Variants in ASPH cause exertional heat illness and are associated with malignant hyperthermia susceptibility.
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ABSTRACT:
SUBMITTER: Endo Y
PROVIDER: S-EPMC9192596 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
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Variants in ASPH cause exertional heat illness and are associated with malignant hyperthermia susceptibility.
Endo Yukari Y Groom Linda L Celik Alper A Kraeva Natalia N Lee Chang Seok CS Jung Sung Yun SY Gardner Lois L Shaw Marie-Anne MA Hamilton Susan L SL Hopkins Philip M PM Dirksen Robert T RT Riazi Sheila S Dowling James J JJ
Nature communications 20220613 1
Exertional heat illness (EHI) and malignant hyperthermia (MH) are life threatening conditions associated with muscle breakdown in the setting of triggering factors including volatile anesthetics, exercise, and high environmental temperature. To identify new genetic variants that predispose to EHI and/or MH, we performed genomic sequencing on a cohort with EHI/MH and/or abnormal caffeine-halothane contracture test. In five individuals, we identified rare, pathogenic heterozygous variants in ASPH, ...[more]
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Project description:BACKGROUND:Variants in RYR1 are associated with the majority of cases of malignant hyperthermia (MH), a form of heat illness pharmacogenetically triggered by general anesthetics, and they have also been associated with exertional heat illness (EHI). CACNA1S has also been implicated in MH. The authors applied a targeted next-generation sequencing approach to identify variants in RYR1 and CACNA1S in a cohort of unrelated patients diagnosed with MH susceptibility. They also provide the first comprehensive report of sequencing of these two genes in a cohort of survivors of EHI. METHODS:DNA extracted from blood was genotyped using a "long" polymerase chain reaction technique, with sequencing on the Illumina GAII or MiSeq platforms (Illumina Inc., USA). Variants were assessed for pathogenicity using bioinformatic approaches. For further follow-up, DNA from additional family members and up to 211 MH normal and 556 MH-susceptible unrelated individuals was tested. RESULTS:In 29 MH patients, the authors identified three pathogenic and four novel RYR1 variants, with a further five RYR1 variants previously reported in association with MH. Three novel RYR1 variants were found in the EHI cohort (n = 28) along with two more previously reported in association with MH. Two other variants were reported previously associated with centronuclear myopathy. The authors found one and three rare variants of unknown significance in CACNA1S in the MH and EHI cohorts, respectively. CONCLUSIONS:Targeted next-generation sequencing proved efficient at identifying diagnostically useful and potentially implicated variants in RYR1 and CACNA1S in MH and EHI.
| S-EPMC4472733 | biostudies-literature
Project description:ObjectiveTo describe the possible association (pathophysiologic and clinical features) between exertional heat stroke (EHS) and malignant hyperthermia (MH).BackgroundBoth EHS and MH are acute and life-threatening disorders. It has repeatedly been shown that EHS can occur in well-trained patients with known MH-associated mutation in the RYR1 gene in the absence of any extreme environmental conditions or extreme physical activity, thereby supporting a possible link between EHS and MH. In this case, a highly trained 30-year-old male athlete suddenly collapsed while running. He had initial hyperthermia (40.2°C) and progressive multiple organ failure requiring medical management in an intensive care unit. After he recovered completely, a maximal exercise test was performed and showed an obvious abnormality of oxidative metabolism in muscle; genetic analysis of the RYR1 gene identified a heterozygous missense variation p.K1393R. Consequently, the athlete was given appropriate information and allowed to progressively return to sport competition.Differential diagnosisDoping, use of drugs and toxic agents, exercise-associated hyponatremia, exertional heat illness.TreatmentInitial management started with the basic resuscitative guidelines of airway, breathing, and circulation (intubation). Cooling, administration of fresh frozen plasma, and intensive rehydration resulted in improvement.UniquenessTo our knowledge, ours is the first description of this MH mutation (p.K1393R) in the RYR1 gene that was associated with exertional rhabdomyolysis involving a dramatic impairment of oxidative metabolism in muscle.ConclusionsCommon features are shared by EHS and MH. Careful attention must therefore be paid to athletes who experience EHS, especially in temperate climates or when there are no other predisposing factors.
| S-EPMC4732402 | biostudies-literature
Project description:BackgroundSusceptibility to exertional heat illness (EHI) is considered multifactorial in nature. The aims of this study were to (1) review traditional susceptibility factors identified in cases of EHI and (2) determine how they are related to risk of hospitalisation.MethodsReview of an electronic database of EHI reported in the British Army between 1 September 2007 and 31 December 2014. Cases were categorised by demographic, situational and susceptibility variables. Univariate and multivariate logistic regression was performed for the OR for hospitalisation by risk factor.Results361 reports were included in the analysis. 33.5% of cases occurred in hot climates, 34.6% in temperate climates during summer months and 31.9% in temperate climates outside of summer months. Traditional susceptibility factors were reported in 193 but entirely absent from 168 cases. 137 cases (38.0%) were admitted to hospital. Adjusted OR for hospitalisation was lower for recruits (OR 0.42, 95% CI 0.18 to 0.99, p<0.05) and for personnel wearing occlusive dress (OR 0.56, 95% CI 0.34 to 0.93, p<0.05) or unacclimatised to heat (OR 0.31, 95% CI 0.15 to 0.66, p<0.01).ConclusionsThe global, year-round threat of EHI is highlighted. Absence of susceptibility factors in nearly half of reports highlights the challenge of identifying EHI-prone individuals. Paradoxical association of traditional susceptibility factors with reduced hospitalisation risk may reflect the contemporary contexts in which severe EHI occurs. These findings also suggest a need for better evidence to inform guidelines that aim to prevent severe EHI concurrent to reducing overall morbidity.
| S-EPMC5117044 | biostudies-literature
Project description:ABSTRACT Paralympic athletes may be at increased risk for exertional heat illness (EHI) due to reduced thermoregulatory ability as a consequence of their impairment. This study investigated the occurrence of heat-stress related symptoms and EHI, and the use of heat mitigation strategies in Paralympic athletes, both in relation to the Tokyo 2020 Paralympic Games and previous events. Paralympic athletes competing in Tokyo 2020 were invited to complete an online survey five weeks prior to the Paralympics and up to eight weeks after the Games. 107 athletes (30 [24–38] years, 52% female, 20 nationalities, 21 sports) completed the survey. 57% of respondents had previously experienced heat-stress related symptoms, while 9% had been medically diagnosed with EHI. In Tokyo, 21% experienced at least one heat-stress related symptom, while none reported an EHI. The most common symptom and EHI were, respectively, dizziness and dehydration. In preparation for Tokyo, 58% of respondents used a heat acclimation strategy, most commonly heat acclimatization, which was more than in preparation for previous events (45%; P = 0.007). Cooling strategies were used by 77% of athletes in Tokyo, compared to 66% during past events (P = 0.18). Cold towels and packs were used most commonly. Respondents reported no medically-diagnosed EHIs during the Tokyo 2020 Paralympic Games, despite the hot and humid conditions in the first seven days of competition. Heat acclimation and cooling strategies were used by the majority of athletes, with heat acclimation being adopted more often than for previous competitions.
| S-EPMC10274519 | biostudies-literature
Project description:Calsequestrin 1 (CASQ1) and Ryanodine receptor 1 (RYR1) are two of the main players in excitation-contraction (EC) coupling. CASQ1-knockout mice and mice carrying a mutation in RYR1 (Y522S) linked to human malignant hyperthermia susceptibility (MHS) both suffer lethal hypermetabolic episodes when exposed to halothane (MHS crises) and to environmental heat (heat stroke, HS). The phenotype of Y522S is more severe than that of CASQ1-null mice. As MHS and HS are hypermetabolic responses, we studied the metabolism of adult CASQ1-null and Y522S mice using wild-type (WT) mice as controls. We found that CASQ1-null and Y522S mice have increased food consumption and higher core temperature at rest. By indirect calorimetry, we then verified that CASQ1-null and Y522S mice show an increased oxygen consumption and a lower respiratory quotient (RQ). The accelerated metabolism of CASQ1-null and Y522S mice was also accompanied with a reduction in body fat. Moreover, both mouse models displayed increased oxygen consumption and a higher core temperature during heat stress. The results collected suggest that metabolic rate, oxygen consumption, and body temperature at rest, all more elevated in Y522S than in CASQ1-null mice, could possibly be used as predictors of the level of susceptibility to hyperthermic crises of mice (and possibly humans).
