Clinical 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. The weakness in CCD is not typically 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 pathogenic variants 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 pathogenic variant 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 pathogenic variant. The proportion of AD CCD caused by de novo pathogenic variants is unknown. Each child of an individual with AD CCD has a 50% chance of inheriting the pathogenic variant. The parents of a child with AR CCD are obligate heterozygotes and therefore carry one mutated 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 pathogenic variant(s) have been identified in an affected family member.

Suggestive Findings

Diagnosis of central core disease should be suspected in individuals with the following features – keeping in mind that this disorder has a wide spectrum of symptoms and presentations, from the absence of symptoms to severe features necessitating the use of ventilatory support:

• 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 such as those seen in spondylocostal dysostosis.
• In later-onset disease (rare):
  • Mild symmetric 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.)

Establishing the Diagnosis

The diagnosis of central core disease is established in a proband with (1) a muscle biopsy demonstrating characteristic cores in a significant number of fibers on muscle biopsy, even in individuals who are seemingly asymptomatic and/or (2) molecular genetic testing that detects pathogenic variant(s) in RYR1 (see Table 1).

In the event that molecular testing is done first:

• In a patient with classic clinical presentation of CCD, if the identified RYR1 variant is known to be pathogenic, the necessity of muscle biopsy becomes less important and will only be used for classification.
• In a patient without visible clinical involvement, muscle biopsy will be of importance if there is a need to interpret RYR1 variations of uncertain significance, in the absence of functional studies.

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.

Histologic features of muscle observed in central core disease A-B. Sections from a child age nine years depicting the classic description of CCD

• 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"
• On immunohistochemistry studies, 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 [Herasse 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:

• 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 pathogenic variants 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 the following:

• 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

Clinical Description

The expressivity of central core disease (CCD) is variable even among family members, 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.

Mild disease. 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).

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

Cognition. Intellectual ability is intact.

Laboratory findings

• 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 magnetic resonance imaging. Muscle imaging has demonstrated that certain muscles are selectively and consistently involved in autosomal dominant 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 pathogenic variant, 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 pathogenic variant. The rectus femoris, adductor longus, and gracilis are hypertrophied in some patients. MRI findings in autosomal recessive RYR1-related CCD are not as consistent.

Genotype-Phenotype Correlations

Although most RYR1 pathogenic variants that result in CCD are inherited in an autosomal dominant manner, reports of autosomal recessive inheritance are increasing. It is not possible to predict the mode of inheritance based on the pathogenic variant alone.

Some studies have shown that autosomal recessive CCD, often associated with RYR1 pathogenic variants 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 pathogenic variants 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 pathogenic variants 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 pathogenic variant 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 pathogenic variants 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 pathogenic variants 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 pathogenic variants in the N-terminal domain may have a higher probability of malignant hyperthermia susceptibility than those with pathogenic variants in the C-terminal domain [Wu et al 2006].

Penetrance

In general, the penetrance of CCD-associated RYR1 pathogenic variants is almost 100%. Clinical variability exists to some extent among affected members of the family.

Nomenclature

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 pathogenic variant; thus, "core-rod disease" is not a true synonym for CCD.

Prevalence

An accurate incidence and prevalence of CCD, considered to be the most frequently occurring congenital myopathy, are unknown. By definition, CCD is considered a rare disease by the Office of Rare Disease, implying that it affects fewer than 200,000 in the US population. A recent estimate of 1:100,000 was calculated among patients with genetic muscle disease in Northern England [Norwood et al 2009]. In Japan, the carrier frequency for heterozygous RYR1 pathogenic variants is reported to be as high as 1:2,000 [Wu et al 2006].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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.
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Since prognosis is mainly influenced by respiratory status and scoliosis, treatment geared toward 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.

Surveillance

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 pathogenic variants 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 pathogenic variant identified in the proband in order to caution those with the pathogenic variant 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.

