Anesthesiology & Pain Medicine >> Research >> Focus Areas >> Mitochondrial Biology & Genomics >> ITHS KL2 Translational Research Career Development Program
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Research Focus Areas:
Mitochondrial Biology & Genomics

ITHS KL2 Translational Research Career Development Program

Principal Investigators

J.H. Kim, M.D.

Description

This research plan proposes to use next-generation genetic sequencing technology to answer a decades-old question of great significance to anesthesiologists: what are the genetic determinants of malignant hyperthermia (MH)? Specifically, what genes are involved in the 75% of cases not attributable to ryanodine receptor 1 (RYR1) mutations? MH is an autosomal dominant disorder of muscle metabolism, affecting 1 out of every 3,000 to 30,000 people. Outward signs manifest only after certain medications are given to susceptible individuals, or rarely when they are exposed to extreme levels of heat and stress. When given succinylcholine or inhaled halogenated hydrocarbons, which are commonly used anesthetics, a striking constellation of signs and symptoms may be seen, including hypercarbia, hyperthermia, and muscle contraction, with potential progression to rhabdomyolysis, acidosis, and renal failure. Without recognition and treatment, mortality can be as high as 70%. In about 25% of cases, the suspected causal genetic variant occurs in RYR1 on chromosome 19q13.1. The mutant receptor has been shown in the laboratory to allow unregulated calcium efflux from the sarcoplasmic reticulum into the myocyte, which results in a state of continuous contraction, ATP depletion, release of potassium and creatinine kinase, and finally loss of cell membrane integrity.

The gold standard diagnostic test for those who have either had a suspected episode or know a family member who has had one is the in vitro contracture test (IVCT), an expensive and cumbersome test. In the US, IVCT has high sensitivity (97%), but lower specificity (78%) while requiring an invasive surgical procedure to obtain a biopsy of several grams of muscle tissue. Furthermore, the muscle must immediately be tested for abnormal contracture under standard conditions at 1 of only 6 centers in North America. An attractive alternative is a genetic test, but known RYR1 mutations account for only 25% of confirmed MH. Of the 75% that are negative, about half are estimated to have variants in other loci of the ryanodine receptor gene family and the other half are unknown. A future genetic test panel offers the potential for low-cost screening for individuals with and without a family history. Further, elucidating the etiology of MH may lead to development of safer anesthetic agents.

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