Overview

• Centronuclear myopathies (CNMs): A group of congenital myopathies characterized by centrally placed nuclei in muscle fibers on biopsy.
• Inheritance:
  • X-linked recessive.
  • Autosomal dominant.
  • Autosomal recessive.
• Clinical Features:
  • Generalized weakness, hypotonia, ophthalmoplegia, and respiratory involvement.
  • Delayed motor milestones and skeletal deformities.

Forms of Centronuclear Myopathies

1. X-Linked Recessive CNM (Myotubular Myopathy)

   • Gene: MTM1 (Myotubularin).
   • Pathophysiology: Impairment in signal transduction for late myogenesis and excitation-contraction coupling.
   • Onset: In utero or neonatal.
   • Clinical Features:
     • Severe neonatal hypotonia ("floppy infant syndrome").
     • Facial diplegia and feeding/respiratory difficulties.
     • Thin ribs, contractures (hips, knees), cryptorchidism.
     • Ophthalmoplegia.
     • Pregnancy may be complicated by polyhydramnios.
   • Prognosis:
     • High neonatal mortality.
     • Survivors require permanent respiratory support.
   • Histological Features:
     • Small type 1 fibers with centrally placed nuclei resembling fetal myotubes.
   • Carriers:
     • Obligate carriers usually asymptomatic.
     • Muscle biopsy changes in up to 50% of carriers.
     • Rare manifesting carriers due to skewed X-inactivation.

2. Autosomal Dominant CNM

   • Gene: Dynamin 2 (DNM2).
   • Onset: Variable (congenital to adult).
   • Clinical Features:
     • Weakness:
       • Neck flexors, facial muscles.
       • External ophthalmoplegia and ptosis.
     • Wide range of severity; severe forms often linked to de novo mutations.
   • Histological Features:
     • Centralized nuclei.
     • Radial sarcoplasmic strands on oxidative stains.
   • Additional Cause: Mutations in Amphiphysin 2 (BIN1).
     • Rare variant with similar features.

3. Autosomal Recessive CNM

   • Genes:
     • RYR1 (Ryanodine receptor).
     • BIN1 (Amphiphysin 2).
     • SPEG (Striated muscle preferentially expressed protein kinase).
   • Clinical Features:
     • Onset in infancy or early childhood.
     • Respiratory distress, hypotonia, weak cry, difficulty sucking.
     • Ophthalmoplegia, ptosis, and facial diplegia.
     • Skeletal issues:
       • Delayed motor milestones.
       • Development of contractures and scoliosis.
     • Cardiac involvement in SPEG-related CNM:
       • Associated with dilated cardiomyopathy.
   • Histological Features:
     • Centralized nuclei.
     • Radial sarcoplasmic strands (less apparent in younger children).

Pathological Features

• Muscle biopsy findings:
  • Centralized nuclei occupying a large proportion of muscle fibers.
  • Radial sarcoplasmic strands in DNM2- and BIN1-related CNM.
  • Predominance of small type 1 fibers.
  • May resemble fetal myotubes (in X-linked CNM).

Diagnosis

1. Clinical Evaluation:
   • Assess for hypotonia, weakness, respiratory distress, and ophthalmoplegia.
   • Look for skeletal and cardiac abnormalities.
2. Histological Examination:
   • Muscle biopsy to identify centrally placed nuclei and associated findings.
3. Genetic Testing:
   • Identify mutations in:
     • MTM1 (X-linked).
     • DNM2 (autosomal dominant).
     • RYR1, BIN1, or SPEG (autosomal recessive).
4. Differential Diagnosis:
   • Congenital myotonic dystrophy (exclude via genetic testing).

Management

1. Supportive Care:

   • Respiratory support:
     • Permanent ventilation for severe forms.
   • Physiotherapy:
     • Prevent contractures and improve motor function.
   • Nutritional support for feeding difficulties.
   • Orthopedic interventions:
     • Manage scoliosis and contractures.

2. Monitoring:

   • Regular respiratory and musculoskeletal evaluations.
   • Cardiac screening in SPEG-related CNM.

3. Genetic Counseling:

   • Crucial for families with X-linked or recessive inheritance.

Prognosis

1. X-linked CNM:
   • Severe neonatal forms with high mortality.
   • Long-term survivors require intensive respiratory and supportive care.
2. Autosomal Dominant CNM:
   • Variable severity; milder forms may have a normal lifespan with supportive management.
3. Autosomal Recessive CNM:
   • Dependent on genetic subtype; cardiac involvement in SPEG-related CNM may influence prognosis.

Key Points for Practitioners

• Early diagnosis and supportive care are critical for improving outcomes.
• Genetic testing is essential for accurate diagnosis and family counseling.
• Be vigilant for respiratory and cardiac complications in severe cases.