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V Dubowitz

Publications and source records attributed to V Dubowitz.

At least 91 records · Page 5Linked to original sources
PubMed1995

A gene for autosomal recessive nemaline myopathy assigned to chromosome 2q by linkage analysis.

Clinical genetic evidence suggests the existence of an autosomal recessive form of congenital nemaline myopathy in addition to the autosomal dominant one(s). One mutation in an Australian kindred has been identified as causing an autosomal dominant form of the disease. This mutation in the alpha-tropomyosin gene TPM3 has previously been excluded as causing autosomal recessive nemaline myopathy. We searched systematically for genetic linkage to autosomal recessive nemaline myopathy (NEM2) by studying microsatellite marker alleles in seven multiplex families from Finland, Denmark, Wales, England and The Netherlands. Significant evidence of linkage was found to markers of chromosome 2q, the highest multipoint lod score value being 5.34 for the marker D2S151. Recombinant genotypes in affected individuals demarcate the the region in which the NEM2 gene is likely to reside as a 13 cM region between the markers D2S150 and D2S142. These results confirm the existence of at least one distinctive form of autosomal recessive nemaline myopathy and provide a basis for the identification of its gene.

Australia↗
PubMed1995

Somatosensory and visual evoked potentials in congenital muscular dystrophy: correlation with MRI changes and muscle merosin status.

Congenital muscular dystrophy comprises a heterogeneous group of disorders, that have in common an early onset and a dystrophic picture on the muscle biopsy. The "pure" form of congenital muscular dystrophy is not associated with severe mental retardation or structural changes in the brain, though white matter changes on brain imaging have been detected in a significant proportion of cases. In this study we evaluated the incidence of sensory abnormalities (somatosensory and visual evoked responses) in a group of 17 patients with "pure" congenital muscular dystrophy and correlated the results of the evoked responses with the presence or absence of white matter changes on brain magnetic resonance imaging. Our results show close correlation between the presence of MRI white matter changes and abnormalities in the sensory evoked potentials. Conversely, all patients with normal brain MRI had normal somatosensory evoked potentials (SEP). Visual evoked potentials were less sensitive than somatosensory evoked potentials in detecting abnormalities in children with white matter changes on MRI. With the recent discovery of deficiency in merosin expression in the skeletal muscle of a subgroup of patients with CMD, we also correlated the presence or absence of white matter changes and the SEP responses with the merosin status. The results indicate that all merosin-negative patients had abnormal SEP as well as abnormal MRI, whilst no patient with normal merosin expression had an abnormal scan or abnormal SEP.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Minor neurological and perceptuo-motor deficits in children with congenital muscular dystrophy: correlation with brain MRI changes.

Diffuse white matter changes on magnetic resonance imaging (MRI) have been a consistent feature in some children with the "pure" form of congenital muscular dystrophy (CMD) in which there are no structural changes in the brain or severe mental retardation. The aim of this study was to assess fine motor and perceptuo-motor abilities in children with CMD with and without MRI changes. Twenty-two children with "pure" CMD were investigated with a standard neurological examination and a battery of tests (Manual dexterity from the Movement ABC, test of visual-motor integration, Zurich Neuromotor test) which have already been used to detect minor neurological signs related to white matter changes. The cohort was then divided in two groups for analysis depending on the presence or the absence of diffuse white matter changes. A significant difference was found for all the tests between the group of the CMD children with normal MRI and the group with diffuse white matter changes. The manual dexterity and the Zurich Neuromotor tests showed a greater sensitivity than the test of visual-motor integration, which had some false negatives. It is of interest that in the group with diffuse white matter changes the presence of contractures or weakness did not seem to affect the quality of the performance; all these children scored abnormally on the test, irrespective of the severity or the extent of contractures and weakness. In contrast, in children with normal MRI severe contractures and weakness did affect the performances. Our results demonstrate that perceptuo-motor difficulties and minor neurological soft signs are a consistent feature in CMD children with diffuse MRI changes but not with normal MRI.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Deletions in the survival motor neuron gene on 5q13 in autosomal recessive spinal muscular atrophy.

Autosomal recessive spinal muscular atrophy is a motor neuron disease which affects about 1 in 10,000 births. Recent evidence shows that the candidate region contains multiple copies of genes and pseudogenes and is characterised by genome instability. We have analysed the frequency of deletions in a recently characterised candidate survival motor neuron (SMN) gene. Our data confirm previous analyses and show that this gene is disrupted by deletion in SMA patients. The same deletion frequency is observed in the milder variants of the disease as in patients with the severe form. In addition, we observed one case of a new mutation in a family previously thought not to be segregating for a chromosome 5 linked form of SMA. This assay is a very good diagnostic for SMA although no direct correlation between phenotype and genotype is apparent and carrier status cannot be determined. The implications for the identification of the gene or genes causing the disease are discussed.

