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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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CongenitalMyasthenic Syndromes Shahriar Nafissi, MD Associate Professor of Neurology Tehran University of Medical Sciences
Action potential Ca2+ channel Ca2+ Presynaptic terminal action potential opening voltage-gated Ca2+ channels↑Ca2+ permeability
Ca2+ channel Presynaptic terminal Ca2+ ACh ↑Ca2+ Ach release from synaptic vesicles
Synaptic cleft Na+ ACh Receptor molecule Na+ ACh binding to Ach receptors opening ligand-gated Na+ channels.
Na+ Action potential Action potential Na+ ↑Na+ permeability depolarization action potential generation in the postsynaptic membrane
Acetic acid Choline ACh Acetylcholinesterase ACh receptor site Ach→acetic acid + choline ▲ Ach-Esterase
ACh Acetic acid Synaptic vesicle Choline Choline ACh Presynaptic terminal in the presynaptic terminal Choline + acetic acid → Ach →Synaptic vesicles
Structural Reality By John Heuser and Louise Evans University of California, San Francisco
Ligand- Gated Ion Channel 2α + β + ε + δ
Congenital Myasthenic Syndromes • Group of diseases caused by genetic defects affecting neuromuscular transmission • Heterogeneous inheritance and pathophysiology
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
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
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
24 Yo, referred as congenital myopathy Responsive to Mestinon
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
Electrodiagnostic clues • Repetitive CMAP after single stimulus • Low amplitude CMAP with significant increment after high frequency RNS • Response to Tensilon test
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
Treatment: • AchE Inh. for myasthenic symptoms and prophylaxis • IM AchE Inh. Injection on crisis
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
11 yo, weak since infancy with ptosis, restricted EOM, sluggish pupillary reflex, lordosis • Worsening with Mestinon, some response to pseudo-ephedrine
Repetitive CMAP after single stimuli Decrement after 3 HZ RNS
Catalytic Subunits Collagen Tail Formed by triple-helical association of three collagen strands (ColQ)
Therapy • AchE inhibitors ineffective • Increased muscarinic side effects • Some improve with ephedrine or pseudo-ephedrine
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
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
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
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
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
Family M. Slow channel G153S Intra familial variability for severity mild severe
Pathology: tubular aggregates • Genetics: mutation in AChR subunits • D.D.: • Polyneuropathy • Radial palsy • Limb-Girdle MD • FSHD • Motor Neuron Disease • Mitochondrial disease • Myotonic Dystrophy
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
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
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
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)
Rapsyn Tyrosine kinase function : AChR concentration and linkage to cytoskeleton
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
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