Biomedical subjects
Publications and source records attributed to V Dubowitz.
Twenty two boys with Duchenne muscular dystrophy were entered into a randomised double blind crossover trial to compare respiratory muscle training with a Triflow II inspirometer and 'placebo' training with a mini peak flow meter. Supine posture was associated with significantly impaired lung function, but respiratory muscle training showed no benefit.
Cloned cDNA sequences representing exons from the Duchenne/Becker muscular dystrophy (DMD/BMD) gene were used for deletion screening in a population of 287 males males affected with DMD or BMD. The clinical phenotypes of affected boys were classified into three clinical severity groups based on the age at which ambulation was lost. Boys in group 1 had DMD, losing ambulation before their 13th birthday; those in group 2 had disease of intermediate severity, losing ambulation between the ages of 13 and 16 years; and boys in group 3 had BMD, being ambulant beyond 16 years. A fourth group consisted of patients too young to be classified. Clinical group allocation was made without previous knowledge of the DNA results. A gene deletion was found in 124 cases where the clinical severity group of the affected boy was known. The extent of the deletions was delineated using cDNA probes. There were 74 different deletions. Fifty-five of these were unique to individual patients, but the other 19 were found in at least two unrelated patients. The different clinical groups showed generally similar distributions of deletions, and the number of exon bands deleted (that is, deletion size) was independent of phenotype. Some specific deletion types, however, correlated with the clinical severity of the disease. Deletion of exons containing HindIII fragments 33 and 34 and 33 to 35 were associated with BMD and were not found in patients with DMD. Deletions 3 to 7 occurred in four patients with the intermediate phenotype and one patient with BMD. Other shared deletions were associated with DMD, although in four cases patients with disease of intermediate severity apparently shared the same deletion with boys with DMD. The range of phenotypes observed, and the overlap at the genetic level between severe and intermediate and mild and intermediate forms of dystrophy, emphasizes the essential continuity of the clinical spectrum of DMD/BMD. There were no characteristic deletions found in boys with mental retardation or short stature which differed from deletions in affected boys without these features.
We reviewed the incidence and severity of scoliosis in 37 patients with the intermediate type and 26 with the mild type of spinal muscular atrophy. In the intermediate type, scoliosis has an early onset and rapid progression before puberty, and a spinal fusion will be needed in virtually all cases. This rapid progression occurred despite routine use of a spinal brace. Hip dislocation was frequently present but, in most cases, was secondary to the pelvic tilt and did not contribute to the scoliosis. In the mild type, the scoliosis was more variable. In the 30% of patients who had scoliosis, progression was rapid during puberty but only in those who had lost ambulation. Of the four children with the intermediate type and the seven with the mild type who walked in light-weight orthoses, progression of scoliosis was slow, except in those who had lost ambulation. The ultimate effect of walking in orthoses is difficult to assess because of small numbers, but it seems to slow or at least delay progressive scoliosis.
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An RCA I-lectin binding glycoprotein of Mr = 370 kD is missing from or altered in the plasma membrane of Duchenne muscular dystrophy (DMD) skeletal muscle. In the present study the carbohydrate chain of this glycoprotein was localized to the external face of the plasma membrane in human skeletal muscle, and dystrophin, the protein product of the DMD gene, was localized to the inner (cytoplasmic) face. On double labelled Western blots the two proteins appeared as closely apposed but distinctly separate bands. Comparison of the plasma membrane binding of five lectins with overlapping sugar specificities in skeletal muscle from patients with DMD and the allelic milder disease form, Becker muscular dystrophy (BMD) showed that the RCA I-binding glycoprotein also strongly binds to phytohaemagglutinin, thereby largely characterising the carbohydrate binding site. This glycoprotein was absent or altered in DMD and markedly reduced in clinically manifest BMD but present in preclinical clinical BMD. There was no general depletion of plasma membrane glycoproteins in DMD because consistent plasma membrane binding could be demonstrated by peanut and maclura pomifera lectin. The possible implications of these findings for the pathogenesis of DMD/BMD are discussed.
Eight patients between 4 and 24 years of age with nonprogressive neuromuscular disease sought medical attention because of severe nocturnal hypoventilation. There were two types of findings: subacute with progressive early morning headaches and daytime drowsiness and acute with ventilatory failure and cor pulmonale. Seven patients were ambulant. Seven were successfully treated with either a cuirass negative pressure ventilator or a positive pressure ventilator via a tracheostomy. The ventilatory assistance was only used at night and resulted in rapid resolution of early morning symptoms and a return to full daytime activity. One patient died as a result of an intercurrent respiratory infection before respiratory support could be given. It is important to be aware of this potentially life-threatening complication in patients with an otherwise good prognosis and of the benefit to be derived from active treatment.
