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Central Core Disease

, MD, PhD and , MD, PhD.

Author Information
, MD, PhD
National Center of Neurology and Psychiatry
National Institute of Neuroscience
Tokyo, Japan
, MD, PhD
National Center of Neurology and Psychiatry
National Institute of Neuroscience
Tokyo, Japan

Initial Posting: ; Last Update: May 11, 2010.


Disease characteristics. Central core disease (CCD) is characterized by muscle weakness ranging from mild to severe. Most affected individuals have mild disease with symmetric proximal muscle weakness and variable involvement of facial and neck muscles. The extraocular muscles are often spared. Motor development is usually delayed, but in general, most affected individuals acquire independent ambulation. Life span is usually normal. Severe disease is early in onset with profound hypotonia often accompanied by poor fetal movement, spinal deformities, hip dislocation, joint contractures, poor suck, and respiratory insufficiency requiring assisted ventilation. The outcome ranges from death in infancy to survival beyond age five years. Typically the weakness in CCD is not progressive.

Diagnosis/testing. The diagnosis of CCD is based on clinical findings of muscle weakness, the histopathologic findings of characteristic cores on muscle biopsy, and molecular genetic testing. Most CCD is associated with mutations in RYR1, the gene encoding the ryanodine receptor 1.

Management. Treatment of manifestations: Physical therapy for hypotonia and weakness that may include stretching and mild to moderate low-impact exercise; assistive devices as needed for ambulation; orthopedic surgery as needed for scoliosis, congenital hip dislocation, foot deformities; respiratory support, breathing exercises, chest physiotherapy as needed; dietary supplementation and nasogastric or gastrostomy feeding as needed.

Prevention of secondary complications: Intervention as needed to prevent respiratory compromise from scoliosis; immunization against influenza; prompt treatment of respiratory infection; mobility and physical therapy to prevent joint contractures.

Surveillance: Routine assessment of spine for scoliosis, joints for contractures, respiratory parameters (e.g., respiratory rate, peak expiratory flow rate [PEFR], forced vital capacity [FVC], and forced expiratory volume in one second [FEV1]), motor abilities to determine need for physical therapy, occupational therapy, assistive devices; sleep studies when signs of nocturnal hypoxia are present.

Agents/circumstances to avoid: Although the actual risk for malignant hyperthermia susceptibility is unknown, it is prudent for individuals with CCD to avoid inhalational anesthetics and succinylcholine.

Evaluation of relatives at risk: If the RYR1 mutation is known, it is appropriate to offer at-risk relatives molecular genetic testing to identify those with possible increased malignant hyperthermia susceptibility.

Genetic counseling. Central core disease (CCD) is usually inherited in an autosomal dominant (AD) manner but can be inherited in an autosomal recessive (AR) manner. Most individuals diagnosed with AD central core disease have an affected parent or an asymptomatic parent who has a disease-causing mutation. The proportion of AD CCD caused by de novo mutations is unknown. Each child of an individual with AD CCD has a 50% chance of inheriting the mutation. The parents of a child with AR CCD are obligate heterozygotes and therefore carry one mutant allele. Heterozygotes (carriers) are often asymptomatic. At conception, each sib of an individual with AR CCD has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Prenatal diagnosis for pregnancies at increased risk for AD or AR CCD is possible once the disease-causing mutation(s) have been identified in an affected family member.


Clinical Diagnosis

The diagnosis of central core disease (CCD) is based on a combination of clinical findings of muscle weakness and histopathologic findings of characteristic cores on muscle biopsy (see Testing), and confirmed in most cases by the presence of a disease-causing mutation in the gene RYR1 (see Molecular Genetic Testing).

Because the clinical presentation ranges from the absence of symptoms to severe features including the need for ventilatory support, it is difficult to make the diagnosis of CCD based on clinical findings alone.

Note: Although controversial, the diagnostic criterion for CCD (for the purpose of this review) is the presence of CHARACTERISTIC cores in a significant number of fibers on muscle biopsy, even in individuals who are seemingly asymptomatic.

