| 1. |
- Broman, Marcus Ewert, et al.
(författare)
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Malignant hyperthermia, a Scandinavian update.
- 2015
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Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172. ; 59:8, s. 951-961
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Forskningsöversikt (refereegranskat)abstract
- Malignant Hyperthermia (MH) is a rare pharmacogenetic disorder, triggered by halogenated anesthetics and/or succinylcholine. In susceptible individuals, these drugs can activate an explosive life threatening clinical reaction. Leading symptoms are hypercarbia, muscle rigidity, and metabolic acidosis. MH is inherited in an autosomal-dominant manner and linked to mutations in the large ryanodine 1 gene (RYR1) gene in the majority of cases. Very few MH patients have been found to carry mutations in the CACNA1S gene.
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| 2. |
- Broman, M, et al.
(författare)
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Malignant hyperthermia and central core disease causative mutations in Swedish patients.
- 2007
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Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 51:Nov 1, s. 50-53
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Tidskriftsartikel (refereegranskat)abstract
- Background: Malignant hyperthermia (MH) susceptibility is a pharmacogenetic disorder of intracellular calcium homeostasis. In susceptible individuals, halogenated anaesthetics and/or suxamethonium may trigger an MH reaction. The diagnosis of MH susceptibility is made by an in vitro contracture test of biopsied muscle strips. Methods: In 27 MH susceptible (MHS) probands and four MH negative (MHN) probands, exons 17, 39, 40, 45 and 46 of the RYR1 gene were screened for MH causative mutations. In addition, in three patients with established central core disease (CCD), exons 17, 39, 40, 45 and 46 and exons 95, 100, 101 and 102 were screened for MH and CCD causative mutations. All screenings were performed by direct sequencing of the entire exons. Results: MH causative mutations were found in five of the 27 MHS probands (19%). CCD causative mutations were found in two of three CCD patients in the C-terminal exons. None of the CCD patients showed a mutation in N-terminal exon 17 or in the central exons. Conclusions: In a Swedish population, screening of N-terminal exon 17 and the central exons for MH causative mutations in the RYR1 gene covers 19% of families. Thus, other mutations must also be responsible for MH susceptibility in Sweden. Although the number of CCD patients in this study was small, screening of the C-terminal exons for CCD causative mutations seems to be a promising tool in the process of making a diagnosis.
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| 3. |
- Broman, M, et al.
(författare)
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Mutation screening of the RYR1-cDNA from peripheral B-lymphocytes in 15 Swedish malignant hyperthermia index cases.
- 2009
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Ingår i: British Journal of Anaesthesia. - : Elsevier BV. - 1471-6771 .- 0007-0912. ; 102:5, s. 642-649
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Malignant hyperthermia (MH), linked to the ryanodine receptor 1 gene (RYR1) on chromosome 19, is a potentially lethal pharmacogenetic disorder which may lead to a disturbance of intracellular calcium homeostasis when susceptible individuals are exposed to halogenated anaesthetics, suxamethonium, or both. Central core disease (CCD) is a rare dominantly inherited congenital myopathy allelic to MH-susceptibility. METHODS: In this study, 14 unrelated MH-susceptible probands and one CCD patient from Sweden were screened for mutations in the RYR1. Since the RYR1 is also expressed in B-lymphocytes, RYR1-cDNA was transcribed from total RNA extracted from white blood cells. RESULTS: We detected two known RYR1 mutations and two previously described unclassified sequence variants. In addition, six novel sequence variants were detected. All mutations or sequence variants were verified on genomic DNA. Seven of the probands did not show any candidate mutation, although the total coding region of RYR1 was sequenced. Segregation data in in vitro contracture tested family members of three probands support a causative role of three of the novel sequence variants. CONCLUSIONS: Our study contributes to the genetic aetiology of MH in Sweden, but also raises questions about the involvement of genes other than RYR1 since nearly half of the probands did not show any sequence variants in the total coding region of the RYR1.
