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Biomedical subjects

R Weksberg

Publications and source records attributed to R Weksberg.

At least 73 records · Page 4Linked to original sources
PubMed1994

Neurodevelopment of children exposed in utero to phenytoin and carbamazepine monotherapy.

OBJECTIVE: To compare pregnancy outcome prospectively after phenytoin and carbamazepine monotherapy with outcome in matched mother-child pairs exposed to nonteratogens to evaluate the relative fetal safety of these drugs. DESIGN: A prospective, controlled, and blinded observational study. PATIENTS: Thirty-six mother-child pairs exposed to carbamazepine monotherapy and 34 pairs exposed to phenytoin monotherapy, all prospectively studied, were compared with mother-child pairs exposed to nonteratogens. The controls were matched for maternal age, time of consultation, obstetric history, and socioeconomic status. MAIN OUTCOME MEASURE: The primary end point of interest was the children's global IQ measured by either the Bayley or the McCarthy scale according to their ages. SETTING: A teratology consultation program and two neurology services in Toronto, Ontario. RESULTS: Children exposed to phenytoin in utero had a mean (+/- SD) global IQ 10 points lower (95% confidence interval, 4.9 to 15.8 points) than their matched controls (113.4 +/- 13.1 and 103.1 +/- 25.1; P = .038). The Reynell language development scores followed a similar trend, with children exposed to phenytoin scoring significantly lower than their controls. Phenytoin-exposed children had a global IQ of 84 or less significantly more often than the control group (P < .01). Children exposed in utero to carbamazepine did not differ from their controls on any of the neurobehavioral tests. CONCLUSIONS: Our study suggests a clinically important negative effect of phenytoin on neurobehavioral development, independent of maternal or environmental factors, causing a substantial number of children to achieve a lower score than expected on cognitive tests. No similar effects could be shown after gestational use of carbamazepine.

Carbamazepine↗
PubMed1994

Premature atherosclerosis with photomyoclonic epilepsy, deafness, diabetes mellitus, nephropathy, and neurodegenerative disorder in two brothers: a new syndrome?

We describe two brothers with sensorineural deafness, diabetes mellitus, progressive neurological deterioration with photomyoclonic epilepsy, and progressive deterioration in renal function, resulting in death in the third decade of life. Autopsy showed diffuse atherosclerosis and arteriolosclerosis of the systemic vasculature. There was no evidence of these abnormalities in the patients' 2 sisters or either parent. Mitochondrial enzyme analysis documented partial deficiencies of Complex III and IV of the respiratory chain. This deficiency was expressed in skin fibroblasts, kidney and liver but not in muscle. This suggests that the disease-causing mutation is either in the mitochondrial or nuclear DNA. Various modes of inheritance are considered, including maternal, autosomal recessive, or X-linked recessive. We suggest this is a new genetic syndrome characterized by an underlying metabolic disease and premature atherosclerosis, possibly of mitochondrial origin.

Adult↗
PubMed1994

Localization of Beckwith-Wiedemann and rhabdoid tumor chromosome rearrangements to a defined interval in chromosome band 11p15.5.

Chromosome rearrangements have provided useful landmarks to identify disease loci and have served as starting points for positional cloning strategies for candidate genes. We have used fluorescence in situ hybridization (FISH) and pulsed-field gel electrophoresis (PFGE) to map three Beckwith-Wiedemann syndrome (BWS) breakpoints and a rhabdoid tumor breakpoint more precisely. These breakpoints mapped to the interval between D11S679 and the insulin-like growth factor 2 (IGF2) gene on 11p15.5. A cosmid (c15-2) was identified that mapped centromeric to the BWS t(11;16) and the rhabdoid tumor-associated t(11;22), telomeric to the BWS t(11;22), and was found to span the BWS-associated inv(11) breakpoint. Pulsed-field gel analysis placed all four breakpoints into a 250-675 kb interval distal to D11S679 and at least 270 kb centromeric to the IGF2 and H19 loci. These data locate all three BWS rearrangements and the rhabdoid tumor t(11;22) breakpoint in the same region of 11p15.5, suggesting that they may be affecting the same locus or closely linked loci. Cosmid c15-2 provides a well-defined starting point in the search for candidate disease genes.

