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Congenital myasthenic syndrome

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Congenital myasthenic syndrome

  1. 1. Dr. Parag Moon SR1, Dept. of Neurology GMC Kota.
  2. 2.  Congenital myasthenic syndromes (CMSs) form a heterogeneous group of genetic diseases characterized by a dysfunction of neuromuscular transmission.  Incidence-one in 500 000
  3. 3.  Presynaptic (generally caused by an anomaly of choline acetyltransferase ChAT),  Synaptic (corresponding to an anomaly of the acetylcholinesterase collagen tail)  Postsynaptic (secondary to an anomaly of acetylcholine receptor or rapsyn).
  4. 4. Congenital myasthenic syndromes caused by ChAT mutations  Manifest at birth or in the neonatal period with bulbar disorders and respiratory insufficiency with apnoea or even sudden death.  Triggered by fever, fatigue and overexertion.  Apart from these bouts, the myasthenic signs are often modest or not present.
  5. 5.  CHAT gene encoding ChAT, located on 10q11.2.  ChAT is a presynaptic protein localized in the nerve terminals, where it catalyses acetylcholine production.  Mutations lead to a reduction or even abolition of the catalytic capacity of the enzyme  14 mutations reported
  6. 6.  Microelectrophysiology-after prolonged10 Hz repetitive stimulation, a reduction in amplitude of the miniature endplate potentials.  Ultrastructural examination-when muscle is at rest, the synaptic vesicles are of reduced size  Cholinesterase inhibitors are effective.
  7. 7. 1. Lambert–Eaton-like CMS  Diminished action potentials markedly potentiated by tetanic stimulation  Good response to guanidine  No mutation found in calcium channel 2. Sporadic myasthenic syndrome with associated signs of cerebellar ataxia  Marked reduction in the spontaneous or nerve stimulation-induced release of acetylcholine quanta.
  8. 8. Acetylcholinesterase deficiency  Autosomal recessive  Symptoms usually arise in the neonatal period  Slowed but inconstant pupil responses to light.  Repetitive compound muscle action potential (CMAP) after single stimulation  Absence of response to cholinesterase inhibitors
  9. 9.  Genetics- Mutations in the COLQ gene coding for the collagenic tail of acetylcholinesterase  Twenty-four recessive mutations  No effective treatment
  10. 10.  Broadly categorised in 2 category 1. CMS in connection with a kinetic anomaly of the acetylcholine receptor 2. CMS with a decreased number of acetylcholine receptors at the neuromuscular junction
  11. 11. 1. Slow channel syndrome  Autosomal dominant  Characterized by a prolonged opening time of the acetylcholine receptor.  Fifteen missense point mutations causing a gain of function of the acetylcholine receptor  M1 for mutations of the a and b subunits  M2 more frequent, affecting the a, b, d and e subunits.
  12. 12.  Clinical expression may vary from early onset and severe to late onset and moderate  Prevalent atrophic deficit of the finger extensors and cervical muscles is highly suggestive  Repetitive CMAP after a single stimulation  No response to cholinesterase inhibitors  Treatment- Quinidine can normalize prolonged opening time of channel  Fluoxetine
  13. 13. 2) Fast channel syndromes  Autosomal recessive although a case of autosomal dominant transmission reported  Microelectrophysiology –shortening of the acetylcholine receptor opening time  Clinical severity is variable.  Responsive to the combination of 3,4- diaminopyridine and cholinesterase inhibitors.
  14. 14.  Genetics-Eight mutations were identified affecting a, d and e subunits  Located either in the extracellular domain, in the M3 transmembrane domain or in the cytoplasmic loop between the M3 and M4 domains (e mutations only).
  15. 15.  Half of all CMS  Autosomal recessive  Cholinesterase inhibitors are effective  3,4-diaminopyridine can provide additional benefit.
