Neuromuscular Disorders And Malignant Hyperthermia

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Neuromuscular disorders and Malignant HyperthermiaDr L Heytens Dr J De PuydtOnderzoeksgroep MHUniversiteit AntwerpenCampus Drie Eiken Wilrijk Scientific expert with Norgine NV

“fortunate” characteristics of MH rare 1/50.000 - genetic prevalence 1/3000 known for 60y1960 well manageable last fatal case Belgium 20 y molecular genetic diagnosis “feasible”

downside Rare ‘malignant’ / feared / lack of experience Autosomal dominant inheritance family concern Mortality still 10% Molecular genetics as diagnostic technique: far more complex than anticipated

Start “fairly well known” pathophysiology clinical diagnosis treatmentFocus “less well known” Clinical variabilityMolecular geneticsanesthesia in MHSusceptible/suspected-individualspredisposing NMD - ‘RYR1-myopathy’

Denborough MH, Lovell RRH.Anesthetic deaths in a family. Lancet ii, 45, Metabolic myopathy Acute rhabdomyolysis triggered by volatileanesthetics and succinylcholine Dominant inheritance pattern

Metabolic myopathy: “dysfunction of excitation-contraction coupling”J Lunardi, Grenoble

Nat Struct Mol Biol 2005;12: 539-544. MSamso, T Wagenknecht, PD Allen

PathophysiologyRYR1-mutations Exposure to volatile anaesthetics/succinylcholineMassive calcium-release from SRMuscular contractionGlycogenolysisEntry into mitochondriaeATP-depletioncellular degradationlactic acidHeat productionRigidityhyperthermiaincreased nMyoglobinHyper KhypoxemiaacidosisCardiac arrestAcute renal failure

MH : “fulminant” phenomenon‘hypermetabolism’ : rapidly evolvinghypercapnia, tachycardia, rigidity, hyperthermia biochemical signs of rhabdomyolysis/muscle breakdowne.g.high CK, myoglobinuriaacidosishyperK

Case 1 9y03/2009Circumcision at 7 mSurgery : adenoidectomyIV induction sufenta/propofol – mask sevoflurane – ETTwithin 15 min :ETCO2 100 mm Hg / hyperventilationgeneralized rigiditytachycardia 200 bpmtemp 39,4 CK 6.5 meq/LStop sevofluraneDantrolene 1,5mg/kg : normalization clinical parameters / 30 minTransfert CHU Liège CPK postop day 1 138.000 U/L

Treatment of acute episodeMH: presymptomatic screening and treatment 2011. Urwyler A. Eur J Anaesthesiol 28, 237 – 239, 2011Updated guide for the management of malignant hyperthermia. Riazi S. Can J Anaesth 65, 709-721, 2018Vapor-CleanTM charcoal filters

Focus “less well known” 1. Clinical variability


Temp 39,7 CETCO2 90 mm f 24/min TV 700 mlpH 7.2Dantrolene 240 mgCK postop 4745 IU/L – K 6,3 meq/L

Reasons for indolent clinical phenotypes1. Anaesthesia-related factors Volatile anaestheticHal enflurane/isoflurane sevoflurane/desflurane Duration of administration Vol% administered Intravenous vs inhalational induction Volatile anaesthetic /- succinylcholine Mitigating drugs administered simultaneously– non-depolarizing NMB– Clonidine/dexmedetomidine– Beta blocking agents

yo-EM structures of RyR and IP 3 R. Shown are isocontour maps forcryo-EM reconstructions of RyRFilip Van Petegem Ryanodine Receptors: Allosteric Ion Channel GiantsJournal of Molecular Biology, Volume 427, Issue 1, 2015, 31 - 53

2. Genotype-related factors pig 2. Molecular genetics

Summary of findings linkage analysis & mutation search Locus/chromosomal heterogeneity Most often 19q13.1 RYR150 %– But also loci on» 1q32 CACNA1S DHPR-a1S subunit 2%» 12q13.3 STAC3» (7q21.11 CACNB1 DHPR-β1a subunit)» (1q23.2 CASQ1 Calsequestrin)» (19p13.3 JSPR1 JP45 protein) Allelic heterogeneity /- 400 RYR1 mutations reported of which 48 “causative”

RYR1 mutations15364 bp / 106 exons5038 aawww.emhg.orgGain-of-function phenotypesIncreased calcium-conductance

Complexity of molecular genetics :-‘Causative mutations’ in (only) 50 – 70% of proven MH-families-Variations of unknown significance (VUS’s) ( /- 350)--Polymorphisms (x): bp-changeswithout significanceEven combinationsAminoacid changeExonNumber of familiesClassification EMHG vec.1122 5G A*111VUSp.Arg614Cys172causativecausativep. Arg614Leu172p.Val1436Met301VUSp.Ile1571Val332No Val4849Ile1011VUSp.Phel4857Leu101155 families genotypedVUS18 different mutations in25 families


Diagnostic work-upAutosomal dominant inheritance patternSuspicion of MH-episode : risk not restricted to 1 individual corroborative evidence in proband (temp, PaCO2/ETCO2, CPK PO day 1 ) confirmation/refutal of clinical diagnosis risk assesment in relatives

N. G8/6/1974L. St3/1/1974?1 x GA fimosis1x epid1 x GAMH 3rdGAPArthur22/6/2008P probandMHS MH susceptibleGA general anesthesia?Tom5/6/2003?Robin26/8/2004?

