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Biomedical subjects

V Dubowitz

Publications and source records attributed to V Dubowitz.

At least 19 recordsLinked to original sources
PubMed2001

Mild phenotype of nemaline myopathy with sleep hypoventilation due to a mutation in the skeletal muscle alpha-actin (ACTA1) gene.

Nemaline myopathy is a clinically and genetically heterogeneous condition. The clinical spectrum ranges from severe cases with antenatal or neonatal onset and early death to late onset cases with only slow progression. Three genes are known to cause nemaline myopathy: the genes for nebulin (NEB) on chromosome 2q22, slow alpha-tropomyosin (TPM3) on chromosome 1q21 and skeletal muscle alpha-actin (ACTA1) on chromosome 1q42. We present a 39-year-old lady with a mild form of nemaline myopathy, whom we have followed over a period of 25 years. She presented at the age of 7 years with symptoms of mild axial and proximal muscle weakness. The overall course was essentially static, but at 36 years, she went into life-threatening respiratory failure, for which she is currently treated with night-time ventilation. Muscle biopsies at 12, 17 and 39 years of age showed typical nemaline rods, particularly in type 1 fibres. Areas with unevenness of oxidative stain were present in the second and third biopsies. The presence of rods and core-like areas was confirmed on electron microscopy. There was no detectable alteration in actin expression immunocytochemically. A dominant missense mutation in the skeletal muscle alpha-actin gene (ACTA1) was found. This case illustrates the clinical and genetic heterogeneity of nemaline myopathy, and one phenotype of the wide spectrum of severity caused by mutations in the skeletal muscle alpha-actin (ACTA1) gene. In addition, it shows the diversity of pathological features that can occur in congenital myopathies due to mutations in the same gene.

Actins↗
PubMed2000

High resolution magnetic resonance imaging of the brain in the dy/dy mouse with merosin-deficient congenital muscular dystrophy.

Magnetic resonance imaging (MRI) abnormalities in the cerebral white matter are a consistent feature of merosin-deficient human congenital muscular dystrophy, a disease caused by a primary defect in the expression of the laminin alpha2 chain of merosin. To investigate the relationship between imaging changes and merosin deficiency we undertook a MRI study in the dy/dy mouse, an animal model for this form of human congenital muscular dystrophy. High resolution in vivo imaging was performed on anaesthetized animals (two homozygous dy/dy mutants and two heterozygous dy/DY controls, aged 2.5 months) in a dedicated 11.7T magnetic resonance imaging scanner. T(1) and T(2) weighted images were normal in all mice and white matter changes were not seen at a stage of maturity when MRI changes are already very striking in human patients. Cerebral MRI abnormalities do not appear to be a feature of dy/dy mice, despite the virtual absence of merosin expression in the dy/dy mouse brain. Possible causes for this absence of MRI changes, and implications for the pathogenesis of the MRI changes in humans are reviewed.

Animals↗
PubMed2000

Minicore myopathy in children: a clinical and histopathological study of 19 cases.

Minicore myopathy is a congenital myopathy characterized by multifocal areas of degeneration in muscle fibres. Genetic heterogeneity expected on the basis of clinical variability awaits further resolution. We reviewed 19 cases in order to further delineate the phenotype. Marked hypotonia was the predominant presenting feature, with evidence of antenatal onset in 30% of cases. Weakness was most pronounced axially and proximally, often more severely affecting the shoulder girdle. Mild facial involvement was frequent. Varying degrees of scoliosis were obvious in all patients older than 10 years. In addition, two patients who were also the most severely affected had complete external ophthalmoplegia. One patient showed marked distal involvement. Respiratory failure developed in half of all patients after 10 years of age and correlated strongly with the degree of scoliosis. Cardiac involvement occurred mainly secondary to respiratory impairment. The course appeared static in most cases. Loss of independent walking was observed only in one case at the age of 10 years. On ultrasound scan, differential involvement within the quadriceps was documented in several patients. Variability in fibre size, type 1 predominance and atrophy with occasional type 2 hypertrophy were prominent but nonspecific histological changes. Apart from typical minicores, a marked increase in internal nuclei was the most prominent histological feature. With the exception of one family in which two generations were affected, inheritance appeared autosomal-recessive or sporadic in all cases.

Adolescent↗
PubMed2000

Diaphragmatic spinal muscular atrophy with bulbar weakness.

We present the clinical and histopathological features of a child affected by diaphragmatic spinal muscular atrophy. The child was born with mild distal arthrogryposis, mild hypotonia and developed marked diaphragmatic and bulbar muscle weakness in the first week of life. Electrophysiological and pathological investigations performed at presentation were not conclusive, while the investigations performed at 3 months showed a clear neurogenic picture. Genetic studies excluded involvement of the SMN gene, or of other genes located on chromosome 5q, confirming that this syndrome represents a different entity from typical proximal spinal muscular atrophy.