Beckwith-Wiedemann Syndrome↗
PubMed1993

Variant translocations of chromosome 22 in Ewing's sarcoma.

Relatively few variant translocations have been reported in primary Ewing's sarcomas (ES). We report two new variant translocations, both of which involve chromosomal rearrangements of 22q12. Cytogenetic studies of tumor cells from a 12-year-old girl revealed a variant translocation, t(7;22)(p22;q12), the second example reported of a simple variant of the 22q12 reciprocal translocation in this type of sarcoma. The identity of this rearrangement was confirmed by in situ hybridization. In addition, a complex translocation was identified in a dysmorphic 15-year-old girl, t(4;11;22)(q21;q24;q12). No previous cases of variant translocations in ES have involved band 7p22 or 4q21, and there are no previous reports of an association between congenital abnormalities and unusual karyotype abnormalities in ES. Both variant translocations conserve the junction on the der (22), providing additional cytogenetic evidence that the sequences on chromosome 22 are critical.

Child↗
PubMed1993

Wilms tumor in a patient with Prader-Willi syndrome.

The development of Wilms tumor in a patient with Prader-Willi syndrome prompted us to determine the parental origin of the genes implicated in both disorders because of the sex-specific parent-of-origin effects previously demonstrated for both conditions. A paternal chromosome 15q11-q13 deletion was demonstrated, but no changes were demonstrated in a limited analysis of chromosome 11p, which harbors two Wilms tumor suppressor genes, WT1 and WT2.

Chromosome Deletion↗
PubMed1993

Disruption of insulin-like growth factor 2 imprinting in Beckwith-Wiedemann syndrome.

To study insulin-like growth factor 2 (IGF2) imprinting in BWS (Beckwith-Wiedemann syndrome, an overgrowth syndrome associated with Wilms and other embryonal tumours), we examined allele-specific expression using an Apal polymorphism in the 3' untranslated region of IGF2. Four of six BWS fibroblast strains demonstrated biallelic expression, as did the tongue tissue from one of these patients. Paternal heterodisomy was excluded for all BWS patients with biallelic expression, suggesting strongly that the BWS phenotype in some patients involves disruption of IGF2 imprinting. Constitutional loss of IGF2 imprinting in a subgroup of our BWS patients, and recent reports of loss of imprinting in sporadic Wilms tumour, further strengthens the view that IGF2 overexpression plays an important role in somatic overgrowth and the development of embryonal tumours.

Adolescent↗
PubMed1993

Molecular characterization of cytogenetic alterations associated with the Beckwith-Wiedemann syndrome (BWS) phenotype refines the localization and suggests the gene for BWS is imprinted.

To define the region of 11p15 involved in Beckwith-Wiedemann syndrome (BWS), we have carried out a molecular genetic analysis of six patients with features of BWS and constitutional cytogenetic abnormalities involving chromosome band 11p15. Molecular analysis confirmed the 11p origin of the duplicated material and defined the smallest region of overlap for such duplications, within which a gene involved in BWS must be located. This region encompasses the beta-globin gene complex (HBB) to 11pter. In both of our informative cases, the 11p duplication was found to be of paternal origin. Two BWS associated balanced translocations of 11p15 were studied to localize the breakpoints on 11p15. Somatic cell hybrids, Southern blotting and fluorescent in situ hybridization (FISH) showed that both breakpoints were between D11S12 and the insulin-like growth factor 2 (IGF2) gene. A non-BWS translocation breakpoint was more proximal, between HBB and calcitonin-A (CALCA). Pedigree analysis showed that both BWS associated 11p15 translocations were transmitted by phenotypically normal mothers. The data are compatible with the hypothesis that the BWS gene is imprinted and that the maternally inherited BWS gene is normally suppressed whereas the paternally inherited allele is active. Thus, duplications of paternal origin would lead to increased dosage of the BWS gene. Similarly increased dosage of the BWS gene could account for the findings in maternally inherited 11p15 translocations by altering normal imprinting, so that the translocated maternal allele remains active. This study defines one or more gene loci for BWS on 11p15.5 in the genomic region from D11S12 to IGF2.

