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PubMed1993

Autopsy analyses of the muscular dystrophies.

Life span, causes of death, weight of heart, liver, brain, and main pathological changes of internal organs were analysed on 329 autopsy cases of muscular dystrophies. These included 249 cases of Duchenne muscular dystrophy (DMD), 3 Becker muscular dystrophies (BMD), 14 limb-girdle muscular dystrophies (LGMD), 3 fascioscapulohumeral muscular dystrophies (FSH), 18 Fukuyama type congenital muscular dystrophies (FCMD) and 17 myotonic dystrophies (MyD). In DMD the life span has definitely prolonged in recent years. Pulmonary infection, which was once the major cause of death, has greatly decreased in recent years. Instead, respiratory and cardiac failures caused by dystrophic changes of respiratory and cardiac muscles were more closely related to the causes of death in many recent cases. Myocardial fibrosis was observed in most of the patients with DMD, BMD, LGMD, FCMD and MyD. The distribution of cardiac lesions was similar in BMD, LGMD and FCMD as in DMD. In MyD the disorders involved more frequently conductive muscles resulting in arrhythmias. The dystrophic cardiomyopathy seemed to be a part of the essential changes in all types of muscular dystrophy, although different in intensity and rate of morbidity. Alzheimer's neurofibrillary changes were observed in the brain of some cases of FCMD and MyD, suggesting the possibility of precocious aging of the brain in some patients of the muscular dystrophies.

Adolescent↗
PubMed1993

Duchenne muscular dystrophy: lack of differences in the expression of endogenous carbohydrate- and heparin-binding proteins (lectins) in cultured fibroblasts.

Duchenne muscular dystrophy (DMD), the most severe form of inherited muscular dystrophies, is known to be caused by a deficiency of the protein "dystrophin", but the pathophysiologic consequences of this lack have not as yet been elucidated. Investigations with cultured fibroblasts point to altered adhesion mechanisms in cells from DMD patients. Because endogenous carbohydrate-binding proteins (lectins) play an important role in cell-cell and cell-matrix interactions and therefore might be involved in these alterations, we separated such proteins with specificities for beta-galactosyl-, alpha-mannosyl-, and alpha-glucosyl-residues, as well as heparin-binding proteins from cultured fibroblasts. Owing to enormous interindividual variations among DMD patients and among healthy controls our hypothesis could not be confirmed. In the course of the experiments we could detect a growth-related binding of heparin to nuclei of cells from DMD patients and healthy controls restricted to rapidly growing cultures and telophases of mitoses, but not in contact-inhibited monolayers. This finding suggested a possible involvement of the cellular ligand in growth control and coincided with the occurrence of basic fibroblast growth factor.

Binding Sites↗
PubMed1993

Mild deficiency of dystrophin-associated proteins in Becker muscular dystrophy patients having in-frame deletions in the rod domain of dystrophin.

The dystrophin-glycoprotein complex spans the sarcolemma to provide a linkage between the subsarcolemmal cytoskeleton and the extracellular matrix in skeletal muscle. In Duchenne muscular dystrophy (DMD), the absence of dystrophin leads to a drastic reduction in all of the dystrophin-associated proteins in the sarcolemma, thus causing the disruption of the dystrophin-glycoprotein complex and the loss of the linkage to the extracellular matrix. The resulting sarcolemmal instability is presumed to render muscle fibers susceptible to necrosis. In the present study, we investigated the status of the dystrophin-associated proteins in the skeletal muscle from patients with Becker muscular dystrophy (BMD), a milder allelic form of DMD. BMD patients having in-frame deletions in the rod domain of dystrophin showed a mild to moderate reduction in all of the dystrophin-associated proteins in the sarcolemma, but this reduction was not as severe as that in DMD patients. The reduction of the immunostaining for the dystrophin-associated proteins showed a good correlation with that for dystrophin in both intensity and distribution. Our results indicate that (1) the abnormality of the sarcolemmal glycoprotein complex, which is similar to but milder than that in DMD patients, also exists in these BMD patients and (2) the rod domain of dystrophin is not crucial for the interaction with the dystrophin-associated proteins.

