Ryanodine Receptor 1 Related Myopathies
Synonyms
RYR-1-related disease, RYR1 myopathy, RYR1 muscle disease, RYR1-related disorders,Overview
RYR-1-related diseases are inherited forms of muscle disease resulting in a wide range of symptoms, including muscle weakness, a potentially fatal reaction to general anesthesia (malignant hyperthermia), and rhabdomyolysis. Individuals are born with RYR-1-related diseases, inheriting a defective mutation from one or both parents, or a spontaneous mutation (de novo). Mutations or changes in the RYR1 gene are the most common cause of congenital muscle disease.
The RyR1 receptor is a channel in muscle cells that regulate the flow of calcium, a critical component of muscle contraction. A reduced number and/or abnormal RyR1 channels lead to dysfunctional muscle contractions. There are a wide range of symptoms of RYR-1-related diseases, but they are typically either non-progressive or very slowly progressive.
Symptoms
Common symptoms include weakness of the eye muscles and generalized muscle weakness, typically affecting the muscles closest to the torso of the body. Some individuals experience malignant hyperthermia, muscle cramping and pain, difficulties exercising, and heat intolerance. There are typically no heart problems and intelligence is not affected.
Causes
Humans have two copies (alleles) of each gene, one inherited from the mother and one from the father. RYR1-related diseases can be inherited in a dominant or recessive manner and can also occur due to de novo (spontaneous) RYR1 variants.
Dominant inheritance: only one copy of the gene must possess a disease-causing (pathogenic) variation for the individual to be clinically affected.
Recessive inheritance: both copies of the gene must have pathogenic variations for the individual to be clinically affected. If only one copy has a pathogenic variation, the individual will be a carrier and most likely asymptomatic.
De novo variants: variants which occur “spontaneously” i.e., are not present in either parent.
To date more than 700 RYR1 variants have been identified, however, the majority are categorized as “variants of uncertain significance” (variants for which the association with disease has not been firmly established) [1]. The RYR1 gene contains instructions for the body’s cells to produce a large molecule (protein) called the ryanodine receptor (RyR1). RyR1 is the gatekeeper of calcium within the muscle cell. RyR1 is located on the edge (membrane) of the muscle cell calcium store (sarcoplasmic reticulum). Controlled release of calcium from the sarcoplasmic reticulum is required for skeletal muscle contraction. RYR1 variants can alter the number, structure and/or function of RyR1 channels, which can lead to the wide range of symptoms described in the previous section [18].
Diagnosis
RYR-1-related diseases are diagnosed with genetic testing. In addition, a muscle biopsy can be performed, which allows doctors to examine the muscle under the microscope and look for changes at a cellular level that may be associated with RYR-1-related diseases. MRI also allows the doctors to look for characteristic changes in the muscle at a structural level.
Treatment
At this time, there is no cure or approved treatment for RYR1-related diseases.
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.
The RYR-1 Foundation has developed a comprehensive set of Clinical Care Guidelines for RYR1-related diseases.
Supportive Therapies and Genetic Counseling
Physical therapy can be helpful in managing musculoskeletal symptoms associated with RYR1-related diseases. This includes helping to prevent tight joints (contractures), increasing mobility and developing an exercise regimen to improve endurance. Physical activity is an important component of maintaining a healthy lifestyle and preventing deterioration in muscle function. In individuals with RYR1-related diseases, regular low to moderate intensity, low-impact exercise may be of benefit. Since there are no specific guidelines on physical therapy or physical activity for RYR1-related diseases, it is best practice to speak with a physical therapist or sports medicine physician.
Some individuals with RYR1-related diseases have weakness of their breathing muscles. Ventilatory support provided by a machine can therefore be an important tool for individuals with RYR1-related diseases, especially during sleep. These machines can help prevent potentially life-threatening situations (e.g., nocturnal oxygen desaturation) from occurring. These machines provide either bilevel positive airway pressure (BiPAP) or continuous positive airway pressure (CPAP). It is therefore best practice for individuals with RYR1-related diseases to speak with a pulmonologist experienced in neuromuscular diseases to see what ventilatory support may be needed.
Genetic counselling is an important component of care for individuals with genetic diseases, such as RYR1-related diseases. Certified Genetic Counselors are professionals with specialized education and training and can help to answer patient questions related to genetics and health. This ranges from helping to understand the results of genetic testing, how diseases are inherited, which genetic tests may be most appropriate and risk assessment and education related to specific diseases.