RYR1 variant c.38T&gt;G, p.Leu13Arg causes hypersensitivity of the ryanodine receptor-1 and is pathogenic for malignant hyperthermia

Bersselaar, Luuk R. van den; Greven, T.; Bulger, Terasa; Voermans, Nicol C.; Petegem, Filip Van; Schiemann, Anja; Parker, Remai; Burling, Sophie M.; Jungbluth, Heinz; Stowell, Kathryn M.; Kamsteeg, Erik‐Jan; Snoeck, M.M.J.

doi:10.1016/j.bja.2021.05.008

Cited by 5 publications

(3 citation statements)

References 11 publications

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“…The weight ( P = 0.025) and body mass index (BMI) ( P = 0.001) of the patients were higher compared with healthy controls. In 39 patients (97.5%), MH susceptibility was confirmed by either an EMHG diagnostic RYR1 variant for MH 31 , 32 ( n = 34; 85%) or a positive IVCT ( n = 21; 52.5%). 17 , 33 Some patients ( n = 16; 40%), who were investigated with IVCT, were at a later time found to carry diagnostic RYR1 variants for MH.…”

Section: Resultsmentioning

confidence: 99%

Neuromuscular symptoms in patients with RYR1-related malignant hyperthermia and rhabdomyolysis

Bersselaar

Jungbluth

Kruijt

et al. 2022

Brain Communications

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Malignant hyperthermia and exertional rhabdomyolysis have conventionally been considered episodic phenotypes that occur in otherwise healthy individuals in response to an external trigger. However, recent studies have demonstrated a clinical and histopathological continuum between patients with a history of malignant hyperthermia susceptibility and/or exertional rhabdomyolysis and RYR1-related congenital myopathies. We hypothesize that patients with a history of RYR1-related exertional rhabdomyolysis or malignant hyperthermia susceptibility do have permanent neuromuscular symptoms between malignant hyperthermia or exertional rhabdomyolysis episodes. We performed a prospective cross-sectional observational clinical study of neuromuscular features in patients with a history of RYR1-related exertional rhabdomyolysis and/or malignant hyperthermia susceptibility (n = 40) compared to healthy controls (n = 80). Patients with an RYR1-related congenital myopathy, manifesting as muscle weakness preceding other symptoms as well as other (neuromuscular) diseases resulting in muscle weakness were excluded. Study procedures included a standardized history of neuromuscular symptoms, a review of all relevant ancillary diagnostic tests performed up to the point of inclusion and a comprehensive, standardized neuromuscular assessment. Results of the standardized neuromuscular history were compared to healthy controls. Results of the neuromuscular assessment were compared to validated reference values. The proportion of patients suffering from cramps (P < 0.001), myalgia (P < 0.001) and exertional myalgia (P < 0.001) was higher compared to healthy controls. Health care professionals were consulted because of apparent neuromuscular symptoms by 17/40 (42.5%) patients and 7/80 (8.8%) healthy controls (P < 0.001). Apart from elevated creatine kinase levels in 19/40 (47.5%) patients and mild abnormalities on muscle biopsies identified in 13/16 (81.3%), ancillary investigations were normal in most patients. The Medical Research Council sum score, spirometry and results of functional measurements were also mostly normal. Three of 40 patients (7.5%) suffered from late-onset muscle weakness, most prominent in the proximal lower extremity muscles. Patients with RYR1 variants resulting in malignant hyperthermia susceptibility and/or exertional rhabdomyolysis frequently report additional neuromuscular symptoms such as myalgia and muscle cramps compared to healthy controls. These symptoms result in frequent consultation of health care professionals and sometimes in unnecessary invasive diagnostic procedures. Most patients do have normal strength at a younger age but may develop muscle weakness later in life.