Adolescent↗
PubMed1993

Dystrophin-related protein, utrophin, in normal and dystrophic human fetal skeletal muscle.

Dystrophin is the product of the Duchenne muscular dystrophy (DMD) gene. Dystrophin-related protein (utrophin), an autosomal homologue of dystrophin, was studied in skeletal muscle from normal fetuses aged 9-26 weeks and one stillbirth of 41 weeks' gestation, and compared with low- and high-risk DMD fetuses aged 9-20 weeks. Utrophin was present at the sarcolemma from before 9 weeks' gestation, although there was variability in intensity both within and between myotubes. Sarcolemmal immunolabelling became more uniform, and levels of utrophin increased to a maximum at approximately 17-18 weeks. Levels then declined, until by 26 weeks sarcolemmal labelling was negligible and levels were similar to adult control muscle. By 41 weeks there was virtually no sarcolemmal labelling, although immunolabelling of capillaries was bright. Similar results were obtained with normal and DMD fetal muscle. Utrophin is therefore expressed in the presence and absence of dystrophin and down-regulated before birth in normal fetal muscle fibres. Samples were not available to determine whether or when, utrophin levels decline in DMD fetal muscle. On Western blots, utrophin was shown to have a smaller relative molecular mass than adult dystrophin, but similar to the fetal isoform. Blood vessels were brightly immunolabelled at all ages, although utrophin immunolabelling of peripheral nerves increased with gestational age.

Antibodies, Monoclonal↗
PubMed1993

[Application of combined DNA and dystrophin protein analysis in the diagnosis of Duchenne's and Becker's muscular dystrophy in 102 Dutch patients].

The recent progress in molecular genetic studies on Duchenne and Becker muscular dystrophy (DMD, BMD) had an important spin-off for our diagnostic abilities of both muscle disease. The mapping and isolation of the DMD gene which codes for the 427 kD cytoskeletal protein dystrophin made it possible to diagnose 80-85% of the patients by means of DNA analysis. At present, most of the remaining 15-20% of the patients can be diagnosed by protein analysis. In this report we describe the analysis of dystrophin in a group of 102 Dutch patients with muscular dystrophies. An immunohistochemical and immunobiochemical study of dystrophin was performed on muscle tissue, partly integrated with DNA analysis. In this study we underline the value of dystrophin analysis in all patients suspected of DMD, BMD or other muscular dystrophies, particularly in those without detectable DNA mutations. By means of integrated DNA/dystrophin analysis 98% of the DMD patients and 90% of th BMD patients and their families can now be provided with an unambiguous diagnosis. In particular, discrimination between BMD and other muscular dystrophies has strongly improved.

Adult↗
PubMed1993

Sudden cardiac arrest during adenotonsillectomy in a patient with subclinical Duchenne's muscular dystrophy.

We describe a four-year-old boy of Indian descent who had elective adenotonsillectomy for chronic sore throat and partial airway obstruction. About 10 minutes into the procedure, the patient suddenly developed cardiac asystole. After prolonged cardiac resuscitation, recovery was achieved. No permanent neurologic deficits resulted. The child was later found to have a strong family history of Duchenne's muscular dystrophy (DMD) and an elevated serum creatine kinase level documented since shortly after birth. We reviewed several case reports substantiating the risk for cardiac arrest during general anesthesia in DMD patients, and we concluded that DMD is a little-known risk for cardiac arrest during general anesthesia. The otolaryngologist must be aware of this potential complication, because tonsillectomy and adenoidectomy are commonly indicated for children at an age when DMD may be subclinical.

Adenoidectomy↗
PubMed1996

Development of cardiomyopathy in female carriers of Duchenne and Becker muscular dystrophies.

