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P J Halsall

Publications and source records attributed to P J Halsall.

At least 19 recordsLinked to original sources
PubMed2003

Multicentre evaluation of in vitro contracture testing with bolus administration of 4-chloro-m-cresol for diagnosis of malignant hyperthermia susceptibility.

BACKGROUND AND OBJECTIVE: The in vitro contracture test with halothane and caffeine is the gold standard for the diagnosis of susceptibility to malignant hyperthermia (MH). However, the sensitivity of the in vitro contracture test is between 97 and 99% and its specificity is 78-94% with the consequence that false-negative as well as false-positive test results are possible. 4-Chloro-m-cresol is potentially a more specific test drug for the in vitro contracture test than halothane or caffeine. This multicentre study was designed to investigate whether an in vitro contracture test with bolus administration of 4-chloro-m-cresol can improve the accuracy of the diagnosis of susceptibility to MH. METHODS: Three hundred and fifty-two patients from 11 European MH laboratories participated in the study. The patients were first classified as MH susceptible, MH normal or MH equivocal by the in vitro contracture test according to the European MH protocol. Muscle specimens surplus to diagnostic requirements were used in this study (MH susceptible = 103 viable samples; MH equivocal = 51; MH normal = 204). 4-Chloro-m-cresol was added to achieve a concentration of 75 micromol L(-1) in the tissue bath. The in vitro effects on contracture development and muscle twitch were observed for 60 min. RESULTS: After bolus administration of 4-chloro-m-cresol, 75 micromol L(-1), 99 of 103 MH-susceptible specimens developed marked muscle contractures. In contrast, only two of 204 MH-normal specimens showed an insignificant contracture development following 4-chloro-m-cresol. From these results, a sensitivity rate of 96.1% and a specificity rate of 99.0% can be calculated for the in vitro contracture test with bolus administration of 4-chloro-m-cresol 75 micromol L(-1). Forty-three patients were diagnosed as MH equivocal, but only specimens from 16 patients developed contractures in response to 4-chloro-m-cresol, indicating susceptibility to MH. CONCLUSIONS: The in vitro contracture test with halothane and caffeine is well standardized in the European and North American test protocols. However, this conventional test method is associated with the risk of false test results. Therefore, an improvement in the diagnosis of MH is needed. Regarding the results from this multicentre study, the use of 4-chloro-m-cresol could increase the reliability of in vitro contracture testing.

Biopsy↗
PubMed2003

Anaesthetic management of coronary artery bypass grafting in a patient with central core disease and susceptibility to malignant hyperthermia on statin therapy.

Central core disease and malignant hyperthermia (MH) are both associated with mutations in the RYR1 gene. We report the anaesthetic management of one such patient presenting for coronary artery bypass grafting. Her medication included aspirin 75 mg, atorvastatin 20 mg, isosorbide mononitrate 60 mg, atenolol 25 mg and glyceryl trinitrite sublingual spray as required. The use of aprotinin, statins and moderate hypothermia in patients with central core disease and known susceptibility to MH has not been documented.

Adult↗
PubMed2002

No evidence of mutations in the CACNA1S gene in the UK malignant hyperthermia population.

BACKGROUND: Malignant hyperthermia (MH) is an inherited, potentially fatal, pharmocogenetic disorder triggered by certain anaesthetic agents. In light of the reported genetic heterogeneity for the disorder and the recent introduction of DNA testing guidelines for the trait, we have assessed the role of the CACNA1S gene in MH susceptibility in UK patients. Linkage to this locus has previously been demonstrated in several European MH families. METHODS AND RESULTS: We screened 200 unrelated MH-susceptible individuals for known CACNA1S mutations. With the aim to characterize further novel mutations at this locus, functionally relevant regions of the gene were also sequenced in 10 unrelated individuals from families where the involvement of other MH susceptibility loci was unlikely. No sequence variations were detected in any of the patients investigated. CONCLUSIONS: Defects in CACNA1S are not a major cause of MH in the UK population. Diagnostic screening of this gene is unlikely to be of value to UK MH patients in the near future.

Calcium Channels, L-Type↗
PubMed2000

Multiple interacting gene products may influence susceptibility to malignant hyperthermia.

Malignant hyperthermia (MH) is a potentially lethal disorder triggered in susceptible individuals on exposure to common anaesthetic agents. Crises reflect the consequences of disturbed skeletal muscle calcium homeostasis. MH is an autosomal dominant, genetically heterogeneous trait. Defects in a single major gene have been assumed to determine susceptibility status in individual families. However, in some pedigrees phenotypic and genotypic data are discordant. One explanation, in contrast to the current genetic model, is that susceptibility is dependent upon the effects of more than one gene. Using the transmission disequilibrium test we assessed the involvement of 8 MH candidate loci (RYR1, CACNA1S, CACNA2D1, MHS4 at 3q13.1, MHS6 at 5p, LIPE, DM1, dystrophin) by analysis of data from 130 MH nuclear families. Results suggested that variations in more than one gene may influence MH susceptibility in single families.

Anesthetics, Inhalation↗
PubMed1999

Segregation of malignant hyperthermia, central core disease and chromosome 19 markers.