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| 4. |
- Broman, Marcus, et al.
(författare)
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Next generation DNA sequencing of a Swedish Malignant Hyperthermia cohort.
- 2015
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163. ; 88:4, s. 381-385
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Tidskriftsartikel (refereegranskat)abstract
- Malignant Hyperthermia (MH) related mutations have been identified in the ryanodine receptor type 1 gene (RYR1) and in the dihydropyridine gene (CACNA1S), but about half of the patients do not have causative mutations in these genes. We wanted to study the contribution of other muscle genes to the RYR1 phenotypes.
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| 5. |
- Broman, Marcus, et al.
(författare)
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Screening of the ryanodine 1 gene for malignant hyperthermia causative mutations by high resolution melt curve analysis.
- 2011
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Ingår i: Anesthesia and Analgesia. - 1526-7598. ; 113:5, s. 1120-1128
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Tidskriftsartikel (refereegranskat)abstract
- A diagnosis of malignant hyperthermia (MH) can be determined by performing an in vitro (muscle) contracture test (IVCT) or by identifying a known MH causative mutation in the ryanodine receptor 1 gene (RYR1). Genetic diagnosis has an advantage over IVCT because it is less invasive. Direct sequencing of the very large RYR1 coding region (15.117 bases) is a laborious and expensive task. In this study, we applied the High Resolution Melting (HRM) curve analysis as a tool to screen the entire coding region of the gene.
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| 6. |
- Hallberg, Pär, et al.
(författare)
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Comparison of Clinical Factors Between Patients With Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema and Cough
- 2017
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Ingår i: The Annals of Pharmacotherapy. - Thousand Oaks, USA : Sage Publications. - 1060-0280 .- 1542-6270. ; 51:4, s. 293-300
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Tidskriftsartikel (refereegranskat)abstract
- Background: Angioedema is a rare and serious adverse drug reaction (ADR) to angiotensin-converting enzyme (ACE) inhibitor treatment. Dry cough is a common side effect of ACE inhibitors and has been identified as a possible risk factor for angioedema.Objective: We compared characteristics between patients with ACE inhibitor-induced angioedema and cough with the aim of identifying risk factors that differ between these adverse events.Methods: Data on patients with angioedema or cough induced by ACE inhibitors were collected from the Swedish database of spontaneously reported ADRs or from collaborating clinicians. Wilcoxon rank sum test, Fisher's exact test, and odds ratios (ORs) with 95% CIs were used to test for between-group differences. The significance threshold was set to P <0.00128 to correct for multiple comparisons.Results: Clinical characteristics were compared between 168 patients with angioedema and 121 with cough only. Smoking and concomitant selective calcium channel blocker treatment were more frequent among patients with angioedema than cough: OR = 4.3, 95% CI = 2.1-8.9, P = 2.2 × 10(-5), and OR = 3.7, 95% CI = 2.0-7.0, P = 1.7 × 10(-5) Angioedema cases were seen more often in male patients (OR = 2.2, 95% CI = 1.4-3.6, P = 1.3 × 10(-4)) and had longer time to onset and higher doses than those with cough (P = 3.2 × 10(-10) and P = 2.6 × 10(-4)). A multiple model containing the variables smoking, concurrent calcium channel blocker treatment, male sex, and time to onset accounted for 26% of the variance between the groups.Conclusion: Smoking, comedication with selective calcium channel blockers, male sex, and longer treatment time were associated with ACE inhibitor-induced angioedema rather than cough.
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| 7. |
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| 8. |
- Islander, Gunilla
(författare)
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Anesthesia and spinal muscle atrophy.
