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

Abstract

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 with 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 with healthy controls. Results of the neuromuscular assessment were compared with 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 with healthy controls. Healthcare 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 with healthy controls. These symptoms result in frequent consultation of healthcare 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.

Keywords: RYR1; exertional rhabdomyolysis; malignant hyperthermia; myopathy; ryanodine receptor-1.

Graphical abstract

Figure 1

Selection process and reason for exclusion of study participants. A summary of the selection process and exclusion criteria for this study. ERM = exertional rhabdomyolysis; MH = malignant hyperthermia; MRI = magnetic resonance imaging.

Figure 2

Patient reported neuromuscular symptoms compared with healthy controls. Neuromuscular symptoms as reported in a standardized history (n = 40). For each symptom, the proportion of patients reporting this symptom was compared with healthy controls (n = 80) using the χ² or Fisher’s exact test, when appropriate followed by Bonferroni correction for multiple testing (P-values < 0.0045 were considered significant). The full questionnaire translated from Dutch to English is available as Supplementary File 1.

Figure 3

Healthcare professionals consulted, and ancillary investigations performed because of neuromuscular symptoms before inclusion in this study. A summary of all healthcare professionals consulted (A) and ancillary investigations performed (B) in the study participants. All healthcare professionals were consulted, and ancillary investigations were performed because of neuromuscular symptoms before inclusion. Investigations and physicians during the diagnostic work-up to diagnose malignant hyperthermia susceptibility or to investigate the aetiology of an exertional rhabdomyolysis episode were excluded.

Figure 4

Magnetic resonance imaging, muscle ultrasound images and clinical photographs from study participants. (A) Magnetic resonance imaging Dixon T2 images and Dixon T1 images showing bilateral edema of the gastrocnemius and soleus muscle as well as fatty infiltration of the left gastrocnemius, tibialis anterior and semimembranosus muscles. The muscle magnetic resonance imaging and muscle ultrasound (B and C) were performed because of late-onset proximal muscle weakness. This patients carries the RYR1 c.7300G > A, p.Gly2434Arg variant. (B) Muscle ultrasound imaging showing markedly increased echo intensity (Heckmatt rating scale 4) of the right medial gastrocnemius muscle This ultrasound image is from the same patient whose magnetic resonance images are shown in Fig. 4A and whose muscle ultrasound images are shown in Fig. 4C. (C) Muscle ultrasound images of the right lateral gastrocnemius muscle showing increased echo intensity (Heckmatt rating scale 2). This ultrasound image is from the same patient whose magnetic resonance images are shown in Fig. 4A and whose muscle ultrasound images are shown in Fig. 4B. (D) A study participant with late-onset proximal weakness and atrophy of the lower extremities as demonstrated in Videos 1 and 2. He carries the RYR1 c.10616G > A, p.Arg3539His variant.