Chromosomes, Human, Pair 5↗
PubMed1995

Intravenous immunoglobulin in juvenile dermatomyositis--four year review of nine cases.

Juvenile dermatomyositis is difficult to treat, compounded by complications of the disease itself as well as side effects of treatment. The mainstay of pharmacological management is corticosteroids, to which the disease is usually very responsive, but steroids have well established short and long term side effects. Refractory cases may be resistant to steroids or patients may become dependent on high doses, with relapse in clinical disease precipitated by reduction. Overtreatment with steroids and too rapid a reduction are common errors. Various second line agents have been used with success in complex or refractory cases, including cyclophosphamide, methotrexate, and cyclosporin. Intravenous immunoglobulin has been tried in the management of autoimmune diseases, either as an alternative to cytotoxic treatment or as a steroid sparing agent. The reported benefit in a number of childhood illnesses, including juvenile dermatomyositis, prompted this clinical trial in some of our more refractory cases. Over the past four years, nine children attending a dermatomyositis clinic have been treated with intravenous immunoglobulin. The two main indications were failure of conventional treatment and severe side effects from previous treatment, principally corticosteroids. All nine were still on treatment with various permutations of prednisolone, azathioprine, and cyclosporin. All nine showed clinical improvement at some point in their treatment with intravenous immunoglobulin. Of eight children on concurrent prednisolone, the dose could be reduced in six and kept the same in two.

Age of Onset↗
PubMed1995

Duchenne muscular dystrophy presenting with failure to thrive.

Three patients with Duchenne muscular dystrophy presenting with failure to thrive in infancy are described. Their families noted poor growth and sought medical advice up to six months before the diagnosis was suspected. Growth charts showed weight loss between 4 and 18 months of age. Length growth was affected while growth in head circumference remained unaffected. No causes of failure to thrive were found at presentation. Failure to thrive in Duchenne muscular dystrophy has been described previously but it is neither widely recognised nor understood. Poor growth in the first years and eventual short stature, however, is a well described feature of Duchenne muscular dystrophy. Failure to thrive in our three patients may be an extreme manifestation of this.

Body Height↗
PubMed1995

Genomic rearrangements in childhood spinal muscular atrophy: linkage disequilibrium with a null allele.

Autosomal recessive childhood onset spinal muscular atrophy has been mapped to chromosome 5q13. We report the analysis of a polymorphic microsatellite which shows linkage disequilibrium with the disease. The linkage disequilibrium is observed with a null allele which is seen as the non-inheritance of alleles from one or both parents. The inheritance of a null allele was observed in 26 out of 36 (72%) informative childhood onset spinal muscular atrophy (SMA) families tested, of all types of severity and from a variety of ethnic backgrounds. In seven families segregating for the severe Werdnig-Hoffmann or SMA type I, no alleles were inherited from either parent using this microsatellite. This null allele may represent a deletion which is either closely associated with, or causes, the disease.

Alleles↗
PubMed1995

The myotubular myopathies: differential diagnosis of the X linked recessive, autosomal dominant, and autosomal recessive forms and present state of DNA studies.

Clinical differences exist between the three forms of myotubular myopathy. They differ regarding age at onset, severity of the disease, and prognosis, and also regarding some of the clinical characteristics. The autosomal dominant form mostly has a later onset and milder course than the X linked form, and the autosomal recessive form is intermediate in both respects. These differences are, however, quantitative rather than qualitative. Muscle biopsy studies of family members are useful in some cases, and immunohistochemical staining of desmin and vimentin may help distinguish between the X linked and autosomal forms. Determining the mode of inheritance and prognosis in individual families, especially those with a single male patient, still poses a problem. Current molecular genetic results indicate that the gene for the X linked form is located in the proximal Xq28 region. Further molecular genetic studies are needed to examine the existence of genetic heterogeneity in myotubular myopathy and to facilitate diagnosis.

DNA↗
PubMed1995

A mutation in the dystrophin gene selectively affecting dystrophin expression in the heart.

We have previously shown in a large X-linked pedigree that a deletion removing the dystrophin muscle promoter, the first muscle exon and part of intron 1 caused a severe dilated cardiomyopathy with no associated muscle weakness. Dystrophin expression was present in the muscle of affected males and transcription studies indicated that this dystrophin originated from the brain and Purkinje cell isoforms, upregulated in this skeletal muscle. We have now studied dystrophin transcription and expression in the heart of one member of this family. In contrast to the skeletal muscle, dystrophin transcription and expression were absent in the heart, with the exception of the distal Dp71 dystrophin isoform, normally present in the heart. The 43- and 50-kD dystrophin-associated proteins were severely reduced in the heart, despite the presence of Dp71, but not in skeletal muscle. The absence of dystrophin and the down-regulation of the dystrophin-associated proteins in the heart accounted for the severe cardiomyopathy in this family. The mutation present in these males selectively affects dystrophin expression in the heart; this could be secondary to the removal of cardiac-specific regulatory sequences. This family may represent the first example of a mutation specifically affecting the cardiac expression of a gene, present physiologically in both the skeletal and cardiac muscles.

