Central Core Myopathy - Disorder Mechanisms

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Inheritance

2

Autosomal dominant HP:0000006

Most cases of central core myopathy follow autosomal dominant inheritance with incomplete penetrance and variable expressivity. Dominant mutations are typically missense changes clustered in recognized mutational hotspot regions including the C-terminal transmembrane/pore-forming domain and tend to cause a milder phenotype.

Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE

Show evidence (2 references)

PMID:22473935 SUPPORT Human Clinical

"Dominant mutations, typically missense, were frequently located in recognized mutational hotspot regions, while recessive mutations were distributed throughout the entire coding sequence. "

Large cohort study of 71 families confirms that dominant RYR1 mutations are typically missense and cluster in hotspot regions.

PMID:8220422 SUPPORT Human Clinical

"Central core disease (CCD) is a morphologically distinct, autosomal dominant myopathy with variable clinical features. "

The landmark 1993 Nature Genetics paper establishing the RYR1 link describes CCD as autosomal dominant with variable features.

Autosomal recessive HP:0000007

Autosomal recessive forms of central core myopathy tend to be more severe, with earlier onset, greater weakness, and more functional limitations. Extraocular and bulbar muscle involvement is almost exclusively observed in recessive cases. Recessive mutations are distributed throughout the RYR1 coding sequence and often include nonsense and splice mutations expected to result in reduced RyR1 protein expression.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:22473935 SUPPORT Human Clinical

"As a group, dominant mutations were associated with milder phenotypes; patients with recessive inheritance had earlier onset, more weakness, and functional limitations. Extraocular and bulbar muscle involvement was almost exclusively observed in the recessive group. "

This large cohort study of 71 families (35 dominant, 36 recessive) demonstrates the clinical distinction between dominant and recessive RYR1-related myopathies.

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Pathophysiology

3

Abnormal RyR1 calcium release channel function

RYR1 mutations alter the function of the ryanodine receptor, the principal calcium release channel of the sarcoplasmic reticulum in skeletal muscle. Dominant missense variants often produce hypersensitive or leaky RyR1 channels with lowered threshold for sarcoplasmic reticulum calcium release, while recessive mutations frequently result in reduced RyR1 protein expression or excitation-contraction coupling uncoupling. Both mechanisms disrupt the DHPR-RyR1 signaling axis and calcium homeostasis in skeletal muscle fibers.

Skeletal muscle fiber link Slow muscle cell (type I fiber) link

Regulation of SR calcium release link Calcium ion homeostasis link Regulation of skeletal muscle contraction by calcium signaling link

Show evidence (3 references)

PMID:17504518 SUPPORT Human Clinical

"Altered excitability and/or changes in calcium homeostasis within muscle cells due to mutation-induced conformational changes of the RyR protein are considered the main pathogenetic mechanism(s). "

Comprehensive Orphanet review of CCD establishing that mutation-induced conformational changes in RyR1 leading to altered calcium homeostasis are the main pathogenetic mechanism.

PMID:16917943 SUPPORT Human Clinical

"The RYR1 gene encodes the skeletal muscle isoform ryanodine receptor and is fundamental to the process of excitation-contraction coupling and skeletal muscle calcium homeostasis. "

Review of RYR1 mutations in MH and CCD confirming the role of RYR1 in excitation-contraction coupling and calcium homeostasis.

PMID:16917943 SUPPORT Human Clinical

"In vitro analysis has confirmed that alteration of normal calcium homeostasis is a functional consequence of some of these changes. "

Confirms functional evidence that RYR1 mutations alter calcium homeostasis through in vitro studies.

Mitochondrial depletion and oxidative metabolism deficiency in cores

The central cores that define this myopathy histologically represent focal regions of myofibrillar disorganization with depletion of mitochondria and absence of oxidative enzyme activity. Cores run along the longitudinal axis of type 1 muscle fibers and are visualized as unstained regions on NADH-TR and cytochrome oxidase histochemistry. Mitochondrial calcium overload from dysfunctional RyR1 channels generates energetic strain and oxidative stress, contributing to the ultrastructural disorganization characteristic of cores.

Skeletal muscle fiber link

Response to oxidative stress link Intracellular calcium ion homeostasis link

Show evidence (1 reference)

PMID:17504518 PARTIAL Human Clinical

"Central core disease (CCD) is an inherited neuromuscular disorder characterised by central cores on muscle biopsy and clinical features of a congenital myopathy. "

Establishes the defining histopathological feature of CCD as central cores on muscle biopsy.

Malignant hyperthermia susceptibility

RYR1 mutations predispose to malignant hyperthermia (MH), a pharmacogenetic disorder triggered by volatile anesthetic agents and succinylcholine. The susceptible RyR1 channel exhibits exaggerated calcium release in response to these triggers, causing sustained muscle contraction, hypermetabolism, rhabdomyolysis, and potentially fatal hyperthermia. CCD and MHS are allelic conditions and a single RYR1 mutation may result in either or both phenotypes.

Muscle contraction link Calcium ion homeostasis link

Show evidence (2 references)

PMID:17504518 SUPPORT Human Clinical

"CCD and MHS are allelic conditions both due to (predominantly dominant) mutations in the skeletal muscle ryanodine receptor (RYR1) gene, encoding the principal skeletal muscle sarcoplasmic reticulum calcium release channel (RyR1). "

Establishes that CCD and MHS are allelic conditions caused by mutations in the same RYR1 gene.

PMID:8220423 SUPPORT Human Clinical

"One of these mutations was also detected in an unrelated MH pedigree whose members are asymptomatic of CCD. The data suggest a model to explain how a single mutation may result in two apparently distinct clinical phenotypes. "

Demonstrates that the same RYR1 mutation can cause CCD in one family and isolated MH susceptibility in another, establishing the allelic relationship.

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Pathograph

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Phenotypes

9

Eye 1

External ophthalmoplegia HP_0040284 External ophthalmoplegia (HP:0000544)

Show evidence (1 reference)

PMID:22473935 SUPPORT Human Clinical

"Extraocular and bulbar muscle involvement was almost exclusively observed in the recessive group. "

Extraocular involvement (ophthalmoplegia) is almost exclusively seen in recessive RYR1-related myopathies.

Head and Neck 1

Myopathic facies HP_0040283 Myopathic facies (HP:0002058)

Show evidence (1 reference)

PMID:22473935 SUPPORT Human Clinical

"Extraocular and bulbar muscle involvement was almost exclusively observed in the recessive group. "

Demonstrates that facial and bulbar involvement is characteristic of recessive RYR1-related myopathies.

Limbs 1

Congenital hip dislocation HP_0040282 Congenital hip dislocation (HP:0001374)

Show evidence (1 reference)

PMID:17504518 PARTIAL Human Clinical

"orthopaedic complications are common "

Congenital hip dislocation is one of the common orthopaedic complications in CCD.

Metabolism 1

Malignant hyperthermia susceptibility HP_0040282 Malignant hyperthermia (HP:0002047)

Show evidence (2 references)

PMID:17504518 SUPPORT Human Clinical

"malignant hyperthermia susceptibility (MHS) is a frequent complication "

Establishes MHS as a frequent complication of CCD.

PMID:8220423 SUPPORT Human Clinical

"Central core disease (CCD) of muscle is an inherited myopathy which is closely associated with malignant hyperthermia (MH) in humans. "

Confirms the close association between CCD and MH.

Musculoskeletal 3

Proximal muscle weakness HP_0040281 Proximal muscle weakness (HP:0003701)

Show evidence (2 references)

PMID:17504518 SUPPORT Human Clinical

"CCD typically presents in infancy with hypotonia and motor developmental delay and is characterized by predominantly proximal weakness pronounced in the hip girdle "

Comprehensive review establishing proximal weakness pronounced in the hip girdle as a characteristic feature of CCD.

PMID:29391587 PARTIAL Human Clinical

"Pronounced weakness in axial and proximal muscle groups is a common feature "

Major Nature Reviews Neurology review confirming axial and proximal weakness as common in congenital myopathies including CCD.

Neonatal hypotonia HP_0040282 Neonatal hypotonia (HP:0001319)

Show evidence (1 reference)

PMID:17504518 SUPPORT Human Clinical

"CCD typically presents in infancy with hypotonia and motor developmental delay "

Establishes infantile hypotonia as a typical presenting feature of CCD.

