NORD gratefully acknowledges Joshua J. Todd, PhD, CCRP, National Institutes of Health, Michael F. Goldberg, MD, MPH, Co-Founder and President, RYR-1 Foundation, Robert T. Dirksen, PhD, University of Rochester, and Nicol C. Voermans, MD, PhD, Radboud University (The Netherlands), for the preparation of this report.
RYR1-related diseases affect skeletal muscle and are caused by changes in the RYR1 gene. These changes are referred to as genetic variants (mutations) . RYR1 variants are the most common cause of muscle weakness present from birth (congenital myopathy). The RYR1 gene contains instructions for the body’s cells to produce a protein called the ryanodine receptor (RyR1) which is important for muscle function .
RyR1 proteins are located in skeletal muscles, more specifically on the outer edge (membrane) of a calcium-containing structure (sarcoplasmic reticulum) within muscle cells. For skeletal muscles to contract and produce force, calcium must be released from the sarcoplasmic reticulum in a highly controlled manner into the space outside the cell (cytoplasm). Here the calcium binds to other proteins to initiate muscle contraction and produce force. This process is referred to as “excitation-contraction coupling.” RyR1 acts as a gate for muscle cell calcium stores. RYR1 variants can prevent RyR1 proteins from being fully closed when they are supposed to be (causing calcium leak) or not opening fully when they are supposed to (causing decreased calcium release). Dysfunctional RyR1 can therefore impair excitation-contraction coupling resulting in muscle weakness. A visual representation of this process is available from the RYR-1 Foundation in the Clinical Care Guidelines (Chapter 3). Dysfunctional flow of calcium within muscle cells can also increase production of unstable molecules (free radicals) resulting in oxidative stress (an imbalance between free radicals and antioxidants). RyR1 proteins are susceptible to modification from oxidative stress. This modification can make the existing dysfunction in muscle cell calcium flow worse (increased RyR1 leakiness). Certain RYR1 variants can also result in less RyR1 protein being produced. Collectively these mechanisms, all stemming from defects in the RYR1 gene, are responsible for RYR1-related diseases .
“RYR1-related diseases” is an umbrella term which covers a range of RYR1-related subtypes that affect the neuromuscular system in humans. RYR1-related diseases can be inherited in a dominant or recessive manner or result from de novo (spontaneous) variants . For more information on inheritance of RYR1-related diseases, refer to the RYR-1 Clinical Care Guidelines (Chapter 1). Subtypes of RYR1-related disease have been named based on the following.
Muscle biopsy findings (histopathology). Examples include:
Symptoms (clinical phenotype). Examples include:
Drug-gene interactions (pharmacogenetics). Examples include:
Symptoms of RYR1-related diseases are often present from birth (congenital) or appear in early infancy and can be static, dynamic or a combination of both. Static symptoms (present at all times) include muscle weakness, motor delay, difficulties walking and climbing stairs, scoliosis, facial muscle weakness and eye muscle weakness (ophthalmoparesis) [13, 14]. Dynamic symptoms (come and go based on certain triggers) include heat illness, exercise-induced muscle breakdown (rhabdomyolysis), muscle pain (myalgia), muscle cramps and fatigue .
RYR1 variants are also the leading cause of malignant hyperthermia (MH) susceptibility (MHS) accounting for >60% of cases. MH is a potentially fatal reaction which occurs in susceptible individuals following exposure to volatile anesthetics or depolarizing muscle relaxants which trigger a rapid increase in body temperature (hyperthermia) and muscle breakdown (rhabdomyolysis) . MH reactions are treated with the drug Dantrolene. For more information on MHS, refer to the RYR-1 Clinical Care Guidelines (Chapter 4).
Symptoms experienced by individuals with RYR1-related diseases can be highly variable; however, disease course is often non-progressive or very slowly progressive. Lifespan is generally normal in affected individuals and cognitive development is unaffected. Although there is no cure or approved treatment for RYR1-related diseases, supportive strategies including physical therapy can help manage functional impairments and promote a high quality of life.