Bulbar Palsy, Progressive↗
PubMed2000

Brain magnetic resonance imaging abnormalities in merosin-positive congenital muscular dystrophy.

We report the brain magnetic resonance imaging (MRI) findings in 23 patients with merosin-positive congenital muscular dystrophy (CMD). Twelve patients had normal scans. Eight other children had essentially normal scans but showed mild non-specific periventricular white matter changes. Three children had structural abnormalities on imaging. The first patient, a 15-month-old boy with hypotonia, muscle weakness and global development delay, had moderate cerebellar atrophy and mild dilatation of the lateral ventricles. The second child, a 3-year-old ambulant girl with subtle learning problems, had mild cerebellar hypoplasia and a large subarachnoid space when scanned at 16 months. The third patient, a 15-year-old ambulant male with normal intelligence and complex partial seizures, had polymicrogyria of both temporoparietal lobes on brain MRI. The clinical features and motor ability of children with merosin-positive CMD are variable, although usually milder than merosin-deficient CMD. Our findings confirm that central nervous system involvement can occur in some merosin-positive cases. We suggest performing brain MRI in children with merosin-positive CMD, as this may help in our understanding of this very heterogeneous disease.

Atrophy↗
PubMed2000

Assignment of a form of congenital muscular dystrophy with secondary merosin deficiency to chromosome 1q42.

We have previously reported an autosomal recessive form of congenital muscular dystrophy, characterized by proximal girdle weakness, generalized muscle hypertrophy, rigidity of the spine, and contractures of the tendo Achilles, in a consanguineous family from the United Arab Emirates. Early respiratory failure resulting from severe diaphragmatic involvement was present. Intellect and the results of brain imaging were normal. Serum creatine kinase levels were grossly elevated, and muscle-biopsy samples showed dystrophic changes. The expression of the laminin-alpha2 chain of merosin was reduced on several fibers, but linkage analysis excluded the LAMA2 locus on chromosome 6q22-23. Here, we report the results of genomewide linkage analysis of this family, by use of homozygosity mapping. In all four affected children, an identical homozygous region was identified on chromosome 1q42, spanning 6-15 cM between flanking markers D1S2860 and D1S2800. We have identified a second German family with two affected children having similar clinical and histopathological features; they are consistent with linkage to the same locus. The cumulative LOD score was 3.57 (straight theta=.00) at marker D1S213. This represents a novel locus for congenital muscular dystrophy. We suggest calling this disorder "CMD1B." The expression of three functional candidate genes in the CMD1B critical region was investigated, and no detectable changes in their level of expression were observed. The secondary reduction in laminin-alpha2 chain in these families suggests that the primary genetic defect resides in a gene coding for a protein involved in basal lamina assembly.

Antigens, CD↗
PubMed2000

Mutations in the laminin alpha2-chain gene in two children with early-onset muscular dystrophy.

We investigated two children who presented with delayed motor milestones. The first was a girl who was referred at 20 months because of developmental delay. She walked at 28 months and currently, aged 5 years, is independently mobile but has difficulty rising from the floor or going upstairs. The second was also a girl who presented at 6 weeks of age with hypotonia. Her motor milestones were delayed and she walked at the age of 2 years and 8 months and is currently independently mobile at the age of 3 years. Serum creatine kinase was elevated and a muscle biopsy showed dystrophic changes in both children. Immunohistochemistry of the laminin alpha2 chain of merosin was very similar in both cases: using a C-terminal antibody that recognizes an 80 kDa fragment, there was a mild reduction in expression on most fibres, while the staining with another antibody that recognizes a 300 kDa fragment showed a very marked reduction. Mutational analysis of the laminin alpha2 chain gene in the first patient showed that one of the two alleles had a de novo single nucleotide deletion at position 5702, causing a frameshift. In the other allele, we identified two point mutations present in cis; one was a G-->C transition at position +5 while the second was a T-->C transition at position +6 of the conserved donor splicing consensus sequence of introns 37 and 63, respectively. Transcription analysis of the corresponding cDNA region did not show any alternative splicing occurring as a result of these splice site mutations. Therefore, these mutations probably affect the splicing efficiency. Interestingly, the second child carried in both alleles the same two splicing consensus sequence mutations found in cis in the first patient. Our data provide further evidence that mutations in the laminin alpha2 chain gene are responsible not only for the severe form of congenital muscular dystrophy with onset at birth, but also for milder phenotypes, with later onset, in which the synthesis of a partially functional protein, or of a normal protein but in reduced quantity, is possible. The finding that these two unrelated patients had the same unusual mutation in common might suggest that this is a relatively commonly allele responsible for partial merosin deficiency in the UK.

Age of Onset↗
PubMed1999

Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy.

