Overview

• Nemaline Myopathy (NM): A congenital myopathy characterized by rod-like inclusions (nemaline bodies) in skeletal muscle fibers.
• Inheritance:
  • Autosomal dominant (AD), autosomal recessive (AR), or sporadic (new dominant mutations).
• Pathogenesis:
  • Mutations in genes encoding:
    • Thin filament proteins of muscle.
    • Sarcomere protein regulation components.

Clinical Forms

1. Typical Congenital NM

   • Onset: Birth or first year of life.
   • Features:
     • Hypotonia, weakness, feeding difficulties.
     • Delayed motor milestones, waddling gait, or speech abnormalities.
     • Facial weakness is common.
     • Weakness:
       • Both distal and proximal muscles (genetic subtype clue).
       • Respiratory muscle involvement (often subclinical hypoventilation).
     • Cardiac involvement: Rare.
   • Prognosis:
     • Muscle weakness often static or slowly progressive.
     • Most patients lead active lives.

2. Severe Congenital NM

   • Onset: Birth.
   • Features:
     • Severe hypotonia, fetal akinesia, limited postnatal movement.
     • Feeding difficulties (sucking and swallowing issues).
     • Respiratory insufficiency and recurrent pneumonia.
   • Prognosis:
     • High mortality in first weeks/months due to respiratory failure.
     • Rare survivors may achieve independent walking.

Diagnostic Features

1. Histological Findings

   • Nemaline bodies:
     • Rod-like inclusions derived from lateral Z-line expansion.
     • Stained with modified Gomori trichrome:
       • Appear red/purple against a blue-green myofibrillar background.
   • Additional pathological features:
     • Type I fiber predominance.
     • Fiber atrophy and/or hypertrophy.

2. Genetic Findings

   • Mutations identified in 10 genes (examples in Table 26.1):
     • Thin filament proteins:
       • α-tropomyosinslow (TPM3), nebulin (NEB), skeletal α-actin (ACTA1), β-tropomyosin (TPM2), troponin T (TNNT1), cofilin (CFL2), leiomodin 3 (LMOD3).
     • Sarcomere regulators:
       • KBTBD13, KLHL40, KLHL41.
   • Recessive nebulin (NEB) mutations:
     • Account for ~50% of NM cases.
   • Sporadic dominant ACTA1 mutations:
     • Account for 20–25% of cases (up to 50% in newborn lethal presentations).

Clinical Features by Gene Mutation

1. α-tropomyosinSLOW (TPM3)

   • Inheritance: AD, AR.
   • Protein: Tropomyosin 3.
   • Clinical Features:
     • Variable severity; may present in childhood.
     • Prominent features:
       • Foot drop.
       • Neck weakness.

2. Skeletal muscle α-actin (ACTA1)

   • Inheritance: AD, AR, sporadic.
   • Protein: α-Actin 1.
   • Clinical Features:
     • Accounts for 15–25% of NM cases.
     • Severity ranges from severe neonatal to adult onset.
     • Causes 50% of severe lethal NM.
     • Majority involve de novo dominant mutations.
     • Rarely associated with cardiac involvement.

3. β-tropomyosin (TPM2)

   • Inheritance: AD.
   • Protein: Tropomyosin 2.
   • Clinical Features:
     • Foot drop and neck weakness.
     • May co-occur with:
       • Distal arthrogryposis.
       • Large joint contractures.
       • Cardiomyopathy.

4. Nebulin (NEB)

   • Inheritance: AR.
   • Protein: Nebulin.
   • Clinical Features:
     • Most common genetic cause (~50% of NM cases).
     • Typical congenital presentation is the most frequent form.
     • Prominent:
       • Lower facial and neck weakness.
       • Foot drop.

5. Troponin T1 (TNNT1)

   • Inheritance: AR.
   • Protein: Troponin T1.
   • Clinical Features:
     • Neonatal onset with:
       • Hypotonia.
       • Contractures.
       • Tremors.
     • Progressive weakness, severe pectus carinatum.
     • Early childhood death due to respiratory insufficiency.
     • First reported in Amish populations.

6. Cofilin (CFL2)

   • Inheritance: AR.
   • Protein: Cofilin 2.
   • Clinical Features:
     • Only two families reported.
     • No facial weakness or foot drop.

7. Kelch repeat and BTB domain-containing 13 (KBTBD13)

   • Inheritance: AD.
   • Protein: Kelch repeat protein.
   • Clinical Features:
     • Childhood onset.
     • Proximal weakness with slowness of muscle movements.
     • Spares facial, cardiac, and respiratory muscles.