Scoliosis HP_0040282 Scoliosis (HP:0002650)

Show evidence (1 reference)

PMID:17504518 PARTIAL Human Clinical

"orthopaedic complications are common "

Orthopaedic complications including scoliosis are identified as common in CCD.

Nervous System 1

Delayed gross motor development HP_0040282 Delayed gross motor development (HP:0002194)

Show evidence (1 reference)

PMID:17504518 SUPPORT Human Clinical

"CCD typically presents in infancy with hypotonia and motor developmental delay "

Motor developmental delay is identified as a typical presenting feature.

Respiratory 1

Respiratory insufficiency HP_0040283 Respiratory insufficiency (HP:0002093)

Show evidence (1 reference)

PMID:29391587 PARTIAL Human Clinical

"involvement of extraocular, cardiorespiratory and/or distal muscles can implicate specific genetic defects "

Cardiorespiratory involvement is noted as a feature that can occur in congenital myopathies.

🧬

Genetic Associations

1

RYR1 mutations (Causative)

Show evidence (4 references)

PMID:8220422 SUPPORT Human Clinical

"The only amino acid substitution found was an Arg2434His mutation, resulting from the substitution of A for G7301. This mutation was linked to CCD with a lod score of 4.8 at a recombinant fraction of 0.0 in 16 informative meioses in a 130 member family, suggesting a causal relationship to CCD. "

Landmark 1993 Nature Genetics paper that first identified a specific RYR1 mutation (Arg2434His) as causative of central core disease through linkage analysis in a large family.

PMID:16917943 SUPPORT Human Clinical

"Mapping to chromosome 19q13.2, the gene comprises 106 exons and encodes a protein of 5,038 amino acids. Mutations in the gene have been found in association with several diseases: the pharmacogenetic disorder, malignant hyperthermia (MH); and three congenital myopathies, including central core..."

Comprehensive review of RYR1 mutations establishing the gene structure and its association with CCD, MH, and other congenital myopathies.

PMID:22473935 SUPPORT Human Clinical

"Ryanodine receptor 1 (RYR1) mutations are a common cause of congenital myopathies associated with both dominant and recessive inheritance. "

Large cohort study confirming RYR1 mutations as a common cause of congenital myopathies with both inheritance patterns.

+ 1 more reference

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Treatments

5

Avoidance of malignant hyperthermia triggers

Action: Anesthesia precautions Ontology label: pharmacotherapy MAXO:0000058

Strict avoidance of volatile anesthetic agents (halothane, sevoflurane, desflurane, isoflurane) and depolarizing neuromuscular blocking agents (succinylcholine) during surgical procedures. Total intravenous anesthesia (TIVA) with agents such as propofol is recommended. Management must anticipate susceptibility to potentially life-threatening reactions to general anaesthesia.

Show evidence (1 reference)

PMID:17504518 SUPPORT Human Clinical

"Management is mainly supportive and has to anticipate susceptibility to potentially life-threatening reactions to general anaesthesia. "

Establishes the critical importance of anesthetic precautions in CCD management.

Dantrolene for malignant hyperthermia

Action: Dantrolene therapy Ontology label: pharmacotherapy MAXO:0000058

Agent: dantrolene ↗

Dantrolene sodium is the specific treatment for acute malignant hyperthermia episodes. It acts by inhibiting calcium release from the sarcoplasmic reticulum via the ryanodine receptor. Dantrolene should be immediately available whenever a susceptible patient undergoes anesthesia.

Physical therapy and rehabilitation

Action: Physical therapy Ontology label: physical therapy MAXO:0000011

Regular physical therapy focusing on maintaining range of motion, preventing contractures, and maximizing functional capacity. Exercise programs should be tailored to individual ability.

Orthopedic management

Action: Orthopedic surgery Ontology label: surgical procedure MAXO:0000004

Surgical and conservative management of musculoskeletal complications including scoliosis, hip dislocation, and foot deformities. Bracing and assistive devices may be needed.

Genetic counseling

Action: Genetic counseling Ontology label: genetic counseling MAXO:0000079

Genetic counseling for affected families to discuss inheritance patterns, recurrence risk, and implications for family members regarding malignant hyperthermia susceptibility. Mutational analysis of RYR1 may provide genetic confirmation of the diagnosis.

