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V Dubowitz

Publications and source records attributed to V Dubowitz.

At least 73 records · Page 4Linked to original sources
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↗
PubMed1996

Diagnosis of merosin (laminin-2) deficient congenital muscular dystrophy by skin biopsy.

BACKGROUND: The alpha2 chain of laminin-2 (merosin), encoded by a gene on chromosome 6q22, is deficient in about half the cases of congenital muscular dystrophy. Diagnosis of this condition has relied on immunocytochemical analysis of the alpha2 chain in muscle biopsy specimens. We have observed that normal skin also expresses laminin alpha2 in the basement membrane at the junction of the dermis and epidermis. Here we have investigated laminin alpha2 deficiency in skin biopsy specimens from two patients with congenital muscular dystrophy. PARTICIPANTS: Two patients with severe congenital muscular dystrophy gave informed consent to a skin biopsy. The girl was aged 10 and the boy was aged 7. The specimens were labelled with a commercially available mouse monoclonal antibody and a rat monoclonal antibody (4H8-2), which recognise an 80 and a 380 kDa fragment of the alpha2 chain, respectively. The antibodies were visualised by standard methods. A muscle biopsy specimen was available for each case, and was processed with the skin biopsy samples (from the girl a few months previously, from the boy at age 14 days). Skin biopsies were done on four controls with normal expression of laminin alpha2 on their skeletal muscle fibres. FINDINGS We did not detect laminin alpha2 in skin specimens from either case, although the controls were positive. The muscle biopsy specimens from the girl showed a few fibres, with traces of laminin alpha2; those from the boy showed no laminin alpha2. INTERPRETATION: Skin biopsy specimens will provide a useful alternative to muscle biopsy samples for the assessment of laminin-2 (merosin) status in congenital muscular dystrophy.

Biopsy↗
PubMed1996

Paramyotonia congenita: the R1448P Na+ channel mutation in adult human skeletal muscle.

Twitch force and Na+ currents were investigated in a muscle biopsy specimen from a patient with paramyotonia congenita carrying the dominant Arg-1448-Pro mutation in the skeletal muscle sodium channel. Cooling of the muscle fibers caused sustained membrane depolarization that resulted in reduced twitch force. Membrane repolarization, produced by a K+ channel opener, partly prevented and antagonized the drop in twitch force. Patch-clamp recordings on sarcolemmal blebs revealed a distinctly slower Na+ current decay on paramyotonia congenita muscle compared to control muscle. In addition, patches with mutant Na+ channels showed a significantly higher frequency of steady-state openings, which increased with cooling. Activation of mutant channels was not affected, whereas the steady-state inactivation curve was shifted by -5 mV and showed less voltage dependence. We suggest that the weakness of cooled muscle can be explained by a combination of the increased steady-state Na+ current and the left-shifted inactivation curve.

Adult↗
PubMed1996

Sequential study of central and peripheral nervous system involvement in an infant with merosin-deficient congenital muscular dystrophy.

Diffuse white matter changes on brain imaging and peripheral neuropathy are associated features of merosin-deficient congenital muscular dystrophy (CMD). In this report we describe the early manifestation and evolution of brain changes, and the involvement of the peripheral nervous system in a female infant with merosin-deficient CMD diagnosed in the neonatal period who had sequential clinical, neurophysiological and magnetic resonance imaging (MRI) assessment. Both MRI and nerve conduction velocity in the first week of life failed to demonstrate any abnormality. By 6 months of age both nerve conduction and MRI were abnormal. White matter changes became more evident on a further scan at 1 yr of age and this pattern remained unchanged on the following scan performed at 17 months of age. Our findings suggest a failure in the physiological maturation process of myelination of both the central and peripheral nervous system.

Central Nervous System Diseases↗
PubMed1996

Abnormalities in alpha-, beta- and gamma-sarcoglycan in patients with limb-girdle muscular dystrophy.

We have identified 12 cases from a group of 45 patients with early onset limb-girdle muscular dystrophy (LGMD), who have a deficiency of the 50 kDa dystrophin-associated glycoprotein, alpha-sarcoglycan. An additional male sibling of one case was also studied clinically. All 12 patients showed a concomitant, but variable, deficiency of alpha-, beta- and gamma-sarcoglycan. None of our patients had a defect in only one component of the sarcoglycan complex. Molecular analysis confirmed that a total absence of one sarcoglycan, associated with reduced expression of the other two, indicates a primary defect. Immunocytochemistry is thus useful for directing molecular studies. Morphological features not usually observed in Xp21 dystrophies were peripheral accumulations of mitochondria, discrete core-like areas, and nemaline rods in one case. Clinical severity and progression was variable between and within families but early loss of ambulation, at or before the age of 12 years, was associated with a total absence of gamma-sarcoglycan. Common clinical features were calf hypertrophy, contractures of the tendo achilles, lumbar lordosis, winging of the scapulae, weak hamstrings and weak neck muscles. All cases had grossly elevated serum creatine kinase. In contrast to patients with Duchenne muscular dystrophy (DMD), our patients with sarcoglycan deficiencies had normal early motor milestones, normal intellect, and good respiratory and cardiac function. Our data confirm that the sarcoglycan complex acts as a unit and that morphological and clinical features can distinguish patients with defects in the sarcoglycans from those with Xp21 dystrophy. In our group of patients prognosis is better than in DMD, but clinical variability makes this difficult to predict in isolated cases.

Age of Onset↗
PubMed1996

Sleep studies and supportive ventilatory treatment in patients with congenital muscle disorders.

Eight ambulant children aged 6-13 years, four with congenital myopathy, two with congenital muscular dystrophy and two with the rigid spine syndrome, presented with recurrent chest infections, morning headaches, shallow breathing at night, or respiratory failure. Polysomnography confirmed the presence of nocturnal hypoxaemia with oxygen saturation on average less than 90% for 49% of sleep and less than 80% for 19% of sleep accompanied with severe hypoventilation. Additionally there was sleep disturbance characterised by an increased number of wake epochs from deep sleep (in comparison to 10 non-hypoxaemic subjects). The severity of sleep hypoxaemia did not correlate with symptoms. Treatment with night time nasal ventilation was started and repeat polysomnography showed normal overnight oxygen saturation and a reduced number of wake epochs during deep sleep. It is important to be vigilant for sleep hypoventilation in these patients and sleep studies should be part of the routine respiratory evaluation. Treatment with nasal ventilation is effective in reversing the nocturnal respiratory failure without significant disturbance to life style.

Adolescent↗
PubMed1996

Gene deletions in spinal muscular atrophy.

Two candidate genes (NAIP and SMN) have recently been reported for childhood onset spinal muscular atrophy (SMA). Although affected subjects show deletions of these genes, these deletions can lead to either a very mild or a severe phenotype. We have analysed a large number of clinically well defined patients, carriers, and normal controls to assess the frequency and extent of deletions encompassing both of these genes. A genotype analysis indicates that more extensive deletions are seen in the severe form of SMA than in the milder forms. In addition, 1 center dot 9% of phenotypically normal carriers are deleted for the NAIP gene; no carriers were deleted for the SMN gene. Our data suggest that deletions in both of these genes, using the currently available assays, are associated with both a severe and very mild phenotype.

Chromosomes, Human, Pair 5↗
PubMed1995

Characterization of genetic deletions in Becker muscular dystrophy using monoclonal antibodies against a deletion-prone region of dystrophin.

We have produced a new panel of 20 monoclonal antibodies (mAbs) against a region of the dystrophin protein corresponding to a deletion-prone region of the Duchenne muscular dystrophy gene (exons 45-50). We show that immuno-histochemistry or Western blotting with these "exon-specific" mAbs can provide a valuable addition to Southern blotting or PCR methods for the accurate identification of genetic deletions in Becker muscular dystrophy patients. The antibodies were mapped to the following exons: exon 45 (2 mAbs), exon 46 (6), exon 47 (1), exons 47/48 (4), exons 48-50 (6), and exon 50 (1). PCR amplification of single exons or groups of exons was used both to produce specific dystrophin immunogens and to map the mAbs obtained. PCR-mediated mutagenesis was also used to identify regions of dystrophin important for mAb binding. Because the mAbs can be used to characterize the dystrophin produced by individual muscle fibres, they will also be useful for studying "revertant" fibres in Duchenne muscle and for monitoring the results of myoblast therapy trials in MD patients with deletions in this region of the dystrophin gene.

Amino Acid Sequence↗
PubMed1995

Familial concordance of brain magnetic resonance imaging changes in congenital muscular dystrophy.

Cerebral white matter changes have been described in a significant number of individual patients with "pure" congenital muscular dystrophy without clinical evidence of central nervous system involvement. The cause for the imaging changes is unknown but it is possible that they are the result of abnormal expression in the brain of the gene also responsible for the muscular dystrophy. In this study magnetic resonance imaging of the brain was performed on seven sibling pairs with congenital muscular dystrophy and normal intelligence to establish whether imaging changes are consistent within families. Diagnosis of congenital muscular dystrophy was based on clinical and muscle biopsy findings. Children from two families had normal scans; the remaining five sibling pairs showed white matter changes and within each family the changes were virtually identical in severity and distribution. Our data indicate that the central nervous system changes are consistent within individual families, suggesting that they probably relate to the mutation in the congenital muscular dystrophy genes involved in the respective families.

Adolescent↗
PubMed1995

Clinical phenotype in congenital muscular dystrophy: correlation with expression of merosin in skeletal muscle.

It has recently been shown that merosin, an extracellular matrix protein linked to the dystrophin-associated glycoproteins, is deficient in a proportion of patients with classical congenital muscular dystrophy (CMD). We have undertaken a detailed study of the clinical features and brain imaging in 24 cases of CMD in relation to the merosin status. Immunocytochemistry showed that merosin was present in 13 cases and markedly deficient in 11. In the merosin-positive cases, the maximum motor achievement was independent walking in 11, walking with support in one and sitting unsupported in one (currently 18 months old). In contrast, none of the merosin-deficient cases achieved independent ambulation. Two achieved walking with support, nine standing with support. In addition, nine of the 11 merosin-deficient cases had a creatine kinase level greater than 2000 whereas only one merosin-positive case had this degree of elevation. Magnetic resonance imaging of the brain was carried out on 15 of the children. All eight merosin-positive cases had normal scans whereas all seven of the merosin-deficient cases had significant changes in the white matter. This study has demonstrated that children with merosin-deficient CMD have a more severe clinical phenotype and associated white matter changes on brain imaging.

Child↗
PubMed1995

Expression of laminin subunits in congenital muscular dystrophy.

The expression of laminin subunits M, A, B1 and B2 was studied immunocytochemically in 25 cases of classical congenital muscular dystrophy (CMD), 11 hypotonic infants, 20 cases of a variety of inherited and acquired neuromuscular disorders, and 11 controls. Merosin, as indicated by labelling for the M chain, was deficient in 12 (48%) of the cases of classical CMD. Seven cases had no detectable labelling for the M chain whereas five showed traces, including three cousins from the same family. This suggests that very low expression may relate to a possible difference in the molecular defect, compared with cases completely devoid of the M chain. The A chain was abundant in regenerating fibres and in immature fibres expressing fetal myosin. In all merosin-deficient cases the A chain was over-expressed but this was not due to immaturity. A secondary reduction in sarcolemmal expression of the B1 chain occurred in five merosin-deficient cases, whilst expression in vascular tissue was normal. B1 was also reduced in one merosin-positive case of CMD, suggesting that other subunits may be involved in other forms of CMD. No differences in the expression of the B2 chain were observed in any of the cases studied. No abnormality in laminin subunits was found in controls or other neuromuscular disorders.

Adolescent↗
PubMed1995

Congenital symmetrical weakness of the upper limbs resembling brachial plexus palsy: a possible sequel of drug toxicity in first trimester of pregnancy?

We report a 14-month-old girl with a symmetrical paralysis from birth, limited to the upper limbs and resembling a severe, complete bilateral brachial plexus palsy. The presence of dimples over the wrists, shoulders and scapulae and abnormal palmar dermatoglyphics suggested an early prenatal onset. Previous reports and the course of the disease in our case suggest this sporadic condition is not progressive. Although no definitive causative factor has been identified in previously reported cases, the affection in our case is possibly related to Debendox (Bendectin) and nitrofurantoin taken in early pregnancy for nausea and renal tract infection, respectively.

Age of Onset↗