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Muscular body build and male sex are independently associated with malignant hyperthermia susceptibility

Authors:
  • North American MH Registry of MHAUS

Abstract

Purpose: Malignant hyperthermia susceptibility (MHS) is a disorder of the regulation of calcium in skeletal muscle. Muscular individuals have been shown to have a 13.6-fold increased risk of death during malignant hyperthermia (MH) episodes and are more likely to experience a recurrence after initial treatment. Twenty-five percent of severe MH episodes have occurred in elite athletes. This study investigated the association between MHS and muscular body build. Methods: Data were obtained from existing reports in the North American Malignant Hyperthermia Registry, including the Report of Muscle Biopsy and Contracture Testing (caffeine-halothane contracture test [CHCT]) as well as Adverse Metabolic or Muscular Reaction to Anesthesia (AMRA) reports. Malignant hyperthermia susceptible individuals were compared with MH negative individuals with regard to body build and reason for testing. Males were also compared with females. Both the CHCT and the AMRA forms were reviewed for comments. Results: Of the 1,292 individuals diagnosed with MHS by CHCT, males were more likely to be diagnosed with the disorder than females (odds ratio [OR], 2.33; 95% confidence interval [CI], 1.99 to 2.7; P < 0.001). Muscular individuals were more likely to be diagnosed with MHS than non-muscular individuals (OR, 1.94; 95% CI, 1.51 to 2.49; P < 0.001). Males were more likely to be tested after having a possible MH episode (OR, 2.33; 95% CI, 1.45 to 2.1; P < 0.001). Logistic regression showed that male sex (OR, 2.28; 95% CI, 1.93 to 2.7; P < 0.001) and muscular body build (OR, 2.17; 95% CI, 1.21 to 3.9; P = 0.01) were independently predictive of MHS. The interaction between muscular body build and male sex was not significant (P = 0.13). Indications for testing, MH episode vs family history of MH, did not differ between muscular and non-muscular individuals (P = 0.44). Eight of 839 AMRAs and two reports of CHCT had comments describing athletic abilities. Ryanodine receptor type 1 (RYR1) gene mutations were found in five of these athletes. Conclusion: Muscular body build and male sex are strongly associated with MHS.
REPORTS OF ORIGINAL INVESTIGATIONS
Muscular body build and male sex are independently associated
with malignant hyperthermia susceptibility
Un corps muscle
´et le sexe masculin sont associe
´s de fac¸on
inde
´pendante a
`une susceptibilite
´a
`l’hyperthermie maligne
Brian Butala, DO .Barbara Brandom, MD
Received: 25 May 2016 / Revised: 5 November 2016 / Accepted: 1 January 2017
ÓCanadian Anesthesiologists’ Society 2017
Abstract
Purpose Malignant hyperthermia susceptibility (MHS) is
a disorder of the regulation of calcium in skeletal muscle.
Muscular individuals have been shown to have a 13.6-fold
increased risk of death during malignant hyperthermia
(MH) episodes and are more likely to experience a
recurrence after initial treatment. Twenty-five percent of
severe MH episodes have occurred in elite athletes. This
study investigated the association between MHS and
muscular body build.
Methods Data were obtained from existing reports in the
North American Malignant Hyperthermia Registry,
including the Report of Muscle Biopsy and Contracture
Testing (caffeine-halothane contracture test [CHCT]) as
well as Adverse Metabolic or Muscular Reaction to
Anesthesia (AMRA) reports. Malignant hyperthermia
susceptible individuals were compared with MH negative
individuals with regard to body build and reason for
testing. Males were also compared with females. Both the
CHCT and the AMRA forms were reviewed for comments.
Results Of the 1,292 individuals diagnosed with MHS by
CHCT, males were more likely to be diagnosed with the
disorder than females (odds ratio [OR], 2.33; 95%
confidence interval [CI], 1.99 to 2.7; P \0.001).
Muscular individuals were more likely to be diagnosed
with MHS than non-muscular individuals (OR, 1.94; 95%
CI, 1.51 to 2.49; P \0.001). Males were more likely to be
tested after having a possible MH episode (OR, 2.33; 95%
CI, 1.45 to 2.1; P\0.001). Logistic regression showed that
male sex (OR, 2.28; 95% CI, 1.93 to 2.7; P \0.001) and
muscular body build (OR, 2.17; 95% CI, 1.21 to 3.9; P =
0.01) were independently predictive of MHS. The
interaction between muscular body build and male sex
was not significant (P = 0.13). Indications for testing, MH
episode vs family history of MH, did not differ between
muscular and non-muscular individuals (P = 0.44). Eight
of 839 AMRAs and two reports of CHCT had comments
describing athletic abilities. Ryanodine receptor type 1
(RYR1) gene mutations were found in five of these athletes.
Conclusion Muscular body build and male sex are
strongly associated with MHS.
Re
´sume
´
Objectif La susceptibilite´a` l’hyperthermie maligne
(SHM) est un trouble de la re´gulation du calcium dans
les muscles squelettiques. Il a e´te´de´montre´ que les
personnes muscle´es couraient un risque 13,6 fois plus
e´leve´dede´ce`s pendant des e´pisodes d’hyperthermie
maligne (HM) ainsi qu’un risque plus e´leve´de
re´currence apre`s un premier traitement de la maladie.
Vingt-cinq pour cent des e´pisodes graves d’HM sont
survenus chez des athle`tes de pointe. Cette e´tude a examine´
l’association entre la SHM et la constitution musculaire.
Me
´thode Des donne´es ont e´te´ obtenues a` partir de
rapports existants dans le Registre nord-ame´ricain de
l’hyperthermie maligne (North American Malignant
Hyperthermia Registry), y compris le Rapport de biopsie
musculaire et de test de contracture (Report of Muscle
B. Butala, DO (&)
Allegheny Health Network, Department of Anesthesiology,
Allegheny General Hospital, 302 E North Ave, Pittsburgh,
PA 15212, USA
e-mail: brian.butala@ahn.org; brian.butala@gmail.com
B. Brandom, MD
North American Malignant Hyperthermia Registry of MHAUS,
UPMC Mercy Hospital, University of Pittsburgh, Pittsburgh, PA,
USA
123
Can J Anesth/J Can Anesth
DOI 10.1007/s12630-017-0815-2
Biopsy and Contracture Testing) (test de contracture a`la
cafe´ine et a` l’halothane [CHCT]) ainsi que les rapports de
re´actions me´taboliques ou musculaires ne´gatives a`
l’anesthe´sie (Adverse Metabolic or Muscular Reaction to
Anesthesia - AMRA). Les personnes susceptibles a`
l’hyperthermie maligne ont e´te´ compare´es aux personnes
ne´gatives a` l’HM quant a` leur constitution physique et a`la
raison de leur test. On a e´galement fait une comparaison
hommes-femmes. Les formulaires de CHCT et d’AMRA ont
e´te´ passe´s en revue afin d’en extraire tout commentaire ou
remarque.