OBJECTIVE: To characterize the presence and behavior of the dystrophinopathic myocardial damage in female carriers of a gene defect at the Xp21 locus of the X chromosome that causes Duchenne and Becker muscular dystrophies (DMD and BMD). DESIGN: Cohort study from April 1, 1985, to April 30, 1995, with cardiologic follow-up performed yearly for a minimum of 3 to a maximum of 10 years. SETTING: Counseling center for genetic muscular disorders. PATIENTS: A total of 197 women and girls aged 5 to 60 years ascertained to be carriers of the DMD (n = 152) or BMD (n = 45) gene. MAIN OUTCOME MEASURES: Cardiac status at yearly examinations as determined by 12-lead electrocardiogram (ECG), 24-hour ambulatory ECG, M-mode and 2-dimensional echocardiography, and carotid pulse tracing. Myocardial scintigram was performed on each individual at least twice during the study. Immunohistochemical analysis of dystrophin from myocardium and/or skeletal muscle biopsy was performed in 12 carriers. RESULTS: Preclinical or clinically evident myocardial involvement was found in 166 cases (84.3%), without significant differences in percentage and behavior between DMD and BMD carriers. Its occurrence increased significantly with age, from 54.5% (18 cases) in carriers aged between 5 and 16 years to 90.2% (148 cases) in carriers older than 16 years. Dystrophin anomalies were detected at the membrane level of the myocardial fibers in all endomyocardial biopsy specimens. CONCLUSIONS: Genetic anomalies can be considered the primary cause of myocardial damage in carriers of dystrophinopathic myopathies; myocardial damage shows the same behavior already described in DMD and BMD patients and progresses from preclinical to dilated cardiomyopathy, passing through stages of myocardial hypertrophy or dysrhythmias.

Adolescent↗
PubMed1996

Molecular analysis of recombination in a family with Duchenne muscular dystrophy and a large pericentric X chromosome inversion.

It has been demonstrated in animal studies that, in animals heterozygous for pericentric chromosomal inversions, loop formation is greatly reduced during meiosis. This results in absence of recombination within the inverted segment, with recombination seen only outside the inversion. A recent study in yeast has shown that telomeres, rather than centromeres, lead in chromosome movement just prior to meiosis and may be involved in promoting recombination. We studied by cytogenetic analysis and DNA polymorphisms the nature of meiotic recombination in a three-generation family with a large pericentric X chromosome inversion, inv(X)(p21.1q26), in which Duchenne muscular dystrophy (DMD) was cosegregating with the inversion. On DNA analysis there was no evidence of meiotic recombination between the inverted and normal X chromosomes in the inverted segment. Recombination was seen at the telomeric regions, Xp22 and Xq27-28. No deletion or point mutation was found on analysis of the DMD gene. On the basis of the FISH results, we believe that the X inversion is the mutation responsible for DMD in this family. Our results indicate that (1) pericentric X chromosome inversions result in reduction of recombination between the normal and inverted X chromosomes; (2) meiotic X chromosome pairing in these individuals is likely initiated at the telomeres; and (3) in this family DMD is caused by the pericentric inversion.

Chromosome Inversion↗
PubMed1995

[Cardiac dysfunction in female gene carriers of Duchenne muscular dystrophy].

