RYR1-related myopathies: a wide spectrum of phenotypes throughout life

Background and purpose Although several recent studies have implicated RYR1 mutations as a common cause of various myopathies and the malignant hyperthermia susceptibility (MHS) trait, many of these studies have been limited to certain age groups, confined geographical regions or specific conditions. The aim of the present study was to investigate the full spectrum of RYR1‐related disorders throughout life and to use this knowledge to increase vigilance concerning malignant hyperthermia. Methods A retrospective cohort study was performed on the clinical, genetic and histopathological features of all paediatric and adult patients in whom an RYR1 mutation was detected in a national referral centre for both malignant hyperthermia and inherited myopathies (2008–2012). Results The cohort of 77 non‐related patients (detection rate 28%) included both congenital myopathies with permanent weakness and ‘induced’ myopathies such as MHS and non‐anaesthesia‐related episodes of rhabdomyolysis or hyperCKemia, manifested throughout life and triggered by various stimuli. Sixty‐one different mutations were detected, of which 24 were novel. Some mutations are present in both dominant (MHS) and recessive modes (congenital myopathy) of inheritance, even within families. Histopathological features included an equally wide spectrum, ranging from only subtle abnormalities to prominent cores. Conclusions This broad range of RYR1‐related disorders often presents to the general paediatric and adult neurologist. Its recognition is essential for genetic counselling and improving patients' safety during anaesthesia. Future research should focus on in vitro testing by the in vitro contracture test and functional characterization of the large number of RYR1 variants whose precise effects currently remain uncertain.