Novel Variants in Individuals with RYR1-Related Congenital Myopathies: Genetic, Laboratory, and Clinical Findings

Abstract

The ryanodine receptor 1-related congenital myopathies (RYR1-RM) comprise a spectrum of slow, rare neuromuscular diseases. Affected individuals present with a mild-to-severe symptomatology ranging from proximal muscle weakness, hypotonia and joint contractures to scoliosis, ophthalmoplegia, and respiratory involvement. Although there is currently no FDA-approved treatment for RYR1-RM, our group recently conducted the first clinical trial in this patient population (NCT02362425). This study aimed to characterize novel RYR1 variants with regard to genetic, laboratory, muscle magnetic resonance imaging (MRI), and clinical findings. Genetic and histopathology reports were obtained from participant’s medical records. Alamut Visual Software was used to determine if participant’s variants had been previously reported and to assess predicted pathogenicity. Physical exams, pulmonary function tests, T1-weighted muscle MRI scans, and blood measures were completed during the abovementioned clinical trial. Six novel variants (two de novo, three dominant, and one recessive) were identified in individuals with RYR1-RM. Consistent with established RYR1-RM histopathology, cores were observed in all biopsies, except Case 6 who exhibited fiber-type disproportion. Muscle atrophy and impaired mobility with Trendelenburg gait were the most common clinical symptoms and were identified in all cases. Muscle MRI revealed substantial inter-individual variation in fatty infiltration corroborating the heterogeneity of the disease. Two individuals with dominant RYR1 variants exhibited respiratory insufficiency: a clinical symptom more commonly associated with recessive RYR1-RM cases. This study demonstrates that a genetics-led approach is suitable for the diagnosis of suspected RYR1-RM which can be corroborated through histopathology, muscle MRI and clinical examination.

Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches

“…Advancements in next-generation sequencing (NGS) technologies have made it possible to screen for variants in large genes such as RYR1 and assess genotype–phenotype correlations [31, 32]. RYR1 variants have been implicated in sarcoplasmic reticulum (SR) calcium Ca 2+ release dysfunction (RyR1 channel hyper/hyposensitivity and chronic Ca 2+ leak) [33].…”

“…Clinical features include hypotonia in infancy, delayed motor milestones, axial muscle involvement, proximal weakness, myalgia, muscle stiffness, hip dislocation, spinal deformities, and exertional weakness with or without rhabdomyolysis. Extraocular muscle weakness and bulbar and respiratory involvement are not typical [33, 60]; however, strabismus has been reported in dominant cases [31, 61]. Recessively inherited or de novo dominant RYR1 -related CCD present with more severe features such as fetal akinesia syndrome (severe hypotonia, multiple arthrogryposis, respiratory failure) [8, 61, 62].…”

Correlation of phenotype with genotype and protein structure in RYR1-related disorders

“…Forming an exceptionally large, 2.2 MDa homotetramer, RyR1 is localized to the sarcoplasmic reticulum (SR) of skeletal muscle and functions to release sarcoplasmic calcium (Ca 2+ ) stores into the cytosol upon depolarization of the neuromuscular junction, enabling excitation–contraction coupling [77]. The largest RyR1 domain is the cytosolic shell (CS), also referred to as the RyR1 foot region, which constitutes the first 3613 amino acid residues and is immersed in the intracellular myoplasm [13].…”

A Web-Based Pharmacogenomics Search Tool for Precision Medicine in Perioperative Care

“…With the use of pharmacogenetics, patients could be screened for an increased probability of negative outcomes. Mutations mostly involving the RYR1 gene and the CACNA1S gene (to a lesser extent) [ 25 ] lead to an uncontrolled release of calcium from the sarcoplasmic reticulum responsible for the characteristic signs and symptoms of MH [ 26 ].…”