Base Sequence↗
PubMed1995

Demyelinating peripheral neuropathy in merosin-deficient congenital muscular dystrophy.

It has recently been shown that merosin, a laminin variant, is deficient in a proportion of patients with congenital muscular dystrophy. Merosin is a heterotrimer composed of the alpha 2, beta 1, and gamma 1 subunits, and further studies have shown that it is the alpha 2 subunit that is deficient in these patients. Because the alpha 2 subunit is also expressed in S-merosin, found in Schwann cells, we have investigated whether peripheral nerve function is also affected in these patients. Motor nerve conduction velocities and sensory distal latencies were examined in 25 cases of congenital muscular dystrophy and the results correlated with the merosin expression in their muscle biopsies. All but two of the 10 merosin-deficient cases had reduced motor nerve conduction, whereas all the merosin-positive cases had normal results. Analysis of the biopsies of these two cases showed that they produced merosin in reduced amounts, in contrast to all other merosin-deficient patients that produced no or only traces of merosin. Sensory nerve studies showed no difference between the two groups. These results indicate that a peripheral demyelinating neuropathy is a feature of merosin-deficient congenital muscular dystrophy. The fact that the alpha 2 subunits is also expressed in Schwann cells supports the idea that the alpha 2 gene, located on chromosome 6, is the candidate gene for merosin-deficient congenital muscular dystrophy.

Adolescent↗
PubMed1995

In vivo sodium channel structure/function studies: consecutive Arg1448 changes to Cys, His, and Pro at the extracellular surface of IVS4.

Structure/function relationships in ion channels have been intensively studied through expression of cloned channel subunits in heterologous cellular environments. Considerable information has been gleaned via this approach. However, it is prominent role in vivo: there are many differences between heterologous systems and functioning nerves and muscle in vivo, any one of which is likely to affect channel function. Examples of such variables include glycosylation status of the channel protein, association of muscle-specific membrane or cytoskeletal proteins, and fluctuations of intracellular and extracellular fluid milieu as a function of fluctuating cellular physiology. The identification of single amino acid changes in the voltage-sensitive muscle sodium channel alpha subunit in human and horse genetic disease has permitted a new approach to the study of structure/function relationships in ion channels. Importantly, the interactions between the environment and the abnormal channel can be studied in this in vivo system. Here we report the identification of a novel human sodium channel mutation (R1448P), which causes a severe type of cold-sensitive myotonia and weakness. This patient is compared to a series of other patients having R1448C, and R1448H mutations. We show that the severity of the amino acid change correlates with the severity of clinical symptoms. This data shows that different amino acid replacements in the extracellular surface of domain IV S4 are important for channel function, despite the paucity of heterologous expression data suggesting functional importance of this region. The extreme cold sensitivity of the proline substitution at R1443 suggests that cold temperatures may affect the structural integrity of the channel, and that proline may destabilize the normal structure.

Amino Acids↗
PubMed1995

Transcription of the dystrophin gene in normal tissues and in skeletal muscle of a family with X-linked dilated cardiomyopathy.

We recently described a family where a deletion of the dystrophin gene was associated with a severe dilated cardiomyopathy without skeletal muscle weakness. The deletion removed the muscle promoter region and the first muscle exon, but not the brain or Purkinje-cell promoters. Dystrophin was detected immunocytochemically in the skeletal muscle from this family, despite the fact that the deletion eliminated the transcriptional start site of the muscle isoform. In order to determine which promoter was driving dystrophin transcription in skeletal muscle of these individuals, we first evaluated the expression of the exon 1 of muscle, brain, and Purkinje-cell isoforms in normal human skeletal and cardiac muscles and in mouse brain and cerebellum. Our data indicate that, with the exception of minimal expression of the brain isoform, only the muscle isoform is significantly transcribed in skeletal muscle, whereas both the exon 1 muscle and brain isoforms are highly expressed in cardiac muscle. In contrast to what is observed in normal muscle, the skeletal muscle of our patients showed expression of both the brain and the Purkinje-cell isoforms. The overexpression, in skeletal muscle, of these two isoforms thus appears to be of crucial importance in preventing a myopathy in these affected males. The reason for the severe cardiomyopathy remains speculative, in the absence of dystrophin data on their heart. However, we have found in the 5' end of intron 1, a region deleted in our cases, regulatory sequences that might be of importance for dystrophin expression in various tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1995

Readjusting the localization of merosin (laminin alpha 2-chain) deficient congenital muscular dystrophy locus on chromosome 6q2.

