Overview

• Multiminicore Disease (MmD): A clinically and genetically heterogeneous congenital myopathy characterized by multiple small cores in muscle fibers on biopsy.
• Main Forms:
  1. Rigid Spine Muscular Dystrophy Type 1 (RSMD1):
     • Caused by recessive SEPN1 mutations.
  2. RYR1-related Multiminicore Myopathy:
     • Allelic to Central Core Disease (CCD).
     • Often associated with ophthalmoplegia.

Clinical Features

1. Rigid Spine Syndrome Phenotype (RSMD1):

   • Cause: Recessive mutations in SEPN1 (Selenoprotein N).
   • Onset: First year of life.
   • Symptoms:
     • Hypotonia and weakness:
       • Predominantly axial weakness.
       • Neck flexors most affected → poor/absent head control in infancy.
     • Joint hyperextensibility.
     • Delayed motor development.
     • Facial weakness: Common.
     • Extraocular muscles spared.
     • Kyphoscoliosis and spinal rigidity:
       • Progressive, especially during adolescence.
       • Often associated with respiratory insufficiency.
     • Respiratory involvement:
       • Progressive insufficiency typically develops in late adolescence or early adulthood.
     • Intellectual performance: Normal.
   • Prognosis:
     • Most remain independently ambulant despite respiratory challenges.

2. RYR1-Related Multiminicore Myopathy:

   • Cause: Recessive mutations in RYR1 (ryanodine receptor).
   • Symptoms:
     • Similar distribution of weakness and wasting as RSMD1.
     • Ophthalmoplegia:
       • Extraocular muscle involvement (e.g., limited abduction, upward gaze).
     • Bulbar involvement:
       • May be pronounced (e.g., swallowing difficulties).
     • Respiratory insufficiency:
       • Milder compared to RSMD1.
   • Prevalence:
     • More common than SEPN1-associated RSMD1.

Pathological Features

• Muscle Biopsy Findings:
  • Multiple small cores:
    • Regions of reduced oxidative enzyme activity in muscle fibers.
  • Cores are smaller and more numerous than in Central Core Disease (CCD).

Genetics

1. SEPN1-Related MmD:

   • Gene: Selenoprotein N (SEPN1).
   • Inheritance: Autosomal Recessive (AR).

2. RYR1-Related MmD:

   • Gene: Ryanodine receptor 1 (RYR1).
   • Inheritance: Autosomal Recessive (AR).
   • Overlap with Central Core Disease (CCD).

Diagnosis

1. Clinical Evaluation:

   • Weakness, hypotonia, and axial muscle involvement.
   • Check for associated kyphoscoliosis and respiratory function.

2. Histological Examination:

   • Muscle biopsy showing multiple small cores.

3. Genetic Testing:

   • Identifies causative SEPN1 or RYR1 mutations.

4. Differential Diagnosis:

   • Other congenital myopathies (e.g., CCD, Nemaline Myopathy).
   • Non-myopathic causes of hypotonia and weakness.

Management

1. Supportive Care:

   • Respiratory support:
     • Non-invasive ventilation for respiratory insufficiency.
   • Physiotherapy:
     • Maintain mobility and prevent contractures.
   • Orthopedic management:
     • Treat kyphoscoliosis and spinal rigidity.

2. Monitoring:

   • Regular respiratory and musculoskeletal assessments.
   • Early detection and intervention for scoliosis and respiratory decline.

3. Genetic Counseling:

   • Important for families with affected individuals.

Prognosis

1. SEPN1-Associated MmD (RSMD1):

   • Progressive kyphoscoliosis and respiratory insufficiency during adolescence.
   • Most patients remain ambulant into adulthood.

2. RYR1-Associated MmD:

   • Generally milder respiratory impairment.
   • Pronounced bulbar involvement and ophthalmoplegia in some cases.

Key Points for Practitioners

• Distinguish between SEPN1-related and RYR1-related forms based on clinical and genetic findings.
• Early intervention in scoliosis and respiratory care is critical for quality of life.
• Be vigilant about malignant hyperthermia risk in RYR1-related MmD.

Pathological Features of Minicores

• Histological Characteristics:
  • Minicores:
    • Multiple focal defects in oxidative enzyme activity visible in histochemical preparations.
    • Found in both type I and type II muscle fibers.
  • Associated histological features:
    • Increased fiber-size variability.
    • Presence of central nuclei.
    • Hypotrophy of type I fibers.
    • Type I fiber predominance.

Rare Genetic Associations with Core Myopathies

1. MYH7 (Myosin Heavy Chain 7):

   • Associated with core myopathies and cardiomyopathy.
   • Clinical features may include:
     • Limb-girdle or scapuloperoneal weakness.
     • Cardiac involvement requiring monitoring.

2. TTN (Titin):

   • Rarely associated with core myopathies.
   • Mutations linked to cardiomyopathy and structural muscle abnormalities.

Core-Rod Myopathy

• Definition:

  • A rare overlap myopathy with features of central cores and nemaline bodies on muscle biopsy.
  • Cores and rods may occur in the same or separate muscle fibers.

• Genetic Causes:

  1. RYR1 (Ryanodine Receptor 1):
     • Most common cause of true core-rod myopathy.
     • Both dominant and recessive mutations reported.
  2. NEB (Nebulin):
     • Uncommon cause of recessive core-rod disease.

• Clinical Features:

  • Features of core myopathies (e.g., proximal weakness, respiratory involvement).
  • Features of nemaline myopathies (e.g., facial weakness, distal involvement).

Clinical and Diagnostic Considerations

• Minicore Myopathies:

  • Diagnostic features include histological evidence of minicores and associated structural abnormalities.
  • Genetic testing is essential to identify specific causative mutations.

• Core-Rod Myopathy:

  • Presence of both cores and rods may indicate genetic overlap (e.g., RYR1 or NEB mutations).
  • Advanced imaging (MRI) may aid in differential diagnosis.
  • Muscle biopsy remains critical for confirming pathology.

• Cardiomyopathy Association:

  • Always evaluate for cardiac involvement in patients with MYH7 or TTN mutations.

Management

1. Supportive Care:

   • Respiratory support as needed.
   • Physiotherapy to optimize motor function.
   • Orthopedic care for scoliosis and other deformities.

2. Cardiac Monitoring:

   • Necessary for MYH7 or TTN-related myopathies.

3. Genetic Counseling:

   • Important for families with inherited forms of core myopathies.

4. Malignant Hyperthermia Precautions:

   • Required for RYR1 mutations.

Prognosis

• Minicore Myopathies:
  • Variable severity based on genetic cause.
  • Prognosis generally good with supportive management.
• Core-Rod Myopathy:
  • Depends on the degree of respiratory and motor involvement.
  • Genetic subtype plays a key role in determining outcomes.