Lecture Notes

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.

  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).

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