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The Israel Medical Association Journal... Apr 2023
Topics: Humans; Malignant Hyperthermia
PubMed: 37129134
DOI: No ID Found -
Ugeskrift For Laeger Mar 2023Hyperthermia is a severe complication to intake of methamphetamines due to generalised overactivation of metabolism and muscle activity combined with vasoconstriction....
Hyperthermia is a severe complication to intake of methamphetamines due to generalised overactivation of metabolism and muscle activity combined with vasoconstriction. In this case report, a patient presented to the emergency department after injection of 2 g "crystal meth", and advanced into fatal hyperthermia and organ failure in the intensive care unit. Treatment of substance-induced hyperthermia is symptomatic and reducing metabolism with benzodiazepines and actively lowering body temperature with ice packs and cold intravenous fluids are appropriate interventions. Dantrolene may be used but is still to be properly investigated.
Topics: Humans; Methamphetamine; Fatal Outcome; Malignant Hyperthermia; Hyperthermia, Induced
PubMed: 36999287
DOI: No ID Found -
Genetics in Medicine : Official Journal... Jul 2021As a ClinGen Expert Panel (EP) we set out to adapt the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) pathogenicity...
PURPOSE
As a ClinGen Expert Panel (EP) we set out to adapt the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) pathogenicity criteria for classification of RYR1 variants as related to autosomal dominantly inherited malignant hyperthermia (MH).
METHODS
We specified ACMG/AMP criteria for variant classification for RYR1 and MH. Proposed rules were piloted on 84 variants. We applied quantitative evidence calibration for several criteria using likelihood ratios based on the Bayesian framework.
RESULTS
Seven ACMG/AMP criteria were adopted without changes, nine were adopted with RYR1-specific modifications, and ten were dropped. The in silico (PP3 and BP4) and hotspot criteria (PM1) were evaluated quantitatively. REVEL gave an odds ratio (OR) of 23:1 for PP3 and 14:1 for BP4 using trichotomized cutoffs of ≥0.85 (pathogenic) and ≤0.5 (benign). The PM1 hotspot criterion had an OR of 24:1. PP3 and PM1 were implemented at moderate strength. Applying the revised ACMG/AMP criteria to 44 recognized MH variants, 29 were classified as pathogenic, 13 as likely pathogenic, and 2 as variants of uncertain significance.
CONCLUSION
Curation of these variants will facilitate classification of RYR1/MH genomic testing results, which is especially important for secondary findings analyses. Our approach to quantitatively calibrating criteria is generalizable to other variant curation expert panels.
Topics: Bayes Theorem; Genetic Testing; Genetic Variation; Genome, Human; Humans; Hyperthermia; Mutation; Ryanodine Receptor Calcium Release Channel; Virulence
PubMed: 33767344
DOI: 10.1038/s41436-021-01125-w -
Brazilian Journal of Anesthesiology... 2023
Topics: Humans; Malignant Hyperthermia
PubMed: 36963956
DOI: 10.1016/j.bjane.2023.03.001 -
Human Molecular Genetics Nov 2022The ClinGen malignant hyperthermia susceptibility (MHS) variant curation expert panel specified the American College of Medical Genetics and Genomics/Association of...
The ClinGen malignant hyperthermia susceptibility (MHS) variant curation expert panel specified the American College of Medical Genetics and Genomics/Association of Molecular Pathologists (ACMG/AMP) criteria for RYR1-related MHS and a pilot analysis of 84 variants was published. We have now classified an additional 251 variants for RYR1-related MHS according to current ClinGen standards and updated the criteria where necessary. Criterion PS4 was modified such that individuals with multiple RYR1 variants classified as pathogenic (P), likely pathogenic (LP), or variant of uncertain significance (VUS) were not considered as providing evidence for pathogenicity. Criteria PS1 and PM5 were revised to consider LP variants at the same amino-acid residue as providing evidence for pathogenicity at reduced strength. Finally, PM1 was revised such that if PS1 or PM5 are used PM1, if applicable, should be downgraded to supporting. Of the 251 RYR1 variants, 42 were classified as P/LP, 16 as B/LB, and 193 as VUS. The primary driver of 175 VUS classifications was insufficient evidence supporting pathogenicity, rather than evidence against pathogenicity. Functional data supporting PS3/BS3 was identified for only 13 variants. Based on the posterior probabilities of pathogenicity and variant frequencies in gnomAD, we estimated the prevalence of individuals with RYR1-related MHS pathogenic variants to be between 1/300 and 1/1075, considerably higher than current estimates. We have updated ACMG/AMP criteria for RYR1-related MHS and classified 251 variants. We suggest that prioritization of functional studies is needed to resolve the large number of VUS classifications and allow for appropriate risk assessment. RYR1-related MHS pathogenic variants are likely to be more common than currently appreciated.
Topics: Humans; Genetic Testing; Genetic Variation; Malignant Hyperthermia; Ryanodine Receptor Calcium Release Channel; United States; Virulence
PubMed: 35849058
DOI: 10.1093/hmg/ddac145 -
Pflugers Archiv : European Journal of... Jul 2020Ca1.1 is specifically expressed in skeletal muscle where it functions as voltage sensor of skeletal muscle excitation-contraction (EC) coupling independently of its... (Review)
Review
Ca1.1 is specifically expressed in skeletal muscle where it functions as voltage sensor of skeletal muscle excitation-contraction (EC) coupling independently of its functions as L-type calcium channel. Consequently, all known Ca1.1-related diseases are muscle diseases and the molecular and cellular disease mechanisms relate to the dual functions of Ca1.1 in this tissue. To date, four types of muscle diseases are known that can be linked to mutations in the CACNA1S gene or to splicing defects. These are hypo- and normokalemic periodic paralysis, malignant hyperthermia susceptibility, Ca1.1-related myopathies, and myotonic dystrophy type 1. In addition, the Ca1.1 function in EC coupling is perturbed in Native American myopathy, arising from mutations in the Ca1.1-associated protein STAC3. Here, we first address general considerations concerning the possible roles of Ca1.1 in disease and then discuss the state of the art regarding the pathophysiology of the Ca1.1-related skeletal muscle diseases with an emphasis on molecular disease mechanisms.
Topics: Adaptor Proteins, Signal Transducing; Animals; Calcium Channels, L-Type; Channelopathies; Humans; Muscle, Skeletal; Mutation
PubMed: 32222817
DOI: 10.1007/s00424-020-02368-3 -
CMAJ : Canadian Medical Association... Jun 2022
Topics: Humans; Malignant Hyperthermia; Rhabdomyolysis; Succinylcholine
PubMed: 35760427
DOI: 10.1503/cmaj.146480-l