Show evidence (1 reference)

PMID:17504518 PARTIAL Human Clinical

"Mutational analysis of the RYR1 gene may provide genetic confirmation of the diagnosis. "

Supports the role of genetic testing and counseling in CCD diagnosis and family management.

{ }

Source YAML

click to show

name: Central Core Myopathy
creation_date: '2026-02-13T18:01:36Z'
updated_date: '2026-02-27T21:52:54Z'
category: Mendelian
description: >
  Central core myopathy (central core disease, CCD) is a congenital myopathy caused
  predominantly by mutations in the RYR1 gene encoding the skeletal muscle ryanodine
  receptor (RyR1), the principal sarcoplasmic reticulum calcium release channel.
  It is characterized histopathologically by central cores — areas of sarcomeric
  disorganization and mitochondrial depletion running along the longitudinal axis
  of type 1 muscle fibers. Clinical features include proximal muscle weakness,
  hypotonia, delayed motor milestones, orthopaedic complications, and susceptibility
  to malignant hyperthermia. Inheritance is most commonly autosomal dominant with
  incomplete penetrance and variable expressivity, though autosomal recessive forms
  exist and tend to be more severe. First described by Shy and Magee in 1956, CCD
  was the first congenital myopathy defined by a specific histological abnormality.
disease_term:
  preferred_term: central core myopathy
  term:
    id: MONDO:0007294
    label: central core myopathy
parents:
- Congenital myopathy
- RYR1-related myopathy
prevalence:
- population: All-age populations
  percentage: 0.37 per 100,000
  notes: >-
    Population studies usually report prevalence for core myopathies or
    congenital myopathies as groups rather than for central core myopathy
    alone. Meta-analysis estimated pooled all-age prevalence for core myopathy
    at 0.37 per 100,000, and an Orphanet review noted that central core disease
    is probably the most common congenital myopathy.
  evidence:
  - reference: PMID:34795634
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "0.37 (95% CI 0.21-0.53) for core myopathy"
    explanation: This meta-analysis provides the best available pooled population estimate for the core-myopathy group that includes central core myopathy.
  - reference: PMID:17504518
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prevalence is unknown but the condition is probably more common than other congenital myopathies."
    explanation: This disease-specific review clarifies that central core disease itself lacks a separate direct population estimate but is likely the commonest congenital myopathy.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >
    Most cases of central core myopathy follow autosomal dominant inheritance
    with incomplete penetrance and variable expressivity. Dominant mutations
    are typically missense changes clustered in recognized mutational hotspot
    regions including the C-terminal transmembrane/pore-forming domain and
    tend to cause a milder phenotype.
  evidence:
  - reference: PMID:22473935
    reference_title: "Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Dominant mutations, typically missense, were frequently located in
      recognized mutational hotspot regions, while recessive mutations were
      distributed throughout the entire coding sequence.
    explanation: >
      Large cohort study of 71 families confirms that dominant RYR1 mutations
      are typically missense and cluster in hotspot regions.
  - reference: PMID:8220422
    reference_title: "A mutation in the human ryanodine receptor gene associated with central core disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Central core disease (CCD) is a morphologically distinct, autosomal
      dominant myopathy with variable clinical features.
    explanation: >
      The landmark 1993 Nature Genetics paper establishing the RYR1 link
      describes CCD as autosomal dominant with variable features.
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    Autosomal recessive forms of central core myopathy tend to be more severe,
    with earlier onset, greater weakness, and more functional limitations.
    Extraocular and bulbar muscle involvement is almost exclusively observed
    in recessive cases. Recessive mutations are distributed throughout the
    RYR1 coding sequence and often include nonsense and splice mutations
    expected to result in reduced RyR1 protein expression.
  evidence:
  - reference: PMID:22473935
    reference_title: "Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      As a group, dominant mutations were associated with milder phenotypes;
      patients with recessive inheritance had earlier onset, more weakness,
      and functional limitations. Extraocular and bulbar muscle involvement
      was almost exclusively observed in the recessive group.
    explanation: >
      This large cohort study of 71 families (35 dominant, 36 recessive)
      demonstrates the clinical distinction between dominant and recessive
      RYR1-related myopathies.
pathophysiology:
- name: Abnormal RyR1 calcium release channel function
  description: >
