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Last updated: 11/18/2024
Years published: 2017, 2021, 2024
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, 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.
Summary
RYR1-related diseases affect skeletal muscle and are caused by changes (variants) in the RYR1 gene 1. 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 2.
RyR1 proteins are located in skeletal muscle cells, where they control calcium release essential for muscle contraction, a process called excitation-contraction coupling. When triggered, RyR1 channels release calcium, initiating contraction. Variants in the RYR1 gene can disrupt this mechanism by causing the RyR1 channels to leak calcium or not release enough, leading to muscle weakness.3
RYR1-related diseases can be inherited in a dominant or recessive manner or result from de novo (spontaneous) variants 4,5.
Introduction
“RYR1-related diseases” is an umbrella term which covers a range of RYR1-related subtypes that affect the neuromuscular system in humans.
Historically, individuals with RYR1-RM were diagnosed based on muscle biopsy features like central cores, rods and fiber type disproportion, though these are not unique to RYR1-RM and may change over time. As more diseases linked to RYR1 variants have emerged—such as King-Denborough syndrome, exercise-induced rhabdomyolysis and adult-onset myopathies—diagnostic overlap has increased. To encompass the expanding range of RYR1-related conditions, including newly identified adult-onset cases, it was suggested to use the term “RYR1-related disorders (RYR1-RD)” as a unified nomenclature for this complex disease spectrum.
Orphanet, the European rare disease database has a list a number of conditions as related to the RYR1 gene. OMIM, Online Mendelian Inheritance in Man has a list of conditions related to RYR1 gene variants.
Some researchers have classified the RYR1-related disorders in several subtypes based on the following criteria.
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 8.
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) 11. MH reactions are treated with the drug Dantrolene.
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:
Main symptoms reported in people affected with RYR1-related diseases include:
RYR-1-related disease subtypes have historically been defined by muscle biopsy findings (histopathology) and/or symptoms (clinical phenotype) 20. It is important to note that many of these subtypes can be caused by changes in other genes.
Subtypes based on muscle biopsy findings
RYR1 variants lead to changes within the muscle cell that can be visualized on muscle biopsy tissue under the microscope. This is done using staining techniques in the laboratory (histopathology). Although histopathology remains an important step in diagnosing neuromuscular disorders, genetic testing is required to link the muscle biopsy findings to a specific gene, such as RYR1. This is because similar muscle biopsy findings can be observed across different neuromuscular disorders. These findings may also change over time (e.g., may not be present when biopsied at a young age).18,19, 20
The earliest reports of these muscle biopsy findings predate genetic testing. As such, many early cases cannot be definitively linked to RYR1. However, following the advent of genetic testing, the link between RYR1 and certain muscle biopsy findings became clearer. Several subtypes are described below.
Central core disease (CCD): First described by Magee and Shy in 1956 21. CCD is usually inherited in a dominant manner. When looked at under the microscope, CCD muscle fibers are stained dark but also have light areas in the middle of fibers which have no stain. These light areas represent an absence of mitochondrial activity 22. Mitochondria are the structures responsible for generating energy for the cell.
CCD causes mild to very severe muscle weakness, however, most affected individuals experience persistent, mild muscle weakness that may worsen over time. This weakness affects the muscles near the trunk of the body (proximal muscles), particularly in the upper legs and hips. Muscle weakness can also cause affected infants to appear “floppy” and result in a delay of motor milestones such as sitting, standing and walking. Severely affected infants experience profoundly weak muscle tone (hypotonia), resulting in feeding difficulties and serious or life-threatening breathing problems. CCD is also associated with abnormalities of the skeleton such as excessive curvature of the spine (scoliosis), hip dislocation and joint deformities called contractures that restrict the movement of certain joints. Individuals with CCD are usually able to walk throughout their lifetime 4.
Multiminicore disease (MmD): MmD was first described as multicore disease by Engel and colleagues in 1971 23. MmD is inherited in a recessive manner and causes muscle weakness and related health problems ranging from mild to life-threatening. When looked at under the microscope, MmD muscle fibers are stained dark but also have several light areas within each muscle fiber that have no stain resulting in a “moth-eaten” appearance. As in CCD, these areas without staining represent an absence of mitochondrial activity.
In general, MmD causes more severe symptoms than CCD 24. Researchers have identified four distinct forms of MmD:
Muscle weakness causes affected infants to appear “floppy” with poor muscle tone (hypotonia) and results in delay of motor milestones such as sitting, standing and walking. Stiffness of the chest wall and the spine has been associated with MmD. When combined with weakness of the muscles needed for breathing, severe or life-threatening respiratory problems can occur. Almost all children with MmD develop an abnormal curvature of the spine (scoliosis), which appears during childhood and steadily worsens over time. 4. More information about MmD can be found here.
Congenital fiber type disproportion (CFTD): First described by Brooke and colleagues in 1969 25, CFTD is inherited in a recessive manner 6. When looked at under the microscope, CFTD muscle tissue has type 1 (slow-twitch) muscle fibers that are consistently smaller than type 2 (fast-twitch) muscle fibers.