| S-EPMC9406760 | biostudies-literature
Project description:Environmental heat stress represents a pervasive threat to warfighters, athletes, and occupational workers, impacting performance and increasing the risk of injury. Exertional heat illness (EHI) is a spectrum of clinical disorders of increasing severity. While frequently predictable, EHI can occur unexpectedly and may be followed by long-term comorbidities, including cardiovascular dysfunction and exercise intolerance. The objective of this study was to assess genetic factors contributing to EHI. Whole-exome sequencing was performed in a cohort of 53 cases diagnosed with EHI. Rare variants in prioritized gene sets were analyzed and classified per published guidelines. Clinically significant pathogenic and potentially pathogenic variants were identified in 30.2% of the study cohort. Variants were found in 14 genes, including the previously known RYR1 and ACADVL genes and 12 other genes (CAPN3, MYH7, PFKM, RYR2, TRPM4, and genes for mitochondrial disorders) reported here for the first time in EHI. Supporting structural and functional studies of the TRPM4 p.Arg905Trp variant show that it impairs the thermal sensitivity of the TRPM4 channel, revealing a potentially new molecular mechanism contributing to EHI susceptibility. Our study demonstrates associations between EHI and genes implicated in muscle disorders, cardiomyopathies, thermoregulation, and oxidative phosphorylation deficiencies. These results expand the genetic heterogeneity of EHI and shed light on its molecular pathogenesis.
| S-EPMC11508780 | biostudies-literature
Project description:IntroductionPrecipitating factors that contribute to the severity of exertional heat stroke (EHS) are unclear. The purpose of this study was to determine the effect of prior illness (PI) on EHS severity.MethodsWe performed a retrospective clinical record review of 179 documented cases of EHS at the Marine Corps Base in Quantico, Virginia.ResultsApproximately 30% of EHS cases had a medically documented PI. Anthropometrics (height, weight, body mass index) and commonly associated risk factors for EHS (age, number of days in training, wet bulb globe temperature, sleep patterns) did not differ between PI and no illness (NI) groups. PI patients presented with higher maximal rectal core temperatures (40.6 ± 1.0°C vs. 40.3 ± 1.2°C; P = 0.0419), and elevated pulse rates (118.1 ± 16.7 bpm vs. 110.5 ± 24.2 bpm; P = 0.0397). At the point of care, biomarker values were similar between PI and NI groups, with the exception of a trend toward elevated monocytes in those with PI (7.9 ± 2.9% vs 6.7± 2.7%; P = 0.0521). Rate and duration of cooling were similar between PI and NI patients.ConclusionThis study indicates that PI has a minimal effect on the patient presentation, severity and treatment outcome of EHS. The results of this study have important implications for military, civilian, and occupational populations who are at risk for EHS.
| S-EPMC6701802 | biostudies-literature
Project description:PurposeMalignant hyperthermia (MH) is a pharmacogenetic disorder arising from uncontrolled muscle calcium release due to an abnormality in the sarcoplasmic reticulum (SR) calcium-release mechanism triggered by halogenated inhalational anesthetics. However, the molecular mechanisms involved are still incomplete.MethodsWe aimed to identify transient receptor potential vanilloid 1 (TRPV1) variants within the entire coding sequence in patients who developed sensitivity to MH of unknown etiology. In vitro and in vivo functional studies were performed in heterologous expression system, trpv1-/- mice, and a murine model of human MH.ResultsWe identified TRPV1 variants in two patients and their heterologous expression in muscles of trpv1-/- mice strongly enhanced calcium release from SR upon halogenated anesthetic stimulation, suggesting they could be responsible for the MH phenotype. We confirmed the in vivo significance by using mice with a knock-in mutation (Y524S) in the type I ryanodine receptor (Ryr1), a mutation analogous to the Y522S mutation associated with MH in humans. We showed that the TRPV1 antagonist capsazepine slows the heat-induced hypermetabolic response in this model.ConclusionWe propose that TRPV1 contributes to MH and could represent an actionable therapeutic target for prevention of the pathology and also be responsible for MH sensitivity when mutated.