Beckwith-Wiedemann Syndrome↗
PubMed1992

Loss of heterozygosity mapping in Wilms tumor indicates the involvement of three distinct regions and a limited role for nondisjunction or mitotic recombination.

Loss of heterozygosity (LOH) for polymorphic markers is a frequently occurring event in some tumors, reflecting the role of allele loss in the development of these tumors. We have determined LOH in 38 cases of Wilms tumor for the 2 known loci on chromosome arm 11p and for a newly detected locus on chromosome arm 16q. Only 7 of the 38 tumors studied showed reduction to homozygosity of 11p13 markers. In 4 of these tumors, reduced expression of WT1 and WIT1, genes located at 11p13 and implicated in Wilms tumorigenesis, was noted. However, this was also found in 2 of 7 tumors showing LOH exclusively of 11p15 markers and in 15 of the remaining 24 tumors in which there was no LOH for 11p markers. This suggests that events not involving mitotic recombination or chromosome nondisjunction are the most common mechanisms for mutations at the 11p Wilms tumor locus. We also noted that mitotic recombination involving 11p15 loci occurred in addition to reduced expression of the 11p13 locus genes in 2 tumors, suggesting a possible interaction between these 2 loci. In addition, LOH for 16q markers was observed in 6 tumors. In one case this was coincident with reduction of WT1 and WIT1 gene expression, and in 3 other cases it occurred in addition to 11p LOH. This indicates that an additional locus on 16q is likely to be involved in Wilms tumorigenesis.

Adolescent↗
PubMed1992

Pregnancy outcome and infant development following gestational cocaine use by social cocaine users in Toronto, Canada.

To determine the effect of first trimester cocaine use on pregnancy outcome we conducted a prospective cohort study of 30 women admitting to social cocaine use (SCU) during early pregnancy, 20 users of cannabis during the first trimester and 30 matched recreational drug-free control subjects. The groups were of similar age, marital status, and obstetric history and were predominantly white. They were of similar socioeconomic status (SES), however the spouses of the cocaine users were of significantly lower SES than those of both control groups (p less than 0.005). The number of years of education of the cocaine users and the fathers of the SCU-exposed fetuses was significantly lower than that of the recreational drug-free control subjects (p = 0.004), however, female IQ was similar among the three groups (109.1 +/- 12.4 cocaine; 109.1 +/- 25.2 cannabis; 114.1 +/- 11.7 drug-free). Alcohol and cigarette use was greater among the cocaine users than among subjects of the recreational drug-free control group (p less than 0.025). Cocaine and the associated lifestyle were not associated with any adverse obstetric or neonatal endpoint (pregnancy weight gain, incidence of delivery complications, gestational age, birth weight, Apgar scores, and rates of major and minor malformations). There were no differences between groups in attaining developmental milestones. Mental and motor scores on the Bayley Scales of Infant Development and Vineland Adaptive Behavior Scales were identical among the three groups, studied at a mean of 19.7 months of age. We conclude that outcome of pregnancy of social cocaine users and subsequent infant physical and cognitive development are within normal limits at 1.6 years of age.

Adolescent↗
PubMed1991

Marshall-Smith syndrome: new radiographic, clinical, and pathologic observations.

Radiographic, clinical, and histologic findings in two infants and a neonate with a syndrome of profoundly accelerated skeletal maturation included features closely resembling those of Marshall-Smith (MS) syndrome, but patients had dysmorphic ears as well as distinctive generalized skeletal abnormalities suggestive of a bone dysplasia. Among these was an instability at the craniocervical junction with severe spinal stenosis. These previously unrecognized abnormalities may represent uncommon manifestations within the spectrum of MS syndrome or indicate the existence of a separate disorder.

