Mitochondrial Dysfunction In Sickle Cell Trait Carriers With A History Of Exercise Collapse

PURPOSE: Sickle cell trait (SCT) increases the risk of sudden death and rhabdomyolysis (ER) in athletes and Service Members (SM) during intense exercise. The term “exercise collapse associated with SCT” (ECAST) was introduced in 2012 to assist in case descriptions and advancing scientific research. This study presents clinical and genetic findings of two ECAST cases. METHODS: SCT positive African Americans (18-50 years old [y/o]) with (case; n = 2) or without (control; n = 2) history of ECAST were enrolled and age-matched. Demographics, physical traits, and medical and family histories were extracted via medical records and a questionnaire. Blood samples were collected for whole exome sequencing and mitochondrial bioenergetic profiling. RESULTS: Case A: 26y/o male SM collapsed outdoors during a physical fitness test (PFT) run. He had shortness of breath (SOB), severe muscle cramping, leg and back pain, and dark urine. He was diagnosed with ER (peak creatine kinase [CK] > 300,000 U/L), multiple lower limb compartment syndrome, and acute renal failure. He received hemodialysis and muscle fasciotomies. No personal or family history of exertion-related events (ERE). Case B: 30y/o male SM collapsed during a PFT indoors. He had muscle pain and weakness, SOB, and sweaty, cool, clammy skin. He was alert and oriented, but very weak. Albuterol slightly improved his breathing, but he remained partially obtunded. Peak CK = 3,103 U/L. No personal or family history of ERE. Control A: 29y/o male. No history of ECAST. Control B: 28y/o female SM. No history of ECAST.Cases carried genetic mutations (Case A: POLG p.Gly848Ser; Case B: RRM2B p.Met282Ile) associated with autosomal recessive mitochondrial DNA depletion syndrome (MDS). Controls were negative for gene mutations related to MDS. Mitochondrial bioenergetic profiling of blood mononuclear cells indicated lower oxygen consumption rates, reserve capacity and mitochondrial resilience index (bioenergetic health) in cases compared to controls. CONCLUSIONS: Both cases had genetic mutations known to cause MDS and blood cells exhibited impaired bioenergetic mitochondrial profiles, which suggests a role of mitochondrial dysfunction in the development of ECAST. Further large-scale studies are needed to determine the contribution of mitochondrial dysfunction to ECAST. Supported by: The study is funded by the Defense Health Agency