WFH Guidelines for the Management of Hemophilia, 3rd edition

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane, isoflurane and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stressors such as vigorous exercise and heat. The incidence of MH reactions ranges from 1:10,000 to 1: 250,000 anesthetics. However, the prevalence of the genetic abnormalities may be as great as one in 400 individuals. MH affects humans, certain pig breeds, dogs and horses. The classic signs of MH include hyperthermia, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response. The syndrome is likely to be fatal if untreated. An increase in end-tidal carbon dioxide despite increased minute ventilation provides an early diagnostic clue. In humans the syndrome is inherited in an autosomal dominant pattern, while in pigs it is autosomal recessive. Uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation leads to the pathophysiologic changes. In most cases, the syndrome is caused by a defect in the ryanodine receptor. Over 400 variants have been identified in the RYR1 gene located on chromosome 19q13.1, and at least 34 are causal for MH. Less than 1 % of variants have been found in CACNA1S but not all of these are causal. Diagnostic testing involves the in vitro contracture response of biopsied muscle to halothane, caffeine, and in some centres ryanodine and 4-chloro-m-cresol. Elucidation of the genetic changes has led to the introduction of DNA testing for susceptibility to MH. Dantrolene sodium is a specific antagonist and should be available wherever general anesthesia is administered. Increased understanding of the clinical manifestation and pathophysiology of the syndrome, has lead to the mortality decreasing from 80 % thirty years ago to <5 % in 2006.

/pdf/malignant-hyperthermia-a-review-2x5lvwo62i.pdf

Malignant hyperthermia: a review

This article reviews advancements in the genetics of malignant hyperthermia, new technologies and approaches for its diagnosis, and the existing limitations of genetic testing for malignant hyperthermia. It also reviews the various RYR1-related disorders and phenotypes, such as myopathies, exertional rhabdomyolysis, and bleeding disorders, and examines the connection between these disorders and malignant hyperthermia.

Malignant Hyperthermia in the Post-Genomics Era: New Perspectives on an Old Concept.

Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative

The identification in a patient of 1 of the 50 variants in the RYR1 or CACNA1S genes reviewed here should lead to a presumption of malignant hyperthermia susceptibility (MHS). MHS can lead to life-threatening reactions to potent volatile anesthetic agents or succinylcholine. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of these agents in patients with these RYR1 or CACNA1S variants (updates at https://cpicpgx.org/guidelines and www.pharmgkb.org).

https://ascpt.onlinelibrary.wiley.com/doi/pdf/10.1002/cpt.1319

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for the Use of Potent Volatile Anesthetic Agents and Succinylcholine in the Context of RYR1 or CACNA1S Genotypes

Current screening methods for factor VIII gene (F8) mutations can reveal the causative alteration in the vast majority of haemophilia A patients Yet, standard diagnostic methods fail in about 2 % of cases This study aimed at analysing the entire intronic sequences of the F8 gene in 15 haemophilia A patients by next generation sequencing All patients had a mild to moderate phenotype and no mutation in the coding sequence and splice sites of the F8 gene could be diagnosed so far Next generation sequencing data revealed 23 deep intronic candidate variants in several F8 introns, including six recurrent variants and three variants that have been described before One patient additionally showed a deletion of 92 kb in intron 1, mediated by Alu-type repeats Several bioinformatic tools were used to score the variants in comparison to known pathogenic F8 mutations in order to predict their deleteriousness Pedigree analyses showed a correct segregation pattern for three of the presumptive mutations In each of the 15 patients analysed, at least one deep intronic variant in the F8 gene was identified and predicted to alter F8 mRNA splicing Reduced F8 mRNA levels and/or stability would be well compatible with the patients’ mild to moderate haemophilia A phenotypes The next generation sequencing approach used proved an efficient method to screen the complete F8 gene and could be applied as a one-stop sequencing method for molecular diagnostics of haemophilia A

Identification of deep intronic variants in 15 haemophilia A patients by next generation sequencing of the whole factor VIII gene.

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. We designed a gene panel for sequence enrichment targeting 64 genes of proteins involved in the homeostasis of the striated muscle cell. Next-generation sequencing (NGS) resulted in >50,000 sequence variants which were further analyzed by software filtering criteria to identify causative variants. In four of five patients we identified previously reported RYR1 mutations while the fifth patient did not show any candidate variant in any of the genes investigated. In two patients pathogenic variants were found in other genes known to cause a muscle disorders. All but one patient carried likely benign rare polymorphisms. The NGS technique proved convenient in identifying variants in the RYR1. However, with a clinically variable phenotype-like MH, the pre-selection of genes poses problems in variant interpretation.

Next-generation DNA sequencing of a Swedish malignant hyperthermia cohort

Haemophilia A (HA) is caused by a broad spectrum of different mutation types in the factor VIII gene (F8). In our patient cohort of more than 2600 HA patients as well as in other published studies, the most frequent cause are missense mutations in different F8 exons or the recurrent intron 22 inversion. Some exons and several specific nucleotide positions represent hot spots for point mutations in the examined cohort. About 4 % of cases remain without mutation after routine HA diagnostic methods including inversion PCRs, Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Deep intronic mutations cannot be detected by current standard HA diagnostics but have been reported for several genetic disorders. However, next generation sequencing (NGS) of the whole genomic sequence of the F8 gene allows to identify deep intronic variants. Conclusion: In general, NGS provides an effective approach to screen for different HA causing mutation types in the F8 gene.

Mutational spectrum and deep intronic variants in the factor VIII gene of haemophilia A patients. Identification by next generation sequencing.

Mini-gene assays confirm the splicing effect of deep intronic variants in the factor VIII gene -

Mini-gene assays confirm the splicing effect of deep intronic variants in the factor VIII gene

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Papers

Identification of deep intronic variants in 15 haemophilia A patients by next generation sequencing of the whole factor VIII gene.

Next-generation DNA sequencing of a Swedish malignant hyperthermia cohort

Mutational spectrum and deep intronic variants in the factor VIII gene of haemophilia A patients. Identification by next generation sequencing.

Mini-gene assays confirm the splicing effect of deep intronic variants in the factor VIII gene