Atlanto-Axial Joint↗
PubMed1991

A mutation in the pro alpha 2(I) gene (COL1A2) for type I procollagen in Ehlers-Danlos syndrome type VII: evidence suggesting that skipping of exon 6 in RNA splicing may be a common cause of the phenotype.

Fibroblasts from a proband with Ehlers-Danlos syndrome type VII synthesized approximately equal amounts of normal and shortened pro alpha 2(I) chains of type I procollagen. Nuclease S1 probe protection experiments with mRNA demonstrated that the pro alpha 2(I) chains were shortened because of a deletion of most or all of the 54 nucleotides in exon 6, the exon that contains codons for the cleavage site for procollagen N-proteinase. Sequencing of genomic clones revealed a single-base mutation that converted the first nucleotide of intron 6 from G to A. Therefore, the mutation was a change, in the -GT-consensus splice site, that produced efficient exon skipping. Allele-specific oligonucleotide hybridizations demonstrated that the proband's mother, father, and brother did not have the mutation. Therefore, the mutation was a sporadic one. Analysis of potential 5' splice sites in the 5' end of intron 6 indicated that none had favorable values by the two commonly employed techniques for evaluating such sites. The proband is the fourth reported proband with Ehlers-Danlos syndrome VII with a single-base mutation that causes skipping of exon 6 in the splicing of RNA from either the COL1A1 gene or COL1A2 gene. No other mutations in the two type I procollagen genes have been found in the syndrome. Therefore, such mutations may be a common cause of the phenotype. The primers developed should be useful in screening for the same or similar mutations causing the disease.

Alleles↗
PubMed1990

Molecular characterization of Beckwith-Wiedemann syndrome (BWS) patients with partial duplication of chromosome 11p excludes the gene MYOD1 from the BWS region.

The molecular characterization of two patients with features of Beckwith-Wiedemann syndrome (BWS) and chromosome abnormalities is consistent with the association of this phenotype with a duplication of a portion of chromosome 11. Quantitative Southern blot analysis of DNA from patient A defines a large inherited duplicated segment of chromosome 11. For patient B, a de novo duplication of unknown origin has been shown to contain a segment of 11p15. This chromosome segment includes the genes for insulin-like growth factor 2, beta-hemoglobin, calcitonin A (CALCA), and parathyroid hormone (PTH). However, the myogenic differentiation factor, MYOD1, is not included in the duplicated segment. This demonstrates that MYOD1 is proximal to CALCA and PTH and excludes MYOD1 as the BWS gene. These data place the BWS gene distal to MYOD1 on 11p15.

Beckwith-Wiedemann Syndrome↗
PubMed1989

Neuroblastoma after prenatal exposure to phenytoin: cause and effect?

We evaluated the causality of the association between intrauterine exposure to phenytoin and postnatal neuroblastoma using an in vitro lymphocyte toxicity assay for phenytoin-induced reactions in an unusual sibship. In addition, we investigated intrauterine phenytoin exposure in a case series of infants and children with neuroblastoma diagnosed over 17 years at our center. The response of lymphocytes from our index case with neuroblastoma exposed in utero to phenytoin was within the normal range, whereas the mother and a sibling with fetal hydantoin syndrome (FHS) exhibited an intermediate toxicity. None of the 188 cases of childhood neuroblastoma diagnosed between 1969 and 1988 had been exposed in utero to phenytoin, indicating that, statistically, the drug cannot be associated with neuroblastoma in more than two cases with this malignancy in our cohort, or in 1.5% of all cases of neuroblastoma. Although our data do not suggest an association between phenytoin in pregnancy and postnatal neuroblastoma, it is still possible that there is an increased risk for neuroblastoma in children with FHS.

Bone and Bones↗
PubMed1988

Bloom syndrome: a single complementation group defines patients of diverse ethnic origin.

