Novel Interventions for Heat/Exercise Induced Sudden Death and Fatigue
Abstract
Our goal is to identify ryanodine receptor type 1 (RYR1), calcium channel, voltage-dependent, L type, alpha 1S subunit (CACNA1S), and calsequestrin 1 (CASQ1) gene mutations associated with enhanced susceptibility to Exertional Heat Stroke (EHS), Exertional Rhabdomyolysis (ER), and Malignant Hyperthermia (MH) by enrolling subjects diagnosed with these conditions and performing genetic screening. During the project period, 8 additional subjects were enrolled, bringing the total to 45: 32 index cases and 13 family members from 3 of the index cases. Of the 32 index cases, 7 subjects have known MH-causative RYR1 gene mutations (Arg163Cys, Gly2434Arg, Arg2454Cys, Arg2163His, and Ala2350Thr), 2 have known MH-associated RYR1 variants, 3 have novel RYR1 variants, 14 have no RYR1 mutations or variants, and 2 are still in progress. One subject had a known MH-causative mutation and a novel variant. Of the 13 family members screened from 3 index cases, 7 family members were found to share the same known MH-causative RYR1 gene mutation. Of the known MH-causative mutations, the Arg2454Cys was identified in an African American with a positive CHCT and a history of ER. Identification of this mutation in a subject with ER strengthens the link between MHS and ER. Although we have not yet found an AICAR derivative that prevents the hypermetabolic response in mice, we have recently explored the use of other drugs that can reduce RyR1 leak. One such drug is rapamycin. We have shown that rapamycin reduces the probability of a hypermetabolic response in YS mice.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2013
- Accession Number
- ADA592166
Entities
People
- John Capacchione
- Susan L. Hamilton
Organizations
- Baylor College of Medicine