    RYR1 mutations alter the function of the ryanodine receptor, the principal
    calcium release channel of the sarcoplasmic reticulum in skeletal muscle.
    Dominant missense variants often produce hypersensitive or leaky RyR1
    channels with lowered threshold for sarcoplasmic reticulum calcium release,
    while recessive mutations frequently result in reduced RyR1 protein
    expression or excitation-contraction coupling uncoupling. Both mechanisms
    disrupt the DHPR-RyR1 signaling axis and calcium homeostasis in skeletal
    muscle fibers.
  gene:
    preferred_term: RYR1
    description: >
      Ryanodine receptor 1, a large homotetrameric calcium release channel of
      the sarcoplasmic reticulum that is fundamental to excitation-contraction
      coupling and skeletal muscle calcium homeostasis.
    modifier: ABNORMAL
    term:
      id: hgnc:10483
      label: RYR1
  cell_types:
  - preferred_term: Skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  - preferred_term: Slow muscle cell (type I fiber)
    term:
      id: CL:0000189
      label: slow muscle cell
  biological_processes:
  - preferred_term: Regulation of SR calcium release
    term:
      id: GO:0010880
      label: regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
  - preferred_term: Calcium ion homeostasis
    term:
      id: GO:0055074
      label: calcium ion homeostasis
  - preferred_term: Regulation of skeletal muscle contraction by calcium signaling
    term:
      id: GO:0014722
      label: regulation of skeletal muscle contraction by calcium ion signaling
  evidence:
  - reference: PMID:17504518
    reference_title: "Central core disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Altered excitability and/or changes in calcium homeostasis within muscle
      cells due to mutation-induced conformational changes of the RyR protein
      are considered the main pathogenetic mechanism(s).
    explanation: >
      Comprehensive Orphanet review of CCD establishing that mutation-induced
      conformational changes in RyR1 leading to altered calcium homeostasis
      are the main pathogenetic mechanism.
  - reference: PMID:16917943
    reference_title: "Mutations in RYR1 in malignant hyperthermia and central core disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      The RYR1 gene encodes the skeletal muscle isoform ryanodine receptor
      and is fundamental to the process of excitation-contraction coupling and
      skeletal muscle calcium homeostasis.
    explanation: >
      Review of RYR1 mutations in MH and CCD confirming the role of RYR1 in
      excitation-contraction coupling and calcium homeostasis.
  - reference: PMID:16917943
    reference_title: "Mutations in RYR1 in malignant hyperthermia and central core disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      In vitro analysis has confirmed that alteration of normal calcium
      homeostasis is a functional consequence of some of these changes.
    explanation: >
      Confirms functional evidence that RYR1 mutations alter calcium
      homeostasis through in vitro studies.
- name: Mitochondrial depletion and oxidative metabolism deficiency in cores
  description: >
    The central cores that define this myopathy histologically represent focal
    regions of myofibrillar disorganization with depletion of mitochondria and
    absence of oxidative enzyme activity. Cores run along the longitudinal axis
    of type 1 muscle fibers and are visualized as unstained regions on NADH-TR
    and cytochrome oxidase histochemistry. Mitochondrial calcium overload from
    dysfunctional RyR1 channels generates energetic strain and oxidative stress,
    contributing to the ultrastructural disorganization characteristic of cores.
  cell_types:
  - preferred_term: Skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: Response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
  - preferred_term: Intracellular calcium ion homeostasis
    term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
  evidence:
  - reference: PMID:17504518
    reference_title: "Central core disease."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Central core disease (CCD) is an inherited neuromuscular disorder
      characterised by central cores on muscle biopsy and clinical features
      of a congenital myopathy.
    explanation: >
      Establishes the defining histopathological feature of CCD as central
      cores on muscle biopsy.
- name: Malignant hyperthermia susceptibility
  description: >
    RYR1 mutations predispose to malignant hyperthermia (MH), a pharmacogenetic
    disorder triggered by volatile anesthetic agents and succinylcholine. The
    susceptible RyR1 channel exhibits exaggerated calcium release in response
    to these triggers, causing sustained muscle contraction, hypermetabolism,
    rhabdomyolysis, and potentially fatal hyperthermia. CCD and MHS are allelic
    conditions and a single RYR1 mutation may result in either or both
    phenotypes.
  biological_processes:
  - preferred_term: Muscle contraction
    term:
      id: GO:0006936
      label: muscle contraction
