This article will review relevant mechanisms and markers associated with overtraining syndrome (OTS), and discuss signs and symptoms, differential diagnosis, and current assessment tools for fatigue within the context of overtraining. The findings are drawn from original research and review articles referenced by PubMed and ScienceDirect databases. Sources were selected for their contributions to the current knowledge of biological, psychological, and molecular mechanisms. Data were reviewed for relevance to OTS and then evaluated against criteria that included significant OTS outcomes and findings. Information was systematically analyzed to identify patterns, dependencies, connections, and causal factors. Comparative analysis was confounded by inconsistent metrics, terminology, and variable methodology; potential biomarkers, treatment and prevention approaches, and future research directions are identified. Diagnosing OTS is difficult because underlying cause(s) are unknown; one must exclude other factors that degrade performance and mood status. Many studies are confounded by inadequate experimental designs, poor measures of performance, and different methods for characterizing OTS. OTS is complex because the demands of excessive training in combination with other biologic, psychological, and social stressors are difficult to quantify. However, changes in mood are always noted. Interrelations among dietary patterns; social, psychological and physiological profiles; and the neuroendocrine, immune, and central nervous systems are complex and not adequately elucidated.
Background
Malignant 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. Our aim was to pilot a strategy for the RYR1 and CACNA1S genes.
Methods
Exome 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.
Results
We identified 70 RYR1 and 53 CACNA1S variants among 870 exomes. Sixty-three RYR1 and 41 CACNA1S variants passed the quality and frequency metrics but we excluded synonymous variants. In RYR1, we 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 us to be of unknown pathogenicity.
Conclusions
Exome 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.
Prevention of malignant hyperthermia (MH) requires an understanding of RYR1 variant pathogenicity to assess the risk of exposure to triggering agents. Personalized medicine, especially secondary findings and eventually genomic screening, will contribute toward this goal. Methods We specified ACMG/AMP criteria for variant interpretation for RYR1 and MH. Proposed rules were piloted on 84 variants. We applied quantitative evidence calibration for several criteria using likelihood ratios based on the Bayesian framework.
ResultsSeven ACMG/AMP criteria were adopted without changes, ten were adopted with RYR1specific modifications, and nine were dropped. The in silico (PP3 and BP4) and hot spot criteria (PM1) were evaluated quantitatively. REVEL gave an OR of 23:1 for PP3 and 16:1 for BP4 using trichotomized cut-offs of >0.85 (pathogenic) and <0.5 (benign). The PM1 hotspot criterion had 105 and is also made available for use under a CC0 license.
The identification in a patient of 1 of the 50 variants in the RYR1 or CACNA1S genes reviewed here should lead to a presumption of malignant hyperthermia susceptibility (MHS). MHS can lead to life‐threatening reactions to potent volatile anesthetic agents or succinylcholine. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of these agents in patients with these RYR1 or CACNA1S variants (updates at https://cpicpgx.org/guidelines and http://www.pharmgkb.org).
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