Rare Disease Database

Mutations in the RYR-1 gene can lead to changes in the muscle cell that result in varying appearances based on muscle biopsy. These include central core disease (CCD), centronuclear myopathy (CNM), multiminicore disease (MMD), and congenital fiber-type disproportion (CFTD). These various terms have been a source of confusion for patients and physicians. It is critical to remember that regardless of the microscopic appearance of the muscle biopsy, genetic testing is required to confirm the diagnosis of RYR-1-related diseases.

“Central core” is the term used by pathologists to describe muscle biopsy tissue that is devoid of a particular stain in the middle of a muscle fiber, giving the “core” appearance. CCD causes muscle weakness that ranges from almost asymptomatic to very severe. Most people with CCD experience persistent, mild muscle weakness that may worsen with time. This weakness affects the muscles near the center of the body (proximal muscles), particularly muscles in the upper legs and hips. Muscle weakness can also cause affected infants to appear “floppy” and can delay the development of motor skills such as sitting, standing, and walking. In severe cases, affected infants experience profoundly weak muscle tone (hypotonia), resulting in feeding difficulties, and serious or life-threatening breathing problems. CCD is also associated with skeletal abnormalities such as abnormal curvature of the spine (scoliosis), hip dislocation, and joint deformities called contractures that restrict the movement of certain joints. Individuals with CCD tend to remain ambulatory throughout their lifetime. (For more information about this condition, search for “central core disease” in the Rare Disease Database.)

CNM has been associated with several different genetic conditions, including RYR-1 mutations. Individuals with CNM generally begin experiencing muscle weakness at any time from birth to early adulthood. Muscle weakness due to CNM can lead to delayed development of motor skills (crawling or walking), and can be slowly progressive. Some affected individuals may require wheelchair assistance. Other symptoms include: mild to severe breathing problems, ptosis (upper eyelid drooping), weakness in facial muscles, foot abnormalities, a high arch in the roof of the mouth (high-arched palate), and scoliosis. (For more information about this condition, search for “centronuclear myopathy” in the Rare Disease Database.)

MMD causes muscle weakness and related health problems that range from mild to life-threatening. Researchers have identified at least four forms of MMD, which can be distinguished by their characteristic signs and symptoms. The most common form, called the classic form, causes muscle weakness beginning in infancy or early childhood. This weakness is most noticeable in muscles of the trunk and neck (axial muscles) and is less severe in the arm and leg muscles. Muscle weakness causes affected infants to appear “floppy” (hypotonic) and can delay the development of motor skills such as sitting, standing, and walking. The disease causes muscles of the chest wall and spine to stiffen. When combined with weakness of the muscles needed for breathing, this stiffness leads to severe or life-threatening respiratory problems. Almost all children with MMD develop an abnormal curvature of the spine (scoliosis), which appears during childhood and steadily worsens over time. It should be noted that certain individuals with MMD have mutations in the RYR-1 gene, while other individuals have mutations in other genes (e.g. SEPN1).

People with CFTD typically experience muscle weakness, particularly in the muscles of the shoulders, upper arms, hips, and thighs. Weakness can also affect the muscles of the face, muscles that control eye movement (ophthalmoplegia), and muscle 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 this disorder 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). (For more information about this condition, search for “congenital fiber type disproportion” in the Rare Disease Database.)

Malignant hyperthermia (MH)-susceptible individuals may experience normal everyday functioning without any muscle weakness. However, when exposed to certain anesthetic agents, patients can experience an episode of MH. MH is an abnormal increase in body heat and metabolism with associated muscle rigidity and increased heart rate. Body temperature may exceed 110 degrees F. along with associated muscle breakdown. Severe complications of MH include: brain damage, internal bleeding, cardiac arrest, and/or multisystem organ failure. Associated cardiovascular complications can be fatal. Anyone with an RYR-1 mutation(s) is advised to take “malignant hyperthermia precautions” if anesthesia is required for a medical/surgical procedure. (For more information about this condition, search for “malignant hyperthermia” in the Rare Disease Database.)

Patients with MH-susceptible RYR-1 mutations are also at risk for rhabdomyolysis as well as other heat and exertion-related muscle pain and cramping. Rhabdomyolysis is the general term for muscle breakdown associated with a wide variety of external triggers, including: strenuous exercise beyond the limit of fatigue, 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 (muscle pain) 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 hyperCKaemia, acute renal failure, compartment syndrome, disseminated intravascular coagulation, cardiac arrhythmias secondary to electrolyte imbalances, and possibly cardiac arrest if left untreated. Therefore, individuals with RYR-1 mutations, especially those known to be associated with MH-susceptibility, should be aware of the triggers of rhabdomyolysis and may want to consult with a physician prior to the initiation of an exercise regimen and/or sports. There may be a role for dantrolene as a prophylactic agent to prevent rhabdomyolysis and other exertional and heat-related muscle symptoms.