Biomedical subjects
Publications and source records attributed to V Dubowitz.
This paper reviews recent advances in the molecular genetics of the muscular dystrophies and their implications for potential treatment. A brief review is also included of recent advances in locating the gene for the spinal muscular atrophies.
Continuous EEG monitoring is considered to be a sensitive indicator of changes in cerebral function. This paper describes a system for cotside display and analysis of EEG discontinuity and amplitude in one-minute epochs, with provision for simultaneous recording of the EEG. It has been successfully used to monitor continuously the EEGs of more than 30 babies in a neonatal intensive care unit for periods of up to nine days. This system rapidly provides indications of changes in cerebral function, which can allow early intervention and possible prevention of morbidity.
14 patients, aged 2-28 years, with neuromuscular disorders and symptomatic sleep hypoventilation received night-time intermittent positive-pressure ventilation with a nasal mask. 9 were treated de novo and 5 had previously been maintained on a cuirass or iron lung. Nasal ventilation was very effective in 10 patients but was not tolerated in 4 of the 5 youngest patients. Nasal ventilation was preferable to other methods of ventilation because the system was non-invasive, quiet, portable, and easy to use and because it allowed considerable independence.
Normal skeletal muscle does not express class I MHC antigens. In contrast, these antigens are strongly expressed at the periphery of muscle fibres in patients with juvenile dermatomyositis (JDM) and Duchenne muscular dystrophy (DMD). Interferons can induce the expression of class I antigens, but in this study interferon-gamma could not be detected in JDM muscle biopsy specimens using four different immunocytochemical techniques. However, an infiltrate of mononuclear cells capable of synthesising interferons was present in biopsies from JDM and DMD patients. The predominant cell types detected in both diseases were macrophages and T lymphocytes, these two cell types comprising more than 80% of the infiltrating mononuclear cells. A striking predominance of CD4+ helper/inducer T cells was observed. The majority of these cells expressed class II MHC antigens and were, therefore, considered to be activated. Additional evidence for the functional activity of CD4+ T cells was derived from the finding that it was this population of cells from JDM biopsies which proliferated in response to interleukin-2 in vitro. T cell subsets in peripheral blood were also investigated in JDM and DMD patients. Only in the case of JDM were any significant differences from normal observed, where a significant reduction in the number of peripheral blood CD8+ T cells resulted in an elevation of CD4+/CD/8+ ratios. The role of CD4+ T cells and aberrant class I MHC antigen expression in mediating muscle damage in JDM and DMD is discussed.
To evaluate the therapeutic possibilities of chronic electrical stimulation, muscle function studies and quantitative tests of physical assessment were used to monitor the response of quadriceps femoris to prolonged low frequency stimulation. Comparative studies of the maximum voluntary and electrically elicited responses of muscles of young ambulant children with Duchenne muscular dystrophy, when compared to those of normal children's muscles, revealed lower values of maximum voluntary contraction, significant slowing (P less than 0.001) of mean relaxation times and a higher resistance to fatigue testing. Intermittent chronic low frequency stimulation resulted in a significant (P less than 0.01) increase in mean maximum voluntary contraction of the stimulated muscles compared with the mean force exerted by the unstimulated control muscles. There are clear therapeutic possibilities for the use of chronic low frequency stimulation in these children.
A subgenomic restriction fragment from cDNA prepared from Coxsackie B2 virus (CVB2) RNA was subcloned into a riboprobe vector allowing the production of enteroviral group-specific RNA probes complementary to either the positive (genomic) or negative (template) strand of enteroviral RNA. These riboprobes were used to follow productive infection of cultured cells by CVB2; as expected, positive strand RNA was synthesized in approximately 100-fold excess over negative strand. RNA was extracted from muscle biopsy samples from patients with chronic fatigue syndrome and probed for the presence of enteroviral RNA. In cases where enteroviral RNA was detected the amounts of positive and negative strands of enteroviral RNA were approximately equal, in contrast to the situation in lytic infection of cultured cells. This suggests that enterovirus persistence in muscle is due to a defect in control of viral RNA synthesis.
A baby girl with coarse facial features, hepatosplenomegaly, and developmental delay had raised free sialic acid concentrations in her urine and cultured fibroblasts. She died aged 13 months. Sialic acid is an important constituent of many glycoproteins and glycolipids; impaired release from the lysosome may be the underlying biochemical defect.