The congenital nemaline myopathies are rare hereditary muscle disorders characterized by the presence in the muscle fibers of nemaline bodies consisting of proteins derived from the Z disc and thin filament. In a single large Australian family with an autosomal dominant form of nemaline myopathy, the disease is caused by a mutation in the alpha-tropomyosin gene TPM3. The typical form of nemaline myopathy is inherited as an autosomal recessive trait, the locus of which we previously assigned to chromosome 2q21.2-q22. We show here that mutations in the nebulin gene located within this region are associated with the disease. The nebulin protein is a giant protein found in the thin filaments of striated muscle. A variety of nebulin isoforms are thought to contribute to the molecular diversity of Z discs. We have studied the 3' end of the 20. 8-kb cDNA encoding the Z disc part of the 800-kDa protein and describe six disease-associated mutations in patients from five families of different ethnic origins. In two families with consanguineous parents, the patients were homozygous for point mutations. In one family with nonconsanguineous parents, the affected siblings were compound heterozygotes for two different mutations, and in two further families with one detected mutation each, haplotypes are compatible with compound heterozygosity. Immunofluorescence studies with antibodies specific to the C-terminal region of nebulin indicate that the mutations may cause protein truncation possibly associated with loss of fiber-type diversity, which may be relevant to disease pathogenesis.

Australia↗
PubMed1999

Is there selection in favour of heterozygotes in families with merosin-deficient congenital muscular dystrophy?

Merosin-deficient congenital muscular dystrophy is an autosomal recessive neuromuscular disorder caused by partial or total absence of laminin-2 (merosin) in the skeletal muscle. Affected children have severe weakness, hypotonia at birth, high creatine kinase (CK) levels (more than 10 times normal) and are not able to walk or stand unsupported. Linkage and mutation analysis demonstrated that the gene encoding for the laminin-alpha2 chain, mapped on chromosome 6q22-23, is invariably responsible for this form of congenital muscular dystrophy. We investigated the pattern of inheritance of the haplotypes associated with the mutated allele in 29 informative merosin-deficient families, using tightly linked informative polymorphic microsatellite markers. This allowed us to identify heterozygous individuals from normal homozygotes, who are clinically, pathologically and biochemically indistinguishable. By linkage analysis, we found a statistically significant increase in the number of heterozygous individuals carrying either the paternal or the maternal haplotypes associated with the mutated allele. This could suggest a selection in favour of the alleles carrying mutations at the laminin alpha2-chain locus.

Female↗
PubMed1999

Optimality score for the neurologic examination of the infant at 12 and 18 months of age.

The aim of this study was to develop and validate a simple, quantifiable, neurologic examination for infants between 2 and 24 months of age. The assessment consists of 37 items, divided into 3 sections. The first section includes 26 items assessing cranial nerve function, posture, movements, tone, and reflexes; the second section of 8 items documents the development of motor function, and the third section of 3 items evaluates the state of behavior. We applied this assessment to a cohort of ninety-two 12-month-old infants and forty-three 18-month-old infants, with no known perinatal risk factors. The proforma presented has been designed according to the frequency distribution of the neurologic findings in this cohort. Each item is scored individually, and a global score is the sum of all individual scores. The quantitative score enhances the value of this examination, both in clinical practice and in research settings.

Behavior↗
PubMed1999

Merosin-deficient congenital muscular dystrophy: the spectrum of brain involvement on magnetic resonance imaging.

Children with merosin-deficient congenital muscular dystrophy (CMD) have striking white matter changes on T-2 weighted brain magnetic resonance imaging (MRI). There have been occasional cases with structural abnormalities, mainly involving the occipital cortex. We report our brain imaging findings in 14 children with merosin-deficient CMD. Ten cases had a severe reduction or absence of merosin on immunocytochemistry and four cases had partial reduction. All 14 cases had white matter changes, which appeared after the first 6 months of life and persisted with time. The changes were diffuse and the oldest child scanned (14 years) also showed involvement of the U fibres. Five children with total absence of merosin also had structural abnormalities. One child had moderate mental retardation and epilepsy, mainly characterised by complex partial seizures, with atypical absences, which had been difficult to treat. Brain MRI showed marked occipital agyria and pontocerebellar hypoplasia. The gyral pattern of the rest of the brain looked normal. The four other cases, all with normal intelligence, also had cerebellar hypoplasia with variable involvement of the pons. They did not, however, have neuronal migration defects. It is recognised that several forms of congenital muscular dystrophy, namely Fukuyama CMD, muscle-eye-brain disease and Walker-Warburg syndrome, have structural brain abnormalities and associated severe mental retardation. Our cases demonstrate that a range of structural malformations can also be found in a significant number of children with merosin-deficient CMD.

Adolescent↗
PubMed1999

Cognitive abilities in children with congenital muscular dystrophy: correlation with brain MRI and merosin status.