- 2013
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Ingår i: Paediatric Anaesthesia. - : Wiley. - 1460-9592. ; 23:9, s. 804-816
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Forskningsöversikt (refereegranskat)abstract
- Spinal muscle atrophy (SMA) is autosomal recessive and one of the most common inherited lethal diseases in childhood. The spectrum of symptoms of SMA is continuous and varies from neonatal death to progressive symmetrical muscle weakness first appearing in adulthood. The disease is produced by degeneration of spinal motor neurons and can be described in three or more categories: SMA I with onset of symptoms before 6 months of age; SMAII with onset between 6 and 18 months and SMA III, which presents later in childhood. Genetics: The disease is in more than 95% of cases caused by a homozygous deletion in survival motor neuron gene 1 (SMN1). Pathophysiology: The loss of full-length functioning SMN protein leads to a degeneration of anterior spinal motor neurons which causes muscle weakness. Anesthetic risks: Airway: Tracheal intubation can be difficult. Respiration: Infants with SMA I almost always need postoperative respiratory support. Patients with SMA II sometimes need support, while SMA III patients seldom need support. Circulation: Circulatory problems during anesthesia are rare. Anesthetic drugs: Neuromuscular blockers: Patients with SMA may display increased sensitivity to and prolonged effect of nondepolarizing neuromuscular blockers. Intubation without muscle relaxation should be considered. Succinylcholine should be avoided. Opioids: These should be titrated carefully. Anesthetic techniques: All types of anesthetic technique have been used. Although none is absolutely contraindicated, none is perfect: anesthesia must be individualized. Conclusion: The perioperative risks can be considerable and are mainly related to the respiratory system, from respiratory failure to difficult/impossible intubation.
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| 9. |
- Islander, Gunilla
(författare)
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In vitro contracture testing for the diagnosis of malignant hyperthermia susceptibility
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Malignant hyperthermia (MH) susceptibility is a rare inherited muscular disorder, which may cause a lethal increase in metabolism during anaesthesia with certain commonly used anaesthetic. Susceptible individuals are without any signs or symptoms. It is important to identify individuals at risk, since the MH reaction is preventable. Susceptibility to MH is diagnosed with an in vitro contracture test (IVCT) performed on viable skeletal muscle. The muscle is exposed to halothane/caffeine in an organ bath. An increase in baseline tension >=0.2g is abnormal. There have been few thorough validations of the IVCT and false diagnoses do occur, which make genetic research difficult. We have investigated 1) the reliability of a negative diagnosis, 2) the inheritance pattern suggested by IVCT and 3) the validation the IVCT results in 706 patients in 175 families. Fourteen patients diagnosed MH negative revealed no signs of MH when exposed to anaesthetics known to cause MH. Judged from outcome of IVCT in 101 families, there is more than one mode of inheritance. The IVCT was validated with comparisons within and between laboratories, between different types of tests and within and between monozygotic twins. We found that increase in baseline tension exceeding 0.5g were almost always reproducible within and between laboratories, between different types of tests and within and between monozygotic twins. Our conclusions are that 1. There are no indications of false negative diagnoses. 2. There could be more than one mode of inheritance. 3. For scientific purposes when a high specificity is needed the threshold could be increased to 0.5g. However the clinical diagnostic cut off limits should be unchanged.
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| 10. |
- Islander, Gunilla, et al.
(författare)
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Male preponderance of patients testing positive for malignant hyperthermia susceptibility.
- 2007
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Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 51:5, s. 614-620
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Tidskriftsartikel (refereegranskat)abstract
- Malignant hyperthermia susceptibility is diagnosed using an in vitro contracture test (IVCT). In families in which the mutation is known, genetic tests are also available. The inheritance pattern is regarded as autosomal dominant, which predicts equal proportions of men and women affected. The aim of this study was to investigate whether there were sex differences in the diagnostic outcome of the 1407 patients tested for malignant hyperthermia in Sweden between 1985 and 2005. Methods: Information about sex, diagnosis, IVCT result and kinship was analysed. Comparisons were made between the two sexes. Probands and relatives were analysed separately in order to eliminate bias caused by the type of surgery performed in the two sexes. Results: Males, more than females, revealed a pathological outcome in IVCT. Amongst male relatives, the fraction of pathological outcome in IVCT was 0.70 [95% confidence interval (CI), 0.66-0.74]; the corresponding value for females was 0.40 (95% CI, 0.36-0.44). Conclusion: A significant difference was observed in the sex distribution of outcome of IVCT, with significantly more males revealing a pathological IVCT. This indicates the influence of one or several factors related to sex in the outcome of IVCT, for example different expression of calcium handling proteins in the sexes, a complex pattern of inheritance or unknown environmental factors.
