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V Dubowitz

Publications and source records attributed to V Dubowitz.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1999

Clinical spectrum and diagnostic difficulties of infantile ponto-cerebellar hypoplasia type 1.

We present the clinical and histopathological features and the diagnostic difficulties encountered in five children affected by a motor neuron disorder other than spinal muscular atrophy. Investigations performed suggested the diagnosis of ponto-cerebellar hypoplasia type 1 (PCH-1). Severe respiratory difficulty was present at birth in two of these children; hypotonia, arthrogryposis, microcephaly and nystagmus were present in all. Early and progressive bulbar involvement with swallowing difficulties and stridor was also a common feature in these infants. Severe cognitive delay was invariably present. Brain magnetic resonance imaging showed ponto-cerebellar hypoplasia in four children while striking atrophy of the cerebellar vermis and cerebellar hemispheres were present in the fifth child. Electrophysiological and pathological investigations of proximal muscles performed at presentation in all these children were not conclusive, while the post-mortem studies, or the study of distal muscles during life, showed a clear neurogenic picture. Genetic studies excluded involvement of the SMN gene, or of other genes located on chromosome 5q, confirming that ponto-cerebellar hypoplasia type 1 is a different entity from typical proximal spinal muscular atrophy.

Abnormalities, Multiple↗
PubMed1999

Feeding problems in merosin deficient congenital muscular dystrophy.

Feeding difficulties were assessed in 14 children (age range 2-14 years) with merosin deficient congenital muscular dystrophy, a disease characterised by severe muscle weakness and inability to achieve independent ambulation. Twelve of the 14 children were below the 3rd centile for weight. On questioning, all parents thought their child had difficulty chewing, 12 families modified the diet, and 13 children took at least 30 minutes to complete a meal. On examination the mouth architecture was abnormal in 13 children. On videofluoroscopy only the youngest child (2 years old), had a normal study. The others all had an abnormal oral phase (breakdown and manipulation of food and transfer to oropharynx). Nine had an abnormal pharyngeal phase, with a delayed swallow reflex. Three of these also showed pooling of food in the larynx and three showed frank aspiration. These six cases all had a history of recurrent chest infections. Six of eight children who had pH monitoring also had gastro-oesophageal reflux. As a result of the study five children had a gastrostomy, which stopped the chest infections and improved weight gain. This study shows that children with merosin deficient congenital muscular dystrophy have difficulties at all stages of feeding that progress with age. Appropriate intervention can improve weight gain and reduce chest infections. The severity of the problem has not been previously appreciated in this disease, and the study shows the importance of considering the nutritional status in any child with a primary muscle disorder.

Adolescent↗
PubMed1998

An early onset muscular dystrophy with diaphragmatic involvement, early respiratory failure and secondary alpha2 laminin deficiency unlinked to the LAMA2 locus on 6q22.

We present four subjects from one family and one subject (with an affected sibling who had died) from a second, unrelated family, with early onset, Duchenne-like, muscular dystrophy who presented with proximal girdle weakness, calf and generalized muscle hypertrophy, selective wasting of the sternomastoid muscles, rigidity of the spine and contractures of the tendo Achilles. Intellect was normal. Serum creatine kinase was grossly elevated and the muscle biopsies showed a dystrophic picture. All five subjects have developed early respiratory failure due to severe diaphragmatic involvement; two have already died aged 4 and 7 years of age and the remaining three are dependent on night time ventilation. There has been very little deterioration over time in the skeletal muscle function, and the survivors remain ambulant, the oldest being 11 years. Immunocytochemical studies of the muscle biopsy showed a normal pattern for dystrophin and the dystrophin-associated glycoproteins, but a reduction of the laminin alpha2 chain of merosin. Magnetic resonance imaging of the brain was normal. The disease did not link to the LAMA2 locus for laminin alpha2 on chromosome 6q, so that these families seem to represent a new form of autosomal recessive muscular dystrophy with a secondary merosin deficiency. The primary protein deficiency has not yet been identified.

Age Factors↗
PubMed1998

X-linked myotubular myopathy--a long-term follow-up study.