Diagnosis / phenotyping Clinical evidence of hypermetabolism(hypercapnia, hyperthermia, acidosis, arrhythmia, rigidity) Biochemical evidence of rhabdomyolysis(high CK, acidosis/hyperK, myoglobinuria, )Suspicion of MH How to confirm/refute In vitro contracture testing– Caffeine / halothane– Ryanodine / 4 chloro-m-cresol EMHG MHAUS

IVCT-criteria EMHGSensitivity 99,0% (95% confidence interval 94,8 -100%)Specificity 93,6% (95% confidence interval 89,2 – 96,5%)Ording, 1997Halothane contracture testNormal responseHalothane contracture testMHS-response

Proband parents: RYR1-sequencing106 exon transcript

Genetics in MH-Confirmative if ‘diagnostic mutation’ (20%) – doubtful if VUSAbsence of mutation does not exclude MHSFamily screening applicable in select familiesCombined information from IVCT and RYR1-sequencingExpensive

3. Anesthesia in MH-susceptible or suspected individuals : non-triggering anesthetic technique local or locoregional anesthesiaGeneral anesthesia : any drug, except triggering substances TIVAPretreatment with dantrolene not indicatedScheduled as ‘first’Adequately prepare the anesthesia workstationPreparation of modern anesthesia workstations for malignant hyperthermia-susceptible patients.A review of past and present practice. Kim W. Anesthesiology, 114, 205 – 212, 2011.Preparation of Datex-Ohmeda Aestiva and Aisys anaesthetic machines for use inmalignant hyperthermia susceptible patients. Jones C, Bennett K, Bulger T, Pollock N.Anaesth Intensive Care 40, 490 – 497, 2012.

Preparation of modern anesthesia workstations for malignant hyperthermia-susceptible patients.A review of past and present practice. Kim W. Anesthesiology, 114, 205 – 212,

4. Neuromuscular disorders and predisposition to MHIncreased risk for: Congenital myopathies– “core diseases” RYR1Central core diseaseMultiminicore diseaseCentronuclear myopathyCongenital fiber type disproportion (CFTD)Congenital myopathy with cores and rodsHypokalemic periodic paralysis (RYR1, CACNA1S)King-Denborough syndrome (dysmorphic features, myopathy, MH-susceptibility)‘exercise induced rhabdomyolysis’ /- 10% RYR1-mutationsMHSCore-myopathiesEIRKing-Denborough .RYR1myopathies

Congenital myopathies :histopathological changes early-onset weaknesscore myopathiesCentral core diseaseMultiminicore diseasenemaline myopathycentronuclear myopathyCCD / MmDMH-susceptible ( /-100 / 50%)

Exertional rhabdomyolysisAcronym RHABDO(Scalco, 2016)R:Recurrent episodes of exertional rhabdomyolysisH:HyperCKaemia persists 8 weeks after the eventA:Accustomed physical exerciseB:Blood CK 50xULN ( 10000ULN in female Caucasian patients)D:Drugs/medication/supplements cannot sufficiently explain the rhabdomyolysis severityO:Other family members affected / Other exertional symptoms (cramps, myalgia)

In summary : MH Metabolic myopathy Excitation-contraction coupling RYR/DHPR/related proteincomplexD calciumhomeostasisHypermetabolism /acute rhabdomyolysis Hypercapnia : most consistent sign Delayed and/or slow-onset frequent Familial risk mandates correct diagnosis in proband and ‘select’ relatives‘risk containment’ Genetic diagnosis possible but complex ‘screening’ only in select families with known causative mutation Predisposition to MH in RYR1-myopathies(congenital myopathies, familial hypokalemic PP, exertional rhabdomyolysis)

Preparation of modern anesthesia workstations for malignant hyperthermia-susceptible patients. A review of past and present practice. Kim W. Anesthesiology, 114, 205 –212, 2011. Preparation of Datex-Ohmeda Aestiva and Aisys anaesthetic machines for use in malignant hyperthermia susceptible patients. Jones C, Bennett K, Bulger T, Pollock N.

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