Clinical history. Although central core disease has a wide spectrum of symptoms and presentations, the following clinical findings can provide clues to the diagnosis:

  • In early-onset disease:
    • Hypotonia and generalized weakness, often accompanied by perinatal complications including poor fetal movement, respiratory insufficiency, and poor suck
    • Delayed motor milestones (Independent ambulation is commonly achieved between ages three and four years, but varies depending on the severity of the disease.)
    • Spinal deformities, congenital hip dislocation, high-arched palate, foot deformities, and joint contractures. Rarely, patients may show severe skeletal malformations like those seen in spondylocostal dysostosis.
  • In later-onset disease (rare):
    • Mild symmetrical myopathy, predominantly involving the proximal muscles
    • Mildly affected facial muscles
    • Occasional involvement of the extraocular muscles (Ophthalmoplegia is relatively common in the autosomal recessive forms.)


Muscle biopsy

Histologic examination of muscle is essential to the diagnosis of central core disease. Diagnostic findings are the presence of a significant number of cores in type 1 fibers with the following characteristics (Figure 1B):

Figure 1


Figure 1. Histologic features of muscle observed in central core disease
A-B. Sections from a nine-year-old depicting the classic description of CCD
A. Pronounced type 2 fiber deficiency is seen with myosin ATPase staining with acidic (more...)

  • Often well demarcated
  • May be centrally or peripherally located in the fibers
  • Run down an appreciable length of the fiber on longitudinal sections
  • Devoid of mitochondria
  • Do not stain with oxidative enzyme stains (e.g., NADH-tetrazolium reductase, succinate dehydrogenase, cytochrome c oxidase)
  • Deficient in phosphorylase activity and glycogen
  • Sometimes surrounded by a thin rim of high oxidative enzyme activity, giving the appearance of "rimmed cores"
  • Immunohistochemistry studies demonstrate distinct staining patterns that are restricted to the cores: RyR1 protein was focally depleted within the cores, while other proteins including DHPR[alpha]1s, triadin, SERCA1/2, and calsequestrin accumulated within or around the cores [Murriel et al 2007].

Less common but nonetheless important pathologic findings in the spectrum of cores include the following [Ferreiro et al 2002b, Jungbluth et al 2002, Sewry et al 2002]:

  • More than one core can be observed within a single muscle fiber.
  • The number of type 1 fibers with cores varies.
  • The diameter of cores can vary.
  • Foci of multiple minicores in focal areas can occur.

Other pathologic characteristics of muscle include:

  • Type 1 fiber predominance or uniformity
  • Mild to moderate fiber size variation
  • Minimal to moderate endomysial fibrosis. Marked fibrosis and increase in adipose tissue have been noted in several cases.
  • Occasional increase in internal and central nuclei

Note: (1) Nemaline bodies occurring together with cores have been seen in genetically confirmed cases of CCD. When rods are numerous this has sometimes been referred to as core-rod disease. In a large French pedigree demonstrating autosomal dominant inheritance, the association of this disease with RYR1 mutations was confirmed [Monnier et al 2000]. Interestingly, some cases of nemaline myopathy may also show cores [Jungbluth et al 2002], blurring the pathologic distinction between the two disorders. (2) Facial muscle involvement and high-arched palate are almost always observed in infantile or childhood nemaline myopathy, but are rarely seen in CCD.

Ultrastructural studies show:

  • Virtual absence of mitochondria and sarcoplasmic reticulum (SR) in the core region. SR accumulation within the cores has been described on EM.
  • Irregular zigzag pattern or complete disruption of the Z-lines but often preservation of the striation pattern
  • Reduction in the intermyofibrillar space

Molecular Genetic Testing

Genes. Most cases of CCD are associated with mutations in RYR1, the gene encoding the ryanodine receptor 1.

