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Congenital Myasthenic Syndromes

Congenital Myasthenic Syndromes. Shahriar Nafissi, MD Associate Professor of Neurology Tehran University of Medical Sciences. Physiology. The Neuromuscular Junction. Action potential. Ca 2+ channel. Ca 2+. Presynaptic terminal.

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Congenital Myasthenic Syndromes

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  1. CongenitalMyasthenic Syndromes Shahriar Nafissi, MD Associate Professor of Neurology Tehran University of Medical Sciences

  2. Physiology

  3. The Neuromuscular Junction

  4. Action potential Ca2+ channel Ca2+ Presynaptic terminal action potential  opening voltage-gated Ca2+ channels↑Ca2+ permeability

  5. Ca2+ channel Presynaptic terminal Ca2+ ACh ↑Ca2+ Ach release from synaptic vesicles

  6. Synaptic cleft Na+ ACh Receptor molecule Na+  ACh binding to Ach receptors  opening ligand-gated Na+ channels.

  7. Na+ Action potential Action potential Na+ ↑Na+ permeability depolarization action potential generation in the postsynaptic membrane

  8. Acetic acid Choline ACh Acetylcholinesterase ACh receptor site Ach→acetic acid + choline ▲ Ach-Esterase

  9. ACh Acetic acid Synaptic vesicle Choline Choline ACh Presynaptic terminal in the presynaptic terminal Choline + acetic acid → Ach →Synaptic vesicles

  10. Structural Reality By John Heuser and Louise Evans University of California, San Francisco

  11. Ligand- Gated Ion Channel 2α + β + ε + δ

  12. Congenital Myasthenic Syndromes • Group of diseases caused by genetic defects affecting neuromuscular transmission • Heterogeneous inheritance and pathophysiology

  13. Classification • Presynaptic Defect • Choline Acetyl Transferase deficiency • Paucity of synaptic vesicles • Lambert-Eaton like CMS • Synaptic Defect • Endplate ACh Esterase deficiency • Postsynaptic Defects • Kinetic abnormality of AChR • AChR deficiency • Rapsyn • Dok-7 • SCN4A • MuSK • No identified Defect

  14. percentage of CMS subtypes in different centers

  15. Diagnostic Clues in CMS • Weakness/fatigability of limbs and oculobulbar muscles • Early onset (since neonatal period) • Positive family history • EDX findings (RNS, SFEMG) • Response to anti-cholinesterases • Absence of anti-AChR, MuSK , VGCC antibodies

  16. DiagnosticDifficulties • Diagnostic problems • Late onset (in adult) • No response to anticholinesterases • No family history • Episodic symptoms • No ophthalmoplegia or cranial involvement • Decrement may not be present in all muscles, or present only intermittently • Misdiagnosed as • congenital myopathy • Seronegative MG (late onset) • Metabolic myopathies

  17. 24 Yo, referred as congenital myopathy Responsive to Mestinon

  18. Electrodiagnosis • Decrement after 2-3 HZ RNS • Absent in ChAT def., Na-Channel CMS, Some cases of Rapsyn • If negative, try higher frequencies • Try conditioning with 5 minutes 10HZ stimulation • Single-Fiber EMG

  19. Electrodiagnostic clues • Repetitive CMAP after single stimulus • Low amplitude CMAP with significant increment after high frequency RNS • Response to Tensilon test

  20. Presynaptic Syndromes

  21. Choline-Acetyl Transferase deficiency (ChAT def.) • ± neonatal hypotonia, gradually improve • Attacks of apnea, bulbar paralysis precipitated after infection, fever, excitement • No symptoms or mild-myasthenic symptoms between attacks • Reduced number of attacks with increasing age

  22. Treatment: • AchE Inh. for myasthenic symptoms and prophylaxis • IM AchE Inh. Injection on crisis

  23. Synaptic DefectEndplate ACh Esterase deficiency

  24. AChEsterase

  25. Clinical Features • Myasthenic symptoms since birth or early childhood • delayed milestones • Weakness facial, axial, limb± ophthalmoplegia • Fatigable lordosis and scoliosis • Finger extensor weakness • Slow pupillary light response