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| 11. |
- Islander, Gunilla, et al.
(författare)
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Reproducibility of in vitro contracture test results in patients tested for malignant hyperthermia susceptibility.
- 2002
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Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172. ; 46:9, s. 1144-1149
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The in vitro contracture test (IVCT) is the golden standard to diagnose malignant hyperthermia susceptibility (MHS). A high reproducibility is important for a high validity of a test. METHODS: We have therefore analyzed IVCT in 838 patients, investigated in two laboratories. Each halothane and caffeine test was performed in two muscle strips. The test results were analyzed with respect to reproducibility of abnormal outcomes within pairs of tested muscle strips and size of contractures, thresholds and quality criteria. The patients were tested according to the European Malignant Hyperthermia Group protocol (EMHG). To fulfill quality criteria in the EMHG protocol the twitch height should be 10 mN (1 g) or more. For the caffeine test a minimum contracture of 50 mN (5 g) or more at 32 mmol l-1 caffeine could be used as an alternative quality criterion RESULTS: There was better reproducibility with larger contractures. The correlation between size of contractures and fraction of muscle strips with abnormal contractures was 0.77 or larger. Contractures < 5 mN (0.5 g) were reproducible in less than half of the tests. There was no difference in reproducibility or size of contractures between tests fulfillling all quality criteria and those not fulfillling these criteria. CONCLUSIONS: IVCT responses close to cut off limits, i.e. <5 mN (0.5 g) in the EMHG protocol, are less reproducible and must scientifically be considered as less reliable. The clinical cut off limits must remain unchanged for reasons of clinical safety. The outcome of quality measurements does not influence the test results.
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| 12. |
- Rasmussen, Eva Rye, et al.
(författare)
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Genome-wide association study of angioedema induced by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment.
- 2020
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Ingår i: The Pharmacogenomics Journal. - : Springer Science and Business Media LLC. - 1470-269X .- 1473-1150. ; 20:6, s. 770-783
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Tidskriftsartikel (refereegranskat)abstract
- Angioedema in the mouth or upper airways is a feared adverse reaction to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, which is used for hypertension, heart failure and diabetes complications. This candidate gene and genome-wide association study aimed to identify genetic variants predisposing to angioedema induced by these drugs. The discovery cohort consisted of 173 cases and 4890 controls recruited in Sweden. In the candidate gene analysis, ETV6, BDKRB2, MME, and PRKCQ were nominally associated with angioedema (p < 0.05), but did not pass Bonferroni correction for multiple testing (p < 2.89 × 10-5). In the genome-wide analysis, intronic variants in the calcium-activated potassium channel subunit alpha-1 (KCNMA1) gene on chromosome 10 were significantly associated with angioedema (p < 5 × 10-8). Whilst the top KCNMA1 hit was not significant in the replication cohort (413 cases and 599 ACEi-exposed controls from the US and Northern Europe), a meta-analysis of the replication and discovery cohorts (in total 586 cases and 1944 ACEi-exposed controls) revealed that each variant allele increased the odds of experiencing angioedema 1.62 times (95% confidence interval 1.05-2.50, p = 0.030). Associated KCNMA1 variants are not known to be functional, but are in linkage disequilibrium with variants in transcription factor binding sites active in relevant tissues. In summary, our data suggest that common variation in KCNMA1 is associated with risk of angioedema induced by ACEi or ARB treatment. Future whole exome or genome sequencing studies will show whether rare variants in KCNMA1 or other genes contribute to the risk of ACEi- and ARB-induced angioedema.