Other loci. Studies have shown that mutations of the RYR1-associated proteins encoded by the genes FKBP1B and CACNA1S cause excitation-contraction (EC) uncoupling in vitro, similar to the effect of some RYR1 mutants [Avila et al 2003a, Lyfenko et al 2004, Weiss et al 2004], raising a possibility that mutations in FKBP1B and/or CACNA1S may also be responsible for CCD. It is possible that other disorders with EC uncoupling could be within the spectrum of CCD, but more studies are warranted.

Other candidate genes to be considered include those that code for proteins involved or associated with the triadin, which is the anatomic site of EC uncoupling, and include triadin, junctin, histidine-rich calcium-binding protein, calsequestrin, JP-45, and mitsugamin-29 [Treves et al 2005] and dihydropyridine receptor, calmodulin, and inositol phospate 3 receptor. To date, no mutation in these genes encoding these proteins has been associated with CCD.

Clinical testing

  • Sequence analysis of select exons. The RYR1 mutations associated with CCD identified so far are clustered in three relatively restricted regions ("hot spots"), which encode domain 1 (exons 1-17), domain 2 (exons 39-46), and domain 3 (exons 90-104) of the ryanodine receptor 1 [Treves et al 2005] (Figure 2).

    Although most mutations associated with CCD are clustered in the C-terminal domain 3, which comprises the transmembrane/luminal and pore-forming region of the channel, recent studies have shown that mutations in CCD are likewise found in domains 1 and 2, in which mutations are more commonly associated with malignant hyperthermia (see Allelic Disorders).

    Sequence analysis of select exons in known mutational hotspot regions detected mutations in 47%-67% of affected individuals [Monnier et al 2001, Davis et al 2003, Shepherd et al 2004]; extending the central "hotspot" to include exons 47 and 48 may increase mutation detection rate to 89% [Wu et al 2006].
  • Sequence analysis of the entire coding region. Because the RYR1 gene encodes the ryanodine receptor 1, one of the largest known proteins, direct sequencing of all exons is labor-intensive, but also most informative. Among 27 individuals diagnosed with CCD on muscle biopsy, sequence analysis of the entire coding region documented RYR1 mutations in 93% [Wu et al 2006], suggesting that CCD may not be a genetically heterogeneous disease, as previously thought. Because of the large size of the gene, sequence analysis of cDNA is an alternate approach to sequence analysis of each exon of the genomic DNA. The entire RYR1 cDNA of affected individuals has been sequenced by a number of groups [Lynch et al 1999, Monnier et al 2000, Ferreiro et al 2002a, Romero et al 2003, Zhou et al 2006a, Zhou et al 2006b].
Figure 2


Figure 2. RYR1 mutation map for CCD
The three shaded mutational hot spot areas:
Exons 1-17 (domain 1)
Exons 39-46 (domain 2)
Exons 90-104 (domain 3)
Closed circles = missense mutations
Open circles = (more...)

Table 1. Summary of Molecular Genetic Testing Used in Central Core Disease

Gene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method
RYR1Sequence analysis of select exons 1 Sequence variants 47%-80% 2
cDNA sequence analysis Variable
gDNA sequence analysis >90% 3

1. Exons sequenced vary by laboratory.

2. In autosomal dominant CCD

3. Results from Wu et al [2006]

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

If only one mutation is identified in a simplex case (i.e., a single occurrence in a family), it is difficult to distinguish between the following:

To resolve this issue, the following can be considered:

  • Testing both parents for the mutation, when possible, can confirm or exclude a de novo mutation.
  • If autosomal recessive inheritance is suspected, the entire coding sequence of the gene should be sequenced in an effort to identify the mutation on the second allele.

Note: The pathogenicity of a mutation may be established by functional studies or testing in an animal model if one exists.

Testing Strategy

To confirm the diagnosis of CCD in a proband

  • If clinical evaluation reveals characteristic findings (see Clinical Diagnosis), muscle biopsy to establish the diagnosis based on histologic findings
  • Molecular genetic testing of RYR1 to confirm the diagnosis

Carrier testing for relatives at risk of being heterozygous for autosomal recessive CCD requires prior identification of the disease-causing mutations in the family.