Re
´sultats Parmi les 1292 personnes ayant rec¸u un
diagnostic de SHM apre`s avoir passe´ un test de CHCT, les
hommes e´taient plus enclins a`eˆtre diagnostique´s avec ce
trouble que les femmes (rapport de cotes [RC], 2,33;
intervalle de confiance [IC] 95 %, 1,99 a` 2,7; P \0,001).
Les personnes muscle´es couraient un risque plus e´leve´de
diagnostic de SHM que les personnes non muscle´ es (RC,
1,94; IC 95 %, 1,51 a` 2,49; P \0,001). Les hommes
couraient un risque plus e´leve´ de passer un test apre`s avoir
subi un possible e´pisode d’HM (RC, 2,33; IC 95 %, 1,45 a`
2,1; P\0,001). L’analyse de re´gression logistique a montre´
que le sexe masculin (RC, 2,28; IC 95 %, 1,93 a` 2,7; P \
0,001) et un corps muscle´ (RC, 2,17; IC 95 %, 1,21 a` 3,9;
P = 0,01) e´taient des pre´dicteurs inde´ pendants de SHM.
L’interaction entre avoir un corps muscle´ et le sexe masculin
n’e´tait pas significative (P = 0,13). Les indications pour
envisager un test, pre´voir un e´pisode d’HM vs les
ante´ce´ dents familiaux d’HM ne diffe´raient pas entre les
personnes muscle´es et non muscle´es (P = 0,44). Huit des 839
AMRA et deux rapports de CHCT comportaient des
commentaires de´crivant des capacite´s athle´tiques. Des
mutations du ge`ne RYR1 (re
´cepteur de ryanodine de type
1) ont e´te´ observe´es chez cinq de ces athle`tes.
Conclusion Un corps muscle´ et le sexe masculin sont
associe´s de fac¸on significative a` une susceptibilite´a`
l’hyperthermie maligne.
Malignant hyperthermia (MH) is a disorder of the
regulation of calcium in skeletal muscle. In response to
certain anesthetic
1,2
agents or other stressors, such as
exercise,
3-5
excessive calcium in the muscle cell increases
metabolism to the point of producing lethal temperatures.
Mutations in the ryanodine receptor type 1 (RYR1)
6
gene
are the most frequent genetic changes found in individuals
with malignant hyperthermia susceptibility (MHS).
Mutations in the alpha one subunit of the voltage-gated
calcium channel (the dihydropyridine receptor)
7
are less
common than RYR1 mutations.
6,8
The STAC 3 protein has
also been found to be associated with MHS in some
myopathic patients.
9
There are 35 mutations in the RYR1
gene and two in the CACNA1S gene, encoding the alpha
one subunit of the dihydropyridine receptor, that have been
shown to be MH causative.
10
Even with an emerging
genetic understanding of MHS, the gold standard for a
diagnosis of MH risk in North America remains the
caffeine-halothane contracture test (CHCT), which is
reported to be 97% sensitive and 78% specific.
11
Muscular individuals have been shown to have a
13.6-fold increased risk of death from MH episodes
12
and are more likely to experience recurrence of MH
episodes after initial treatment.
13
Twenty-five percent of
severe MH episodes have occurred in elite athletes.
12
There have also been other reports of athletes suffering
MH episodes both with
14,15
and without exposure to
anesthesia.
16-18
It was previously noted that three of 25
Danish individuals who experienced MH episodes were
elite athletes competing at the international and Olympic
levels.
18
Thus, for this study, we looked for more evidence
in the North American Malignant Hyperthermia Registry
(NAMHR) that muscularity and athleticism were
associated with MHS.
Methods
After institutional review board approval, data were
obtained from reports existing in the NAMHR from
January 1, 1987 to December 31, 2014, including the
Report of Muscle Biopsy and Contracture Testing and the
Adverse Metabolic or Muscular Reaction to Anesthesia
(AMRA) report. The CHCT is completed by physicians in
the MH diagnostic testing centres, and the AMRA is
completed by the anesthesiologist or other healthcare
provider who observed a possible or actual MH event.
The CHCT and AMRA contain a check box for body build
that includes options for normal, lean, muscular, obese,
postpartum, and other. The judgment of body build is
subjective on the part of the physician completing the
report and not based on objective measurement of fat or
muscle. For purposes of analysis, the cases were sorted into
categories of muscular and non-muscular, first on the basis
of responses to this check box. If comments reported
muscular in a text field as well as noting body build other
than muscular in the check box, the case was put into the
muscular group for analysis. All forms contain a section for
comments. Since 2002, forms include a check box for
‘regular regimen of physical activity’’. The CHCT form
contains the question ‘‘What was the reason for MH
diagnostic muscle biopsy?’’ with options for fulminant MH
episode, possible MH episode with associated AMRA,
possible MH episode without AMRA, family history,
control, and other. For the purposes of analysis, fulminant
B. Butala, B. Brandom
123
MH episodes and possible MH episodes as the reason for
biopsy are grouped together and referred to as possible MH
episode. These are the probands.
Three thousand twenty-four CHCT reports from
individuals in the USA or Canada were examined. These
CHCTs were performed after 1979 and before 2013 and
include cases in previously published studies from the
NAMHR. We excluded 103 of these reports with equivocal
results. At the time of testing, the director of the MH
diagnostic centre indicated equivocal result to mean that
risk of MHS could not be determined. The magnitude of
the contractures in the presence of halothane or caffeine
were not evaluated in this report. Reports with unknown
sex (12), absent or other body type (335), and 12 reports of
CHCT performed prior to standardization
19
were also
excluded (Figure). Eight hundred thirty-nine AMRAs were
reviewed for comments, and CHCT reports were also
reviewed for comments regarding athletic achievement and
genetic test results.
Analysis was performed using Fisher’s exact test for
categorical variables. The associations between CHCT
result and body build, CHCT result and body build in male
and female sex, body build and indication for testing, as
well as sex and CHCT result were examined with Fisher’s
exact test in SPSSÒ(versions 22, 23, & 24; IBM, NY,
USA). Since muscularity may be associated with being
male, we used logistic regression to determine if
muscularity was independently predictive of MHS (over
and above sex). We used MHS as the dependent variable
and muscularity and sex (as well as their interaction) as the
independent variables. There was no correction of Pvalues
for multiple comparisons.
