By Michael Rubin, MD

Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Rubin reports no financial relationships relevant to this field of study.

Synopsis: Ryanodine receptor gene mutations are among the most common genetic disorders found in a variety of congenital myopathies, both mild and severe.

Source: Snoeck M, et al. RYR1-related myopathies: A wide spectrum of phenotypes throughout life. Eur J Neurol 2015;22:1094-1112.

Increased skeletal muscle cytoplasmic calcium, released from its main store in the sarcoplasmic reticulum (SR), is the first trigger initiating muscle contraction. It results from a propagated post-synaptic potential reaching the transverse (T) tubules, which make close contact with the SR at so-called “triads,” formed by two SR terminal cisternae on each side of a T tubule. Called excitation-contraction coupling, the transformation of an action potential into calcium release is performed by a macromolecular complex, the calcium release complex (CRC), the main players of which include the dihydropyridine receptor (DHPR) and the ryanodine receptor (RYR1). Opening of the RYR1 receptor, triggered by a conformational change of DHPR, allows massive calcium influx, which interacts with the myofilaments, resulting in contraction. Muscles relax when RYR1 closes and calcium is taken back into the SR. Located on chromosome 19q13.2, the RYR1 gene consists of 5038 amino acids, and both malignant hyperthermia and congenital myopathies are associated with its dysfunction. What is the full range of RYR1-related disorders?

To answer this question, a retrospective, observational, cohort study, with a cross-sectional design, was carried out on all pediatric and adult patients seen between 2008-2012 at Radboud University Medical Center and the Malignant Hyperthermia Investigation Unit, Nijmegen, Netherlands, a national referral center for malignant hyperthermia and congenital myopathies. Among 272 patients tested, RYR1 mutations were found in 77 non-related patients, 16 of which were of undetermined significance. Clinical history and ancillary investigation results on these patients were obtained through neurologists and geneticists of the national neuromuscular network.

Among the 77 patients, 61 different mutations were detected, of which 24 were novel. Inheritance was autosomal dominance in 64% and recessive in 15%, with the remainder of undetermined pathogenicity and inheritance pattern. Median age of onset and diagnosis were 8 and 29 years, respectively, with onset ranging from birth to late adulthood.

“Induced myopathies” were seen in 51%, including malignant hyperthermia susceptibility in 38%, as determined by a positive halothane-caffeine in vitro contracture test (IVCT) performed on freshly biopsied quadriceps muscle, exercise-induced rhabdomyolysis in 12%, and hyperCKemia in 1%. Permanent weakness was found in the remaining 49%, encompassing central core disease and multicore disease in 30% and 9%, respectively, and facial akinesia, nemaline myopathy, centronuclear myopathy, and King-Denborough syndrome, an autosomal dominant disorder characterized by a triad of dysmorphic features, malignant hyperthermia susceptibility, and myopathy, in 1% each. Axial myopathy, and congenital myopathy not otherwise specified, were each found in 3%.


Commentary

Congenital myopathies related to RYR1 mutations are among the most frequent congenital myopathies, most of which are moderate in severity, but 15% of which are associated with severe neonatal disease resulting in respiratory failure and death within weeks, a third of whom demonstrate arthrogryposis at birth. Pathophysiological mechanisms associated with RYR1 mutations include either gain of function of the ryanodine channel, resulting in increased calcium release, generalized muscle contraction, and a hypermetabolic state as seen in malignant hyperthermia, or a loss of function, resulting in uncoupling of the dihydropyridine receptor and the ryanodine receptor, causing congenital myopathies. Some patients, mostly with recessive forms of disease, have a mutation causing a reduction in RYR1 amount.