Note: (1) In the majority of cases CCD is inherited in an autosomal dominant manner; therefore, carrier testing is relevant in only that minority of CCD in which inheritance is autosomal recessive. (2) Carriers are heterozygous for one of the mutations causing autosomal recessive CCD and are not at risk of developing CCD.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for pregnancies at increased risk for autosomal dominant CCD require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

The expressivity of central core disease (CCD) is variable, ranging clinically from mild (i.e., almost asymptomatic) to severe (i.e., ventilator-dependent) and histologically varying in the extent and localization of cores in the muscle fibers.

Most individuals have mild disease characterized by mild, symmetric weakness that preferentially affects the proximal muscles. The facial and neck muscles may be mildly involved in some cases. The extraocular muscles are often spared in the classic, autosomal dominant form, but are typically involved in the autosomal recessive form. Motor development is usually delayed, but in general, most affected individuals acquire independent ambulation. Hypotonia in infancy and respiratory insufficiency can also occur in those with mild disease. Life span is usually normal.

Muscle cramps have been documented in some individuals with CCD, and this may be associated with MH susceptibility.

Severe disease is characterized by infantile onset associated with profound hypotonia and respiratory dysfunction requiring continuous assisted ventilation. In severely affected individuals, death may result from respiratory infection or respiratory insufficiency.

Fetal akinesia has been associated with both autosomal dominant and autosomal recessive forms of RYR1-related CCD [Romero et al 2003]. The clinical phenotype consisted of severe hypotonia, arthrogryposis multiplex congenita, amyotrophy, and respiratory failure, requiring mechanical ventilation. The outcome, however, was variable (ranging from early death to survival beyond age five years).

Typically CCD is not progressive, although slow progression has been reported . Scoliosis can be progressive, resulting in respiratory insufficiency.

Intellectual ability is intact.

Other. Serum creatine kinase concentration may be normal or mildly elevated.

Electromyography may confirm the presence of myopathy and reveal brief, short action potentials and early recruitment.

Muscle imaging has demonstrated that certain muscles are selectively involved in RYR1-related myopathies, including quadriceps, sartorius, adductor magnus, soleus, gastrocnemius, and peroneal group; certain muscles are relatively spared, including rectus femoris, gracilis, adductor longus, and tibialis anterior [Jungbluth et al 2004]. These findings were supported by Fischer et al [2006] who described distinct MRI findings in persons with CCD who have an RYR1 mutation, including predominant involvement of the gluteus maximus, adductor magnus, sartorius, vastus intermediolateralis, soleus, and lateral gastrocnemius muscles, as compared to those who do not have an RYR1 mutation.

Genotype-Phenotype Correlations

Although most RYR1 mutations that result in CCD are inherited in an autosomal dominant manner, reports of autosomal recessive inheritance are increasing. At the moment, it is not possible to predict the mode of inheritance based on the mutation alone.

Some studies have shown that autosomal recessive CCD, often associated with RYR1 mutations outside the C-terminal region, can be severe [Romero et al 2003, Zhou et al 2006b]. Thus, it may be possible to consider most autosomal dominant forms of CCD as milder in phenotype than autosomal recessive forms of CCD.

In a study of 25 individuals with genetically-confirmed CCD, Wu et al [2006] determined that:

  • The 16 individuals with C-terminal RYR1 mutations had certain clinical features including hypotonia during infancy, delayed motor development, and limb muscle weakness and certain pathologic findings on muscle biopsy that delineate C terminal mutations from other groups including (1) type 2 fiber deficiency and interstitial fibrosis, (2) characteristic cores with clearly demarcated borders that are observed in almost all type 1 muscle fibers, (3) higher than average frequency of "rimming" on the borders of these cores.
  • Most individuals with CCD with at least one RYR1 mutation outside the C-terminal region had only mild musculoskeletal abnormalities such as joint contractures and scoliosis. Inheritance was autosomal dominant, consistent with previous reports of mild CCD phenotype.

