Variants in RYR1 give rise to a wide spectrum of neuromuscular conditions including congenital myopathies, exertional rhabdomyolysis (ERM) and malignant hyperthermia (MH) susceptibility. MH susceptible individuals often experience muscle cramps and myalgia and may develop proximal or axial muscle weakness later in life. With therapies for RYR1-related disorders under development and clinical trials anticipated, there is an urgent need for natural history data on patient-reported outcome measures. Furthermore, these data may inform the prognosis of patients newly diagnosed with RYR1-related MH and ERM. This prospective, longitudinal observational questionnaire study aimed to expand the knowledge concerning fatigue, anxiety, depression, pain, functional impairment and quality of life in patients with MH and ERM. In this study, 50 participants fulfilled the Sickness Impact Profile, RAND36, McGill Pain Questionnaire, Checklist Individual Strength and Hospital Anxiety and Depression Scale questionnaires at baseline. Forty-three participants completed the questionnaires at all three time points (baseline, 6 and 12 months). Many patients with RYR1 variants resulting in MH susceptibility and/or ERM reported symptoms of fatigue and experienced impaired sleep/rest, ambulation, activities of daily living and recreation, resulting in a lower quality of life; this was more pronounced in patients who also report overt neuromuscular symptoms. There were no differences in anxiety and depression compared to controls. Study results were consistent throughout the one year follow up period. These patient reported outcome measures are therefore particularly useful as outcome measures in clinical trials of investigational therapies aimed at reducing intermittent exertional symptoms.