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| 13. |
- Riazi, Sheila, et al.
(författare)
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Pre-operative exercise and pyrexia as modifying factors in malignant hyperthermia (MH)
- 2022
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Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966. ; 32:8, s. 628-634
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Tidskriftsartikel (refereegranskat)abstract
- Malignant hyperthermia (MH) is a life-threatening reaction triggered by volatile anesthetics and succinylcholine. MH is caused by mutations in the skeletal muscle ryanodine receptor (RYR1) gene, as is rhabdomyolysis triggered by exertion and/or pyrexia. The discrepancy between the prevalence of risk genotypes and actual MH incidence remains unexplained. We investigated the role of pre-operative exercise and pyrexia as potential MH modifying factors. We included cases from 5 MH referral centers with 1) clinical features suggestive of MH, 2) confirmation of MH susceptibility on Contracture Testing (IVCT or CHCT) and/or RYR1 genetic testing, and a history of 3) strenuous exercise within 72 h and/or pyrexia >37.5 °C prior to the triggering anesthetic. Characteristics of MH-triggering agents, surgery and succinylcholine use were collected. We identified 41 cases with general anesthesias resulting in an MH event (GA+MH, n = 41) within 72 h of strenuous exercise and/or pyrexia. We also identified previous general anesthesias without MH events (GA-MH, n = 51) in the index cases and their MH susceptible relatives. Apart from pre-operative exercise and/or pyrexia, trauma and acute abdomen as surgery indications, emergency surgery and succinylcholine use were also more common with GA+MH events. These observations suggest a link between pre-operative exercise, pyrexia and MH.
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| 14. |
- Robinson, R, et al.
(författare)
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Several interacting genes influence the malignant hyperthermia phenotype
- 2003
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 1432-1203 .- 0340-6717. ; 112:2, s. 217-218
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Tidskriftsartikel (refereegranskat)abstract
- Malignant hyperthermia (MH), a potentially lethal disorder of skeletal muscle calcium homeostasis, manifests only on exposure to certain anaesthetic drugs. The mode of inheritance appears to be autosomal dominant with both locus and allelic heterogeneity having been reported. Association analysis of eight MH candidate loci in UK families has indicated that several genes influence susceptibility in individual families, rather than MH simply being a major gene defect. In support of this hypothesis, we present data on a replica analysis of an independent sample of European MH families.
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| 15. |
- Sundblom, Jimmy, 1981-, et al.
(författare)
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A family with discordance between Malignant hyperthermia susceptibility and Rippling muscle disease
- 2013
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Ingår i: Journal of Anesthesia. - : Springer Science and Business Media LLC. - 0913-8668 .- 1438-8359. ; 27:1, s. 128-131
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Tidskriftsartikel (refereegranskat)abstract
- Rippling muscle disease (RMD) is a benign disorder affecting striated muscle.Malignant hyperthermia (MH) susceptibility is a potentially lethal disorder in which otherwise healthy individuals can develop an extreme hypermetabolism and muscle rigidity/rhabdomyolysis during anesthesia with potent inhalational agents and/or succinylcholine. Disturbed calcium homeostasis has been suggested as the cause of RMD symptoms. Uncontrolled increase in intracellular calcium concentration starts a MH reaction.PurposeTo investigate if there is a relation between RMD and MH susceptibility in a family with both RMD and MH susceptibility.Materials and methodsTen members of a family segregating RMD had, prior to RMD diagnosis, been investigated for MH susceptibility. Results from MH and RMD investigations and anesthesia outcomes were cross-referenced and evaluated to find connections or phenotype variations predicted by in vitro contracture test results.ResultsThere was no relation between RMD and MH susceptibility. There were no adverse anesthesia reactions recorded in this family.ConclusionsRMD and MH susceptibility did not co-segregate. RMD patients should probably not be considered at risk for MH reactions.
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| 16. |
- Sundblom, Jimmy, et al.