Malignant hyperthermia susceptibility (MHS)-related RYR1 mutations are predominantly located in the hydrophilic N-terminal and central portions of the ryanodine receptor 1 (RyR1) protein, whereas CCD-related RYR1 substitutions mainly occur in the hydrophobic pore-forming region of the channel [Monnier et al 2000, Monnier et al 2001, Davis et al 2003, Zorzato et al 2003]. Previous reports have asserted that persons without muscle disease who are susceptible to malignant hyperthermia (MH) have mutations in the C-terminal region of ryanodine receptor 1; however, limited histopathologic evaluation of these individuals has revealed the presence of cores that are not characteristic of the cores of CCD [Ibarra et al 2006]; thus, they are most appropriately labeled as having "MH with cores."

Individuals with CCD who have mutations in the N-terminal domain may have a higher probability of malignant hyperthermia susceptibility than those with mutations in the C-terminal domain [Wu et al 2006].


In general, the penetrance of CCD is variable. Mutations in the C-terminal region of ryanodine receptor 1, including p.Ile4898Thr [Lynch et al 1999] and p.Tyr4796Cys [Monnier et al 2000] in the luminal domain were associated with more severe phenotype, and, hence, full penetrance, and autosomal dominant inheritance.


Anticipation is not observed.


CCD has also been referred to as Shy-Magee syndrome, after the individuals who initially reported it.

Some cases called core-rod disease are not associated with a RYR1 mutation; thus, "core-rod disease" is not a true synonym for CCD.


The precise incidence and prevalence of CCD, considered to be the most frequently occurring congenital myopathy, are unknown.

Differential Diagnosis

The clinical findings of central core disease (CCD) are variable and not disease specific; they can be seen in other congenital myopathies. Thus, from a clinical standpoint CCD cannot be readily distinguished from other congenital myopathies, such as multiminicore disease, CNMDU1 (see Allelic Disorders), the intermediate form of nemaline myopathy, fingerprint body myopathy, congenital fiber-type disproportion, hyaline body myopathy, reducing body myopathy, and cylindrical spirals myopathy.

The phenotype of CCD is relatively heterogeneous with a variable age of onset. Thus, CCD must be considered in persons of all ages with scoliosis or severe spinal deformity, unexplained muscle weakness, and multiple joint problems [Mertz et al 2005, Sestero & Perra 2005].

The 'central core' histologic changes are nonspecific and may occur in other myopathies. Cores that have been noted in CCD have also been reported with mutations in the following genes:

  • SEPN1. Mutations in this gene are also associated with minicores [Ferreiro et al 2002b], but no individual with a SEPN1 mutation and the typical long, well-delimited central cores characteristic of CCD has been reported.
  • MYH7, in hypertrophic cardiomyopathy
  • ACTA1 and TNNT1 in nemaline myopathy [Ilkovski et al 2001]. ACTA1 mutations were found in a congenital myopathy with few cores on muscle biopsy [Kaindl et al 2004]; like other disorders with cores, however, these disorders are better considered as myopathies with cores, not CCD.
  • CFL2, encoding cofilin-2, has recently been associated with nemaline myopathy with minicores [Agrawal et al 2007].
  • Structures similar to cores have been observed in the myofibers of individuals with neurogenic atrophy but are more appropriately called "target fibers" in this setting because of the darker band around the pale central area, giving it a target-like appearance. In addition, core-like lesions devoid of this band can also be seen in these conditions.


Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with central core disease (CCD), the following evaluations are recommended:

  • Neurologic examination with attention to features of congenital myopathy (hypotonia, failure to thrive, joint contractures, scoliosis), weakness of the limbs, and muscle cramps
  • Physical and occupational therapy assessments
  • Evaluation for feeding difficulties, including assessment for sucking and ability to swallow
  • Pulmonary function testing in most patients, especially those with scoliosis, hypotonia, signs of respiratory distress, and/or history of recurrent chest infections. History should be taken for symptoms of nocturnal hypoxia including early morning headaches, daytime drowsiness, loss of appetite, and deteriorating school performance.

Treatment of Manifestations

Since prognosis is mainly influenced by respiratory status and scoliosis, treatment geared towards these manifestations is essential.

Treatment depends on the severity of symptoms, but mainly consists of supportive measures and rehabilitation that address the following problems:

  • Hypotonia and weakness. Patients may benefit from physical therapy. Interventions may include stretching programs and mild to moderate low-impact exercise; activities should be balanced in such a way that exhaustion is avoided.
  • Scoliosis and joint contractures. Some patients may only require physical therapy, while others may need orthopedic surgery (e.g., scoliosis surgery, corrective surgery for congenital hip dislocation and foot deformities).
  • Respiratory. Patients with more severe symptoms may require respiratory support. Breathing exercises and chest physiotherapy for handling secretions may also be beneficial.
  • Feeding difficulties. Individuals may require diet supplementation and feeding by means of nasogastric/orogastric routes or gastrostomy.

Prevention of Secondary Complications

Secondary complications can include respiratory compromise from scoliosis; hence, orthopedic intervention may reduce the risk of this problem.

Immunization against influenza is encouraged.

Prompt treatment of respiratory infection is important.

Joint contractures may be prevented by encouraging mobility and by active participation in physical therapy.


The following are appropriate:

  • Routine assessment of the spine for scoliosis and joints for contractures
  • Routine assessment of respiratory parameters such as respiratory rate, peak expiratory flow rate (PEFR), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1)
  • Sleep studies especially when patients show signs of nocturnal hypoxia
  • Regular assessment of motor abilities in order to determine need for physical therapy, occupational therapy, and assistive devices for ambulation, such as a wheelchair

Agents/Circumstances to Avoid

Although it is unknown how CCD is associated with malignant hyperthermia susceptibility or which mutations in RYR1 are absolutely related to MH susceptibility, it is prudent for individuals with CCD to avoid inhalational anesthetics and succinylcholine. See Malignant Hyperthermia Susceptibility for more details.

Individuals suspected of having MH susceptibility are advised to avoid extremes of heat, but this does not mean restriction of athletic activity.

Evaluation of Relatives at Risk

Because CCD is associated with an increased risk for MH susceptibility, it is appropriate to test at-risk relatives of a proband (whether symptomatic or not) for the RYR1 mutation identified in the proband in order to caution those with the mutation about potential risks of inhalational anesthetics and succinylcholine. See Malignant Hyperthermia Susceptibility for more details.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Central core disease (CCD) is usually inherited in an autosomal dominant manner, but it can be inherited in an autosomal recessive manner [Ferreiro et al 2002a, Jungbluth et al 2002, Romero et al 2003, Wu et al 2006, Zhou et al 2006b, Kossugue et al 2007].

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

  • Most individuals diagnosed with autosomal dominant CCD have an affected parent or an asymptomatic parent who has a disease-causing mutation.
  • A proband with autosomal dominant CCD may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown.
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include muscle biopsy and molecular genetic testing. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although most individuals diagnosed with CCD have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or reduced penetrance. (2) If the parent is the individual in whom the mutation first occurred s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with autosomal dominant CCD has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are often asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with autosomal recessive CCD are obligate heterozygotes (carriers) for a disease-causing mutation.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for family members at risk of being heterozygous for autosomal recessive CCD is possible if the disease-causing mutations have been identified in the family.

Related Genetic Counseling Issues

See Evaluation of Relatives at Risk for information on testing of relatives for malignant hyperthermia susceptibility.