Patients of diverse ethnic background were recruited in order to examine whether genetic heterogeneity could be demonstrated in Bloom syndrome (BS). Although most cells from BS patients exhibit high sister-chromatid exchange (SCE), lymphoid cells from some patients exhibit dimorphism for high and low SCE. We addressed the issue of dominance or recessivity of the low-SCE BS phenotype. A high-SCE lymphoblast line, HB1, was mutagenized, and a clone, HB10T, carrying the markers ouabain resistance and thioguanine resistance, was isolated to serve as a fusion parent. Two independent low-SCE BS lines were fused with HB10T, and hybrids were selected in HAT medium supplemented with ouabain. The hybrids, which were tetraploid, exhibited the expected phenotypes when exposed to ouabain and thioguanine. In every case, these hybrids had low SCE levels, establishing dominance of the low-SCE phenotype. The same methodology was also used to assess genetic heterogeneity in BS. A complementation analysis was carried out using high-SCE lymphoblast cell lines derived from BS patients. HB10T was fused with five other high-SCE BS lines. No correction of the high SCE characteristic of BS cells was seen in hybrid lines derived from patients of Ashkenazi Jewish, French-Canadian, Mennonite, or Japanese extraction. Thus, a single gene is responsible for the high-SCE phenotype in BS patients of diverse ethnic origin.

Adolescent↗
PubMed1987

Structural alterations of DNA ligase I in Bloom syndrome.

Cell lines derived from seven patients with Bloom syndrome all contain a DNA ligase I with unusual properties. Six lines were shown to have a reduced level of this enzyme activity and the residual enzyme was anomalously heat-labile. The seventh line contained a dimeric rather than monomeric form of ligase I. Several cell lines representative of other inherited human syndromes have apparently normal DNA ligases. The data indicate that Bloom syndrome is due to a defect in the structure of DNA ligase I caused by a "leaky" point mutation occurring at one of at least two alternative sites.

Bloom Syndrome↗
PubMed1987

Bridging markers defining the map position of X linked hypophosphataemic rickets.

Hypophosphataemic rickets is commonly an X linked dominant hereditary disorder associated with a renal tubular defect in phosphate transport and bone deformities. The gene causing this disorder has been mapped to Xp22.31----p21.3 by using cloned human X chromosome sequences identifying restriction fragment length polymorphisms (RFLPs) in linkage studies of affected families. The hypophosphataemic rickets gene locus (HPDR) was previously mapped distal to the X linked polymorphic locus DXS41 (99.6) but its position in relation to the distal loci DXS43 (D2) and DXS85 (782) was not established. In order to obtain a precise mapping of the disease locus in relation to these genetic loci, additional affected families informative for these X linked markers have been investigated. The combined results from the two studies have established linkage with the loci DXS41 (99.6) and DXS43 (D2); peak lod score for DXS41 (99.6) = 7.35, theta = 0.09, and peak lod score for DXS43 (D2) = 4.77, theta = 0.16. Multilocus linkage analysis mapped the hypophosphataemic rickets gene distal to the DXS41 (99.6) locus and proximal to the DXS43 (D2) locus, thereby revealing two bridging genetic markers for the disease.

Chromosome Mapping↗
PubMed1985

Infant outcome following mid-trimester amniocentesis: development and physical status at age six months.

Ninety-one infants whose mothers had had amniocentesis, because age increased their risk for a fetal chromosome abnormality, were compared with 53 infants whose mothers chose not to have the test. Mental and motor development and temperament were studied to assess potential influence of amniocentesis on the brain. Physical growth was assessed and the infants were examined for orthopaedic abnormalities and needle injury. The results indicated that amniocentesis does not appear to influence infant mental and motor development, temperament, physical growth or the risk of orthopaedic abnormalities. However, amniocentesis is not entirely free of risk because several of the infants had needle marks. Reassessment of the cohort at age 4 and 7 years and will provide information on the potential longer term consequences of mid-trimester amniocentesis.

Adult↗