  26. 11 yo, weak since infancy with ptosis, restricted EOM, sluggish pupillary reflex, lordosis • Worsening with Mestinon, some response to pseudo-ephedrine

  27. Repetitive CMAP after single stimuli Decrement after 3 HZ RNS

  28. Catalytic Subunits Collagen Tail Formed by triple-helical association of three collagen strands (ColQ)

  29. Therapy • AchE inhibitors ineffective • Increased muscarinic side effects • Some improve with ephedrine or pseudo-ephedrine

  30. 20 yo, Ptosis since infancy Delayed walking, Ophthalmoparesis generalized weakness No reponse to mestinon, 3,4-DAP, Quinidine, fluoxetine Improved with ephedrine Mutation found in ColQ

  31. 16 yo, Lordotic gait from beginning, WCB from 11 No ptosis or ophthalmoparesis proximal > distal Diagnosed as DMD AChRAb negative Worse with Mestinon 14-33% decrement Repetitive CMAP

  32. Post-Synaptic Syndromes

  33. Post-Synaptic Syndromes • Kinetic abnormalities of AChR • Slow-Channel Syndrome • Fast Channel Syndrome • Low-Expressor AChR Deficiency • Rapsyn Deficiency • Sodium-Channel Myasthenia • Dok-7 Synaptopathy

  34. Slow-Channel Syndrome • Autosomal Dominant • Selective weakness of cervical, scapular, finger ext., • Eye movements: spared or mildly affected • Early onset: gradually progressive • Late onset and mild • Fluctuating • Severely affected muscles become atrophic

  35. EMG • Repetitive CMAP after single stimuli • Decrement only in weak muscles • Pathogenesis • Prolonged AChR opening ↑ cations and Ca++ Ca++ excess activation of protease, lipase, free radicals end-plate myopathy • Depolarization block

  36. Family M. Slow channel G153S Intra familial variability for severity mild severe

  37. Pathology: tubular aggregates • Genetics: mutation in AChR subunits • D.D.: • Polyneuropathy • Radial palsy • Limb-Girdle MD • FSHD • Motor Neuron Disease • Mitochondrial disease • Myotonic Dystrophy

  38. Therapy • AChE Inh. Ineffective or only temporary improvement • Probably accelerate progression by cationic overload • Long-lived open channel AChR blockers • Quinidine 200 mg × 3-4/d • Fluoxetine 80 mg/d

  39. Ach Receptor Deficiency ε/

  40. Low-Expressor AChR mutations • Reduced AChR expression to < 15% • Mild to severe phenotype • Most cases mutation in ε-subunit of AchR fetal AchR harboring γ-subunit is substituted • Mutations in both alleles of a non-ε subunit incompatible with life • Most respond well to AChE Inh ± DAP

  41. 18 yo, referred as MG for a consult before rhinoplasty • Has always been weak in physical activity and if doing so, fatigued very fast. • Fluctuating ptosis and diplopia. • Stable and non-progressive during these years and worse in the evening • Significant subjective and objective improvement with Mestinon

  42. Myasthenic symptoms since infancy • Very good response to mestinon • Both have been misdiagnosed as myasthenia gravis and both thymectomised • Mutation in CHRNE ( ε-subunit of AchR)

  43. Rapsyn Tyrosine kinase function : AChR concentration and linkage to cytoskeleton

  44. Rapsyn Deficiency • Has a crucial role in concentrating AChR in post-synaptic membrane • Birth or neonatal ± Arthrogryposis • Sometimes juvenile-adult onset • Facial deformity: prognathism, malocclusion • Severe masticatory weakness • Ptosis without ophthalmoparesis • Cervical, truncal, limb usually spared

  45. Stable and benign course • EMG • Decrement not present in all • Single-Fiber EMG • Partial to well response to AChE Inh • Addition of 3,4-DAP sometimes beneficial

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