Introduction

• Congenital Myopathies: Group of inherited muscle disorders presenting with:
  • Hypotonia and weakness from birth.
  • Characteristic histological and/or electron microscopic changes in muscle tissue.
• Clinical severity: Wide variation within and across forms.
• Overlap with other neuromuscular disorders:
  • Muscular dystrophies.
  • Congenital myasthenic syndromes.
  • Metabolic myopathies (e.g., Pompe disease).
  • Spinal muscular atrophy (SMA).
  • Non-primary muscular disorders (e.g., Prader-Willi syndrome, neurometabolic disorders).

Clinical Features

1. Common Features

   • Generalized hypotonia: "Floppy infant syndrome."
   • Weakness:
     • Prominent facial weakness ± ptosis.
     • Hypotonic ‘frog-leg’ posture.
     • Respiratory muscle involvement: May require ventilatory support.
     • Bulbar muscle weakness: Feeding and speech difficulties.
   • Extraocular muscle involvement: May present later.
   • Hyporeflexia: Depressed or absent reflexes.
   • Intact sensation and normal intelligence.
   • CK levels: Normal or mildly elevated.
   • EMG: Normal or shows myopathic pattern.

2. Differentiation from Other Disorders

   • No histopathological evidence of muscular dystrophy.
   • Differential diagnosis includes:
     • Prader-Willi syndrome.
     • Neurometabolic disorders.
     • Non-neuromuscular causes of neonatal hypotonia.

Diagnostic Tools

1. Histopathology

   • Muscle biopsy:
     • Key to classification (e.g., rods, cores, central nuclei).
     • Examples:
       • Nemaline myopathy: Rods.
       • Central core disease: Cores.
       • Centronuclear myopathy: Central nuclei.
       • Congenital fibre type disproportion: Type 1 fibre hypotrophy.

2. Imaging

   • Muscle ultrasound and MRI:
     • Recognizes selective muscle involvement.
     • Aids in differentiation among subtypes.
     • Interpreted alongside clinical features and biopsy.

3. Molecular Genetic Testing

   • Increasing use of next-generation sequencing (NGS):
     • Often prioritizes or obviates muscle biopsy.
     • Identifies genetic heterogeneity and overlap.
     • Example:
       • RYR1 mutations:
         • Autosomal dominant/recessive.
         • Associated with multiple phenotypes:
           • Central core disease.
           • Core-rod myopathy.
           • Multiminicore disease.
           • Centronuclear myopathy.

4. Other Investigations

   • Routine blood tests (e.g., CK levels).
   • Neurological assessments (e.g., reflexes, EMG).

Classification

• Historically based on muscle biopsy features:
  • Nemaline myopathy: Rods.
  • Central core disease: Cores.
  • Multiminicore disease: Multiminicores.
  • Centronuclear myopathy: Central nuclei.
  • Congenital fibre type disproportion: Type 1 fibre hypotrophy.
• Current classification incorporates genetic findings.

Genetic Basis

1. Genetic Heterogeneity

   • A single histological phenotype can arise from multiple genetic mutations.
   • Example: Nemaline myopathy: 10 known loci.

2. Pleiotropy

   • A single gene mutation can cause diverse pathological features.
   • Example: RYR1 gene: Multiple associated phenotypes.

3. Role of Genetic Testing

   • Provides definitive diagnosis.
   • Guides prognosis and management.
   • Reduces reliance on muscle biopsy.

Differential Diagnosis

• Neuromuscular Disorders
  • Muscular dystrophies.
  • SMA.
  • Congenital myasthenic syndromes.
  • Metabolic myopathies (e.g., Pompe disease).
• Non-Primary Neuromuscular Causes
  • Prader-Willi syndrome.
  • Neurometabolic conditions.

Key Management Points

• Multidisciplinary approach:
  • Neurology: Clinical diagnosis and follow-up.
  • Genetics: Molecular confirmation.
  • Physiotherapy: Muscle strengthening and contracture prevention.
  • Respiratory support: As required.
  • Nutritional support: For feeding difficulties.
• Genetic counseling for families.

Future Directions

• Greater reliance on genomic technologies:
  • Broader use of NGS.
  • Improved understanding of genotype-phenotype correlations.
• Integration of clinical, histological, imaging, and genetic data to refine diagnosis and management.

Summary

• Congenital myopathies present primarily with neonatal hypotonia and weakness.
• Diagnosis requires a combination of clinical, histological, imaging, and genetic findings.
• Genetic testing is increasingly replacing muscle biopsy as the first-line investigation.
• Management is multidisciplinary, with advances in genetic research paving the way for personalized care.