Malignant hyperthermia susceptibility in patients with exertional rhabdomyolysis: a retrospective cohort study and updated systematic review.
BACKGROUND
Two potentially fatal syndromes, malignant hyperthermia (MH), an adverse reaction to general anesthesia, and exertional rhabdomyolysis (ER) share some clinical features, including hyperthermia, muscle rigidity, tachycardia, and elevated serum creatine kinase. Some patients with ER have experienced an MH event and/or have been diagnosed as MH susceptible (MHS). In order to assess the relationship between ER and MH further, we conducted a retrospective cohort study summarizing clinical and genetic information on Canadian patients with ER who were diagnosed as MHS. In addition, a systematic literature review was performed to compile further evidence on MH susceptibility and RYR1 and CACNA1S variants associated with rhabdomyolysis.


METHODS
Demographic, clinical, and genetic information was collected on Canadian MHS patients who presented with rhabdomyolysis. In addition, we performed a systematic review of the literature published during 1995-2016 on genetic screening of the RYR1 and CACNA1S genes in patients with ER.


RESULTS
Retrospective data on Canadian MHS patients with ER showed that ten out of 17 patients carried RYR1 or CACNA1S variants that were either known MH-causative mutations or potentially pathogenic variants. The systematic review revealed 39 different rare RYR1 variants, including 13 MH-causative/associated mutations and five rare potentially deleterious CACNA1S variants in 78% of patients with ER.


CONCLUSIONS
Findings from the Canadian patient cohort and the systematic review all signal a potential association between MH susceptibility and ER. The presence of MH-causative mutations and putative deleterious RYR1 variants in ER patients without a history of adverse anesthetic reactions suggests their possible increased risk for MH.
Malignant Hyperthermia Investigation Unit, Toronto General Hospital, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada.
Natalia
N
Kraeva
Malignant Hyperthermia Investigation Unit, Toronto General Hospital, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada.
Alexander
A
Sapa
Division of Neurology, Genetics and Genome Biology Program, Hospital for Sick Children, Departments of Paediatrics and Molecular Genetics, University of Toronto, Toronto, ON, Canada.
James J
JJ
Dowling
Malignant Hyperthermia Investigation Unit, Toronto General Hospital, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada. sheila.riazi@uhn.ca.
Sheila
S
Riazi
D015220:Calcium Channels / Q000235:genetics*; D020746:Calcium Channels, L-Type; D002170:Canada; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000453:epidemiology* / Q000235:genetics / Q000503:physiopathology; D009154:Mutation; D005082:Physical Exertion; D012189:Retrospective Studies; D012206:Rhabdomyolysis / Q000453:epidemiology* / Q000235:genetics / Q000503:physiopathology; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*
C412223:CACNA1S protein, human; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel