Exertional heat illness (EHI) is a clinically important disorder, notifiable in military personnel, and is characterised by an inability to thermoregulate. Research investigating the genetic risk factors contributing to this potentially fatal condition is limited and the pathophysiology of EHI remains poorly understood. EHI shares a similar clinical manifestation to malignant hyperthermia (MH), a pharmacogenetic disorder associated with calcium dysregulation in skeletal muscle. Interestingly, 34% of the EHI patients in this study developed muscle contractures during an in vitro contracture test (IVCT), the gold-standard diagnostic test for MH susceptibility.
The coding regions of fifty genes relating to calcium homeostasis and energy metabolism were sequenced in sixty-four EHI patients using a next-generation sequencing (NGS) approach. Many of these genes have been previously implicated in MH, congenital myopathies and metabolic disorders. Seventy-nine rare (minor allele frequency ≤1%) and potentially pathogenic (CADD-score ≥15) non-synonymous variants were identified across twenty-four genes, potentially conferring susceptibility to EHI. Around 75% of MH susceptible individuals in the UK carry a diagnostic ryanodine receptor type-1 (RYR1) variant. Uncharacterised RYR1 variants were identified in 38% of EHI patients in this study, 16% of which were annotated as rare and potentially pathogenic.
Global gene expression profiles were examined in a heterozygous RyR1 R163C mutant mouse model associated with EHI and MH to investigate the acute heat stress response. These mice demonstrated elevated basal O2 consumption and increased expression of heat shock proteins (HSPs) after heat exposure. RNA-seq was also used to explore the exertional heat stress response in a cohort of EHI, MH and healthy control volunteers. Elevated HSPs were detected in the blood of MH individuals along with a basal reduction of key oxidative phosphorylation enzymes, both suggestive of oxidative stress. In contrast, increased expression of metabolic enzymes required for acetyl-coA synthesis were detected in both EHI and MH susceptible patients relative to controls.
This thesis highlights the likely role of calcium dysregulation and energy metabolism in the pathophysiology of this complex disorder.
