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A D Stewart

Publications and source records attributed to A D Stewart.

At least 19 recordsLinked to original sources
PubMed1998

Genetic heterogeneity and HOMOG analysis in British malignant hyperthermia families.

Malignant hyperthermia (MH) is an autosomal dominant genetic condition that presents in susceptible people undergoing general anaesthesia. The clinical disorder is a major cause of anaesthetic morbidity and mortality. The UK Malignant Hyperthermia Group has performed genetic linkage analysis on 20 large, well defined malignant hyperthermia families, using hypervariable markers on chromosome 19q13.1, including the candidate MH gene RYR1, the gene coding for the skeletal muscle ryanodine receptor protein. The results were analysed using LINKAGE to perform two point and multipoint lod scores, then HOMOG to calculate levels of heterogeneity. The results clearly showed genetic heterogeneity between MH families; nine of the families gave results entirely consistent with linkage to the region around RYR1 while the same region was clearly excluded in three families. In the remaining eight MHS families there were single recombinant events between RYR1 and MH susceptibility. HOMOG analysis was of little added benefit in determining the likelihood of linkage to RYR1 in these families. This confirmation of the presence of heterogeneity in the UK MH population, along with the possibility of the presence of two MH genes in some pedigrees, indicates that it would be premature and potentially dangerous to offer diagnosis of MH by DNA based methods at this time.

Chromosomes, Human, Pair 19↗
PubMed1997

An analysis of the predictive probability of the in vitro contracture test for determining susceptibility to malignant hyperthermia.

An objective estimate of the likelihood of correct designation of malignant hyperthermia (MH) susceptibility from in vitro contracture test (IVCT) results is essential if genetic linkage studies of MH are to be more informative. The aim of this study was to generate and test statistical models that could be used to predict the probability of susceptibility of an individual to MH from the results of their IVCTs. Logistic regression of the IVCT results of an index group of 50 patients (age range 9-73 years; MH susceptible [MHS], n = 13; MH normal [MHN], n = 32; MH equivocal [MHE], n = 5) who were either at low risk of MH or were proband cases were used to generate models to predict probability of MH susceptibility. Models incorporated data from individual contracture tests or from combinations of tests (static halothane, dynamic halothane, caffeine, ryanodine) performed according to the protocols of the European Malignant Hyperthermia Group. Of the individual contracture tests, the ryanodine test was most closely correlated with MH status. Discriminatory ability of the models was assessed using receiver operating characteristic (ROC) curves. Inclusion of predictor variables from the ryanodine, caffeine, and dynamic halothane tests improved upon the discriminatory ability of the models incorporating variables from individuals tests and was considered to be the best model. The reproducibility of this model was confirmed using an ROC curve constructed using data from 47 patients (age range 10-62 years; MHS, n = 15; MHN, n = 28; MHE, n = 4) who were classified in a way similar to the index group. A further group of 153 patients (age range 9-74 years; MHS, n = 44; MHN, n = 92; MHE, n = 17) who were consecutively tested relatives of susceptible individuals was used to assess the generalizability of the best model. The model met the criteria for a useful discriminatory model with this group of patients, 125 of whom (including 9 MHE patients) could be designated as positive or negative for MH with a likelihood of more than 95%. The logistic regression models provide objective likelihoods for the MH phenotype that could be usefully incorporated into genetic linkage studies of the condition.

Adolescent↗
PubMed1997

The G1021A substitution in the RYR1 gene does not cosegregate with malignant hyperthermia susceptibility in a British pedigree.

A single base change in the RYR1 gene encoding the skeletal muscle ryanodine receptor (calcium-sensitive calcium-release channel of the sarcoplasmic reticulum), resulting in the substitution of G1021 by A, has been proposed to underlie malignant-hyperthermia (MH) susceptibility in as many as 10% of cases in the European population. As part of our mutation-screening program in MH-susceptible (MHS) individuals, we have investigated this substitution in individuals from 151 unrelated British MHS families and have detected G1021A heterozygotes in 7 families. This mutation was not found in 156 unrelated MH-negative (MHN) individuals. We also examined eight families with central core disease (CCD): the mutation did not occur in any family members of any disease status (affected or unaffected for CCD, MHS, or MHN). In one large family, the G1021A mutation was found but did not show complete cosegregation with MH susceptibility: it occurred in only 7/12 MHS individuals in the kinship, and susceptibility was inherited from parents who were G1021 homozygotes, as well as from parents who were heterozygotes. On the basis of these findings, it is clearly unreliable at present to offer presymptomatic DNA testing for MH status, even in families in which a mutation has been detected.