CFTD causes muscle weakness, particularly in the muscles of the shoulders, upper arms, hips and thighs. Weakness can also affect facial muscles, extraocular muscles that control eye movement (ophthalmoplegia) and muscles of the upper eyelid (ptosis). Individuals with CFTD generally have a long face, a high arch in the roof of the mouth (high-arched palate) and crowded teeth. Affected individuals may have joint deformities (contractures) and an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). Approximately 30% of people with CFTD experience mild to severe breathing problems related to weakness of muscles needed for breathing. Some people who experience these breathing problems require use of a machine to help regulate their breathing at night, and occasionally during the day as well. About 30% of affected individuals have difficulty swallowing due to muscle weakness in the throat. Rarely, people with this condition have a weakened and enlarged heart muscle (dilated cardiomyopathy) 26. Causative gene variants for CFTD have been identified in other genes as well, ACTA1, TPM3 and SELENON.
Centronuclear myopathy (CNM): First described by Spiro and colleagues in 1966 27, CNM is inherited in a recessive manner. When looked at under the microscope, CNM muscle fibers show nuclei (structures containing chromosomes) that are localized to the center of muscle fibers, rather than to the periphery. This muscle biopsy finding has also been identified in several other genetic neuromuscular disorders including MTM1, BIN1 and DNM2-related myopathies.
CNM can cause muscle weakness at any time from birth to early adulthood. Muscle weakness due to CNM can lead to delayed motor milestones (crawling or walking) and can be slowly progressive. Some affected individuals may require wheelchair assistance. Other symptoms include mild to severe breathing problems, upper eyelid drooping(ptosis), weakness in facial muscles, foot abnormalities, high arch in the roof of the mouth (high-arched palate) and abnormal curvature of the spine (scoliosis) 5.
Other RYR1-related disease subtypes based on histopathology include dusty core disease (DuCD) 28, congenital neuromuscular disease with uniform type 1 fiber (CNMDU1) 29 and core-rod myopathy 30.
Subtypes based on clinical phenotypes
Many RYR1-related diseases have been characterized by their associated symptoms (clinical phenotype). Several of these subtypes are described below.
Malignant hyperthermia susceptibility (MHS): MHS was first described in humans by Denborough and Lovell in 1960 31. People with MHS may experience normal everyday functioning without any muscle weakness. However, when exposed to certain anesthetic agents or depolarizing muscle relaxants, patients can experience an episode of malignant hyperthermia (MH). MH episodes are characterized by an abnormal increase in body heat and metabolism with associated muscle rigidity and increased heart rate. The body temperature may exceed 110 degrees Fahrenheit and muscle breakdown can co-occur. Severe complications of MH include brain damage, internal bleeding, cardiac arrest, and/or multisystem organ failure. Associated heart and vascular complications can be fatal. Patients who develop an MH episode are treated with the drug dantrolene 11. Guidelines for interpreting whether RYR1 variants are disease-causing (pathogenic) for MH are currently being developed 32.
Rhabdomyolysis-myalgia syndrome and heat-related illness: Individuals who are MH susceptible due to one or more RYR1 variants are also at risk for muscle breakdown (rhabdomyolysis) as well as other heat and exertion-related muscle pain (myalgia) and cramping symptoms 8. Rhabdomyolysis is associated with a range of external triggers, including strenuous exercise beyond the limit of fatigue, heat stress, illicit drug or alcohol abuse, use of supplements or certain medications, recent viral illness or muscle trauma. Signs and symptoms of rhabdomyolysis include severe muscle pain, sudden elevation and subsequent fall of serum creatine phosphokinase (CPK) levels and products of muscle breakdown in the urine (myoglobinuria). The course of rhabdomyolysis is mostly characterized by myalgia with mild to moderate CPK increases. In these mild cases, many patients will not seek medical attention. However, in some cases, the clinical course is severe, resulting in profound elevations in CPK levels (hyperCKaemia), acute renal failure, increased pressure within muscles (compartment syndrome), formation of blood clots (disseminated intravascular coagulation), cardiac arrhythmias secondary to electrolyte imbalances and possibly cardiac arrest if left untreated 33.
Other syndromes and conditions associated with RYR1 variations include King-Denborough syndrome 7, fetal akinesia deformation syndrome (FADS) 34, 35, lethal multiple pterygium syndrome (LMPS) 34, exertional heat illness (EHI) 36, late-onset axial myopathy 9, distal myopathy 37, samaritan myopathy 38 and atypical periodic paralysis. 39
RYR1-relatted diseases are caused by changes (variants) in the RYR1 gene.
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. 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 gene 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 3.
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. 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.
Inheritance
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) variant for the individual to be clinically affected.
Recessive inheritance: both copies of the gene must have pathogenic variants for the individual to be clinically affected. If only one copy has a pathogenic variant, 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, meaning that are not inherited. For more information on inheritance of RYR1-related diseases, refer to the RYR-1 Clinical Care Guidelines
RYR1-related diseases are rare and classified as an orphan disease with an estimated prevalence of least 1:90,000 in the United States 19. 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.
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.
Anyone with a potentially pathogenic RYR1 variant is advised to take MH precautions. This includes wearing an MH alert bracelet and speaking with the physician about having a RYR1 variant before undergoing anesthetic procedures or using muscle relaxants. More information on MH precautions and questions to ask the doctor are provided here and in the RYR-1 Clinical Care Guidelines.
Two organizations provide information and support for malignant hyperthermia:
In addition, people with one or more RYR1 variants associated with MH should be aware of the rhabdomyolysis triggers and may want to consult with a sports medicine physician before starting an exercise regimen and/or sports.
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 weaknesses in 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. Genetic Counselors are health 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 40.
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 41. 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:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
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