The neuromuscular and multisystem features of RYR1-related malignant hyperthermia and rhabdomyolysis

Abstract

Introduction: Malignant hyperthermia (MH) and exertional rhabdomyolysis (ERM) have long been considered episodic phenotypes occurring in response to external triggers in otherwise healthy individuals with variants in RYR1. However, recent studies have demonstrated a clinical and histopathological continuum between patients with RYR1-related congenital myopathies and those with ERM or MH susceptibility. Furthermore, animal studies have shown non-neuromuscular features such as a mild bleeding disorder and an immunological gain-of-function associated with MH/ERM related RYR1 variants raising important questions for further research. Awareness of the neuromuscular disease spectrum and potential multisystem involvement in RYR1-related MH and ERM is essential to optimize the diagnostic work-up, improve counselling and and future treatment strategies for patients affected by these conditions. This study will examine in detail the nature and severity of continuous disease manifestations and their effect on daily life in patients with RYR1-related MH and ERM.Methods: The study protocol consists of four parts; an online questionnaire study, a clinical observational study, muscle imaging, and specific immunological studies. Patients with RYR1-related MH susceptibility and ERM will be included. The imaging, immunological and clinical studies will have a cross-sectional design, while the questionnaire study will be performed three times during a year to assess disease impact, daily living activities, fatigue and pain. The imaging study consists of muscle ultrasound and whole-body magnetic resonance imaging studies. For the immunological studies, peripheral mononuclear blood cells will be isolated for in vitro stimulation with toll-like receptor ligands, to examine the role of the immune system in the pathophysiology of RYR1-related MH and ERM.This study is funded by the Radboudumc Regional Junior Researcher Grant in collaboration with the Canisius Wilhelmina Hospital. The Radboudumc and Canisius Wilhelmina Hospital were not involved in the design of the study and will not be involved in collection, analysis, and interpretation of data and in writing manuscripts.The authors have no conflicts of interest to disclose.Ethics approval and consent to participate: This study protocol was approved by the regional medical ethics committee (CMO Arnhem-Nijmegen, registration number 2020-6251). All study subjects will need to give written informed consent before participation in this study.Data access statement: The datasets generated during and/or analyzed during the present study are available on reasonable request. The authors declare that they have no competing interestsThe datasets generated during and/or analyzed during the present study are available from the corresponding author on reasonable request. Data sharing not applicable to this article as no datasets were generated or analyzed during the present study.

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

“…6. Personal history of an RYR1 variant detected on diagnostic testing in the neuromuscular clinic for symptoms suggestive of a neuromuscular disorder but without a specific clinical or histopathologic diagnosis and/or fulfilling one of the other referral criteria; these are often coincidentally found RYR1 variants; frequent reasons for RYR1 sequencing in the neuromuscular clinic are myalgia, muscle cramps, and muscle weakness 18,19…”

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

“…The study protocol of the parent project has already been published. 16 Study procedures relevant for this report are reported in Part 1 ‘questionnaire studies’ and Part 2: ‘Clinical studies’. After the publication of the study protocol, 16 an amendment was made to the study design.…”

“… 16 Study procedures relevant for this report are reported in Part 1 ‘questionnaire studies’ and Part 2: ‘Clinical studies’. After the publication of the study protocol, 16 an amendment was made to the study design. The standardized history of neuromuscular symptoms questionnaire (see ‘Study procedures’), was filled out by patients and healthy controls because there are no validated questionnaires available on neuromuscular symptoms.…”

Glycerolipid defects in skeletal muscle contribute to rhabdomyolysis in Tango2 deficiency

“…Rare disease-causing mutations are associated with a small but significant subset (∼15%) of RM patients. Environmental factors such as viral infections (SARS-CoV-2, HIV), physical exertion, certain medications and drugs are major contributing factors in combination with a genetic predisposition (East, Alivizatos, Grundy, Jones, & Farmer, 1988; Knoblauch, Dagnino-Acosta, & Hamilton, 2013; Rawson, Clarkson, & Tarnopolsky, 2017; Szugye, 2020; van den Bersselaar et al, 2021; Wu, Wong, Cheng, & Yu, 2022). Even in genetic forms of RM, environmental factors increase the susceptibility to recurrent episodes of muscle breakdown (Kruijt et al, 2021).…”