Results
Results of CHCTs were reported for 1,284 males and 1,278
females. Muscular body build was reported in 194 of 1,292
individuals diagnosed with MHS by CHCT and in 106 of
1,270 individuals diagnosed as not MH susceptible (MHN)
by CHCT (Table 1). Thus, those with muscular body build
were more likely than those with non-muscular body build
to have CHCT results indicate a diagnosis of MHS (odds
ratio [OR], 1.94; 95% confidence interval [CI], 1.5 to 2.5;
P\0.001). Males were more likely to be diagnosed with
MHS by CHCT (OR, 2.33; 95% CI, 1.99 to 2.7) than
females (P\0.001). Logistic regression showed that
muscularity was indeed predictive of MHS independent of
sex. The OR for muscularity (adjusted for sex) was 2.17
(95% CI 1.21 to 3.9; P= 0.01), consistent with the
unadjusted effect of muscularity on MHS. Being male
continued to be predictive of MHS after adjustment for
muscularity (OR, 2.28; 95% CI, 1.93 to 2.7; P\0.001).
There was no significant interaction (P= 0.13) between
muscularity and sex, indicating that the effect of
muscularity on MHS did not differ appreciably between
males and females (or, equivalently, the effect of sex on
2,562 CHCT reports included for analysis
2,574 CHCT reports
Excluded for procedures prior to standardization (n=12)
2,921 CHCT reports
Excluded for unknown gender (n=12) Excluded for absent or "other" body type
(n=335)
3,024 CHCT reports in the NAMHR
Excluded for equivocal results as judged by diagnostic center director (n=103)
Figure Exclusion algorithm. CHCT = caffeine-halothane contracture test; NAMHR = North American Malignant Hyperthermia Registry
Table 1 Percent muscular build and malignant hyperthermia
susceptibility
Male Female
MHS 166/781 (21.2%) 28/511 (5.5%)
MHN 86/503 (17.1%) 20/767 (2.6%)
MHS = malignant hyperthermia susceptibility; MHN = not malignant
hyperthermia susceptible.
Muscular build and male sex are associated with MH
123
MHS did not differ appreciably between muscular and non-
muscular individuals) (Table 2).
With regard to the indication for testing, 458 of 1,091
(42%) males were tested after having a possible MH
episode compared with 338 of 1,145 (29.5%) females (P\
0.001). There was no difference in the indication for testing
between those with and without muscular build (P= 0.44).
Furthermore, the percentage of muscular probands (those
who underwent CHCT because of an episode of suspected
MH) was no different from that of muscular individuals
who underwent CHCT due to a family history of MH (P=
0.54).
Eight of 839 AMRAs, one of which was linked to a
CHCT report, and two other CHCT reports included
comments describing athletic abilities (Table 3). Four of
these individuals had known MH causative mutations in
RYR1. Two had variants of unproven significance in RYR1,
one of whom also had an RYR1 mutation known to be
causative of MH.
Discussion
In this report, the CHCT outcome diagnostic of MHS was
more strongly related to sex than to report of muscular
body build. Our observation that the odds of MHS is more
than twice as great in males than in females seems
Table 2 Logistic regression of sex, muscular body build status, and
their interaction
Parameter Odds ratio 95% Confidence
interval
Pvalue
Sex 2.28 1.93 to 2.70 \0.001
Muscular 2.17 1.21 to 3.89 0.01
Muscular by sex interaction 0.6 0.32 to 1.16 0.13
Table 3 Athletic ability and malignant hyperthermia
Evidence of athleticism
In comments
Sex Body type RYR1 finding MH Episode
Chronic issues
Previously
published in
reference #
Professional athlete Male Muscular N/A Fulminant MH 12,23
College football player Male Muscular N/A Fulminant MH 12,15,23
Multiple fractures during sports Male Muscular N/A Suspected MH 12,23
Olympic athlete Female N/A N/A Death,
Fulminant MH
12,23
College cheerleader, athletic Female Non-
muscular
p.Gly2434Arg* Death,
Fulminant MH
Larach, 2014
College level volleyball and track to
State competition; cheerleader; gymnast
reported before MH event at \25 yr of age
Female Muscular p.Arg614Cys*
& p.Thr3711Arg
Fulminant MH 6,
Larach, 2014
Regular regimen of physical activity in mixed
martial arts at \25 yr of age
Male Muscular N/A Fulminant MH Larach, 2014
Regular bicycling [20 minday
-1
3 timeswk
-1
prior to MH event at \30 yr of age
Male Muscular p.Gly2434Arg* Fulminant MH 12,23
Runs [6 milesday
-1
; bench presses 300 lb
when had CHCT at 30 yr of age
Male Muscular p.Leu4824Pro No personal MH;
Reported relative died of MH;
CCD histology;
Intolerant to heat
Sei, 2004
Long distance cyclist; semi-pro hockey
player before MH event at *40 yr of age
Male N/A p.Gly2434Arg* Suspected MH;
Postop Rhabdomyolysis,
max CK 70,000 IU;
Exercise-induced
rhabdomyolysis and weakness.
6
Reports with evidence of athleticism and sex; most include body type and some include type 1 ryanodine receptor mutation findings.
*Known MH causative mutation
Previously published in this # citation in this report or in Larach et al. Malignant hyperthermia deaths related to inadequate temperature
monitoring, 2007-2012: A report from the North American MH Registry of MHAUS. Anesth Analg 2014; 119: 1359-66 or in Sei et al. Malignant
hyperthermia in North America genetic screening of the three hot spots in the type I ryanodine receptor gene. Anesthesiology 2004; 101:824-30
CCD = central core disease; CHCT = caffeine-halothane contracture test; CK = creatine kinase; MH = malignant hyperthermia; MHAUS =
Malignant Hyperthermia Association of the United States; N/A = not available; RYR1= type 1 ryanodine receptor
B. Butala, B. Brandom
123
contradictory to the understanding of MHS as an autosomal
dominant condition. Nevertheless, observation of more
males than females with a positive CHCT was first reported
in 2007 in 1,407 patients evaluated in Sweden.
20
More
recently, a consistent parent-of-origin effect was reported
for the transmission of MHS in view of the fact that fathers
had more affected sons than daughters.
21
Malignant
hyperthermia episodes have been reported more often in
males than in females in several different types of
studies.
22-24
One might speculate that males experience
MH more often than females because of environmental
factors. In this report, more males than females presented
for a CHCT due to personal experience of an MH event.