  - preferred_term: Calcium ion homeostasis
    term:
      id: GO:0055074
      label: calcium ion homeostasis
  evidence:
  - reference: PMID:17504518
    reference_title: "Central core disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      CCD and MHS are allelic conditions both due to (predominantly dominant)
      mutations in the skeletal muscle ryanodine receptor (RYR1) gene,
      encoding the principal skeletal muscle sarcoplasmic reticulum calcium
      release channel (RyR1).
    explanation: >
      Establishes that CCD and MHS are allelic conditions caused by mutations
      in the same RYR1 gene.
  - reference: PMID:8220423
    reference_title: "Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      One of these mutations was also detected in an unrelated MH pedigree
      whose members are asymptomatic of CCD. The data suggest a model to
      explain how a single mutation may result in two apparently distinct
      clinical phenotypes.
    explanation: >
      Demonstrates that the same RYR1 mutation can cause CCD in one family
      and isolated MH susceptibility in another, establishing the allelic
      relationship.
phenotypes:
- name: Proximal muscle weakness
  description: >
    Predominantly proximal muscle weakness affecting hip girdle and shoulder
    girdle muscles is a hallmark feature. Weakness is pronounced in the hip
    girdle and is typically static or only slowly progressive.
  frequency: HP_0040281
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  evidence:
  - reference: PMID:17504518
    reference_title: "Central core disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      CCD typically presents in infancy with hypotonia and motor developmental
      delay and is characterized by predominantly proximal weakness pronounced
      in the hip girdle
    explanation: >
      Comprehensive review establishing proximal weakness pronounced in the
      hip girdle as a characteristic feature of CCD.
  - reference: PMID:29391587
    reference_title: "Congenital myopathies: disorders of excitation-contraction coupling and muscle contraction."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Pronounced weakness in axial and proximal muscle groups is a common
      feature
    explanation: >
      Major Nature Reviews Neurology review confirming axial and proximal
      weakness as common in congenital myopathies including CCD.
- name: Neonatal hypotonia
  description: >
    Hypotonia present from birth is a common presenting feature, often leading
    to the initial clinical evaluation. Severity ranges from mild to marked,
    with recessive forms tending to be more severe.
  frequency: HP_0040282
  phenotype_term:
    preferred_term: Neonatal hypotonia
    term:
      id: HP:0001319
      label: Neonatal hypotonia
  evidence:
  - reference: PMID:17504518
    reference_title: "Central core disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      CCD typically presents in infancy with hypotonia and motor
      developmental delay
    explanation: >
      Establishes infantile hypotonia as a typical presenting feature of CCD.
- name: Delayed gross motor development
  description: >
    Motor development is typically delayed, with late achievement of sitting,
    standing, and independent ambulation. Most patients eventually achieve
    independent walking, though this may be delayed.
  frequency: HP_0040282
  phenotype_term:
    preferred_term: Delayed gross motor development
    term:
      id: HP:0002194
      label: Delayed gross motor development
  evidence:
  - reference: PMID:17504518
    reference_title: "Central core disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      CCD typically presents in infancy with hypotonia and motor
      developmental delay
    explanation: >
      Motor developmental delay is identified as a typical presenting feature.
- name: Scoliosis
  description: >
    Scoliosis is a common orthopaedic complication that may require surgical
    correction in severe cases.
  frequency: HP_0040282
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:17504518
    reference_title: "Central core disease."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >
      orthopaedic complications are common
    explanation: >
      Orthopaedic complications including scoliosis are identified as common
      in CCD.
- name: Congenital hip dislocation
  description: >
    Congenital hip dislocation is a characteristic orthopaedic complication
    and may be the presenting feature of the disease.
  frequency: HP_0040282
  phenotype_term:
    preferred_term: Congenital hip dislocation
    term:
      id: HP:0001374
      label: Congenital hip dislocation
  evidence:
  - reference: PMID:17504518
    reference_title: "Central core disease."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >
      orthopaedic complications are common
    explanation: >
      Congenital hip dislocation is one of the common orthopaedic
      complications in CCD.
- name: Malignant hyperthermia susceptibility
  description: >
    Susceptibility to malignant hyperthermia episodes triggered by volatile