Cardiac dysfunction and its correlation with skeletal muscle dysfunction were examined in 16 definite female gene carriers of Duchenne muscular dystrophy (DMD). Five out of 16 carriers (31.3%) had cardiac symptoms and 8 carriers (50.0%) showed an increased cardio-thoracic ratio on chest X-ray. Electrocardiographic abnormalities including a high R:S ratio (> or = 1.0) in the V1 lead, deep Q wave (> 3 mm) in the I, II, aVL, V5, and V6 leads, complete right bundle branch block and premature ventricular beats, were observed in 9 carriers (56.3%). On echocardiographic examination, an increase in the end-diastolic dimension of the left ventricle and a decrease in the ejection fraction suggestive of dilated cardiomyopathy were found in 12 carriers (75.0%). Tl-201 myocardial SPECT scan was performed in 2 symptomatic carriers and showed an area of hypoperfusion in the inferio-posterior wall. These findings were similar to previously reported findings in DMD patients. A biopsy of the myocardium was obtained in one carrier with her informed consent for the biopsy. Immunohistochemical staining demonstrated that 75.4% of the myocardial fibers were negative for dystrophin, suggesting that her cardiac dysfunction is caused by the abnormal expression of dystrophin in the cardiac muscle. On examination of the skeletal muscle function, none of the carriers had clinical evidence of muscle weakness or atrophy. However serum creatine kinase activity was elevated in 14 of 16 carriers (87.5%). Computed tomography (CT) of the lower limb muscles demonstrated widened spaces among muscles and moss-eaten appearance of low density areas within muscles and CT value was decreased, suggesting the subclinical involvement of the skeletal muscle. In the carriers without cardiac symptoms, there was a negative correlation (p < 0.05) between the end-diastolic dimension of the left ventricle and the CT value of the biceps femoris muscle (a muscle with the lowest CT value among the lower limb muscles). This indicates that there was an apparent correlation between the cardiac and skeletal muscle dysfunction. These findings suggest a high frequency of clinical and subclinical involvement of the cardiac and skeletal muscles in DMD carriers. To protect them from cardiac failure, cardiac dysfunction in DMD carriers needs to be examined closely and treated appropriately before the carriers become symptomatic.

Adult↗
PubMed1996

[Tracheal deformity observed in tracheostomized Duchenne muscular dystrophy patients who can speak with appropriately inflated cuff of tracheal tube].

Respiratory failure occurring during late adolescence is a major cause of death in Duchenne muscular dystrophy (DMD). A number of respiratory assistance techniques including tracheostomy and positive pressure mechanical ventilation have been utilized not only to prolong DMD patients' life but also to improve quality of their life. It is surprising that most of the tracheostomized DMD patients can speak under positive pressure ventilatory assistance. Preserved functions of glosso-pharyngo-laryngeal muscles in these patients presumably make it possible to control the air leak around tracheal tube, which does not necessitate tight inflation of the tube cuff. Recently we noticed that some patients are still able to speak even when the cuff is fully inflated. In order to understand the mechanism of this phenomenon, we visualized the topographical relationship between trachea and the tube cuff using computed tomography by filling the cuff with aqueous contrast medium. We obtained following findings: 1) Trachea is flat and deviated from normal midline position, and 2) the tube cuff is located eccentrically in trachea resulting in compression of one side of the inner wall and leaving open space on the other side. We conclude that the tracheal malposition and deformity underlie this strange phenomenon and tight inflation of the cuff to prevent air leak may result in unfavorable complications in DMD patients.

Adult↗
PubMed1997

Genotype-phenotype correlation in Duchenne/Becker muscular dystrophy patients seen at Lucknow.

The molecular basis of two allelic forms of muscular dystrophy, Duchenne (DMD) and Becker (BMD), has been explained by frame shift hypothesis. In order to test this hypothesis, deletional mutations in 59 patients confirmed to have DMD and 11 BMD patients were analysed using multiplex polymerase chain reaction and Southern hybridization with dystrophin cDNA probes. Translational reading frame of the dystrophin gene was derived from 'Border type' analysis of exons flanking the intragenic deletions. The correlation between genotype (reading frame) and phenotype (clinical severity) showed higher number of DMD patients (approximately 20%) deviating from the frame shift hypothesis. The patients who deviated had deletions at the central hot spot region of the dystrophin gene. The presence of these deviations in a large number of DMD patients highlights the difficulties in predicting the clinical progression of the disease based only on DNA profile.

Gene Deletion↗
PubMed1997

Esophageal motility disorders in Mexican patients with Duchenne's muscular dystrophy.