Simplex cases. Kossugue et al [2007] reported several simplex cases with CCD in whom at least one mutation was identified. The cause of CCD in these individuals may be (1) a de novo dominant mutation or (2) autosomal recessive inheritance of a known RYR1 mutation and a second as-yet unidentified mutation.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Although prenatal diagnosis has not been reported, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing allele(s) of an affected family member must be identified or linkage established in the family before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation(s) have been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Malignant Hyperthermia Association of the United States (MHAUS)
    11 East State Street
    PO Box 1069
    Sherburne NY 13460
    Phone: 800-644-9737 (Toll-free Emergency Hotline); 607-674-7901; 315-464-7079
    Fax: 607-674-7910
  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
  • Muscular Dystrophy Campaign
    61 Southwark Street
    London SE1 0HL
    United Kingdom
    Phone: 0800 652 6352 (toll-free); +44 0 020 7803 4800

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Central Core Disease: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
RYR119q13​.2Ryanodine receptor 1Leiden Muscular Dystrophy pages (RYR1)RYR1

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Central Core Disease (View All in OMIM)


Molecular Genetic Pathogenesis

The skeletal muscle isoform of ryanodine receptor 1 (RyR1) mediates Ca2+ release during excitation-contraction (EC) coupling; hence, mutations in the RYR1 gene are expected to cause disturbance in this process. However, the precise pathophysiology of central core disease (CCD) is not fully understood and remains controversial. Two fundamentally distinct cellular mechanisms (leaky channels and EC uncoupling) are proposed to explain how altered release channel function caused by different mutations in RYR1 could result in muscle weakness in CCD [Dirksen & Avila 2002]. Although it is commonly believed that cores are not specific to CCD, it has recently been demonstrated that calcium-handling proteins are abnormally distributed in RYR1-associated core myopathies: RyR1 protein was depleted from the cores, while calsequestrin, SERCA1/2, triadin, and DHPR had accumulated within or around the lesions [Herasse et al 2007]. These findings suggest that EC uncoupling may indeed lead to muscle weakness.

Certain RYR1 mutations are associated with both CCD and MH susceptibility. In a previous report, the effects of mutations that involve CCD plus MH susceptibility and MH susceptibility only on Ca2+ handling and EC coupling have been characterized; it has been suggested that sarcoplasmic reticulum (SR) Ca2+ depletion and increased basal Ca2+ levels are preferentially associated with RYR1 mutations that result in combined MH susceptibility and CCD [Dirksen & Avila 2004]. Furthermore, the authors also found that MH susceptibility-only mutations modestly increase basal release-channel activity in a manner insufficient to alter net SR Ca2+ content ("compensated leak"), whereas the combined MH susceptibility and CCD phenotype arises from mutations that enhance basal activity to a level sufficient to promote SR Ca2+ depletion, elevate [Ca2+]i, and reduce maximal VGCR ("decompensated leak").

Zhou et al [2006a] presented evidence that in individuals with autosomal recessive core myopathies, RYR1 frequently undergoes polymorphic, tissue-specific, and developmentally regulated allele silencing apparently mediated by hypermethylation. The resulting monoallelic expression of RYR1 can unveil recessive mutations in the remaining RYR1 allele in persons with core myopathies. Zhou et al [2006a] also suggested that imprinting is a likely mechanism for this phenomenon, which can play a role in human phenotypic heterogeneity and in irregularities of inheritance patterns.

Normal allelic variants. RYR1 consists of 106 exons (two of which are alternatively spliced) encompassing a total of 160 kb and producing one of the largest proteins in humans with 5038 amino acids [Phillips et al 1996]. Several normal allelic variants have been noted in RYR1, including: p.Ala1832Gly, p.Val2550Leu [Monnier et al 2000]; p.Val4849Ile [Monnier et al 2001]; p.Gly2060Cys, and p.Met485Val [Zhou et al 2006b]. See Table 2.

Table 2. Selected RYR1 Normal Allelic Variants

DNA Nucleotide Change Protein Amino Acid Change Reference Sequences

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​ See Quick Reference for an explanation of nomenclature.