Malignant hyperthermia (MH) is an autosomal dominant disorder presenting under general anaesthesia. It is occasionally associated with a myopathy, central core disease (CCD), named after its predominant histochemical characteristic. The penetration of CCD is variable, but typically affected individuals show delayed motor milestones in infancy and remain physically compromised. It was thought until recently that individuals with CCD were always susceptible to MH. Individuals from eight CCD families were screened for the presence of 13 mutations in the skeletal muscle ryanodine receptor gene, reported previously to be associated with MH and/or CCD: none was detected. In seven of these families, where CCD and MH co-existed, we examined the segregation of CCD, MH susceptibility and chromosome 19q markers. In four families, there was complete co-segregation between MH, CCD and the chromosome 19 markers, but in one large pedigree there was a clear lack of segregation of CCD with either MH or chromosome 19 markers and there was no segregation between MH and these markers. This is unequivocal evidence that CCD, in common with MH, is genetically heterogeneous. In the two other families, CCD segregated with chromosome 19 markers but not all individuals with CCD were susceptible to MH. We recommend determination of MH susceptibility in all patients with CCD, irrespective of the MH status of their relatives with CCD.

Adult↗
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

In vitro contracture test for diagnosis of malignant hyperthermia following the protocol of the European MH Group: results of testing patients surviving fulminant MH and unrelated low-risk subjects. The European Malignant Hyperthermia Group.

BACKGROUND: Determination of sensitivity and specificity of the in vitro contracture test (IVCT) for malignant hyperthermia (MH) susceptibility using the European MH Group (EMHG) protocol has been performed in some laboratories but only on a small sample from the combined EMHG. Thus, the purpose of the present study was to determine combined EMHG sensitivity and specificity of the test. METHODS: Results of IVCT of patients with previous fulminant MH and normal, low-risk subjects (controls) were collected from 22 centres of the EMHG. IVCT was performed according to the EMHG protocol. Patients were included in the study if the clinical crisis had a score of at least 50 points with the Clinical Grading Scale. Low-risk subjects were included provided they did not belong to a family with known MH susceptibility, they had not developed any signs of MH at previous anaesthetics, and they did not suffer from any neuromuscular disease. For inclusion of both MH patients and low-risk subjects, at least 1 muscle bundle in the IVCT should have twitches of 10 mN (1 g) or more. For evaluation of individual tests, only muscle bundles with twitch heights of 10 mN (1 g) or more were used. RESULTS: A total of 1502 probands had undergone IVCT because of a previous anaesthesia with symptoms and signs suggestive of MH. Of these, 119 had clinical scores of 50 and above. From these 119 MH-suspected patients and from 202 low-risk subjects, IVCT data were collected. Subsequently, 14 MH-suspected patients were excluded from further analysis for the following reasons: In 3 patients, the suspected MH episode could be fully explained by diseases other than MH; in 11 MHS patients, IVCT was incomplete (n = 1), data were lost (n = 3), or none of the muscle bundles fulfilled twitch criteria (n = 7). Of the remaining 105 MH-suspected patients, 89 were MHS, 10 MHEh, 5 MHEc, and one MHN. Thus, we observed a diagnostic sensitivity of the IVCT of 99.0% if the MHE group is considered susceptible (95% confidence interval 94.8-100.0%). Of the 202 low-risk subjects, 3 were MHS, 5 MHEh, 5 MHEc, and 189 MHN. This gives a specificity of the IVCT of 93.6% (95% confidence interval 89.2-96.5%). CONCLUSION: The IVCT for diagnosis of MH susceptibility in Europe has a high sensitivity and a satisfactory specificity.

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↗
PubMed1994

The effects of benzamil on in vitro contracture responses of human skeletal muscle to halothane.

1. Inhibition of sodium-calcium exchange using 100 microM benzamil caused contracture development of in vitro skeletal muscle samples from humans susceptible to malignant hyperthermia, but not of samples from normal individuals. 2. This dose of benzamil increased the contracture response of both types of muscle to halothane. 3. At a concentration of 1 microM, benzamil significantly reduced the contracture response to halothane of muscle from malignant hyperthermia individuals. 4. The implications for the role of sodium-calcium exchange in skeletal muscle calcium homeostasis and the pathophysiology of malignant hyperthermia are discussed.

Amiloride↗
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

Comparison of in vitro contracture testing with ryanodine, halothane and caffeine in malignant hyperthermia and other neuromuscular disorders.

In vitro exposure of living skeletal muscle to ryanodine has been proposed as a potentially specific test for malignant hyperthermia (MH). In this study we have compared in vitro contracture responses to halothane, caffeine and ryanodine in skeletal muscle specimens obtained from 155 patients attending for diagnosis of susceptibility of MH and also from six patients having muscle biopsy for diagnosis of other neuromuscular disorders. Although the ryanodine contracture test was not specific for MH, the results suggest it may greatly aid (in conjunction with the standard halothane and caffeine contracture tests) the accurate phenotyping of individuals that is essential for the further genetic analysis of MH.

Caffeine↗
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

Does postoperative pyrexia indicate malignant hyperthermia susceptibility?

We are frequently asked if patients, in whom only postoperative pyrexia has been observed, should be considered as potentially susceptible to malignant hyperthermia (MHS). Of 30 patients of this type studied in this Unit, none was shown to be MHS. We consider that postoperative pyrexia alone is unlikely to signify MH.

Disease Susceptibility↗