Nevertheless, in this cohort, there were similar numbers of
males and females who underwent CHCT. Sex discrepancy
in MH warrants further study.
In the CHCT data in this study, muscular body build was
reported in a minority of individuals diagnosed as MHS by
CHCT; however, there was a significant association
between muscular body build and MHS diagnosed by
CHCT. This observation has not been made previously.
Logistic regression analysis showed that muscular body
build is predictive of MHS independent of sex. There may
be ascertainment bias, as a muscular build may be more
easily recognized in females than in males. Perhaps many
males are subjectively judged to be muscular. Assessment
of a larger population with a more objective quantitative
measurement of muscularity might yield a different result,
as our data may be biased by the subjective nature of the
reporting of body build.
The AMRA data, supplemented by a few CHCT reports,
show that, although MHS individuals may have mutations
in genes encoding proteins involved in the excitation-
contraction coupling mechanism in skeletal muscle, some
of these individuals perform athletically at high levels. The
possibility that an MHS person can be a skilled athlete
widens the phenotypic variability of RYR1 mutations.
Myopathies related to the RYR1 gene, such as King-
Denborough syndrome and central core disease, are not the
only clinical presentations of MHS in daily life.
The nature of the data acquisition in this study may
produce significant bias. Selection bias is present as all
reports were submitted voluntarily, and it may be that only
the most severe or memorable cases were reported. Specific
questions to elicit reporting of athletic accomplishment
were recently added (2015) to reports. Testing for
mutations in RYR1 in MHS individuals was experimental
until 2005. Also, CHCT is expensive and inconvenient to
perform. Patients must travel to only a few available testing
centres for muscle biopsy and contracture testing. As a
result, our data underrepresent those of lower
socioeconomic status. It must be emphasized that all
CHCT investigations are done on individuals with an
indication, which makes it difficult to apply our results to
patients without such medical history.
Conclusion
We report a strong association between muscularity and
MHS. Males were more likely to be diagnosed with MHS
by muscle contracture testing. Optimistically, as the
biology of MH continues to be investigated, the causes of
these findingswill be elucidated.
Acknowledgments We acknowledge the support of the not-for-profit
Malignant Hyperthermia Association of the United States, the
Departments of Anesthesiology and Nurse Anesthesia in the
University of Pittsburgh, and the North American Malignant
Hyperthermia Registry of MHAUS —without the accumulated data,
this report would not have been possible.
Conflicts of interest The authors have no conflict of interest to
report.
Editorial responsibility This submission was handled by Dr. Philip
M. Jones, Associate Editor, Canadian Journal of Anesthesia.
Author contributions Brian Butala and Barbara Brandom
contributed substantially to all aspects of this manuscript, including
conception and design; acquisition, analysis, and interpretation of
data; and drafting the article.
Sources of funding We recognize financial support from the North
American Malignant Hyperthermia Registry and the Malignant
Hyperthermia Association of the United States as well as
administrative support from the Departments of Anesthesiology and
Nurse Anesthesia in the University of Pittsburgh.
References
1. Gronert GA. Malignant hyperthermia. Anesthesiology 1980; 53:
395-423.
2. Louis CF,Zualkernan K,Roghair T,Mickelson JR. The effects of
volatile anesthetics on calcium regulation by malignant
hyperthermia-susceptible sarcoplasmic reticulum. Anesthesiology
1992; 77: 114-25.
3. Capacchione JF,Muldoon SM. The relationship between
exertional heat illness, exertional rhabdomyolysis, and
malignant hyperthermia. Anesth Analg 2009; 109: 1065-9.
4. Brandom BW,Muldoon SM. Unexpected MH deaths without
exposure to inhalation anesthetics in pediatric patients. Pediatr
Anesth 2013; 23: 851-4.
5. Denborough MA. Heat stroke and malignant hyperpyrexia. Med J
Aust 1982; 6: 204-5.
6. Brandom BW,Bina S,Wong CA,et al. Ryanodine receptor type 1
gene variants in the malignant hyperthermia-susceptible
population of the United States. Anesth Analg 2013; 116:
1078-86.
7. Carpenter D,Ringrose C,Leo V,et al. The role of CACNA1S in
predisposition to malignant hyperthermia. BMC Med Genet
2009. DOI:10.1186/1471-2350-10-104.
8. Gonslaves SG,Ng D,Johnston JJ,et al. Using exome data to
identify malignant hyperthermia susceptibility mutations.
Anesthesiology 2013; 119: 1043-53.
Muscular build and male sex are associated with MH
123
9. Horstick EJ,Linsley JW,Dowling JJ,et al. Stac3 is a component
of the excitation-contraction coupling machinery and mutated in
Native American myopathy. Nat Commun 2013; 4: 1952.
10. European Malignant Hyperthermia Group. Genetics in
Malignant Hyperthermia. European Malignant Hyperthermia
Group; 2011; Available from URL: https://emhg.org/genetics/
mutations-in-ryr1/ (accessed November 2016).
11. Allen GC,Larach MG,Kunselman AR. The sensitivity and
specificity of the caffeine-halothane contracture test: a report
from the North American Malignant Hyperthermia Registry of
MHAUS. Anesthesiology 1998; 88: 579-88.
12. Larach MG,Brandom BW,Allen GC,Gronert GA,Lehman EB.
Cardiac arrests and deaths associated with malignant
hyperthermia in North America from 1987 to 2006: a report
from the North American Malignant Hyperthermia Registry of
the Malignant Hyperthermia Association of the United States.
Anesthesiology 2008; 108: 603-11.
13. Burkman JM,Posner KL,Domino KB. Analysis of the clinical
variables associated with recrudescence after malignant
hyperthermia reactions. Anesthesiology 2007; 106: 901-6.
14. Kasi PM. Malignant hyperthermia and idiopathic HyperCKemia.
Case Rep Med 2011. DOI:10.1155/2011/194296.
15. Uskova AA,Matusic BP,Brandom BW. Desflurane, malignant
hyperthermia and release of compartment syndrome. Anesth
Analg 2005; 100: 1357-60.
16. Ogletree JW,Antognini JF,Gronert GA. Postexercise muscle
cramping associated with positive malignant hyperthermia
contracture testing. Am J Sports Med 1996; 24: 49-51.
17. Tobin JR,Jason DR,Challa VR,Nelson TE,Sambuughin N.
Malignant hyperthermia and apparent heat stroke. JAMA 2001;
286: 1168-9.
18. Ording H. Epidemiology of malignant hyperthermia. In: Schulte
am Esch J, Scholz J, Wappier F (Eds). Malignant Hyperthermia.