Nebulin and dystrophin are two high-molecular-mass skeletal muscle proteins that have both been associated with the defective gene in Duchenne muscular dystrophy, although the function of neither protein is known. Other high-molecular-mass, calmodulin-binding proteins have recently been implicated in regulating calcium release from skeletal muscle. Western blots of human skeletal muscle biopsy samples were probed with biotinylated calmodulin; nebulin was identified as a prominent high-molecular-mass calmodulin-binding protein but dystrophin did not bind detectable amounts of biotinylated calmodulin. Dystrophin was absent in a Duchenne muscle biopsy.
It is well established that the properties of muscle fibres are influenced by their neurons and that this is at least in part mediated by the pattern of activity. Application of this knowledge has led to the experimental trial of electrical stimulation in diseased muscle, both in the dystrophic mouse and in children with Duchenne muscular dystrophy. This has shown a beneficial effect of slow frequency stimulation. Another route through which muscle properties can be influenced is by changing the load by procedures such as tenotomy. This has been studied by complete tenotomy in normal animals and recently by selective partial procedures in human disease. Y. Rideau has shown that release of early shortening (contractures) of several muscles, a consistent feature in Duchenne muscular dystrophy, has a beneficial effect on muscle function. From personal observations on a number of Rideau's patients who have undergone this procedure the improvement in function seems disproportionate to what could be explained on simple biomechanical grounds alone and suggests some more fundamental change in the contractile properties of the muscle.
We have investigated 3 children aged 6, 3, and 2 years, from 2 families, with the clinical features of Marinesco-Sjögren syndrome. Muscle biopsy specimens from all 3 were abnormal and showed small vacuoles and slight variation in fiber size. Electron microscopy revealed vacuolation and membranous whorls and, in particular, a unique dense membranous structure associated with nuclei. These cases emphasize the involvement of muscle in Marinesco-Sjögren syndrome and the importance of electron microscopy in differential diagnosis.
A prospective study was done on 222 consecutive new patients referred to our pediatric muscle clinic to assess the diagnostic value of ultrasound imaging. Ultrasound scans were interpreted without knowledge of clinical presentation or results of other tests. Muscular dystrophy produced a brightly speckled pattern of increased echo from the muscle, whereas spinal muscular atrophy showed a moderate increase in muscle echo and associated muscle atrophy. Acute dermatomyositis produced a moderate increase in echo that varied markedly with the direction of the ultrasound beam in relation to the muscle fibres. The ultrasound scan was normal in children with hypotonia of cerebral origin, Prader Willi syndrome, ligamentous laxity, and other "nonneuromuscular" causes. In eight patients ultrasound scanning showed a striking degree of selective involvement of individual components of the quadriceps muscle, which provided considerable diagnostic help for selective needle biopsy. Ultrasound scanning in children has the major advantage of being a noninvasive and pleasant out-patient procedure, which can be readily done on multiple sites. It is a valuable screening test in the investigation of children with neuromuscular disorders.
A randomized double-blind therapeutic trial of isaxonine was completed over a 2-year period for 20 ambulant boys with Duchenne muscular dystrophy aged 5 1/2-10 years. The effect of the drug was monitored by measurement of walking times over 28 and 150 ft, motor ability score, MRC score based on 32 muscle groups, and myometry of 7 muscle groups. The drug had no significant effect on the progression of the disease. The trial had statistical power comparable to previous larger-scale multicenter trials. This reflected the low variability in the patients in relation to the magnitude of the overall deterioration. Measurements of muscle force (myometry and MRC score) had much greater statistical power than measurements of function (motor ability score and walking times) as analyzed by our methods. These observations have important implications for the design of future trials.
A study was undertaken, using methods of stabilometry to compare stability of stance in normal children (n = 37) and those with Duchenne muscular dystrophy (n = 61). The purpose of this study was to monitor changes in the locus of the center of gravity and the range and frequency of sway and to evaluate the effect of orthotic application in an attempt to obtain information that would assist further development of orthoses. In group 1, boys with Duchenne muscular dystrophy who were still walking without assistance (mean age 7.2 +/- 1.76 years), the analysis of sway showed that, between 5 and 6 years of age, the boys already had ranges of anteroposterior (A/P) and lateral (Lat) sway that were significantly greater than those found in normal children (A/P P less than 0.05, Lat P less than 0.01). In group 2, boys with Duchenne muscular dystrophy when orthoses had been introduced (n = 23, mean age 10.4 +/- 1.47 years), the center of gravity was returned to a more normal position. There was a reduction of the anteroposterior range of sway, but the lateral range of sway remained significantly greater (P less than 0.01) as did the frequency of sway in both the anteroposterior and lateral directions (A/P P less than 0.001, Lat P less than 0.001).
