RYR1-Related Diseases

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.

Synonyms of RYR1-Related Diseases

RYR1 myopathy
RYR1 muscle disease
RYR1-related disorders

General Discussion

Summary

RYR1-related diseases affect skeletal muscle and are caused by changes in the RYR1 gene. These changes are referred to as genetic variants (mutations) [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].

Introduction

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 [3].

“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 [5]. 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:

central core disease (CCD) [4]
multiminicore disease (MmD) [4]
centronuclear myopathy (CNM) [5]
congenital fiber-type disproportion (CFTD) [6]

Symptoms (clinical phenotype). Examples include:

King-Denborough syndrome (KDS) [7]
rhabdomyolysis-myalgia syndrome [8]
late-onset axial myopathy [9]
atypical periodic paralysis [10]

Drug-gene interactions (pharmacogenetics). Examples include:

malignant hyperthermia susceptibility (MHS) [11]
statin-induced myopathy [12]

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. 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.

Signs & Symptoms

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:

Weakness of the extraocular eye muscles (ophthalmoparesis)
Weakness of the facial muscles
Weakness of muscles closest to the torso (proximal muscle weakness)
Muscle cramping and pain (myalgia)
Decreased tolerance to exercise and heat

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 [13]. 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) [11]. 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 [15] (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 [8]. 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).

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].

Affected Populations

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.

Related Disorders

RYR-1-related disease subtypes have historically been defined by muscle biopsy findings (histopathology) and/or symptoms (clinical phenotype) [20].

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).

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]. More information about CCD can be found here.

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:

Classic form: most common form associated with neck (axial) and trunk muscle weakness beginning in infancy or early childhood, abnormal curvature of the spine (scoliosis), respiratory impairment, and hyperlaxity (increased flexibility) of limb joints.
Ophthalmoplegia form: associated with paralysis or weakness of eye muscles with generalized muscle weakness and severe facial weakness.
Early-onset form: associated with arthrogryposis (joint contractures from birth).
Slowly progressive form: associated with hand muscle involvement.

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. Although MmD is most frequently associated with RYR1 variants, MmD has also been reported in individuals with variants in other genes such as SEPN1 [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]. More information on CFTD can be found here.

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]. More information on CNM can be found here.

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 phenotype

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]. MHS individuals 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. 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 cardiovascular 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]. Anyone with a potentially pathogenic RYR1 variant is advised to take MH precautions. This includes wearing a MH alert bracelet and speaking with your physician about your RYR1 variant before undergoing anesthetic procedures or using muscle relaxants. More information on MH precautions and questions to ask your physician are provided here and in the RYR-1 Clinical Care Guidelines (Chapter 4).

Two organizations exist that are dedicated to malignant hyperthermia:

Malignant Hyperthermia Association of the United States: MHAUS
European Malignant Hyperthermia Group: EMHG

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 patients 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]. Therefore, individuals 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 prior to the initiation of an exercise regimen and/or sporting activities.

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].

Diagnosis

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.

Standard Therapies

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.

Investigational Therapies

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/for-patients-and-families/information-resources/news-patient-recruitment/

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/

NORD Member Organizations

RYR-1 Foundation
- PO Box 13312
- Pittsburgh, PA 15243 USA
- Website: http://www.ryr1.org

Other Organizations

Malignant Hyperthermia Association of the United States
- 1 North Main St
- PO Box 1069
- Sherburne, NY 13460 USA
- Phone: (607) 674-7901
- Email: [email protected]
- Website: http://www.mhaus.org

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Years Published

2017, 2021

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