The signs and symptoms of RYR1-related diseases are highly variable, sometimes even among affected individuals within the same family. In general, greater disease severity is associated with a recessive inheritance pattern, however, there are exceptions.
Common symptoms related to skeletal muscles include:
Breathing problems: It is very important to be aware of breathing problems associated with RYR1-related diseases since this can be severe to life-threatening in some patients. Weakness of breathing (respiratory) muscles can occur in affected individuals because the muscles that support breathing (diaphragm and accessory abdominal muscles) are skeletal muscles. Breathing problems can range from mild impairment of respiratory function, to sleep apnea requiring breathing support during sleep (CPAP/BiPAP), to severe breathing problems require continuous support via mechanical ventilation . For more information on breathing problems associated with RYR1-related diseases, refer to the RYR-1 Clinical Care Guidelines (Chapter 5).
Malignant hyperthermia: Some RYR1 variants are associated with susceptibility to malignant hyperthermia (MH), a severe and potentially fatal reaction to certain inhaled anesthetics (sedating or paralyzing drugs given by a doctor for medical/surgical procedures) or depolarizing muscle relaxants (succinylcholine) . Anyone with a potentially disease-causing (pathogenic) RYR1 variant should take malignant hyperthermia precautions if anesthesia or succinylcholine is required for a medical/surgical procedure. Although rare, there are also case reports of episodic RYR1-related crises  (also referred to as “MH-like events,” or “awake MH”) in which individuals develop life-threatening reactions to non-anesthetic stimuli such as environmental heat stress or viral illness [16, 17]. For more information on MH, refer to the RYR-1 Clinical Care Guidelines (Chapter 4).
Exertional rhabdomyolysis: Certain RYR1 variants may also lower the threshold for onset of muscle fiber breakdown upon physical exertion (exertional rhabdomyolysis), accounting for up to 30% of reported cases . Symptoms include muscle pain, exercise intolerance, and cold-induced muscle stiffness. Affected individuals are often asymptomatic prior to being exposed to one or more triggers which include exercise in the heat, viral illness and use of statin medications. A subset of individuals with RYR1-related exertional rhabdomyolysis also test positive for malignant hyperthermia susceptibility. Preventative measures for exertional rhabdomyolysis include limiting exercise in hot and humid environments and consulting a sports medicine specialist or physical therapist to help develop a structured incremental exercise program at lower intensities. For more information on exertional rhabdomyolysis, refer to the RYR-1 Clinical Care Guidelines (Chapter 4).
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) . 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 .
RYR1-related diseases are rare and classified as an orphan disease with an estimated prevalence of least 1:90,000 in the United States . This estimate was based on a pediatric population study. Based on this, the overall frequency in the general population is likely to be higher. True disease prevalence is difficult to calculate since many cases go misdiagnosed or undiagnosed. There are also reports of slightly increased prevalence in certain ethnic and geographic populations.
The most definitive diagnostic test for RYR1-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 muscle fibers that may be associated with RYR1-related disease (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 forms of muscular dystrophies and myopathies, including subtypes of RYR1-related diseases.
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.
As of January 2021, one phase II clinical trial has been completed in individuals with RYR1-related diseases. This randomized, double-blind, placebo-controlled trial tested the effectiveness of an antioxidant compound (N-acetylcysteine) on oxidative stress and motor function in ambulatory individuals .
A pilot study in patients with CCD and MmD demonstrated that salbutamol, a drug which causes relaxation of the airway smooth muscle (beta-adrenergic receptor agonist) may be of benefit to those with RYR1-related diseases . Although improvements in muscle and lung function were observed, these exploratory findings have not been further investigated in a larger controlled clinical trial. There are also anecdotal reports of potential benefit following treatment with pyridostigimine [42, 43].
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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