February 03, 2022
Years published: 1986, 1990, 1992, 1994, 2001, 2003, 2007, 2022
NORD gratefully acknowledges Tokunbor A. Lawal, PhD, NIH Independent Research Scholar, National Institute of Nursing Research, for assistance in the preparation of this report.
Central core disease (CCD) is a rare genetic neuromuscular disorder that is classified as a congenital myopathy, meaning that it is present at birth (congenital) and is a disorder that causes muscle weakness (myopathy). Affected infants have low muscle tone (hypotonia) resulting in abnormal “floppiness”, muscle weakness and a variety of skeletal abnormalities such as side-to-side curvature of the spine (scoliosis). Muscle weakness normally affects the proximal muscles, which are those muscles closest to the center of the body such as the muscles of the shoulder, pelvis and upper arms and legs. Affected infants may experience delays in acquiring motor milestones such as crawling or walking. Some individuals with CCD may be susceptible to developing malignant hyperthermia, a condition in which individuals develop adverse reactions to certain anesthetic drugs during surgical procedures. CCD may be very mild or may cause serious complications. Most cases are inherited in an autosomal dominant pattern and associated with stable or slowly progressive muscle disease and a good prognosis. Some cases are inherited in an autosomal recessive pattern and are more likely to be associated with severe complications.
The disorder derives its name from characteristic, abnormal areas within the centers of muscle fibers. These abnormal “central cores” are detected during microscopic examination of small samples of muscle tissue (muscle biopsy). The muscle biopsy may reveal characteristic findings such as a lack of mitochondria, the part of the cell that releases energy, or absence of the sarcoplasmic reticulum, a membrane-bound structure in muscle fibers.
The specific symptoms and severity of CCD vary greatly from person to person. Some individuals may develop very mild muscle disease that may go unnoticed or get a congenital myopathy incidental finding report from a next-generation sequencing (NGS) genetic test; others may develop serious muscle disease that can delay motor milestones or cause serious breathing (respiratory) difficulties. In most patients, muscle weakness in CCD is not progressive or only progresses very slowly.
Infants with CCD typically have diminished muscle tone (hypotonia), resulting in abnormal “floppiness”. Weakness of the proximal muscles occurs early during infancy. The proximal muscles are those muscles closest to the center of the body such as the muscles of the shoulder, pelvis and upper arms and legs. In CCD, the hip-girdle area is especially affected by muscle weakness. In some patients, muscle cramps or stiffness may occur especially upon exertion. Muscle weakness may cause delays in reaching milestones that require the coordination and development of muscles (motor milestones) such as crawling, standing and walking. Intelligence is unaffected.
Certain facial muscles may be affected in individuals with CCD. Rarely, individuals may develop wasting of facial muscles. Mild facial muscle involvement may not be noticeable, except for the inability to bury the eyelashes resulting from weakness of muscles surrounding the eyes (signe de cils). In classic, autosomal dominant CCD, the muscles around the eyes are not affected, an important finding that distinguishes CCD from other congenital myopathies. In the autosomal recessive form of CCD, these muscles may be affected.
A variety of skeletal abnormalities often occur in individuals with CCD including abnormal side-to-side curvature of the spine (scoliosis) and congenital dislocation of the hip, a condition in which the hip joint is too shallow causing the upper bone of the leg (femur) to pop out of the joint. These skeletal findings may be present at birth. Additional skeletal symptoms may occur including front-to-back curvature of the spine (kyphosis), dislocation of the kneecap (patella), clubfoot (talipes equinovarus), flattening of the arch of the foot (flatfoot or pes panus) and an abnormally high arch of the foot (pes cavus). Abnormal tightening of certain joints, resulting in restricted or stiff movements (contractures) occurs rarely. The Achilles tendon is most common site for contracture.
Some patients with CCD may present with severe symptoms at birth or early during infancy. Severe symptoms associated with CCD may be caused by a prolonged decrease or absence of movements by the fetus (fetal akinesia sequence). Such symptoms include profoundly low muscle tone (hypotonia or floppiness), reduced mobility of many joints of the body due to the overgrowth (proliferation) of fibrous tissue in the joints (arthrogryposis multiplex congenita) and breathing difficulties that may require a mechanical device to assist breathing. Some severely affected infants may not be able to walk independently.
Individuals with CCD have susceptibility to developing malignant hyperthermia, an autosomal dominant genetic disorder in which affected individuals are susceptible to adverse reactions to certain anesthetic drugs. The drugs that trigger malignant hyperthermia are the volatile inhalation gases including sevoflurane, desflurane, isoflurane, halothane, enflurane, methoxyflurane and depolarizing muscle relaxants such a succinylcholine. The characteristics of a malignant hyperthermia episode are variable and include muscle rigidity, high blood pressure (hypertension), increased levels of carbon dioxide in the blood or exhaled gas, a rapid irregular heart rate, rapid deep breathing, bluish skin color (cyanosis), acidity of the blood and muscle damage. Body temperature can rise rapidly (hyperthermia), but sometimes only occurs late in an episode. When an episode is not recognized and treated, internal bleeding, brain damage, skeletal muscle degeneration (rhabdomyolysis) and kidney and heart failure can result.
Most cases of CCD are thought to be caused by specific variants (mutations) in the ryanodine receptor (RYR1) gene.