Pabst Science Publishers; 2000: 26-7.
19. Larach MG. Standardization of the caffeine halothane muscle
contracture test. North American Malignant Hyperthermia Group.
Anesth Analg 1989; 69: 511-5.
20. Islander G,Rydenfelt K,Ranklev E,Bodelsson M. Male
preponderance of patients testing positive for malignant
hyperthermia susceptibility. Acta Anaesthesiol Scand 2007; 51:
614-20.
21. Robinson RL,Carpenter D,Halsall PJ,et al. Epigenetic allele
silencing and variable penetrance of malignant hyperthermia
susceptibility. Br J Anaesth 2009; 103: 220-5.
22. Brady J,Sun L,Rosenberg H,Li G. Prevalence of malignant
hyperthermia due to anesthesia in New York State, 2001-2005.
Anesth Analg 2009; 109: 1162-6.
23. Larach MG,Gronert GA,Allen GC,Brandom BW,Lehman EB.
Clinical presentation, treatment, and complications of malignant
hyperthermia in North America from 1987 to 2006. Anesth Analg
2010; 110: 498-507.
24. Sumitani M,Uchida K,Yasunaga H,et al. Prevalence of
malignant hyperthermia and relationship with anesthetics in
Japan: data from the diagnosis procedure combination database.
Anesthesiology 2011; 114: 84-90.
B. Butala, B. Brandom
123
... While many children experienced life-threatening responses to heat, adults with similar RYR1 mutations generally experienced only muscle cramps or exercise intolerance (Supplementary Datas 1 and 2). Similar to previously reported findings for anesthetic-induced MH cases 41,42 , the proportion of heatsensitive patients observed in male carriers of RYR1 variants was significantly higher compared to that of the female carriers (Fig. 1b, c). Analysis for the pathogenicity of the heat-sensitivity associated variants in RYR1 using the HumDiv-trained PolyPhen model 43 confirmed that most of the variants are predicted to be deleterious (Fig. 1d). ...
... MHS has also been associated with a muscular phenotype in human males 41 . While we did not detect significance differences in body weight, lean mass, metabolic rate, energy preference, and activity between YS and WT mice at basal condition, we found a small but significant decrease in overall fat mass in the YS mice, despite increased food consumption (Supplementary Fig. 3). ...
Article
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Mutations in the skeletal muscle Ca 2+ release channel, the type 1 ryanodine receptor (RYR1), cause malignant hyperthermia susceptibility (MHS) and a life-threatening sensitivity to heat, which is most severe in children. Mice with an MHS-associated mutation in Ryr1 (Y524S, YS) display lethal muscle contractures in response to heat. Here we show that the heat response in the YS mice is exacerbated by brown fat adaptive thermogenesis. In addition, the YS mice have more brown adipose tissue thermogenic capacity than their littermate controls. Blood lactate levels are elevated in both heat-sensitive MHS patients with RYR1 mutations and YS mice due to Ca 2+ driven increases in muscle metabolism. Lactate increases brown adipo-genesis in both mouse and human brown preadipocytes. This study suggests that simple lifestyle modifications such as avoiding extreme temperatures and maintaining thermo-neutrality could decrease the risk of life-threatening responses to heat and exercise in individuals with RYR1 pathogenic variants.
... 69%-79% in four retrospective studies ( Table 2); interestingly, male predominance is also a feature observed in MH reactions [19,20]. In addition, muscular individuals have been shown to have a 13.6-fold increased risk of death during MH events [21,22]. The observation that MH reactions occur more than twice as much in males compared to females seems contradictory to the understanding that MH susceptibility has an autosomal dominant inheritance pattern, possibly reflecting hormonal or other sex-dependent variables (Box 2). ...
Article
Variants in the ryanodine receptor-1 gene (RYR1) have been associated with a wide range of neuromuscular conditions, including various congenital myopathies and malignant hyperthermia (MH). More recently, a number of RYR1 variants, mostly MH-associated, have been demonstrated to contribute to rhabdomyolysis events not directly related to anesthesia in otherwise healthy individuals. This review focuses on RYR1-related rhabdomyolysis, in the context of several clinical presentations (i.e., exertional rhabdomyolysis, exertional heat illnesses and MH), and conditions involving a similar hypermetabolic state, in which RYR1 variants may be present (i.e., neuroleptic malignant syndrome and serotonin syndrome). The variety of triggers that can evoke rhabdomyolysis, on their own or in combination, as well as the number of potentially associated complications, illustrates that this is a condition relevant to several medical disciplines. External triggers include but are not limited to strenuous physical exercise, especially if unaccustomed or performed under challenging environmental conditions (e.g., high ambient temperature or humidity), alcohol/illicit drugs, prescription medication (in particular statins, other anti-lipid agents, antipsychotics and antidepressants) infection, or heat. Amongst all patients presenting with rhabdomyolysis, a genetic susceptibility is present in a proportion, with RYR1 being one of the most common genetic causes. Clinical clues for a genetic susceptibility include recurrent rhabdomyolysis, creatine kinase (CK) levels above 50 times the upper limit of normal, hyperCKemia lasting for 8 weeks or longer, drug/medication doses insufficient to explain the rhabdomyolysis event, and a positive family history. For the treatment or prevention of RYR1-related rhabdomyolysis, the RYR1 antagonist dantrolene can be administered, both in the acute phase, or prophylactically in patients with a history of muscle cramps and/or recurrent rhabdomyolysis events. Aside from dantrolene, several other drugs are being investigated for their potential therapeutic use in RYR1-related disorders. These findings offer further therapeutic perspectives for humans, suggesting an important area for future research.
... 99 An interesting study reported, as preliminary observation, that an increase in muscular mass could be associated with MH-susceptibility. 100 Considering that some individuals with RyR1 variants have enhanced muscle mass and good athletic skills, it would be important to define how to deal with the specific needs of these people, especially concerning physical exercises or sporting activities. ...