Calcium Channels↗
PubMed1995

Molecular basis of inherited factor XIII deficiency: identification of multiple mutations provides insights into protein function.

Factor XIII (FXIII) is a zymogen essential for normal haemostasis. In inherited FXIII deficiency the majority of cases show absence of the FXIIIa subunit. Molecular analysis of PCR-amplified FXIIIa subunit exonic regions, and of RT-PCR amplified cDNA from six patients with FXIIIa subunit deficiency, from five unrelated families, has revealed 10 sequence changes: three mutations resulting in abnormal splicing of pre-mRNA, one nonsense mutation, one deletion/insertion change, three point mutations producing Val34Leu, Asn60Lys and Arg408Gln changes, and two silent mutations. In three families the patients are homozygous for a specific deficiency causing mutation, and patients from the remaining two families are compound heterozygotes. Understanding the molecular pathology of the disorder provides insights into the structure-function relationships of the various domains within the FXIII protein. From a clinical point of view, it enables direct diagnosis at the DNA level and may aid the development of FXIII analogues to promote wound healing.

Base Sequence↗
PubMed1995

Linkage analysis of a large pedigree with hereditary sideroblastic anaemia.

A large pedigree showing a history of pyridoxine responsive X linked sideroblastic anaemia was screened with several polymorphic DNA markers from the X chromosome. Linkage analysis between each marker and disease status was performed, giving a maximum two point lod score of 3.64 at zero recombination with the microsatellite marker PGK1P1 at Xq11.2-12. Close linkage to PGK at Xq13.3, one of the candidate regions for X linked sideroblastic anaemia, was excluded. Linkage to DNA markers distal to PGK and at Xp21 was also excluded. Multipoint linkage analysis was performed with markers located between Xq11.2-21. The maximum map specific lod score obtained was 3.56 at PGK1P1 (Xq11.2-12). Linkage remained significant over the interval 20 cM proximal to PGK1P1 and 5 cM distal to PGK1P1, with definite exclusion around the PGK locus. The most likely location of the gene involved in sideroblastic anaemia in this pedigree is therefore within the pericentromeric region of the X chromosome. This region includes the erythroid 5-aminolaevulinate synthetase gene of the haem synthesis pathway, which is a candidate gene for X linked sideroblastic anaemia located at Xp11.21.

Alleles↗
PubMed1994

Clonality of CD3 negative large granular lymphocyte proliferations determined by PCR based X-inactivation studies.

AIMS: To examine persistent CD3-large granular lymphocytosis (LGL) cases for clonality, both by lineage specific (T cell receptor) and lineage independent (X-inactivation) molecular methods; and to find out whether X-inactivation studies are more appropriate than gene rearrangement studies for this subset of LGL disorders. METHODS: Patients were selected who had LGL of more than six months' duration and identified as CD3- by immunophenotyping. T cell receptor studies and, where possible, X-inactivation studies of the phosphoglycerate kinase (PGK) gene were carried out. Analysis of subpopulations was carried out on cases heterozygous for PGK by the use of a polymerase chain reaction (PCR) method for X-inactivation. RESULTS: Of 17 CD3- LGL cases studied, all were found to be germline for beta, gamma, and delta T cell receptor studies, and immunoglobulin heavy chain genes. However, six of these were analysed by X-inactivation of the PGK gene and two cases gave clonal band patterns but only within the CD3- subpopulation. CONCLUSIONS: Clonal analysis by the lineage independent method of X-inactivation allows clonal expansion undetected by T and B cell specific markers to be identified. It is therefore a more appropriate method for the analysis of CD3- LGL. This has implications for diagnosis in CD3- LGL disorders.

Adult↗
PubMed1993

Genetic linkage analysis of chromosome 19 markers in malignant hyperthermia.

Previous studies have reported that malignant hyperthermia susceptibility is caused in some families by inherited variation in a gene located on the short arm of chromosome 19 near to, or identical with, the ryanodine receptor gene (RYR1); this is expressed in skeletal muscle as a calcium release channel of the sarcoplasm reticulum. In other families, a gene in this location is excluded, but the locations of the genes involved have not yet been defined. We have analysed DNA samples from members of three large British families in whom in vitro muscle contracture tests for malignant hyperthermia susceptibility have been carried out in accordance with the procedure recommended by the European Malignant Hyperthermia Group. The results presented here strongly suggest that the gene for malignant hyperthermia susceptibility in one or more of these three British families is located in the same region of chromosome 19q, although further work is required to decide whether or not the RYR1 gene itself is causative in these families. As genetic heterogeneity could not be excluded, we cannot yet recommend the use of DNA markers to replace in vitro contracture tests in the diagnosis of malignant hyperthermia susceptibility.