X-Linked myotubular myopathy is a well delineated congenital myopathy, with a high neonatal and early childhood mortality. Only a single gene, mapping to Xq28 has been implicated and has recently been characterized. Phenotypic variability, both inter- and intrafamilial, has been recorded. Its severest expression is a uniform disease with polyhydramnios due to prenatal (neuromuscular) swallowing disorder, and partial inability to expand the lungs postnatally leading to early postnatal death in all. The mildest expression appears to be represented by the first family reported in the literature in which intrafamilial phenotypic variability was marked. There was neonatal asphyxia, but recovery took place in most affected patients and very mild expression permitting normal life into adulthood has been found in two patients. A long-term follow-up is given on both these families. Results emphasize the importance of the family history when trying to prognosticate in an individual case.

Adult↗
PubMed1998

An optimality score for the neurologic examination of the term newborn.

We describe the application of a revised version of the Dubowitz neurologic examination of the newborn in 224 low-risk, term newborn infants. The method has been updated by eliminating less useful items and including new items evaluating general movements and patterns of distribution of tone. An optimality score is included to make the evaluation more quantitative and for comparison with sequential examinations with neurophysiologic and imaging findings. The score is based on the distribution of the scores for each item in the population of low-risk term infants. We defined not only the most common pattern for each item but also the variability of the findings by using 10th and 5th centiles. Because most of the items assessing tone and the Moro reflex varied with gestational age between 37 and 42 weeks, the changes were incorporated in the scoring system. The total optimality score was the sum of the optimality scores of individual items. Although the association of 4 or more deviant scores was found in less than 10% of our infants, deviant results on 1 or 2 single items could be observed in a third of this normal population, suggesting that isolated deviant signs have little diagnostic value. In contrast, an abnormal distribution of tone patterns, which we have commonly observed in infants with brain lesions, was not found in this cohort.

Arm↗
PubMed1998

Visual function in children with merosin-deficient and merosin-positive congenital muscular dystrophy.

This study evaluates whether abnormalities of visual function are present in children with congenital muscular dystrophy and whether these, if present, are associated with merosin status or magnetic resonance imaging (MRI) findings. Twenty children (age range 5-17 years) with a diagnosis of classical congenital muscular dystrophy were assessed on visual acuity, stereopsis, and visual fields and the results compared with merosin status and MRI findings. Visual-evoked potential results were available for 14 of 20 children. All 20 children revealed normal results on all the clinical tests assessing visual function, irrespective of their merosin status or of MRI findings. Visual-evoked potentials were normal in the children with merosin-positive congenital muscular dystrophy but were abnormal in those with merosin deficiency. Unlike the other forms of congenital muscular dystrophy, which are associated with structural brain changes and eye involvement, visual function was always normal in the classical form of congenital muscular dystrophy. Interestingly, visual function was normal also in the group of children with merosin-deficient congenital muscular dystrophy who manifested white matter changes involving the occipital lobes on MRI and abnormal visual evoked potentials. Further studies are needed to specify the nature of the white matter changes observed with MRI and the reason for the dissociation between clinical and neurophysiologic findings.

Adolescent↗
PubMed1998

Early presentation of X-linked Emery-Dreifuss muscular dystrophy resembling limb-girdle muscular dystrophy.

Emery-Dreifuss muscular dystrophy is an X-linked neuromuscular disorder caused by defects in the STA gene on Xq28, which codes for a nuclear protein named emerin. Affected patients usually present in early adolescence with scapulo-peroneal muscle weakness and wasting, and contractures of the tendo Achilles, elbows and paraspinal muscles, resulting in spine rigidity. We present here a case of Emery-Dreifuss muscular dystrophy with an unusually severe, early presentation. He presented at 2.5 years with predominantly proximal weakness and mild equinovarus deformity of the right foot. Serum creatine kinase activity was elevated (1994 IU/I) and a muscle biopsy at the age of 4 years showed marked dystrophic abnormalities. Normal expression of dystrophin, and no detectable deletion in the corresponding gene, excluded a diagnosis of Duchenne muscular dystrophy. Similarly, normal expression of alpha-sarcoglycan made a limb-girdle muscular dystrophy caused by a defect in a sarcoglycan unlikely. Several years later, examination of the proband's maternal cousin, aged 14 years, suggested Emery-Dreifuss muscular dystrophy. This was confirmed in both affected boys by the absence of emerin in muscle and leucocytes, and identification of a mutation in exon 4 of the STA gene. Carrier status in both mothers was also confirmed by mutational and protein analysis. Emery-Dreifuss muscular dystrophy should therefore be considered in the differential diagnosis of cases of early onset muscular dystrophy, even in the absence of the typical clinical features.