    anesthetics or depolarizing muscle relaxants is a frequent and potentially
    life-threatening complication requiring precautionary measures for all
    surgical procedures.
  frequency: HP_0040282
  phenotype_term:
    preferred_term: Malignant hyperthermia
    term:
      id: HP:0002047
      label: Malignant hyperthermia
  evidence:
  - reference: PMID:17504518
    reference_title: "Central core disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      malignant hyperthermia susceptibility (MHS) is a frequent complication
    explanation: >
      Establishes MHS as a frequent complication of CCD.
  - reference: PMID:8220423
    reference_title: "Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Central core disease (CCD) of muscle is an inherited myopathy which is
      closely associated with malignant hyperthermia (MH) in humans.
    explanation: >
      Confirms the close association between CCD and MH.
- name: Myopathic facies
  description: >
    Mild facial weakness may be present, more commonly in autosomal recessive
    forms. Extraocular and bulbar muscle involvement is almost exclusively
    observed in the recessive group.
  frequency: HP_0040283
  phenotype_term:
    preferred_term: Myopathic facies
    term:
      id: HP:0002058
      label: Myopathic facies
  evidence:
  - reference: PMID:22473935
    reference_title: "Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Extraocular and bulbar muscle involvement was almost exclusively
      observed in the recessive group.
    explanation: >
      Demonstrates that facial and bulbar involvement is characteristic
      of recessive RYR1-related myopathies.
- name: External ophthalmoplegia
  description: >
    External ophthalmoplegia is observed primarily in autosomal recessive
    forms of RYR1-related myopathy.
  frequency: HP_0040284
  phenotype_term:
    preferred_term: External ophthalmoplegia
    term:
      id: HP:0000544
      label: External ophthalmoplegia
  evidence:
  - reference: PMID:22473935
    reference_title: "Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Extraocular and bulbar muscle involvement was almost exclusively
      observed in the recessive group.
    explanation: >
      Extraocular involvement (ophthalmoplegia) is almost exclusively
      seen in recessive RYR1-related myopathies.
- name: Respiratory insufficiency
  description: >
    Variable respiratory involvement may occur, particularly in more severe
    recessive forms, sometimes requiring respiratory support.
  frequency: HP_0040283
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:29391587
    reference_title: "Congenital myopathies: disorders of excitation-contraction coupling and muscle contraction."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >
      involvement of extraocular, cardiorespiratory and/or distal muscles
      can implicate specific genetic defects
    explanation: >
      Cardiorespiratory involvement is noted as a feature that can occur
      in congenital myopathies.
genetic:
- name: RYR1 mutations
  association: Causative
  gene_term:
    preferred_term: RYR1
    description: >
      Ryanodine receptor 1, encoding a homotetrameric calcium release channel
      of 5,038 amino acids. Mapping to chromosome 19q13.2 and comprising 106
      exons, it is the principal skeletal muscle sarcoplasmic reticulum calcium
      release channel fundamental to excitation-contraction coupling.
    term:
      id: hgnc:10483
      label: RYR1
  notes: >
    RYR1 is the major causative gene for CCD. Over 300 pathogenic variants
    have been identified. Dominant mutations are typically missense changes
    clustered in recognized hotspot regions including the C-terminal
    pore-forming domain. Recessive mutations are distributed throughout the
    entire coding sequence and include nonsense and splice mutations expected
    to result in reduced RyR1 protein. RYR1 mutations are also the most
    frequent genetic cause of congenital myopathies overall.
  evidence:
  - reference: PMID:8220422
    reference_title: "A mutation in the human ryanodine receptor gene associated with central core disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      The only amino acid substitution found was an Arg2434His mutation,
      resulting from the substitution of A for G7301. This mutation was
      linked to CCD with a lod score of 4.8 at a recombinant fraction of
      0.0 in 16 informative meioses in a 130 member family, suggesting a
      causal relationship to CCD.
    explanation: >
      Landmark 1993 Nature Genetics paper that first identified a specific
      RYR1 mutation (Arg2434His) as causative of central core disease through
      linkage analysis in a large family.
  - reference: PMID:16917943
    reference_title: "Mutations in RYR1 in malignant hyperthermia and central core disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Mapping to chromosome 19q13.2, the gene comprises 106 exons and
      encodes a protein of 5,038 amino acids. Mutations in the gene have
      been found in association with several diseases: the pharmacogenetic