| S-EPMC6752298 | biostudies-literature
Project description:Background and objectives: Environmental monitoring allows for an analysis of the ambient conditions affecting a physically active person's ability to thermoregulate and can be used to assess exertional heat illness risk. Using public health models such as the precaution adoption process model (PAPM) can help identify individual's readiness to act to adopt environmental monitoring policies for the safety of high school athletes. The purpose of this study was to investigate the adoption of policies and procedures used for monitoring and modifying activity in the heat in United States (US) high schools. Materials and Methods: Using a cross-sectional design, we distributed an online questionnaire to athletic trainers (ATs) working in high schools in the US. The questionnaire was developed based on best practice standards related to environmental monitoring and modification of activity in the heat as outlined in the 2015 National Athletic Trainers' Association Position Statement: Exertional Heat Illness. The PAPM was used to frame questions as it allows for the identification of ATs' readiness to act. PAPM includes eight stages: unaware of the need for the policy, unaware if the school has this policy, unengaged, undecided, decided not to act, decided to act, acting, and maintaining. Invitations were sent via email and social media and resulted in 529 complete responses. Data were aggregated and presented as proportions. Results: Overall, 161 (161/529, 30.4%) ATs report they do not have a written policy and procedure for the prevention and management of exertional heat stroke. The policy component with the highest adoption was modifying the use of protective equipment (acting = 8.2%, maintaining = 77.5%). In addition, 28% of ATs report adoption of all seven components for a comprehensive environmental monitoring policy. Conclusions: These findings indicate a lack of adoption of environmental monitoring policies in US high schools. Secondarily, the PAPM, facilitators and barriers data highlight areas to focus future efforts to enhance adoption.
| S-EPMC7597963 | biostudies-literature
Project description:BackgroundMalignant hyperthermia susceptibility (MHS) is a life-threatening, inherited disorder of muscle calcium metabolism, triggered by anesthetics and depolarizing muscle relaxants. An unselected cohort was screened for MHS mutations using exome sequencing. The aim of this study was to pilot a strategy for the RYR1 and CACNA1S genes.MethodsExome sequencing was performed on 870 volunteers not ascertained for MHS. Variants in RYR1 and CACNA1S were annotated using an algorithm that filtered results based on mutation type, frequency, and information in mutation databases. Variants were scored on a six-point pathogenicity scale. Medical histories and pedigrees were reviewed for malignant hyperthermia and related disorders.ResultsThe authors identified 70 RYR1 and 53 CACNA1S variants among 870 exomes. Sixty-three RYR1 and 41 CACNA1S variants passed the quality and frequency metrics but the authors excluded synonymous variants. In RYR1, the authors identified 65 missense mutations, one nonsense, two that affected splicing, and one non-frameshift indel. In CACNA1S, 48 missense, one frameshift deletion, one splicing, and one non-frameshift indel were identified. RYR1 variants predicted to be pathogenic for MHS were found in three participants without medical or family histories of MHS. Numerous variants, previously described as pathogenic in mutation databases, were reclassified by the authors as being of unknown pathogenicity.ConclusionsExome sequencing can identify asymptomatic patients at risk for MHS, although the interpretation of exome variants can be challenging. The use of exome sequencing in unselected cohorts is an important tool to understand the prevalence and penetrance of MHS, a critical challenge for the field.
| S-EPMC4077354 | biostudies-literature