We made phenotypic analysis of 14 families with spinal muscular atrophy (SMA) linking to chromosome 5q11.2-13.3 (SMA 5q), and 2 that may not map to this locus, to assess clinical symptoms among SMA families known to result from mutation at the identical gene/locus. Although the current number of families is still small, the correlation of clinical phenotype and molecular genotype supports 2 observations. First, SMA mutations at the 5q locus present with a broad continuum of clinical abnormalities, and 2nd, the single clearly unlinked family presents with an unusual phenotype characterized by relatively late onset and early death. Thus, there are as yet no unambiguous cases of typical SMA families that are clearly unlinked to the locus at 5q-ie, no clear cases of nonallelic heterogeneity. Analysis of SMA 5q families supports the view that, with certain exceptions, there is little phenotypic intrafamilial variability. When families were ranked by severity of disease there was a strong correlation with age of onset. Onset within the 1st few months was associated with early death, but not in all cases. With rare exception, onset after 1 year of age was associated with less severe disease and greater longevity.
Juvenile dermatomyositis in fourteen children who had not responded fully to steroids and other immunosuppressants and who had had chronic active disease for an average of 3 years was successfully treated with cyclosporin. Twelve patients had serious complications of the disease or of previous treatment. The response to cyclosporin included recovery of muscle strength and function and resolution of complications. It was possible to stop steroids or to reduce the steroid dose, which had previously been difficult, in all fourteen patients. In general, a low dose of cyclosporin (2.5-7.5 mg/kg daily) was sufficient and no serious side-effects were seen.
Explore the source record for details and available documents.
Dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene locus, appeared as an immunoreactive triplet of polypeptides in striated muscle tissues from normal mice on Western blot analysis. In smooth muscle tissues, an immunoreactive doublet of corresponding molecular weight was detected. No dystrophin was found in normal mouse brain, not even after enrichment for the Triton X-100 insoluble fraction. Dystrophin was absent from all corresponding tissues from the mdx mutant mouse strain which is known to lack dystrophin. The possibility that these immunoreactive bands represent isoforms is discussed. We have also investigated two other high molecular weight proteins which show secondary abnormalities in DMD muscle, namely nebulin and the 370 kDa Ricinus communis I lectin (RCA I)-binding glycoprotein. Nebulin levels were reduced in skeletal muscle from 6-week-old mdx mice but not in oesophagus from the same animals. By contrast, the RCA I-binding 370 kDa glycoprotein which is greatly reduced in DMD skeletal muscle was present in normal amounts in mdx skeletal muscle. These findings show, for the first time, that mdx myopathy differs from DMD myopathy not only morphologically, but also in its secondary biochemical abnormalities.
The distribution of HLA class I and class II antigens has been investigated in cryostat sections of a series of 200 skeletal muscle biopsy specimens from patients with various neuromuscular disorders. Normal muscle fibres expressed no detectable class I antigens, whereas muscle fibres of patients with inflammatory myopathies and Duchenne (DMD) and Becker (BMD) muscular dystrophy showed consistently strong expression. In other neuromuscular diseases expression of class I antigens was more variable. No expression of class I antigens was observed on muscle fibres in samples from fetuses "at risk" for DMD and BMD or from female carriers of these disorders. The immunocytochemical assessment of HLA class I antigen expression was confirmed by a quantitative radioimmunoassay which demonstrated a 3-fold increase in the level of expression in muscle samples from patients with DMD and juvenile dermatomyositis. Class II antigen expression was never observed on muscle fibres in biopsies from normal individuals or any of the neuromuscular disorders. However, these antigens were expressed by endothelial cells present in these samples. Muscle specimens from fetuses and early in postnatal life showed very limited expression of class II antigens. They were expressed at a reduced level by about 3 months of age, but strong expression of class II antigens was not observed until about 1 year of age. The mechanism of induction of class I antigen expression in diseased muscle is not known. The appearance of class I antigens on diseased muscle may make the affected tissue a target for cytotoxic T cells and may thus have a role in muscle fibre damage in inflammatory myopathies and the X-linked muscular dystrophies.
In the absence of any effective drug treatment, physical methods of management are still the mainstay of treatment. Our current practice in Duchenne muscular dystrophy is to provide lightweight knee-ankle-foot orthoses at the time of loss of ambulation. This prolongs independent walking for an average of two years, and has the effect of delaying the onset of scoliosis, particularly if the boy remains ambulant during the pubertal growth spurt. We are currently assessing the value of radical surgery, performed early in the course of the disease, which may stabilize and prolong independent walking. In non-ambulant patients instrumentation of the spine, using mainly the Luque technique, has revolutionised the treatment of progressive scoliosis. Ventilator support produces clinical improvement in late cases with symptomatic hypoventilation. Its place in the management of asymptomatic patients with nocturnal hypoventilation still needs evaluation, as does the role of early prophylactic respiratory support. We have reviewed the clinical drug trials over the past 10 years. There has been an overall improvement in their quality control.
Nineteen infants with posthaemorrhagic ventricular dilatation had auditory brain stem responses measured during the period of maximal ventricular dilatation. These showed various patterns ranging from normal, through various abnormalities, to complete absence of responses. When serial auditory brain stem responses were studied in parallel with the evolution of posthaemorrhagic ventricular dilatation it was seen that the abnormalities of auditory brain stem response usually resolved irrespective of the persistence or progression of ventricular dilatation. No correlation was found between cerebrospinal fluid pressure and prolonged interpeak intervals on the auditory brain stem response. In three patients with posthaemorrhagic ventricular dilatation improvement in the auditory brain stem response occurred when cerebrospinal fluid was withdrawn. Intermittent withdrawal of cerebrospinal fluid (by ventricular tap or lumbar puncture) in two of these infants was followed by improvement in the auditory brain stem response after a period of 24 hours (but not sooner). In one infant born at full term improvement in the auditory brain stem response was noted one week after shunting.
The clinical features of 14 neonates with congenital myotonic dystrophy were retrospectively reviewed. These babies represent all the new cases of congenital myotonic dystrophy seen in this department since 1982. Twelve babies were referred because of either difficulties in diagnosis or difficulties in the management of their respiratory problems. Of the 14 babies, 13 had birth asphyxia, 11 were premature, and four had intrauterine growth retardation. Ten babies required artificial ventilation from birth. Abnormalities on chest radiography included thin ribs (n =9) and raised right hemidiaphragms (n = 5). Recurrent episodes of collapse and consolidation of the lungs secondary to poor swallowing occurred in all ventilated babies. All babies ventilated for longer than four weeks died of respiratory complications before the age of 15 months. One baby was successfully extubated after diaphragmatic plication, but he died a few months later. Duration of ventilation was the best guide to prognosis.
We recruited 275 full term and preterm infants into a prospective evaluation of continuous four channel electroencephalographic (EEG) monitoring in the diagnosis and prognosis of neonatal seizures. EEG seizure activity was found in 55 infants; clinical signs were completely simultaneous in only 12 of these, they were present but limited in another 20, and were completely absent in the remaining 23. EEG seizure activity, with or without clinical signs, were equally associated with serious cerebral lesions and with adverse clinical outcome. The four channel EEG recording provided sufficient data on abnormality to be prognostically specific in 79% of the 43 infants who either died or had serious neurological impairment.
During a two year period prospective continuous electroencephalographic (EEG) monitoring of 275 infants identified seizure activity in 55 cases, 31 of whom were treated with anticonvulsant drugs on clinical grounds. EEG and clinical response was complete in only two and equivocal in another six. Clinical response with persistent EEG seizures occurred in 13 and neither clinical nor EEG response in 10. There was no significant improvement in the generally poor neurological outcome compared with that in 24 infants whose seizures were not treated because of limited or absent clinical manifestations. Background EEG abnormality (as an index of associated cerebral dysfunction) was a guide to potential lack of response to anticonvulsant drugs; it was also predictive of subsequent clinical outcome irrespective of treatment. This study shows that commonly used anticonvulsant drugs (phenobarbitone, paraldehyde, phenytoin, and diazepam) have little effect on seizure control or neurological outcome in neonatal seizures associated with haemorrhagic, hypoxic, or ischaemic cerebral lesions. In view of the variable clinical appearance of EEG seizure activity, continuous EEG monitoring should be an essential feature of further study of neonatal anticonvulsant treatment.
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.