The aim of the study was to evaluate whether children with merosin-positive or merosin-deficient congenital muscular dystrophy (CMD) show any cognitive impairment and whether this is related to brain abnormalities on magnetic resonance imaging (MRI). Twenty-two patients (age range: 5.8-15.3 years) were assessed by the Wechsler Intelligence Scales. Twelve were merosin-positive and ten merosin-deficient. One child had severe mental retardation and could not be tested. The full scale IQ in the remaining 21 ranged from 51 to 134, the verbal IQ ranged from 78 to 136 and the performance from 51 to 136. Of the twelve children with normal merosin one had a mild delay (IQ < 75) and two were borderline (IQ 75-95). Of the ten children with merosin-deficiency, one showed severe mental retardation and could not be tested, one showed a mild delay and two had borderline results. While the children with merosin deficiency with the typical diffuse white matter changes on MRI had normal scores, the children who in addition had cerebellar hypoplasia had lower performance IQ. The child with cortical dysplasia had severe mental retardation. Our results suggest that the spectrum of cognitive abilities in CMD is very wide even within genetically homogeneous conditions.

Adolescent↗
PubMed1999

No evidence of association between apolipoprotein E genotype and phenotypic severity in childhood onset proximal spinal muscular atrophy.

The survival motor neuron (SMN) gene is present in two copies on chromosome 5q13 and the evidence is now compelling that mutations in the telomeric copy (SMNt) of the gene underlie childhood onset proximal spinal muscular atrophy (SMA). There is a correlation between the number of centromeric SMN gene copies (SMNc) and the clinical severity of the disease but this relationship is not absolute. Allelic variants of the apolipoprotein E (APOE) gene encoded on chromosome 19q are known to influence the prognosis and risk in a number of neurological disorders. We have therefore genotyped 166 unrelated cases of SMA to determine whether the presence of specific APOE genotypes correlates with severity of disease. The study failed to show the influence of any particular APOE genotype on disease severity, with specifically APOE epsilon4 being no more common in the milder SMA forms and APOE epsilon2 not over represented in type I SMA. A limited study of 23 SMA families also failed to show any influence of APOE genotype on SMA disease severity. Factors other than APOE genotype must therefore be responsible for determining SMA disease severity.

Apolipoprotein E2↗
PubMed1999

Clinical and genetic heterogeneity in autosomal recessive nemaline myopathy.

Autosomal recessive nemaline (rod) myopathy is clinically and genetically heterogeneous. A clinically distinct, typical form, with onset in infancy and a non-progressive or slowly progressive course, has been assigned to a region on chromosome 2q22 harbouring the nebulin gene Mutations have now been found in this gene, confirming its causative role. The gene for slow tropomyosin TPM3 on chromosome 1q21, previously found to cause a dominantly inherited form, has recently been found to be homozygously mutated in one severe consanguineous case. Here we wished to determine the degree of genetic homogeneity or heterogeneity of autosomal recessive nemaline myopathy by linkage analysis of 45 families from 10 countries. Forty-one of the families showed linkage results compatible with linkage to markers in the nebulin region, the highest combined lod scores at zero recombination being 14.13 for the marker D2S2236. We found no indication of genetic heterogeneity for the typical form of nemaline myopathy. In four families with more severe forms of nemaline myopathy, however, linkage to both the nebulin and the TPM3 locus was excluded. Our results indicate that at least three genetic loci exist for autosomal recessive nemaline myopathy. Studies of additional families are needed to localise the as yet unknown causative genes, and to fully elucidate genotype-phenotype correlations.

Child↗
PubMed1999

Very severe spinal muscular atrophy (SMA type 0): an expanding clinical phenotype.

The classical form of severe spinal muscular atrophy (SMA type 1; Werdnig-Hoffmann disease) has a very consistent clinical phenotype that is well recognized by paediatricians. It usually presents at birth or within the first few months of life. There is general hypotonia, with axial and limb weakness; the legs are affected more than the arms and proximal muscles more than distal, leaving residual spontaneous activity in the feet and in the forearms and hands. Facial muscles are spared so that the infant usually has a bright normal expression. The intercostal muscles are always affected, whereas the diaphragm is spared, allowing adequate spontaneous respiratory activity until the infants are precipitated into respiratory failure by an incidental respiratory infection, or aspiration. With rare exception they die by 2 years of age with a median around 7 months and with about 80% of the children dying by the time they are 1 year old. There is a consistent homozygous deletion in exons 7 and 8 of the telomeric copy of the survival motor neuron (SMN) gene. In the current issue of the journal, MacLeod and her colleagues have documented five cases of more severe spinal muscular atrophy, with a history of diminished fetal movements in utero and presenting at birth with asphyxia and severe weakness.

Cell Survival↗