children have a marked increase in adipose tissue and a decrease in lean tissue compared with reference healthy controls. Mean fat mass calculated by MR is significantly higher than mean fat mass obtained using anthropometric measurements ( p<0.001). Our MR study proved to be accurate and easy to apply, although it was time-consuming. We recommend it in monitoring the progression of the disease and planning DMD patients' diet.

Adipose Tissue↗