Age of Onset↗
PubMed1998

Fifty year follow-up of a patient with central core disease shows slow but definite progression.

The follow-up of a patient with central core disease (CCD) over 50 years showed that although initially the condition was moderately non-progressive, progression of a significant degree did eventually occur. Histopathological and electron microscopic data were available from muscle biopsies carried out at the ages of 19 and 55 years, and show a marked predominance of type 1 fibres with central cores in most fibres at both ages. The four mutations within the RYR1 gene described in association with CCD and three of the more common malignant hyperthermia-associated mutations within RYR1 were not present.

DNA↗
PubMed1998

A severe clinical and pathological variant of central core disease with possible autosomal recessive inheritance.

Central core disease (CCD) is a well recognized, relatively mild, non- or slowly progressive, dominantly inherited, congenital myopathy due, at least in some families, to mutations in the ryanodine receptor gene on chromosome 19q13.1. We report two unrelated cases with an unusual, early onset congenital myopathy with severe contractures, delayed motor milestones, proximal muscle weakness, normal serum creatine kinase (CK), a non-progressive course, with muscle biopsy findings of central cores and in addition, marked proliferation of connective and adipose tissue, and variation in fibre size. Muscle biopsies from the parents, who were non-consanguineous and healthy, showed minor myopathic changes and uneven staining with oxidative enzymes, but no central cores. The marked histological muscle changes, the distribution of weakness and the non-progressive course of the disease suggest that this is a severe variant of central core disease with secondary dystrophy-like change. The presence of mild changes in the histochemical reactions of biopsies of both parents of these two children supports the hypothesis that they are carriers of a recessive disease gene mutation responsible for this unusually severe form of central core disease.

Biopsy↗
PubMed1998

Laminin alpha 2-chain gene mutations in two siblings presenting with limb-girdle muscular dystrophy.

We report two siblings, an 11-year-old boy and his 7-year-old sister, referred to us with a diagnosis of muscular dystrophy. The boy presented at 22 months with delay in walking. A very high serum creatine kinase (CK) level and a dystrophic muscle biopsy lead to a diagnosis of Duchenne muscular dystrophy prior to the identification of the dystrophin gene. Two years later his sister presented with similar problems. A diagnosis of limb-girdle muscular dystrophy was made when they were shown to have inherited different X-chromosomes and normal expression of dystrophin and all sarcoglycans. Their conditions remained static. Recently a slowing of the peripheral motor nerve conduction velocities and T2-weighted brain magnetic resonance imaging showed increased signal of the white matter, both of which are features of merosin-deficient congenital muscular dystrophy. Immunolabelling using a C-terminal laminin alpha 2 chain antibody showed a reduction in expression, while labelling with another antibody that recognises a 300-kDa fragment showed a very significant reduction. Mutational analysis of the LAMA2 gene showed two mutations: one was a G-->C point mutation at position -1 of intron 28 acceptor splicing site. This mutation induced activation of a cryptic splice at nucleotide 4429 of exon 29 and partial skipping of this exon, with conservation of the open reading frame. The other was a nonsense mutation due to a C_T transition at position 5525 of the cDNA sequence (exon 37), resulting in a stop codon. These data confirm that mutations of the LAMA2 gene that do not completely disrupt the production of the protein can give rise to phenotypes considerably milder than classical merosin-deficient congenital muscular dystrophy. Partial laminin alpha 2 deficiency should be considered in the differential diagnosis of limb-girdle muscular dystrophy.

Base Sequence↗