OBJECTIVE: Myopathies are entities that mainly involve striated muscle. In Duchenne's muscular dystrophy (DMD) there have been reported smooth muscle alterations in the pre-oral phase of swallowing, in gastric emptying, and pseudoobstruction. Nevertheless, esophageal motility alterations are not concluding. The objective of this work was to determine if there are motor esophageal alterations in this patients, and if this alterations are related to the clinical manifestations of disease. STUDY DESIGN: Nine consecutive patients with DMD (mean age 8, range 6-11 years; males) were evaluated, comparing clinical and manometric findings. RESULTS: Esophageal manometry alterations were found in all patients, mainly simultaneous non-peristaltic waves (60.86%) of diminished amplitude, in both striated and smooth muscle. Seventy seven percent presented with upper and lower gastrointestinal symptoms (dysphagia, regurgitation, epigastric pain, constipation, and distention). No correlation was found between esophageal motility alterations and gastrointestinal symptoms, nor with the clinical stage of disease in accordance to Brook (r = 0.27). CONCLUSION: These results show that patients with DMD present esophageal motor disorders in both striated and smooth muscle, as well as upper and lower gastrointestinal symptoms. Specialized motility studies could yield a better understanding of disease, and, possibly with adequate treatment, provide for a better quality of life in children with DMD.

Child↗
PubMed1997

The abnormal expression of utrophin in Duchenne and Becker muscular dystrophy is age related.

Utrophin is a 395 kDa protein with considerable homology to dystrophin. It is highly expressed in the sarcolemma of normal fetal muscle fibres but is confined to neuromuscular and myotendinous junctions, and blood vessels in adult muscle. Sarcolemmal expression occurs on regenerating fibers, irrespective of the disease, and is also seen on mature fibres in Duchenne and Becker muscular dystrophies (DMD, BMD), and inflammatory myopathies. The reasons for the abnormal expression in DMD and BMD are unclear. We have studied this expression of utrophin immunocytochemically on mature fibres in 42 cases of DMD and BMD, aged 3 months-24 years of age. All cases had some mature fibres, with no detectable fetal myosin, that showed sarcolemmal expression of utrophin. The number of these fibers and the intensity of fluorescence was low in young cases before the age of 2 years and increased with age. The fluorescence was graded on a scale of 0 to ++ ++ and there were significantly more cases under 2 years of age (10/12) with a grading of utrophin of only +, compared with those over 2 years (4/30, P < 0.001). Some revertant fibres, but not all, expressed utrophin and dystrophin. Our data show that the abnormal expression of utrophin on mature muscle fibres in DMD and BMD is not a continuation of the expression that occurs in fetal or regenerating muscle, but is a secondary event caused by unknown factors. The immunocytochemical intensity of utrophin is variable between cases and there is no correlation with clinical severity. As all cases studied had some expression of utrophin on mature fibres, this may be a useful additional tool for distinguishing BMD from other dystrophies, especially in cases with minimal abnormalities in dystrophin expression and/or no detectable mutation in the gene.

Adolescent↗
PubMed1998

[Hyponatremia in Duchenne muscular dystrophy on mechanical ventilation].

To evaluate the pathomechanism of hyponatremia occasionally seen in Duchenne muscular dystrophy (DMD) on intermittent positive pressure ventilation (IPPV), we performed a comparative study on 26 DMD patients, 7 IPPV in trachetomized intermittent positive pressure ventilation (TIPPV), 6 nasal intermittent positive pressure ventilation (NIPPV), 6 cuirass respirator (CR), and 7 spontaneous breathings (SB). We followed fluctuation of serum sodium levels for several years. Since the serum sodium level was gradually reduced with years on mechanical ventilation, we speculated positive relationship between hyponatremia and antidiuretic hormone (ADH) secretion. Serum sodium levels of 135.6 +/- 2.8 mEq/L in average on IPPV (TIPPV + NIPPV) patients was significantly lower than the levels of 137.8 mEq/L +/- 0.98 on CR patients and 138.8 +/- 0.69 mEq/L on SB patients. Plasma ADH levels in IPPV patients were not reduced when plasma osmolarity was less than 280 mOSm/L. Previous reports showed that ADH was inappropriately secreted only during IPPV with positive end expiratory pressure (PEEP). Ours is the first report of inappropriate secretion of ADH during IPPV without PEEP. It becomes clear that inappropriate ADH secretion is one of the causes of hyponatremia in DMD, though the exact mechanism is not clear. We should bear in mind the change of serum electrolyte level in ventilated DMD patients, especially patients on antidepressant known to release of ADH.