Pathologic allelic variants. More than 80 reported RYR1 mutations have been associated with the autosomal dominant or autosomal recessive forms of CCD, including 67 missense mutations and five deletions, clustered in three regions of the gene. More than half of the RYR1 mutations are private.

The most common mutations are shown in Table 3 (pdf).

Table 4 (pdf) shows the most common RYR1 pathogenic amino acid variants associated with autosomal dominant central core disease.

Normal gene product. RYR1 encodes the ryanodine receptor 1 protein, a skeletal muscle calcium-release channel located in the sarcoplasmic reticulum (SR). The functional channel is a homotetramer of 560-kd subunits; it releases calcium stored in the SR in response to membrane depolarization transduced by the dihydropyridine receptor (DHPR). The cytoplasmic domain of ryanodine receptor 1, also called the foot structure, comprises the first 4000 amino acids that bridge the gap between the SR and the transverse tubular system. The last 1000 amino acids from the transmembrane domain contain the pore of the channel [Tilgen et al 2001, Lehmann-Horn et al 2003].

Ryanodine receptors belong to the superfamily of intracellular Ca2+ release channels present on endoplasmic reticulum/sarcoplasmic reticulum (SR) membranes, having three different isoforms. Functional units are homotetramers of approximately 5,000 amino acids per subunit coded by 150-kb genes. RYR1, forming the SR calcium release channel, has a large hydrophilic NH2-terminal domain and a hydrophobic COOH-terminal domain containing several transmembrane domains as well as the channel pore. The 563-kd protein is predominantly expressed not only in skeletal muscle but also in human B-lymphocytes and immature murine dendritic cells.

Abnormal gene product. Alterations in the ryanodine receptor 1 protein lead to an abnormal, sustained increase in myoplasmic calcium concentration in skeletal muscle because of a "leaky channel" or uncoupling with its voltage sensor, which is encoded by the voltage-gated calcium channel gene DHPR [Nelson 2001, Wehner et al 2003].

In vitro studies suggest that a high basal activity of the mutant Ca2+ channel could explain the muscle weakness and muscle atrophy observed in persons with CCD in one family [Lynch et al 1999]. In vitro expression of ryanodine receptor 1 with a single mutation (p.Ile4898Thr) in the C-terminal transmembrane/luminal domain in HEK293 cells resulted in loss of channel activation and reduction in ryanodine binding, possibly by disrupting the ligand binding site located in the C terminus of the protein. Further analysis, however, showed that this mutation leads to a significant increase in the sensitivity of the channel to the activating effects of calcium.

The association of C-terminal mutations with clinically evident muscle weakness may be explained by the leaky-channel model and the excitation-contraction (EC) uncoupling model.

  • Some non-C-terminal mutations in ryanodine receptor 1 promote the leak of Ca2+ ions from the SR that may or may not be compensated by the activity of the sarco-endoplasmic reticulum Ca2+ ATPase (SERCA), resulting in elevation of resting cytosolic Ca2+ and depletion of SR Ca2+ stores.

C-terminal mutations, especially those in the pore region of ryanodine receptor 1, may directly affect the channel gating properties, resulting in an abolition of orthograde activation by the voltage-gated L-type Ca2+ channel or, in other words, EC uncoupling. However, no compensatory mechanism increases Ca2+ release as the SERCA pumps do in the leaky model. Nevertheless, the effect of mutations in the C-terminal region remains controversial and at best unlikely because a number of mutations in this area were also shown to be "leaky." Interestingly, several mutations in RYR1 exon 102 were shown to lead to varying degrees of EC uncoupling, indicating that this region is a primary locus of EC uncoupling in CCD [Avila et al 2003b].


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Chapter Notes

Revision History

  • 11 May 2010 (me) Comprehensive update posted live
  • 16 May 2007 (me) Review posted to live Web site
  • 8 December 2006 (in) Original submission
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