Pregnancy Management

Because all patients with CCD are considered to be at risk for malignant hyperthermia, inhalational anesthetics and succinylcholine should be avoided while considering general or regional anesthesia for delivery. Similar to most neuromuscular disorders, clinical progression of disease can be expected in CCD [Sax & Rosenbaum 2006].

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

Mode of Inheritance

Central core disease (CCD) is usually inherited in an autosomal dominant manner, but may 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].

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Most individuals diagnosed with autosomal dominant CCD have an affected parent or an asymptomatic parent who has an RYR1 pathogenic variant.
• A proband with autosomal dominant CCD may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by a de novo pathogenic variant is unknown.
• If the pathogenic variant 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 pathogenic variant 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 pathogenic variant include muscle biopsy and molecular genetic testing.
• The family history of some individuals diagnosed with CCD 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, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations / molecular genetic testing have been performed on the parents of the proband.

Note: If the parent is the individual in whom the pathogenic variant first occurred s/he may have somatic mosaicism for the pathogenic variant 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 of inheriting the RYR1 pathogenic variant is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for CCD because of the possibility of reduced penetrance in a parent.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte 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 pathogenic variant.

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.

Autosomal Recessive Inheritance

Related Genetic Counseling Issues

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

Testing of at-risk asymptomatic relatives of individuals with central core disease is possible after molecular genetic testing has identified the specific pathogenic variant(s) in the family. Such testing should be performed in the context of formal genetic counseling. This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.

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

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with autosomal dominant CCD has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant. 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the RYR1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for CCD are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Molecular Pathogenesis

The skeletal muscle isoform of ryanodine receptor 1 (RyR1) mediates Ca²⁺ release during excitation-contraction (EC) coupling; hence, pathogenic variants in RYR1 are expected to cause disturbance in this process. Two fundamentally distinct cellular mechanisms (leaky channels and EC uncoupling) are proposed to explain how altered release channel function caused by different pathogenic variants 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 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. The muscle weakness can be at least partially explained by a reduced magnitude of voltage-gated Ca2+ release. Recently, it has been shown that RYR1 pathogenic variants can alter the expression of the gene SERCA, which could explain the paradoxic finding of calcium store depletion in the sarcoplasmic reticulum [Vega et al 2011]. Interestingly, the EC coupling changes has been shown to be reversed by administration of calcitonin gene-related peptide, at least in the cell culture model.

Certain RYR1 pathogenic variants are associated with both CCD and MH susceptibility. The effects of pathogenic variants 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 pathogenic variants that result in combined MH susceptibility and CCD [Dirksen & Avila 2004]. Furthermore, the authors found that MH susceptibility-only pathogenic variants 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 pathogenic variants 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 pathogenic variants 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.

Gene structure. RYR1 consists of 106 exons (2 of which are alternatively spliced) encompassing a total of 160 kb and producing one of the largest proteins in humans with 5,038 amino acids [Phillips et al 1996]. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. Several benign 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.

Pathogenic variants. More than 200 reported RYR1 pathogenic variants have been associated with the autosomal dominant or autosomal recessive forms of CCD, and most of them are pathogenic missense variants few deletions and cryptic site variants, clustered in three regions of the gene. More than half of the RYR1 pathogenic variants are private.

The RYR1 pathogenic variants 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).

Figure 2.

RYR1 pathogenic variant map for CCD The three shaded mutational hot spot areas:

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

The most common pathogenic variants 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 4,000 amino acids that bridge the gap between the SR and the transverse tubular system. The last 1,000 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 mutated 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 pathogenic variant (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 pathogenic variant leads to a significant increase in the sensitivity of the channel to the activating effects of calcium.

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

Some non-C-terminal pathogenic variants 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 pathogenic variants, 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 pathogenic variants in the C-terminal region remains controversial because a number of pathogenic variants in this area were also shown to be "leaky." Interestingly, several pathogenic variants 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 2003].

Literature Cited

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Revision History

• 7 November 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation
• 4 December 2014 (me) Comprehensive update posted live
• 11 May 2010 (me) Comprehensive update posted live
• 16 May 2007 (me) Review posted live
• 8 December 2006 (in) Original submission