In previous studies it was shown that a D-galactose-specific lectin, Ricinus communis I (RCA I), does not bind to the plasma membrane of muscle fibres from patients with Duchenne muscular dystrophy (DMD) in contrast to normal muscle. We have now studied RCA I binding to the membranes of developing human fetal muscle in fetuses at 95% risk of DMD (n = 6) and normal controls (n = 5) with a developmental range of 12-20 weeks of gestation. The results were compared to the membrane appearance with conventional ultrastructure. Binding of RCA I to the muscle basement membrane was consistently strong from the early stages of myogenesis, such as in fusing myoblasts/myocytes. RCA I binding to the plasma membrane was weak but detectable in both DMD and normal fetuses at 12-14 weeks of gestation. Both the normal and diseased condition showed an increase of RCA I labelling of the muscle plasma membrane at 15-17 weeks and strong labelling at 18-20 weeks of gestation. No difference was observed in the RCA I localization of normal and diseased human fetal muscle plasma membrane. It is concluded that (a) the plasma membrane in developing fetal muscle undergoes a maturation process between 12 and 20 weeks gestational age leading to an increase in expression of RCA I binding carbohydrate moieties; and (b) that the absence of RCA I binding glycoprotein in mature DMD muscle plasma membrane reflects a change acquired during the course of disease.
Skeletal muscle from patients with 5 different forms of muscular dystrophy and from 6 fetuses at high risk (95%) for Duchenne muscular dystrophy (DMD) were probed with specific antibodies for the presence of dystrophin and nebulin. Dystrophin was absent in all 5 patients with DMD and 4 of 6 fetuses at high risk for DMD and present in trace amounts in the remaining two. Dystrophin was also undetectable in one borderline DMD/Becker muscular dystrophy (BMD) case and reduced in 2 of 4 cases of BMD. In contrast, dystrophin was present in all 16 biopsies from 4 other types of muscular dystrophy (congenital, limb girdle, Emery-Dreifuss and facioscapulohumeral). Nebulin profiles varied with the type, severity and duration of the dystrophic process. Nebulin was present in 5 of 6 DMD fetal samples but vastly reduced or absent in all samples of clinically manifest DMD.
Twenty probands with juvenile dermatomyositis and their relatives were studied to determine the inherited segregation patterns of class I, II, and III HLA region markers including C4A, C4B, Bf, and C2 complement polymorphisms. The extended haplotype B8, DR3, C4A*Q0, C4B*1, C2*C, and Bf*S was present in 13 of the 20 probands. Three other probands also carried a haplotype with a null allele for C4A and two further probands carried a null allele for C4B; only two probands had no detectable C4 null allele. These data confirm previous studies showing high frequencies of B8 and DR3 in patients with juvenile dermatomyositis, but show that there is a higher association with null alleles of C4. This suggests that the C4 genes are either themselves the disease-susceptibility genes or are in very strong linkage disequilibrium with such genes.
We reviewed the incidence and severity of scoliosis in 93 boys with Duchenne muscular dystrophy who had been rehabilitated in light-weight knee-ankle-foot orthoses at the point of loss of ambulation, between the ages of 6 and 12 years. There was an inverse relationship between the severity of the scoliosis and the age walking was lost in the orthoses. The scoliosis was less severe in the 20 boys (22%) who walked in their orthoses beyond 13 years of age than in those who stopped walking in their orthoses before 13 years. There was also a rapid deterioration in the scoliosis between the ages of 13 and 15 years in boys who had stopped walking in their orthoses before the age of 13 years, while in comparison, boys of the same age who were ambulant in their orthoses beyond 13 years showed a much slower rate of deterioration. These results strongly suggest that walking in orthoses beyond the age of 13 years prevented rapid progression of scoliosis between 13 and 15 years of age, ie, during the pubertal growth spurt.
The contribution of early continuous four-channel EEG monitoring to the evaluation of intraventricular hemorrhage in acutely ill preterm infants mechanically ventilated for acute respiratory distress was assessed in a prospective study of 54 infants of less than 34 weeks' gestation. Early abnormal EEG results correlated significantly with later outcome. They often preceded ultrasound evidence of hemorrhage and provided prognostically significant functional correlation with the grade of hemorrhage. Continuous EEG monitoring allows collection of significant data with minimal interference and could contribute to clinical management of high-risk preterm infants.
Coxsackie-B-virus-specific probes prepared by reverse transcription of purified virus genomic RNA and molecular cloning techniques were used in quantitative slot-blot hybridisations to test for the presence of virus RNA in skeletal muscle biopsy samples. The samples tested were from two patients with adult polymyositis, seven with juvenile dermatomyositis, four with Duchenne muscular dystrophy, and six normal controls. Of the nine patients with inflammatory muscle disease, five were positive for Coxsackie-B-virus RNA; no viral sequences were found in the ten Duchenne muscular dystrophy and control biopsy samples.