NORD gratefully acknowledges Michael F. Goldberg, MD, MPH, Co-Founder and President, RYR-1 Foundation, for the preparation of this report.
RYR-1-related diseases are conditions caused by changes (mutations) in the RYR-1 gene. RYR-1 mutations are typically associated with core myopathies and are the most common overall cause of congenital myopathy. A myopathy can cause “static” or “dynamic” symptoms. “Static” symptoms are present at all times (weakness, motor delay, difficulties walking, scoliosis, facial weakness, ophthalmoparesis [eye muscle weakness], inability to climb stairs, etc.). “Dynamic” symptoms are transient based on certain triggers or precipitants (malignant hyperthermia, exercise induced breakdown of skeletal muscle [rhabdomyolysis], myalgia [muscle pain], muscle cramps, fatigue, etc.). Individuals with RYR-1-related diseases can experience “static” symptoms, “dynamic” symptoms, or a combination of both.
The term "congenital myopathy" refers to a group of muscle conditions that are caused by a genetic mutation that you are born with. The RYR-1 gene provides instructions for production of the RYR-1 receptor. The RYR-1 receptor is a channel in the sarcoplasmic reticulum in skeletal muscle cells that regulates the flow of calcium, a critical component of muscle contraction. A reduced number and/or abnormal RYR-1 receptors can lead to dysfunctional muscle contraction, weakness, susceptibility to malignant hyperthermia, rhabdomyolysis, as well as other exercise- and/or heat-induced symptoms. There is a wide range of symptoms for RYR-1-related muscle weakness, but they are typically either non-progressive or very slowly progressive.
Common symptoms related to muscle weakness include weakness of the eye muscles (opthalmoparesis) and generalized muscle weakness, typically affecting the muscles closest to the torso of the body (proximal muscle weakness). Some individuals experience muscle cramping and pain, reduced exercise tolerance, and intolerance to heat.
Breathing problems associated with RYR-1-related diseases can range from non-existent to severe and are due to weakness in the muscles of the chest wall. Mild breathing problems can include sleep apnea, requiring breathing support during sleep (CPAP/BiPAP). Severe breathing problems require continuous support via mechanical ventilation.
Mutations in the RYR-1 gene have also been associated with susceptibility to malignant hyperthermia (MH), a severe and potentially fatal reaction to certain types of anesthesia (sedating or paralyzing drugs given by a doctor for medical/surgical procedures). Anyone with an RYR-1 gene mutation should take “malignant hyperthermia precautions” if anesthesia is required for a medical/surgical procedure. In addition, there are case reports of “wake MH”–i.e. an episode of MH that is unrelated to the administration of anesthesia.
RYR-1-related diseases are due to a mutation or mutations in the RYR-1 gene. The RYR-1 gene encodes the RYR-1 receptor, a calcium channel in the sarcoplasmic reticulum in skeletal muscle; the flow of calcium through the RYR-1 receptor is a critical component of excitation-contraction coupling to initiate muscle contraction. A mutation in the RYR-1 gene can alter the number, structure, and/or function of the RYR-1 receptor, which can lead to a wide range of symptoms, as detailed above. There are many different mutations that can occur in the RYR-1 gene which have differing clinical consequences.
There are two main types of inheritance patterns for changes in the RYR-1 gene: autosomal recessive and autosomal dominant. In understanding inheritance patterns of a genetic disease, it should be remembered that all individuals have two “copies” of each gene, one inherited from the mother and one from the father. Recessive means that both copies (alleles) of the gene must have mutations for the patient to be affected clinically; if only one allele possesses a mutation, the patient will be a carrier and will generally not be affected clinically. Dominant means that only one allele of the gene must possess a mutation for the individual to be clinically affected.
There is a third inheritance pattern, called spontaneous or de novo mutations. These are the terms used when the mutation in the affected individual’s RYR-1 gene is not present in either parent.
RYR-1-related diseases are classified as an orphan disease. The prevalence is approximately 1/90,000 in the United States. The disorder most likely goes misdiagnosed or undiagnosed making it difficult to determine the true frequency in the general population. There are also reports of slightly increased prevalence in certain ethnic and geographic populations.
The most definitive diagnostic test for RYR-1-related diseases is genetic testing. A genetic test is often ordered due to clinical suspicion related to clinical signs and symptoms, family history, muscle biopsy, and muscle MRI. Muscle biopsy evaluates for changes in the muscle cell that may be associated with mutations in the RYR-1 gene (e.g. CCD, MMD, CNM, CFTD). Muscle MRI allows the physician to evaluate for muscle damage throughout the body, with varying patterns being associated with various forms of muscular dystrophies and myopathies, including subtypes of RYR-1 myopathy.
At this time, no cure or treatment exists for RYR-1 myopathy.
For acute episodes of MH, dantrolene is administered emergently. In addition, for affected individuals with a history of rhabdomyolysis and/or exertional or heat-related muscle symptoms, dantrolene has been reported as a prophylactic agent. Please consult with your physician.
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