Adult↗
PubMed1976

Creatine-phosphokinase (CPK) activity in relatives of patients with X-linked muscular dystrophies: a Brazilian study.

Serum CPK was measured in 135 families with Duchenne muscular dystrophy (DMD) and 19 with the Becker type (BMD). Increased CPK was found in 62% of the carriers of DMD and 62.5% of the BMD. Two certain carries of DMD and one of their daughters showed clinical signs of myopathy. Three studied DMD pregnant carriers suggest that there is a decrease in CPK levels around the 4th-5th months of gestation. In genetic counselling of suspected carriers the CPK activity of their normal daughters should always be considered. Our data suggest strongly that CPK activity decreases in carriers with increasing age.

Age Factors↗
PubMed1976

Carrier detection and genetic counselling in Duchenne muscular dystrophy: a follow-up study.

Assay of serum creatine kinase activity is useful in the detection of carriers of the X-linked gene for Duchenne muscular dystrophy (DMD). For genetic counselling this assay has been used in conjunction with pedigree analysis to improve estimates of the risk that a female relative of a DMD patient is a carrier. To measure the impact of the program, follow-up information was obtained from women who had received genetic counselling for DMD. Their responses showed that the risk of producing an affected son had been a major factor in their attitude toward family planning, and their reproductive performance correlated inversely with their genetic risk. The decision by the majority of proven carriers to prevent the birth of further male offspring was reflected in a recent decline in the frequency of a known family history of DMD among newly ascertained cases.

Abortion, Therapeutic↗
PubMed1976

Regeneration in Duchenne muscular dystrophy. Electromyographic evidence.

Eight patients with Duchenne muscular dystrophy (DMD) and seven normal children of similar age were studied with a new electromyographic method for coherent displays of potentials. Five hundred motor unit potentials (MUPs) were analyzed in 20 proximal and distal muscles representing a wide spectrum of dystrophy. The progressive MUP disintegration by dropping out of muscle fibers was documented, as well as a high incidence of spontaneous fibrillation. A total of 386 late component (LC) potentials followed the 500 MUPs at consistent latencies. No LC occurred in normal children. The LCs result from motor axon sprouts innervating muscle fibers that are newly formed either by segmentation of existing muscle fibers (focal neucrosis and membrane repair) or by muscle regeneration. Axons in DMD can thus collaterally innervate additional muscle fibers. These processes must delay the onset and progression of clinical weakness in DMD patients.

Adolescent↗
PubMed1996

Regional localization of two MRX genes to Xq28 (MRX28) and to Xp11.4-Xp22.12 (MRX33).

Two genes responsible for a nonspecific form of X-linked mental retardation (MRX28 and MRX33) were localized by linkage analysis with 40 highly polymorphic DNA markers situated along the entire the X chromosome. In family 1, the gene could be mapped within a 14-cM interval at Xq28, distal to the recombining marker DXS1113 (MRX28). The maximum LOD score was 2.75, with DXS52 at phi = .0. In family 2, the gene was localized within a 30-cM interval at Xp11.4-22.12 between the recombining markers DXS365 and MAOB, including the DMD gene (MRX33). Maximum LOD scores of 2.82 were obtained with markers DMD-STR49, DMD-DysII, CYBB, and DXS1068.

Child, Preschool↗