Investigating myopathic causes of rhabdomyolysis

Rhabdomyolysis is an acute, and frequently severe, pathological event, characterized by rapid necrosis and destruction of striated muscle tissue. It is clinically characterized by muscle pain, weakness and emission of dark urine. The mechanisms that lead to rhabdomyolysis are various and different, and share common alterations such as dysfunction of the pumps Na + / K + and Ca2 + ATPase, and rupture of the sarcolemma, which in turn determine calcium homeostasis alterations, mitochondrial dysfunction, proteases activation, reduced availability of ATP and, overall, cell apoptosis and rhabdomyolysis. Several causes can initiate this vicious circle, both acquired and genetic. When facing an episode of rhabdomyolysis, the identification of the etiological cause can be extremely complex, long, and costly. Nevertheless, the correct identification of the underlying cause is of utmost importance for the correct information regarding prognosis (risk of recurrence) and for the family genetic counselling. Despite the application of extended diagnostic work up frequently it is not easy to distinguish if the rhabdomyolysis episode is due to a genetic disorder or whether it is the result of an abnormal effort, of an infectious episode or effect of a toxic. The main objective of this study is the evaluation of the diagnostic process of rhabdomyolysis, and to propose an updated, comprehensive, rational and cost effective protocol based on the latest information and techniques. We first studied the diagnostic process currently in use for rhabdomyolysis in a large retrospective study including 208 patients (aim 1). We characterized the clinical, molecular and radiological features of a new genetic cause of rhabdomyolysis, the CASQ1-related myopathy (aim 2). We determined the clinical spectrum of limb-girdle muscular dystrophy 2E (LGMD2E), investigating the risk of rhabdomyolysis of this disease (aim 3). We demostrated the role of EMG with provocative test (Long Exercise Test) as a sensitive and specific diagnostic test in the work up of rhabdomyolysis, especially in Glycogenosis type V (aim 4). We proposed a multi gene panel that should be studied by Next Generation Sequencing (NGS) in patients presenting rhabdomyolysis (aim 5) In conclusion, the results of this study suggest a new diagnostic algorithm for rhabdomyolysis. In this algorithm, the clinical features and few first-line tests (blood tests, EMG, acylcarnitines, grip test) exclude the most frequent causes or the treatable ones. The subsequent muscle biopsy will identify certain myopathies and guide toward the use of specific genetic panels for metabolic myopathies, muscular dystrophies or mitochondrial diseases that should be studied by NGS. The diagnostic algorithm that we propose will allow cost reduction and time optimization, and hopefully will increase the rate of etiological diagnosis of rhabdomyolysis, a serious event with major impact on patients' lives that, to date, remains poorly diagnosed.