      disorder, malignant hyperthermia (MH); and three congenital myopathies,
      including central core disease (CCD), multiminicore disease (MmD), and
      in an isolated case of a congenital myopathy characterized on histology
      by cores and rods.
    explanation: >
      Comprehensive review of RYR1 mutations establishing the gene structure
      and its association with CCD, MH, and other congenital myopathies.
  - reference: PMID:22473935
    reference_title: "Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Ryanodine receptor 1 (RYR1) mutations are a common cause of congenital
      myopathies associated with both dominant and recessive inheritance.
    explanation: >
      Large cohort study confirming RYR1 mutations as a common cause of
      congenital myopathies with both inheritance patterns.
  - reference: PMID:29391587
    reference_title: "Congenital myopathies: disorders of excitation-contraction coupling and muscle contraction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      RYR1 mutations are the most frequent genetic cause, and CCD and MmD
      are the most common subgroups.
    explanation: >
      Nature Reviews Neurology review confirming RYR1 as the most frequent
      genetic cause of congenital myopathies.
treatments:
- name: Avoidance of malignant hyperthermia triggers
  description: >
    Strict avoidance of volatile anesthetic agents (halothane, sevoflurane,
    desflurane, isoflurane) and depolarizing neuromuscular blocking agents
    (succinylcholine) during surgical procedures. Total intravenous anesthesia
    (TIVA) with agents such as propofol is recommended. Management must
    anticipate susceptibility to potentially life-threatening reactions to
    general anaesthesia.
  treatment_term:
    preferred_term: Anesthesia precautions
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  evidence:
  - reference: PMID:17504518
    reference_title: "Central core disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Management is mainly supportive and has to anticipate susceptibility to
      potentially life-threatening reactions to general anaesthesia.
    explanation: >
      Establishes the critical importance of anesthetic precautions in CCD
      management.
- name: Dantrolene for malignant hyperthermia
  description: >
    Dantrolene sodium is the specific treatment for acute malignant hyperthermia
    episodes. It acts by inhibiting calcium release from the sarcoplasmic
    reticulum via the ryanodine receptor. Dantrolene should be immediately
    available whenever a susceptible patient undergoes anesthesia.
  treatment_term:
    preferred_term: Dantrolene therapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: dantrolene
      term:
        id: CHEBI:4317
        label: dantrolene
- name: Physical therapy and rehabilitation
  description: >
    Regular physical therapy focusing on maintaining range of motion, preventing
    contractures, and maximizing functional capacity. Exercise programs should
    be tailored to individual ability.
  treatment_term:
    preferred_term: Physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
- name: Orthopedic management
  description: >
    Surgical and conservative management of musculoskeletal complications
    including scoliosis, hip dislocation, and foot deformities. Bracing
    and assistive devices may be needed.
  treatment_term:
    preferred_term: Orthopedic surgery
    term:
      id: MAXO:0000004
      label: surgical procedure
- name: Genetic counseling
  description: >
    Genetic counseling for affected families to discuss inheritance patterns,
    recurrence risk, and implications for family members regarding malignant
    hyperthermia susceptibility. Mutational analysis of RYR1 may provide
    genetic confirmation of the diagnosis.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:17504518
    reference_title: "Central core disease."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Mutational analysis of the RYR1 gene may provide genetic confirmation
      of the diagnosis.
    explanation: >
      Supports the role of genetic testing and counseling in CCD diagnosis
      and family management.
notes: >
  Central core myopathy was first described by Shy and Magee in 1956 and was the
  first congenital myopathy defined by a specific histological abnormality. The
  molecular basis was established in 1993 when Zhang et al. and Quane et al.
  independently identified RYR1 mutations in CCD families. The disease has
  significant allelic overlap with malignant hyperthermia susceptibility (MHS1),
  and a single mutation may result in either or both phenotypes. The clinical
  spectrum of RYR1-related myopathies extends beyond central core disease to
  include multiminicore disease, centronuclear myopathy, and congenital fiber
  type disproportion, reflecting complex genotype-phenotype relationships. In
  the majority of patients, weakness is static or only slowly progressive, with
  a favourable long-term outcome. Prevalence is unknown but the condition is
  probably more common than other congenital myopathies.
datasets: