Overview

• Central Core Disease (CCD): A congenital myopathy characterized by central cores in muscle fibers on biopsy.
• Associated with mutations in the RYR1 gene, which encodes the skeletal muscle ryanodine receptor.
• Inheritance:
  • Traditionally Autosomal Dominant (AD) with variable penetrance.
  • Recessive inheritance recognized, especially in severe cases.
  • De novo mutations are common.

Clinical Features

1. Typical Phenotype:

   • Onset: Infancy.
   • Symptoms:
     • Weakness, hypotonia, and poor muscle bulk.
     • Proximal musculature and lower extremities most affected.
     • Mild facial and neck weakness.
     • Extraocular muscles typically spared.
   • Motor milestones:
     • Delayed but most achieve ambulation.
   • Musculoskeletal deformities:
     • Kyphoscoliosis.
     • Congenital hip dislocation.
     • Pes cavus and pes planus.
     • Thoracic deformities.
   • Respiratory insufficiency: Rare.
   • Cardiac involvement: None.
   • Cognition: Normal intellectual performance.

2. Clinical Spectrum:

   • Asymptomatic individuals with isolated hyper-CKemia or mild skeletal deformity.
   • Severe infantile forms:
     • Profound weakness and hypotonia.
     • Neonatal respiratory failure.
     • Arthrogryposis.

3. RYR1-Related Myopathy Spectrum:

   • Overlap with multiminicore disease and other core myopathies.
   • Evolution of pathological changes from multiminicores to central cores in the same patient.

4. Associated Conditions:

   • Malignant Hyperthermia (MH):
     • CCD is allelic to MH susceptibility.
     • Anesthetic precautions are critical:
       • Avoid triggering agents (e.g., volatile anesthetics, succinylcholine).
       • Use non-triggering anesthesia and have dantrolene available.

Pathological Features

1. Central Cores:

   • Central, well-circumscribed circular regions in Type 1 muscle fibers.
   • Staining characteristics:
     • Reduced oxidative enzyme activity.
     • Negative for phosphorylase and glycogen.
   • Lack mitochondria and sarcoplasmic reticulum.

2. Fiber Composition:

   • Type 1 fiber predominance.
   • Type 1 fibers smaller than Type 2 fibers.

3. Histological Spectrum:

   • Changes may evolve over time:
     • From multiminicores to central cores.

Genetics

• RYR1 Gene:

  • Encodes the skeletal muscle ryanodine receptor.
  • Facilitates calcium release from the sarcoplasmic reticulum to trigger muscle contraction.
  • Mutations in RYR1 can cause:
    • Central core disease.
    • Multiminicore disease.
    • Malignant hyperthermia susceptibility.

• Genotype-Phenotype Correlation:

  • Dominant mutations:
    • Typically cause CCD.
  • Recessive mutations:
    • Associated with severe neonatal-onset forms, often with respiratory failure and arthrogryposis.

Diagnosis

1. Clinical Evaluation:

   • Assess motor milestones, muscle weakness, and skeletal deformities.
   • Screen for hyper-CKemia.

2. Histological Examination:

   • Muscle biopsy showing central cores.

3. Genetic Testing:

   • Next-generation sequencing to identify RYR1 mutations.

4. Differential Diagnosis:

   • Other RYR1-related myopathies:
     • Multiminicore disease.
   • Non-RYR1-related congenital myopathies:
     • Nemaline myopathy.
     • Centronuclear myopathy.

Management

1. Supportive Care:

   • Physiotherapy: Improve strength and prevent contractures.
   • Orthopedic interventions: Address skeletal deformities (e.g., scoliosis correction).
   • Respiratory support: For severe neonatal-onset cases.

2. Anesthetic Precautions:

   • Avoid MH-triggering agents.
   • Use dantrolene prophylactically if needed.

3. Monitoring:

   • Regular follow-up for musculoskeletal health.
   • Screening for respiratory function in severe cases.

4. Genetic Counseling:

   • Important for families with CCD or MH susceptibility.

Prognosis

• Typical CCD:
  • Static or slowly progressive weakness.
  • Most patients lead active lives.
• Severe Neonatal Forms:
  • High neonatal mortality due to respiratory failure.
  • Survivors may show respiratory and motor improvement with age.

Future Directions

• Improved molecular diagnostics to differentiate CCD from other core myopathies.
• Development of targeted therapies for severe RYR1-related conditions.
• Enhanced understanding of genotype-phenotype relationships for personalized management.