The laminin alpha 2-chain gene mutations (LAMA2) are responsible for about 50% of the cases of classical congenital muscular dystrophy. These patients form a clinically homogenous group presenting merosin (laminin alpha 2-chain) deficiency in muscle biopsies. The LAMA2 gene has been previously localized on 6q22-23 and the disease locus mapped in a 16 cM interval in 6q2 by homozygosity mapping. In the present report we establish, by haplotyping additional microsatellites markers in 18 consanguineous families, that LAMA2 gene is more centromeric than previously thought: between the flanking markers, D6S407 and D6S1705, distant of 3 cM. In this interval the microsatellite D6S1620 is homozygous for all the patients. The localization of LAMA2 gene was confirmed by radiation hybrid mapping. The 3 new highly informative markers can be very useful for prenatal diagnosis.

Chromosome Mapping↗
PubMed1994

Deficiency of the 50 kDa dystrophin-associated glycoprotein and abnormal expression of utrophin in two south Asian cousins with variable expression of severe childhood autosomal recessive muscular dystrophy.

Two male cousins with severe childhood, autosomal recessive, Duchenne-like, muscular dystrophy (SCARMD) have been identified with a deficiency of the 50 kDa dystrophin-associated glycoprotein but normal expression of dystrophin. Both boys were from consanguineous marriages and were Asian, having originated from Pakistan. This is in contrast to all previously reported cases from North Africa. Clinical severity varied and the patients were still able to walk at 13 and 12 yr, respectively. Neither had calf hypertrophy, a feature reported to be almost consistent in the North African patients. Abnormal expression of utrophin, the dystrophin-related protein, was observed on the surface of several non-regenerating muscle fibres, with less intense immunolabelling in the clinically more affected child. This family shows that SCARMD is not confined to North Africa and illustrates a hitherto unreported expression of utrophin in this condition.

Antibodies, Monoclonal↗
PubMed1994

Continuous muscle fibre activity (Isaacs' syndrome) in infancy: a report of two cases.

Two cases of continuous muscle fibre activity in infancy are reported. Both infants were severely affected and died from respiratory failure. Treatment with phenytoin and carbamazepine produced only temporary improvement. Electrophysiological and pharmacological evidence suggests that the site of the lesion in infancy, as in older patients, is in the terminal nerve endings or motor end plate. Continuous muscle fibre activity occurring in infancy seems to be more severe than in older children or adults and seems refractory to treatment.

Baclofen↗
PubMed1994

Infantile axonal neuropathy in two siblings.

Two siblings presented with a recurrent axonal neuropathy associated with intercurrent infection. One child had mild global developmental delay. The CSF was normal and haematological and biochemical tests failed to reveal a metabolic disorder. Nerve conduction studies in both children showed a mixed sensory and motor axonal neuropathy. Sural nerve biopsies showed severe ongoing axonal degeneration. At post mortem examination peripheral nerves showed widespread axonal loss with a marked reduction of anterior horn and posterior root ganglion cells. Mild diffuse endoneurial cell inflammation was present in the peripheral nerves and some posterior roots. We believe that these siblings died from a genetically determined axonal neuropathy with central nervous system involvement.

Axons↗
PubMed1994

Experimental regeneration in canine muscular dystrophy--2. Expression of myosin heavy chain isoforms.

The sequential expression of neonatal, fast and slow myosin heavy chain isoforms was examined during the regeneration of normal and dystrophic dog muscle from 1 to 56 days, following necrosis induced by the venom of Notechis scutatis, to assess the regenerative potential of dystrophic muscle. Regeneration was equally rapid in normal and dystrophic dogs but morphological and immunocytochemical abnormalities were more apparent in the dystrophic fibres. New myotubes were formed by 3 days, and by 4 days all myosin isoforms were expressed. Neonatal myosin persisted in normal dogs after morphological restoration of the muscle and after dystrophin and beta-spectrin expression had returned to normal. Neonatal myosin was considerably reduced by 21 days in normal dogs, but persisted beyond 28 days in dystrophic dogs, suggesting a delay in maturation. At 42 and 56 days, dystrophic dogs showed a population of small fibres expressing neonatal myosin, which may represent a second cycle of degeneration and regeneration. The reciprocal pattern of fast and slow myosin was not fully restored in normal or dystrophic regenerating muscle, and co-expression persisted. Thus, dystrophic muscle retains its potential to regenerate, but maturation is slower than normal. The persistent co-expression of isoforms has implications for the long-term function of fibres formed after myoblast therapy, but the results imply that a stable state can be achieved if dystrophin expression is restored by gene or myoblast transfer therapy.

Animals↗