Chromosome Mapping↗
PubMed1993

Genetic mapping of the beta 1- and gamma-subunits of the human skeletal muscle L-type voltage-dependent calcium channel on chromosome 17q and exclusion as candidate genes for malignant hyperthermia susceptibility.

Malignant hyperthermia susceptibility (MHS) is an autosomal dominant disorder of skeletal muscle which manifests as a life-threatening hypermetabolic crisis triggered by commonly-used inhalation anaesthetics and depolarizing muscle relaxants. Defects in the ryanodine receptor (RYR1) protein have been proposed to underly MHS, but significant genetic heterogeneity in MHS has recently been demonstrated. In order to investigate the potential roles played by other skeletal muscle calcium channels in MHS, we isolated cosmids containing the gene encoding the beta 1-subunit of skeletal muscle L-type voltage-dependent calcium channel (CACNLB1). We identified a new, highly polymorphic dinucleotide repeat motif close to this gene, and linkage analysis placed the marker proximal to the HOX2B locus, previously localized to chromosome segment 17q21-q22. We recently identified a novel marker within the gamma-subunit locus (CACNLG) at band 17q24, and since both markers are within the 17q11.2-q24 region reported to contain the MHS2 locus, we tested them for linkage in MHS families whose disease trait has been shown not to co-segregate with markers for the RYR1 region on chromosome 19q13.1. Our results exclude CACNLB1 and CACNLG as candidate genes for MHS2, and do not support the reported chromosome 17q localization for the MHS2 locus in our families.

Base Sequence↗
PubMed1992

Stenosis of pulmonary veins in Down syndrome.

Two patients with Down syndrome, intracardiac communications and elevated pulmonary arteriolar resistance presented early in life. Both patients had significant stenosis of pulmonary veins. The progressive nature of the stenosis is illustrated in one patient. Pulmonary venous stenosis in Down syndrome has been recorded only twice before in the literature, and may play a part in the early onset of pulmonary vascular occlusive disease in some patients.

Cardiac Catheterization↗
PubMed1989

Epitopes within the HLA-B5,B35 cross-reacting group.

The HLA-B5,B35 cross-reacting group is a large and serologically complex antigen family which includes the World Health Organization-recognized specificities HLA-B5,B51,Bw52,B35,Bw53,B18,Bw70,Bw71, and Bw72. In addition, several variants of antigens in this cross-reacting group have been described in the past but have not yet gained official recognition. A genetic basis for the complexity and the protein and molecular bases of this highly cross-reactive and polymorphic cross-reacting group have yet to be established. The potential contributions of shared amino acid sequences, the occurrence of multiple epitopes on a single HLA-B molecule, and the presence of new HLA-C antigens have been difficult to resolve. To address this issue, we have carefully examined the serologic reactions of more than 900 allo- and monoclonal antibodies (Tenth International Workshop, Third Asia-Oceanic Workshop, and local reagents) versus lymphocytes from 92 individuals of diverse ethnic origin (North American Caucasians, North American blacks, Amerindians, Middle Eastern Caucasians), 84 of whom were informative for the HLA-B5,B35 cross-reacting group and related antigens. Our results demonstrate that the HLA-B5,B35 gene products share different combinations of distinct epitopes. We have constructed a model for the evolution of this cross-reacting group by assigning polarity to distinct diversification steps utilizing principles of maximum parsimony.

Antibodies, Monoclonal↗
PubMed1986

Clinical results of hydrogel lens implantation.

Polymethylmethacrylate has proven to be a useful intraocular lens (IOL) implant material and remains the most widely used material for the fabrication of IOLs. Complications, however, from IOL implantation still occur. A hydrogel lens has been designed for posterior chamber placement. A clinical study from August 1983 to June 1985 was undertaken to determine the safety and efficacy of this new lens manufactured from 38% poly HEMA. The noninflammatory postoperative complications were limited to lens decentration and opacification of the lens capsule. Three cases of posterior capsule opacification required YAG laser capsulotomy. Laser capsulotomy is feasible and the lens appeared to be more resistant to damage from the YAG laser than polymethylmethacrylate lenses. In general, the material appeared to be well tolerated and there have been no cases of persistent iritis or clinically detectable cystoid macular edema. If the visual acuity outcome by age decade for all patients irrespective of follow-up time is considered, 92% of patients achieved 20/40 or better corrected visual acuity.

Aged↗