Article
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INTRODUCTIONː Calcium release through ryanodine receptor type 1 (RyR1) channel triggers skeletal muscle contraction, which is finely regulated during physical activity allowing muscles to adapt to stress. However, both prolonged physical activity and inactivity decrease contractile function. The adaptive mechanisms are related to changes in structure, function, and expression of RyR1 channel. EVIDENCE ACQUISITIONː The research on the effects of physical activities on RyR1 structure and function covered PubMed and Scopus databases from 2008 onward. The search term used was RyR1 combined with exercise, fatigue, exertional rhabdomyolysis, or aging. EVIDENCE SYNTHESISː Physical activity induces RyR1 dynamic post-translational modifications, driven essentially by increased reactive oxygen and nitrogen species. RyR1 redox-dependent modifications increase channel activity, but impaired Ca2+ handling may lead to muscle fatigue. Furthermore, imbalance of redox equilibrium may induce RyR1 fragmentation. During exercise RyR1 is also hyperphosphorylated and dissociated from its stabilizing subunit calastabin1, resulting in ‘‘leaky’’ channels and decreased exercise tolerance. RyR1 modifications also occur during aging. Conversely, reduced RyR1 protein expression occurs in some physiopathological conditions characterized by low-exercise capacity, i.e., heart failure and prolonged bed rest. Impaired muscle performance is also linked to RyR1 mutations, with altered channel structure and/or function. Moreover, in apparently healthy subjects with RyR1 mutations, physical exercise can trigger skeletal muscle stiffness at low temperatures, or exertional rhabdomyolysis. CONCLUSIONSː We provide an overview of the molecular aspects linking skeletal muscle activity to RyR1 modifications, with particular attention to the effects produced by different type of exercises, i.e. aerobic and anaerobic exercise, by some pathophysiological conditions, by age-related loss of muscle function and by RyR1 mutations. Key words: Physical activity - RyR1 - ROS/RNS - Post-translation modifications - Expression
... Another study of 1 238 171 patients undergoing general anesthesia and showed a prevalence of 1.37 per 100 000, and the fatality rate was 6% [14] . The prevalence of MH was more than doubled in male patients than in female patients [11,13,[15][16][17] . It was reported that the muscular body build in males is likely to develop MH [16] . ...
Article
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Malignant hyperthermia (MH) is a rare and life-threatening pharmacogenetic disorder triggered by volatile anesthetics, the depolarizing muscle relaxant succinylcholine, and rarely by strenuous exercise or environmental heat. The exact prevalence of MH is unknown, and it varies from 1:16 000 in Denmark to 1:100 000 in New York State. The underlying mechanism of MH is excessive calcium release from the sarcoplasmic reticulum (SR), leading to uncontrolled skeletal muscle hyper-metabolism. Genetic mutations in ryanodine receptor type 1 ( RYR1) and CACNA1S have been identified in approximately 50% to 86% and 1% of MH-susceptible (MHS) individuals, respectively. Classic clinical symptoms of MH include hypercarbia, sinus tachycardia, masseter spasm, hyperthermia, acidosis, muscle rigidity, hyperkalemia, myoglobinuria, and etc. There are two types of testing for MH: a genetic test and a contracture test. Contracture testing is still being considered as the gold standard for MH diagnosis. Dantrolene is the only available drug approved for the treatment of MH through suppressing the calcium release from SR. Since clinical symptoms of MH are highly variable, it can be difficult to establish a diagnosis of MH. Nevertheless, prompt diagnosis and treatments are crucial to avoid a fatal outcome. Therefore, it is very important for anesthesiologists to raise awareness and understand the characteristics of MH. This review summarizes epidemiology, clinical symptoms, diagnosis and treatments of MH and any new developments.
... 37 Recently, male sex and body build subjectively assessed as muscular have been reported as independent predictors of MH susceptibility. 39 However, whether a larger muscle mass is associated with MH sex discrepancy warrants objective assessment. On the whole, the pathomechanism leading to sex differences in the penetrance of MH is still unknown, but epigenetic RYR1 allele silencing has been ruled out as a cause of reduced penetrance of MH susceptibility in females. ...
Article
What we already know about this topic: Malignant hyperthermia is a rare life-threatening disorder triggered in genetically predisposed individuals by exposure to certain anestheticsThe ryanodine receptor 1 (RYR1) gene, which encodes the Ca2+ release channel of skeletal muscle sarcoplasmic reticulum, is the major malignant hyperthermia-associated locusMalignant hyperthermia diagnostic mutations are more prevalent than the reported incidence of clinical malignant hyperthermia episodes because many mutation carriers are never exposed to anesthetic triggers and some may have several uneventful anesthetics before developing malignant hyperthermia reaction WHAT THIS ARTICLE TELLS US THAT IS NEW: In a multicenter case-control study of 229 genotype-positive subjects with previous recorded exposure to trigger anesthetics, there were 93 malignant hyperthermia cases, for an overall penetrance for the analyzed RYR1 mutations of 40.6%The probability of developing malignant hyperthermia on exposureto triggers was 0.25 among all RYR1 mutation carriers and 0.76 in survivors of malignant hyperthermia reactions (95% CI of the difference 0.41 to 0.59)Young age, male sex, and the use of succinylcholine were major nongenetic risk factors influencing expression of the RYR1 mutations conferring malignant hyperthermia susceptibility BACKGROUND:: Malignant hyperthermia (MH) is a potentially lethal disorder triggered by certain anesthetics. Mutations in the ryanodine receptor 1 (RYR1) gene account for about half of MH cases. Discordance between the low incidence of MH and a high prevalence of mutations has been attributed to incomplete penetrance, which has not been quantified yet. The authors aimed to examine penetrance of MH-diagnostic RYR1 mutations and the likelihood of mutation carriers to develop MH, and to identify factors affecting severity of MH clinical expression. Methods: In this multicenter case-control study, data from 125 MH pedigrees between 1994 and 2017 were collected from four European registries and one Canadian registry. Probands (survivors of MH reaction) and their relatives with at least one exposure to anesthetic triggers, carrying one diagnostic RYR1 mutation, were included. Penetrance (percentage of probands among all genotype-positive) and the probability of a mutation carrier to develop MH were obtained. MH onset time and Clinical Grading Scale score were used to assess MH reaction severity. Results: The overall penetrance of nine RYR1 diagnostic mutations was 40.6% (93 of 229), without statistical differences among mutations. Likelihood to develop MH on exposure to triggers was 0.25 among all RYR1 mutation carriers, and 0.76 in probands (95% CI of the difference 0.41 to 0.59). Penetrance in males was significantly higher than in females (50% [62 of 124] vs. 29.7% [30 of 101]; P = 0.002). Males had increased odds of developing MH (odds ratio, 2.37; 95% CI, 1.36 to 4.12) despite similar levels of exposure to trigger anesthetics. Proband's median age was 12 yr (interquartile range 6 to 32.5). Conclusions: Nine MH-diagnostic RYR1 mutations have sex-dependent incomplete penetrance, whereas MH clinical expression is influenced by patient's age and the type of anesthetic. Our quantitative evaluation of MH penetrance reinforces the notion that a previous uneventful anesthetic does not preclude the possibility of developing MH.
... [5][6][7] The awake episodes are rare, and present with non-specific symptoms ranging from hyperthermia, muscle cramps, exertional pain, and rhabdomyolysis to a lifethreatening hypermetabolic reaction in physically fit and seemingly healthy individuals often without a personal or family history of MH, which makes the diagnosis challenging. [7][8][9][10] We report two fatal cases of awake MH episodes in one extended family with a strong history of anesthetic-induced MH episodes and deaths demonstrating the close connection between anesthesia-induced MH and awake MH episodes. This report is intended to raise awareness among patients and medical personnel (anesthesiologists, emergency department [ED], intensive care physicians, and nurses) to the possibility of life-threatening MH episodes that may develop in MHS individuals in the absence of general anesthesia. ...
Article
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Purpose The present report of two fatal awake malignant hyperthermia (MH) episodes in an MH susceptible (MHS) family is intended to raise awareness among medical personnel and MHS individuals to the possibility of life-threatening non-anesthesia-triggered MH episodes and to provide a strong incentive for development of effective preventive measures. Clinical features Two young athletic males (28 and 16 yr old), members of the same extended family with a history of anesthesia-related MH episodes and deaths, succumbed ten years apart on two different continents, with symptoms unrelated to anesthesia but strikingly similar to typical anesthetic-induced MH. Both suffered an abrupt surge in body temperature, tachycardia, tachypnea, muscle rigidity, hyperkalemia, and respiratory and metabolic acidosis. Despite aggressive resuscitation attempts, both developed cardiac arrest and died shortly upon arrival to hospital emergency departments. Autopsy analyses were negative for drugs, alcohol, or bacterial infection. Individual and familial genetic analyses revealed a novel, potentially pathogenic RYR1 variant (p.Gly159Arg) that co-segregates with the MHS phenotype in the family. Both fatal awake MH episodes are hypothesized to have been triggered by physical exertion compounded with a febrile illness that in one case was due to influenza type A. Conclusions Life-threatening awake MH episodes may develop in some MHS individuals in the absence of anesthetic triggers. Potential triggers can be physical exertion in combination with a febrile illness. Malignant hyperthermia susceptible patients are recommended to be vaccinated against flu and restrict physical activities when febrile, wear an MH alert bracelet, and inform medical personnel of their MH history. Oral dantrolene is suggested to be available to MHS patients for administration with the early signs of awake MH.
... It has long been known that elite athletes appear to be at a greater risk for severe malignant hyperthermia episodes. Indeed, a recent study demonstrated that male sex and muscular body build are both independently predictive of malignant hyperthermia susceptibility [44]. ...
Article
Purpose of review: We will give an overview of neuromuscular disorders that can be linked with malignant hyperthermia or malignant hyperthermia-like reactions, and suggest an appropriate approach to interpret the risks. Recent findings: An increasing number of neuromuscular phenotypes have been linked to malignant hyperthermia susceptibility (MHS). This is for an important part due to the highly variable phenotype associated with mutations in the ryanodine receptor 1 gene (RYR1), the gene most frequently associated with MHS. A RYR1-mutation or a clinical RYR1-phenotype does not automatically translate in MHS, but precautions should be taken nonetheless. In addition, several other genes and phenotypes are now considered to be associated with MHS. In contrast, several neuromuscular diseases that were long thought to be linked to MHS are now known to cause malignant hyperthermia-like reactions instead of malignant hyperthermia. This is highly relevant as not only the given preoperative advice differs, but also acute treatment. Summary: This review provides a summary of current evidence linking certain neuromuscular diseases to malignant hyperthermia or malignant hyperthermia-like reactions. We provide a guide for the clinician, to determine which patients are at risk of malignant hyperthermia or malignant hyperthermia-like reactions perioperatively, and to ensure adequate treatment in case such a severe acute complication occurs.
Article
Introduction Many drugs are known to induce malignant syndromes. The most common malignant syndromes are induced by the use of antipsychotics and anesthetics and the withdrawal of anti-Parkinson drugs. As the clinical manifestations of antipsychotic malignant syndrome, Parkinson’s disease hyperpyrexia syndrome and anesthetic-induced malignant syndrome are very similar, they are easily confused in the clinic. Areas covered We reviewed articles published between 1960 and April 2021 describing malignant syndromes. This paper provides a detailed literature review of malignant syndromes and important guidance for the diagnosis and treatment of malignant syndromes to clinicians. Expert opinion Although malignant syndromes are rare conditions with a low incidence, these conditions usually progress rapidly and can endanger patients’ lives, meriting attention from clinicians. The typical clinical manifestations of malignant syndromes are hyperpyrexia, muscular rigidity, an altered mental status and increased levels of creatine kinase; however, the pathophysiology, treatment and prognosis of different malignant syndromes are quite different. Prompt diagnosis and treatment may significantly improve the prognosis of patients with malignant syndromes.
Sex (a biological determination) and gender (a social construct) are not interchangeable terms and both impact perioperative management and patient safety. Sex and gender differences in clinical phenotypes of chronic illnesses and risk factors for perioperative morbidity and mortality are relevant for preoperative evaluation and optimization. Sex-related differences in physiology, as well as in pharmacokinetics and pharmacodynamics of anesthetic drugs may influence the anesthesia plan, the management of pain, postoperative recovery, adverse effects, patient satisfaction and outcomes. Further studies are needed to characterize outcome differences between men and women in non-cardiac, cardiac and transplantation surgery in order to individualize perioperative management and improve patient safety. Transgender patients represent a vulnerable population who needs special perioperative care. Gender balance increases team performance and may improve perioperative outcomes.
Article
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Malignant hyperthermia susceptibility (MHS) is a life-threatening, inherited disorder of muscle calcium metabolism, triggered by anesthetics and depolarizing muscle relaxants. An unselected cohort was screened for MHS mutations using exome sequencing. The aim of this study was to pilot a strategy for the RYR1 and CACNA1S genes. Exome sequencing was performed on 870 volunteers not ascertained for MHS. Variants in RYR1 and CACNA1S were annotated using an algorithm that filtered results based on mutation type, frequency, and information in mutation databases. Variants were scored on a six-point pathogenicity scale. Medical histories and pedigrees were reviewed for malignant hyperthermia and related disorders. The authors identified 70 RYR1 and 53 CACNA1S variants among 870 exomes. Sixty-three RYR1 and 41 CACNA1S variants passed the quality and frequency metrics but the authors excluded synonymous variants. In RYR1, the authors identified 65 missense mutations, one nonsense, two that affected splicing, and one non-frameshift indel. In CACNA1S, 48 missense, one frameshift deletion, one splicing, and one non-frameshift indel were identified. RYR1 variants predicted to be pathogenic for MHS were found in three participants without medical or family histories of MHS. Numerous variants, previously described as pathogenic in mutation databases, were reclassified by the authors as being of unknown pathogenicity. Exome sequencing can identify asymptomatic patients at risk for MHS, although the interpretation of exome variants can be challenging. The use of exome sequencing in unselected cohorts is an important tool to understand the prevalence and penetrance of MHS, a critical challenge for the field.
Article
BACKGROUND: Malignant hyperthermia susceptibility (MHS) is a life-threatening, inherited disorder of muscle calcium metabolism, triggered by anesthetics and depolarizing muscle relaxants. An unselected cohort was screened for MHS mutations using exome sequencing. The aim of this study was to pilot a strategy for the RYR1 and CACNA1S genes. METHODS: Exome sequencing was performed on 870 volunteers not ascertained for MHS. Variants in RYR1 and CACNA1S were annotated using an algorithm that filtered results based on mutation type, frequency, and information in mutation databases. Variants were scored on a six-point pathogenicity scale. Medical histories and pedigrees were reviewed for malignant hyperthermia and related disorders. RESULTS: The authors identified 70 RYR1 and 53 CACNA1S variants among 870 exomes. Sixty-three RYR1 and 41 CACNA1S variants passed the quality and frequency metrics but the authors excluded synonymous variants. In RYR1, the authors identified 65 missense mutations, one nonsense, two that affected splicing, and one non-frameshift indel. In CACNA1S, 48 missense, one frameshift deletion, one splicing, and one non-frameshift indel were identified. RYR1 variants predicted to be pathogenic for MHS were found in three participants without medical or family histories of MHS. Numerous variants, previously described as pathogenic in mutation databases, were reclassified by the authors as being of unknown pathogenicity. CONCLUSIONS: Exome sequencing can identify asymptomatic patients at risk for MHS, although the interpretation of exome variants can be challenging. The use of exome sequencing in unselected cohorts is an important tool to understand the prevalence and penetrance of MHS, a critical challenge for the field. Comment in Exome sequencing: one small step for malignant hyperthermia, one giant step for our specialty--why exome sequencing matters to all of us, not just the experts. [Anesthesiology. 2013]
Article
Background: Gaps in our understanding of genetic susceptibility to malignant hyperthermia (MH) limit the application and interpretation of genetic diagnosis of the condition. Our aim was to define the prevalence and role of variants in the three genes implicated in MH susceptibility in the largest comprehensively phenotyped MH cohort worldwide. Methods: We initially included one individual from each positive family tested in the UK MH Unit since 1971 to detect variants in RYR1, CACNA1S, or STAC3. Screening for genetic variants has been ongoing since 1991 and has involved a range of techniques, most recently next generation sequencing. We assessed the pathogenicity of variants using standard guidelines, including family segregation studies. The prevalence of recurrent variants of unknown significance was compared with the prevalence reported in a large database of sequence variants in low-risk populations. Results: We have confirmed MH susceptibility in 795 independent families, for 722 of which we have a DNA sample. Potentially pathogenic variants were found in 555 families, with 25 RYR1 and one CACNA1S variants previously unclassified recurrent variants significantly over-represented (P<1×10-7) in our cohort compared with the Exome Aggregation Consortium database. There was genotype-phenotype discordance in 86 of 328 families suitable for segregation analysis. We estimate non-RYR1/CACNA1S/STAC3 susceptibility occurs in 14-23% of MH families. Conclusions: Our data provide current estimates of the role of variants in RYR1, CACNA1S, and STAC3 in susceptibility to MH in a predominantly white European population.
Article
We describe a case of suspected malignant hyperthermia in a healthy 20-yr-old man. The patient underwent urgent release of upper extremity compartment syndrome as a result of traumatic vascular injury. After 3 h of general anesthesia with desflurane, he developed a hypermetabolic state (hypercarbia, hyperthermia, hyperkalemia, and metabolic acidosis), consistent with the diagnosis of malignant hyperthermia. Cardiovascular instability coincided with reperfusion of the injured extremity. Treatment with dantrolene and supporting measures restored cardiovascular stability. Three days later he underwent a successful second surgery under regional block with total IV anesthesia.
Conference Paper
Background: The caffeine-halothane contracture test (CHCT) is the only recognized laboratory test to diagnose malignant hyperthermia (MH). The authors report the results of their analysis of pooled data from the North American Malignant Hyperthermia Registry database to determine the sensitivity and specificity of the CHCT. Methods: The MH CLinical Grading Scale was used to identify 32 case subjects who mere "almost certain" to be MN susceptible based on clinical criteria alone. Their CHCT results were compared with those of a group of 120 control subjects considered to be at low risk for MH, Diagnostic thresholds of the CHCT were adjusted, and its component tests were combined to generate receiver operating characteristic curves. The maximal Youden index for each component test was chosen as the diagnostic threshold indicative of MH susceptibility. Results: The highest sensitivity (97%; 95% CI, 84-100%) was achieved with a two-component test with thresholds of greater than or equal to 0.5 g contracture for 3% halothane, greater than or equal to 0.3 g contracture at 2 mar caffeine, or both, considered positive for MH. The test specificity was 78% (95% CI, 69-85%). The addition of other CHCT component tests did not improve CHCT sensitivity or specificity. Conclusion: The CHCT achieves high sensitivity and acceptable specificity as a clinical laboratory diagnostic test when it is performed according to published standards, However, it cannot be used as a screening test because of the low prevalence of MH in the general population.
Article
To the Editor: Malignant hyperthermia (MH) is an autosomal dominant condition in which certain anesthetics trigger calcium dysregulation in skeletal muscle, resulting in a catastrophic, life-threatening hypermetabolic syndrome.1 More than 50% of families with MH have mutations in the gene encoding the ryanodine receptor (RYR1).2 In a porcine model of MH, nonanesthetic, stress-induced deaths have been reported in pigs homozygous for the Arg614Cys mutation in the RYR1 gene,3 but this phenomenon has not been reported in humans with MH mutations. To our knowledge, we report the first case of nonanesthetic, stress-induced hyperpyrexic death in an individual with a history of MH.
Article
Children, later found to have ryanodine receptor type one variants (RYR1), died without exposure to inhalation anesthetics. Family members with the same RYR1 variants had contracture tests consistent with susceptibility to malignant hyperthermia or in vitro testing showed increased sensitivity to RYR1 agonist.