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Featured researches published by P.J. Halsall.


The Lancet | 1991

Evidence for related myopathies in exertional heat stroke and malignant hyperthermia.

P.M. Hopkins; F.R. Ellis; P.J. Halsall

Malignant hyperthermia may be a human stress syndrome, of which heat stroke is one manifestation. Two men in military service who had episodes of exertional heat stroke, and their immediate family members, were tested for susceptibility to malignant hyperthermia by in-vitro contracture tests on skeletal muscle samples. Muscle from both patients had a normal response to caffeine but an abnormal response to halothane. Muscle from the father of one patient had an abnormal response to halothane, and that from the father of the second patient had an abnormal response to ryanodine. The results indicate that clinical heat stroke may be associated with an underlying inherited abnormality of skeletal muscle that is similar, but not identical, to that of malignant hyperthermia.


BJA: British Journal of Anaesthesia | 2009

Genetic variation in RYR1 and malignant hyperthermia phenotypes

Danielle Carpenter; Rachel L. Robinson; Rupert J. Quinnell; Christopher Ringrose; M. Hogg; F. Casson; Patrick Booms; David Iles; P.J. Halsall; Derek S. Steele; Marie-Anne Shaw; P.M. Hopkins

BACKGROUND Malignant hyperthermia (MH) is associated, in the majority of cases, with mutations in RYR1, the gene encoding the skeletal muscle ryanodine receptor. Our primary aim was to assess whether different RYR1 variants are associated with quantitative differences in MH phenotype. METHODS The degree of in vitro pharmacological muscle contracture response and the baseline serum creatine kinase (CK) concentration were used to generate a series of quantitative phenotypes for MH. We then undertook the most extensive RYR1 genotype-phenotype correlation in MH to date using 504 individuals from 204 MH families and 23 RYR1 variants. We also determined the association between a clinical phenotype and both the laboratory phenotype and RYR1 genotype. RESULTS We report a novel correlation between the degree of in vitro pharmacological muscle contracture responses and the onset time of the clinical MH response in index cases (P<0.05). There was also a significant correlation between baseline CK concentration and clinical onset time (P=0.039). The specific RYR1 variant was a significant determinant of the severity of each laboratory phenotype (P<0.0001). CONCLUSIONS The MH phenotype differs significantly with different RYR1 variants. Variants leading to more severe MH phenotype are distributed throughout the gene and tend to lie at relatively conserved sites in the protein. Differences in phenotype severity between RYR1 variants may explain the variability in clinical penetrance of MH during anaesthesia and why some variants have been associated with exercise-induced rhabdomyolysis and heat stroke. They may also inform a mutation screening strategy in cases of idiopathic hyperCKaemia.


Annals of Human Genetics | 2000

Multiple interacting gene products may influence susceptibility to malignant hyperthermia

Robinson Rl; Curran Jl; F.R. Ellis; P.J. Halsall; W. J. Hall; P.M. Hopkins; David Iles; S P West; Marie-Anne Shaw

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.


Anaesthesia | 1990

Clinical presentation of suspected malignant hyperthermia during anaesthesia in 402 probands

F.R. Ellis; P.J. Halsall; A. S. Christian

As anaesthetists have become more aware of malignant hyperthermia the mortality rate has fallen, but concommitantly the number of dubious and aborted cases has increased. All probands who developed a suspected malignant hyperthermia reaction during anaesthesia and subsequently underwent muscle biopsy were classified according to the clinical presentation. A probability for malignant hyperthermia can be calculated, using the classification, for each type of clinical presentation; this varied from 0.96 to 0.07. Certain clinical features were found to be of more value as predictors than others; these included a high creatine kinase and myoglobinuria. The accuracy of prediction depends on a clear contemporaneous description of the clinical events.


Journal of Medical Genetics | 1998

Genetic heterogeneity and HOMOG analysis in British malignant hyperthermia families.

Rachel L. Robinson; J L Curran; W. J. Hall; P.J. Halsall; P.M. Hopkins; A F Markham; Alistair D. Stewart; S P West; F.R. Ellis

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.


Anaesthesia | 1991

Evaluation of local anaesthetic blockade of the lateral femoral cutaneous nerve

P.M. Hopkins; F.R. Ellis; P.J. Halsall

An assessment of local anaesthetic blockade of the lateral femoral cutaneous nerve using a standard technique was made. The rate of successful blockade was high, but the area of sensory loss was inconsistent between patients and was more anterior and distal than described in textbooks of anatomy.


Anaesthesia | 1991

Hypermetabolism in arthrogryposis multiplex congenita

P.M. Hopkins; F.R. Ellis; P.J. Halsall

Two patients who developed hypermetabolic reactions during anaesthesia and surgery and who were suffering from arthrogryposis multiplex congenita are reported and it is proposed that the reaction is distinct from malignant hyperthermia and independent of the anaesthetic agents used. The implications for anaesthetists involved in the management of patients with arthrogryposis multiplex congenita are discussed.


Anesthesia & Analgesia | 1997

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

P.M. Hopkins; F.R. Ellis; P.J. Halsall; Alistair D. Stewart

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 individual 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. (Anesth Analg 1997;84:648-56)


BJA: British Journal of Anaesthesia | 2009

Epigenetic allele silencing and variable penetrance of malignant hyperthermia susceptibility

Rachel L. Robinson; Danielle Carpenter; P.J. Halsall; David Iles; Patrick Booms; Derek S. Steele; P.M. Hopkins; Marie-Anne Shaw

BACKGROUND Tissue-specific monoallelic silencing of the RYR1 gene has been proposed as an explanation for variable penetrance of dominant RYR1 mutations in malignant hyperthermia (MH). We examined the hypothesis that monoallelic silencing could explain the inheritance of an MH discordant phenotype in some instances. METHODS We analysed parent-offspring transmission data from MH kindreds to assess whether there was any deviation from the expected autosomal dominant Mendelian inheritance pattern. We also evaluated informative single-nucleotide polymorphism (SNP) genotypes in a cohort of unrelated MH patients using genomic DNA (gDNA, prepared from leucocytes) and coding DNA (cDNA, prepared from skeletal muscle). Finally, we examined the segregation of specific mutations at the gDNA and cDNA level within MH families where positive RYR1 gDNA genotype/normal MH phenotype discordance had been observed. RESULTS In 2113 transmissions from affected parents, there was a consistent parent-of-origin effect (P<0.001) with affected fathers having fewer affected daughters (20%, 95% CI 17-22%) than affected sons (25%, 95% CI 23-26%) or unaffected daughters (27%, 95% CI 25-30%). No discrepancies were observed between the RYR1 SNP genotypes recorded at the gDNA and cDNA levels. In 14 MH negative individuals from 11 discordant families, the familial mutation was detected in skeletal muscle cDNA in all cases. CONCLUSIONS Epigenetic allele silencing may play a role in the inheritance of MH susceptibility, but this is unlikely to involve silencing of RYR1.


Anaesthesia | 2007

Diagnosing malignant hyperthermia susceptibility

P.M. Hopkins; P.J. Halsall; F.R. Ellis

Following the demonstration by Kalow et al. [l] that freshly excised, cut muscle bundles from patients who had survived malignant hyperthennia (MH) reactions demonstrated an increased sensitivity to the contracture-inducing effects of caffeine in vitro, and the similar study by Ellis et al. [2] that described the abnormal in vitro contracture response to halothane of muscle bundles from relatives of patients who had fatal MH reactions, in vitro contracture tests using halothane and caffeine on muscle samples taken at open biopsy had become generally accepted as the ‘gold standard’ for the diagnosis of MH susceptibility. The in vitro contracture test, however, is invasive, expensive and time consuming. The familial nature of MH was recognised by Denborough and Love11 in their first report of the condition [3], but it is only with the rapid advances in molecular biology over the past 10 years that a genetic test based on DNA for MH has become a realistic possibility. Indeed, it has been claimed that with our present knowledge, a DNA-based diagnosis of MH susceptibility is possible in some circumstances [4]. A recent meeting, held in London, brought together members of the European MH Group (those involved in contracture testing and geneticists working in the field) to discuss the current place of DNA tests in the diagnosis of MH susceptibility. The views we express here have been formulated as a result of this meeting. Before describing the current extent of our understanding of the genetics of MH we will outline the steps necessary in reaching the stage where a definitive genetic test would become available for a hypothetical inherited disease or condition: (1) Linkage analysis. This is the study of the association of the disease characteristic (phenotype) with DNA markers of known chromosomal location in individual families. A DNA marker that is informative will have several distinguishable allelic variants and it is the consistency of inheritance of a particular marker allele with the disease phenotype that is important. This is because during meiosis (which occurs during gametogenesis) the chromosomes of a pair exchange corresponding lengths of their genetic material in a process known as recombination. Thus, the likelihood of a marker allele and a disease allele becoming separated in the passage of genetic material from one generation to the next depends upon the proximity of the two alleles. Of course any association could be due to chance, so the findings in a particular family are subjected to statistical analysis, the main determinant for a significant result with an informative marker being the size of the family investigated. (2) Identification of the candidate gene. Linkage analysis using a series of markers identifies the region of one chromosome in which the gene responsible for the condition is likely to be found. It may well be that the markers used for linkage were chosen because of their location flanking a known gene that was a physiologically plausible candidate for the affected gene. Otherwise, the genetic material in that region of chromosome needs to be analysed and ‘matched’ with proteins or possibly mRNA in cells that are known to express the disease. (3) Identification of mutations associated with the disease. There are several methods, the details of which are beyond the scope of this editorial, of searching for differences ‘,I1 the sequence of bases found in DNA from diseased compared to normal individuals. Most genes are polymorphic, that is the precise DNA base sequence can vary between individuals with no effect on gene function. When a polymorphism produces a functional abnormality it is referred to as a mutation. As with flanking markers, linkage analysis is used to provide a statistical measure of the association between a mutation and the disease within a family. (4) Determination of the causative nature of a mutation. Geneticists have defined some statistical criteria for accepting a linked mutation to be causative. This, however, does make some assumptions regarding the molecular biology of the disease. The definitive step, therefore, is to introduce the mutatnt gene into a line of normal animals and to observe whether the transgenic animal develops the disease. Current status of MH genetic research. Using DNA marker linkage analysis, we and several other groups have localised the MH defect in some families to the q13.1-13.2 region of chromosome 19 [5-71. In other families, however, there appears to be recombination between markers for this region and MH susceptibility [8-111 indicating either that the linkage with chromosome 19 is a noncausative association or that MH is a genetically heterogeneous condition. Levitt’s group have reported linkage to chromosome 17 [12], but their’s are data grouped from several small families-an inappropriate technique in the presence of heterogeneity [ 131. In sufficiently large families, linkage with chromosome 17 has been excluded [14,15]. Linkage to a third locus in one large family was presented at the London meeting, but confidentiality precludes the details being given here. With other European groups we are involved in a search for possible loci using multiple markers to search the entire genome. This is supported by the Association Francaise Myopathies (AFM); it is known as the Genethon Project. Following the discovery that a mutation in the gene encoding for a calcium release channel of the sarcoplasmic reticulum is consistently found in pigs affected by porcine stress syndrome[l6], a condition similar in some respects to MH, and that this gene is located in the q13.1 region of chromosome 19 in the human, mutations in MH susceptible individuals have been sought. To date, six mutations of this gene have been reported, at least one of which is significantly associated with MH susceptibility. However, it is not possible to state whether, in the MH families that they have been found, any of these mutations are causative. The mutations are not common, certainly in the UK malignant hyperthermia population. Situations where a genetic diagnosis of MH susceptibility might now be considered. As previously stated, Healy

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F.R. Ellis

St James's University Hospital

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Rachel L. Robinson

St James's University Hospital

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S P West

St James's University Hospital

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J L Curran

St James's University Hospital

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W. J. Hall

St James's University Hospital

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