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Section: Resultsmentioning

confidence: 99%

Neuromuscular symptoms in patients with RYR1-related malignant hyperthermia and rhabdomyolysis

Bersselaar

Jungbluth

Kruijt

et al. 2022

Brain Communications

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“…Some of the medical records included in this study cohort have been described before. 8,[11][12][13][14][15][16] Details of the overlapping medical records are summarized in Supplemental Digital Content 1 (http://links.lww.com/ALN/C833).…”

Section: Malignant Hyperthermia Susceptibility Diagnosticsmentioning

confidence: 99%

Referral Indications for Malignant Hyperthermia Susceptibility Diagnostics in Patients without Adverse Anesthetic Events in the Era of Next-generation Sequencing

et al. 2022

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Background The introduction of next-generation sequencing into the diagnosis of neuromuscular disorders has resulted in an increased number of newly identified RYR1 variants. We hypothesize that there is an increased referral of patients to Malignant Hyperthermia (MH)-units without a personal/family history of adverse anesthetic events suspected for MH. This retrospective multicenter cohort study evaluates patient referral indications and outcomes for those without a history of an adverse anesthetic event. Methods Patients referred between 2010-2019 to the MH-units in Antwerp, Lund, Nijmegen and Toronto were included. Previously tested patients and relatives of previously tested patients were excluded. Data collection included demographics, referral details, muscle contracture and genetic testing results including REVEL scores. Referral indications were categorized into those with a personal/family history of adverse anesthetic event and other indications including exertional and/or recurrent rhabdomyolysis, RYR1 variant(s) detected in diagnostic testing in the neuromuscular clinic without a specific diagnosis (in a family member), diagnosed RYR1-related myopathy (in a family member), idiopathically elevated resting creatine kinase values, exertional heat stroke and other. Results A total of 520 medical records were included, with the three most frequent referral indications; personal history of an adverse anesthetic event (211/520; 40.6%), family history of an adverse anesthetic event (115/520; 22.1%), and exertional and/or recurrent rhabdomyolysis (46/520; 8.8%). The proportion of patients referred without a personal/family history of an adverse anesthetic event increased to 43.6% (133/305) between 2015-2019 compared to 28.4% (61/215) in 2010-2014 (P<0.001). Patients with a personal/family history of an adverse anesthetic event were more frequently diagnosed as MH susceptible (133/220; 60.5%) than those without (47/120; 39.2%), (P < 0.001). Due to missing data, 180 medical records were excluded. Conclusion The proportion of patients referred to MH-units without a personal/family history of an adverse anesthetic event has increased, with 39.2% (47/120) diagnosed as MH susceptible.

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“…Although to the team, the suspicion of MH was low, the patient was referred to the national MH Investigation Unit. RYR1 (the gene encoding the skeletal muscle ryanodine receptor-1) analysis using the Sanger method identified 2 RYR1 variants: the pathogenic variant c.38T>G, p.L13R, confirming MH susceptibility, 6 and a variant of unknown significance c.6419G>A, p.R2140Q.…”

Section: Case Reportmentioning

confidence: 99%

Malignant Hyperthermia During Cardiac Surgery Successfully Treated by Deep Hypothermia Using Cardiopulmonary Bypass: A Case Report

et al. 2021

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Malignant hyperthermia (MH) is a life-threatening hypermetabolic disorder triggered by volatile anesthetics and/or succinylcholine. We report a case of a 58-year-old patient with a type-A aortic dissection. After induction of general anesthesia, a hypermetabolic reaction was successfully treated by deep hypothermia using cardiopulmonary bypass. Dantrolene became available in theater after the hypermetabolism was already treated successfully by hypothermia. Because of a low suspicion of MH, dantrolene was not administered when it became available. The patient fully recovered, and MH susceptibility was confirmed. Cardiopulmonary bypass should be considered to treat MH in case dantrolene and conservative therapy are unavailable or insufficient. (A&A Practice. 2021;15:e01546.

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RYR1 variant c.38T>G, p.Leu13Arg causes hypersensitivity of the ryanodine receptor-1 and is pathogenic for malignant hyperthermia

Cited by 5 publications

References 11 publications

Neuromuscular symptoms in patients with RYR1-related malignant hyperthermia and rhabdomyolysis

Neuromuscular symptoms in patients with RYR1-related malignant hyperthermia and rhabdomyolysis

Referral Indications for Malignant Hyperthermia Susceptibility Diagnostics in Patients without Adverse Anesthetic Events in the Era of Next-generation Sequencing

Malignant Hyperthermia During Cardiac Surgery Successfully Treated by Deep Hypothermia Using Cardiopulmonary Bypass: A Case Report

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