The RYR1 gene regulates production of a protein (known as RyR1 calcium-release channel) that plays an essential role in calcium regulation in skeletal (voluntary) muscle. Certain variants in the RYR1 gene are thought to result in abnormalities in the normal flow of electrically charged particles known as calcium ions through pores in cell membranes (calcium channels), potentially leading to impaired maturation of skeletal muscle, abnormalities in muscle contraction and other symptoms and findings associated with the disorder.
Individuals who carry one abnormal RYR1 gene may also be at increased risk for malignant hyperthermia and are advised to avoid exposure to inhaled anesthetics and succinylcholine during invasive or surgical procedures. Changes in the RYR1 gene appear to be responsible for over 50% of the susceptibility to malignant hyperthermia. (For further information on this condition, search for “malignant hyperthermia” in the Rare Disease Database.)
In most patients, CCD is inherited in an autosomal dominant pattern. Rarely, CCD can be inherited in an autosomal recessive pattern and associated with more severe symptoms.
Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. When CCD occurs in the absence of any apparent family history of the disorder, this may be referred to as “de novo”. The risk of passing the abnormal gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Central core disease affects males and females in equal numbers. The exact incidence and prevalence of CCD is unknown. CCD is believed to be the most common form of congenital myopathy, which as a group occurs in 6 out of every 100,000 live births.
The disorder was originally described in 1956 (Shy GM, Magee KR) in five members in three successive generations of a family. However, the disease was not termed “central core disease” until later.
CCD may be diagnosed based upon a thorough clinical evaluation, detection of characteristic physical findings, patient and family history and specialized tests. However, genetic testing is gradually becoming the first step in the diagnostic process, with other evaluations performed to confirm the genetic results. The disorder may sometimes be diagnosed during the first years of life; however, not infrequently, it may not be recognized until later during childhood, adolescence or adulthood following certain associated musculoskeletal abnormalities (see “Symptoms”).
Diagnostic studies may include blood tests, electromyography (EMG), nerve conduction velocity studies, muscle biopsies and/or other tests. Blood studies typically reveal normal or slightly increased levels of the enzyme creatine kinase in the fluid portion of the blood (except during a malignant hyperthermic crisis). EMG is a test that records electrical activity in skeletal (voluntary) muscles at rest and during muscle contraction. Reports indicate that EMG results may be almost normal in people with CCD, particularly in younger children; however, the recorded electrical activity in certain muscle fibers during activity (motor unit action potential) may be of unusually short duration and low amplitude. During a nerve conduction velocity study, motor and sensory nerves are electrically stimulated to assess a nerve’s ability and speed to conduct nerve impulses. Evidence indicates that the results of such a study are usually normal in people with CCD.
Small samples of muscle tissue are also removed and examined microscopically with the use of special stains (histochemistry). Microscopic evaluation typically reveals dense, ill-defined areas within the central portion of muscle fibers (“central cores”) that contain myofibril material. Muscle fibers are thread-like muscle cells within skeletal muscle, which are comprised of slender, usually highly organized strands known as myofibrils. These altered regions or central cores within muscle fibers may appear to lack enzyme activity, contrasting with normal activities in surrounding fibers. Enzymes are proteins that accelerate particular chemical activities in the body. In addition, absence of certain cellular structures called mitochondria may be confirmed with an electron microscope, which uses electron beams rather than visible light for increased magnification. Mitochondria are the rod-like structures (organelles) outside the nuclei of cells that serve as a primary source of cellular energy due to their complex, continual chemical reactions. As a result, they are important to the proper functioning of muscle cells, including those of skeletal muscle.
Additional diagnostic studies may also be recommended to detect and/or characterize particular abnormalities that may be associated with the disorder. For example, advanced imaging techniques may be conducted to characterize certain skeletal abnormalities.
The treatment of CCD is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; specialists who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues in children (pediatric orthopedists); physicians who specialize in physical medicine and rehabilitation (physiatrists); physical therapists; occupational therapists and/or other health care professionals.
Specific therapies for the treatment of CCD are symptomatic and supportive. In cases of “floppiness” during infancy, disease management may require careful attention to posture, the use of appropriate adaptive seating with careful trunk and head support and other measures. In addition, for infants with extremely severe weakness, tube-feeding may be required to ensure proper caloric and nutritional intake.
In some patients, various orthopedic techniques, such as the use of special braces, other devices and/or surgical measures, may be recommended to help prevent and/or treat certain musculoskeletal abnormalities potentially associated with the disorder. Family-centered, early intervention services may also be advised, such as physical and occupational therapy, including assistance with seating and mobility devices; instruction for parents on proper handling, exercising and stretching certain muscles; and/or other measures as appropriate.
Because individuals with CCD may be at risk for malignant hyperthermia when exposed to certain general anesthetics or muscle relaxants, this risk must be taken into consideration by surgeons, anesthesiologists, dentists and other health care workers when making decisions concerning surgery, the use of certain anesthetics and the administration of certain medications. Any surgical procedure, including dental surgery, must be performed in a setting that is well monitored by anesthesiologists with necessary precautions to help prevent or appropriately manage a possible malignant hyperthermic event.
Genetic counseling is recommended for affected individuals and their families.
For additional information on treatment and symptom management, please refer to the RYR-1 Foundation clinical care guidelines (https://www.ryr1.org/ccg) and TREAT NMD family guide (https://treat-nmd.org/wp-content/uploads/2021/07/uncategorized-CMFG-11-4-2019_Update.pdf)
Pre-clinical research discoveries continue to inform the design of clinical trials to investigate and develop effective treatments for CCD.
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
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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