8. Kelch-like family member 40 (KLHL40)

   • Inheritance: AR.
   • Protein: Kelch-like protein 40.
   • Clinical Features:
     • Severe congenital, lethal.
     • Fetal akinesia.
     • Respiratory and bulbar weakness.

9. Kelch-like family member 41 (KLHL41)

   • Inheritance: AR.
   • Protein: Kelch-like protein 41.
   • Clinical Features:
     • Only five families reported.
     • Severity ranges from:
       • Neonatal lethal.
       • Intermediate or typical forms of NM.

10. Leiomodin 3 (LMOD3)

    • Inheritance: AR.
    • Protein: Leiomodin 3.
    • Clinical Features:
      • Typically severe congenital lethal.
      • Occasional typical congenital forms.
      • ~30% involve extraocular muscles.
      • Marked features:
        • Facial weakness.
        • Respiratory and bulbar involvement.
11. Cap Disease
    • Definition: A variant of Nemaline Myopathy characterized by cap-like structures at the periphery of muscle fibers on biopsy.
    • Inheritance: Autosomal Dominant (AD).
    • Genetic Causes and Features:
      1. β-tropomyosin (TPM2):
         • Most common cause of cap disease.
         • Clinical presentation similar to NM due to TPM2:
           • Foot drop.
           • Neck weakness.
           • May have distal arthrogryposis or cardiomyopathy.
      2. α-tropomyosin_SLOW (TPM3):
         • As for NM due to TPM3.
         • Distal and proximal weakness.
      3. Skeletal muscle α-actin (ACTA1):
         • Single case reported.
         • Likely similar to NM due to ACTA1
12. Zebra Body Myopathy
    • Definition: A rare NM variant with zebra-like inclusions seen on muscle biopsy.
    • Inheritance: Autosomal Dominant (AD).
    • Genetic Cause and Features:
      • Skeletal muscle α-actin (ACTA1):
        • Single case reported to date.
        • Features align with NM due to ACTA1:
          • Severe neonatal to adult-onset weakness.
13. Core-Rod Myopathy

• Definition: Overlap syndrome of Nemaline Myopathy (NM) and Central Core Disease (CCD), showing both nemaline rods and core structures in muscle biopsy.
• Inheritance: Autosomal Recessive (AR) or Autosomal Dominant (AD).
• Genetic Causes and Features:
  1. Nebulin (NEB):
     • AR.
     • Single case reported:
       • Severe neonatal presentation.
       • Requires ventilatory support.
       • Multiple joint contractures.
       • Scoliosis.
  2. Ryanodine receptor (RYR1):
     • AD, AR.
     • Features overlap with core myopathies:
       • Proximal weakness.
       • May involve respiratory and extraocular muscles.
  3. Kelch repeat and BTB domain-containing 13 (KBTBD13):
     • AD.
     • Similar features as NM due to KBTBD13:
       • Childhood onset.
       • Proximal weakness.
       • "Slowness" of muscle movement.

Differential Diagnosis

• Other congenital myopathies with overlapping features:
  • Centronuclear myopathy (e.g., MTM1, DNM2).
  • Congenital fiber type disproportion (e.g., RYR1, TPM3).
  • Myosin storage myopathy (e.g., MYH7).
• Non-neuromuscular causes:
  • Prader-Willi syndrome.
  • Neurometabolic disorders.

Diagnostic Approach

1. Clinical Evaluation
   • Assess motor milestones, weakness distribution, and respiratory function.
2. Histological Examination
   • Muscle biopsy with Gomori trichrome stain.
3. Molecular Genetic Testing
   • Next-generation sequencing (NGS) to identify causative mutations.

Management

• Supportive Care:
  • Respiratory support (non-invasive ventilation, tracheostomy if severe).
  • Feeding support (e.g., gastrostomy for feeding difficulties).
  • Physiotherapy and rehabilitation to optimize motor function.
• Monitoring:
  • Regular respiratory assessments for subclinical hypoventilation.
  • Cardiac evaluation (though involvement is rare).
• Genetic Counseling:
  • Inform families about inheritance patterns and recurrence risks.

Future Directions

• Increasing reliance on genetic testing to reduce need for biopsy.
• Ongoing identification of novel genes associated with NM.
• Research on genotype-phenotype correlations to guide prognosis and therapy.