(författare)
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Bedside diagnosis of rippling muscle disease in CAV3 p.A46T mutation carriers
- 2010
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Ingår i: Muscle and Nerve. - : Wiley. - 0148-639X .- 1097-4598. ; 41:6, s. 751-757
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Tidskriftsartikel (refereegranskat)abstract
- Thirty-nine members, ages 1 to 67 years, of a Swedish family with rippling muscle disease (RMD) were investigated to assess genotype-phenotype correlations. Clinical, neurophysiological, and muscle morphological examinations were performed. Genetic analysis was performed in 38 individuals. Twenty-three patients had percussion-induced muscle mounding (PIMM) and percussion-induced rapid contractions (PIRC). Rippling and hyperCKemia were not found in all patients. Weakness was minor or absent. The electromyogram showed absence of electrical activity in ripples and PIMM, and muscle biopsy specimens confirmed caveolin-3 deficiency and absence of caveolae. Genetic analysis revealed a CAV3 c.G136A transition resulting in a p.A46T missense mutation in affected family members. The phenotype in these 23 cases of RMD with this mutation appears to be homogenous, benign, and nonprogressive. The presence of PIMM and PIRC seems to be diagnostic at all ages, whereas the absence of hyperCKemia and rippling does not exclude the diagnosis.
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| 17. |
- Vukcevic, Mirko, et al.
(författare)
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Functional Properties of RYR1 Mutations Identified in Swedish Patients with Malignant Hyperthermia and Central Core Disease
- 2010
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Ingår i: Anesthesia and Analgesia. - 1526-7598. ; 111:1, s. 185-190
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A diagnosis of malignant hyperthermia susceptibility by in vitro contraction testing can often only be performed at specialized laboratories far away from where patients live. Therefore, we have designed a protocol for genetic screening of the RYR1-cDNA and for functional testing of newly identified ryanodine receptor 1 (RYR1) gene variants in B lymphocytes isolated from peripheral blood samples drawn at local primary care centers. METHODS: B lymphocytes were isolated for the extraction of RYR1-mRNA and genomic DNA and for establishment of lymphoblastoid B cell lines in 5 patients carrying yet unclassified mutations in the RYR1. The B lymphoblastoid cell lines were used to study resting cytoplasmic calcium concentration, the peak calcium transient induced by the sarco(endo)plasmic reticulum Ca-ATPase inhibitor thapsigargin, and the dose-dependent calcium release induced by the ryanodine receptor agonist 4-chloro-m-cresol. RESULTS: It was possible to extract mRNA for cDNA synthesis and to create B lymphocyte clones from all samples. All B lymphoblastoid cell lines carrying RYR1 candidate mutations showed significantly increased resting cytoplasmic calcium levels as well as a shift to lower concentrations of 4-chloro-m-cresol inducing calcium release compared with controls. CONCLUSIONS: Peripheral blood samples are stable regarding RNA and DNA extraction and establishment of lymphoblastoid B cell lines after transportation at ambient temperature over large distances by ordinary mail. Functional tests on B cells harboring the newly identified amino acid substitutions indicate that they alter intracellular Ca2+ homeostasis and are most likely causative of malignant hyperthermia. (Anesth Analg 2010;111:185-90)
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| 18. |
- Wadelius, Mia, et al.
(författare)
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Phenotype Standardization of Angioedema in the Head and Neck Region Caused by Agents Acting on the Angiotensin System
- 2014
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Ingår i: Clinical Pharmacology and Therapeutics. - : Nature Publishing Group. - 0009-9236 .- 1532-6535. ; 96:4, s. 477-481
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Forskningsöversikt (refereegranskat)abstract
- Angioedema is a potentially life-threatening adverse reaction to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. To study the genetic etiology of this rare adverse event, international consortia and multicenter recruitment of patients are needed. To reduce patient heterogeneity, we have standardized the phenotype. In brief, it comprises swelling in the head and neck region that first occurs during treatment. It should not coincide with urticaria or have another likely cause such as hereditary angioedema.
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