  16. 16.  Genetics-  60 + mutations identified  Mutations are located on the whole gene encoding the acetylcholine receptor e subunit
  17. 17.  Rapsyn is postsynaptic cytoplasmic protein  Participates in acetylcholine receptor assembly at the neuromuscular junction and allows its anchoring to the cytoskeleton by b-dystroglycan  Autosomal recessive
  18. 18.  Two phenotypes:  (1) a neonatal form,even antenatal (with arthrogryposis multiplex congenita),with major respiratory disorders and severe progression of the disease  (2) mild forms beginning during childhood or in adulthood  Both responds well to cholinesterase inhibitors or combination of cholinesterase inhibitors and 3,4-diaminopyridine
  19. 19.  Plectin is structural protein of the cytoskeleton expressed in several cell types, including skeletal muscle and the postsynaptic membrane.  Presents with progressive myopathy, associated with myasthenic syndrome (involving facial, limb and oculomotor muscles), and epidermolysis bullosa
  20. 20.  Presents since birth with very short bouts (3– 30 min) of respiratory distress and bulbar paralysis.  Electrophysiology of the intercostal Muscle-the impossibility of evoking an action potential after nerve stimulation.  Two mutations of SCN4A were identified.
  21. 21.  Previously named ‘myasthenic myopathy’  Autosomal recessive  Clinically, the absence of oculobulbar signs is remarkable.  Weakness and fatigability involved the girdles.  Tubular aggregates in their muscle biopsy  Responds favourably to cholinesterase inhibitors
  22. 22.  Tubular aggregates at the histological muscle examination  Presents with slowly progressive myopathy beginning in early childhood associated with cardiomyopathy  Favourable response to cholinesterase inhibitors
  23. 23.  Approx. 15% of newborns of myasthenic mother  Passive transfer of antibody directed against fetal AChR  Fetal AChR is structurally different from adult AChR.  Severity of symptoms Correlates with the ratio of fetal to adult AChR antibodies in the mother  Not with the severity or duration of weakness in the mother.
  24. 24.  Hypotonic in utero  Arthrogryposis  Feeding difficulties  Generalized hypotonia  Eager to feed, but ability to suck fatigues quickly  Onset within hours of birth but delay until the 3rdDay  Weakness of cry and lack of facial expression: 50%  Limitation of EOM &Ptosis: 15%
  25. 25.  Respiratory insufficiency : Uncommon  Weakness becomes progressively worse in the first few days and then improves.  Duration of symptoms is 18 Ds (5D-2 mn)  Complete recovery  TNM does not develop into MG later in life
  26. 26.  Diagnosis  High serum concentrations of AChR binding Ab  Temporary reversal of weakness :S/c or I/V inj. Edrophonium chloride, 0.15 mg/kg
  27. 27. Clinical presentation  Suspected in any person presenting with  Fatigable ocular  Bulbar  Limb weakness during infancy or early childhood  With a positive family history(autosomal recessive except slow channel)
  28. 28.  Response to cholinesterase inhibitors (neostigmine test)  Favourable effect of cholinesterase inhibitors seen in all CMS except 1. slow channel syndrome 2. acetylcholinesterase deficiency
  29. 29.  Decremental response in the CMAP:  RNS low frequency (2 Hz) is strongly s/o impaired NM transmission, but may only be present in a few muscle groups.  SFEMG : abnormal jitter and blocking.  AChR and MuSK antibody : Negative (essential prerequisite)
  30. 30.  Rule out myopathy  Predominance of type I fibres and the marked atrophy of type II fibres is suggestive of CMS  Tubular aggregates  NMJ visualized for (acetyl)cholinesterase by histochemical technique of Koelle, fasciculin or specific antibodies,  for acetylcholine receptor by fluorescent a-bungarotoxin
  31. 31.  8 genes tested usually  Acetylcholine receptor subunits (CHRNE, CHRNA1,CHRNB1, CHRND)  Rapsyn (RAPSN)  Collagen tail of acetylcholinesterase (COLQ)  Choline acetyltransferase (CHAT)  Sodium channel (SCN4A).
  32. 32.  Immediate treatment of respiratory distress  Prevention of infections and of malnutrition as a result of swallowing disorders  Orthopaedic surveillance of spinal complications and retractions
  33. 33.  Cholinesterase inhibitors are efficient in all CMSs except slow channel syndrome and acetylcholinesterase deficiency  3,4-Diaminopyridine mode of action is presynaptic, is sometimes effective in pre- or postsynaptic CMSs  Quinidine helpful in slow channel
  34. 34. Thank you
  35. 35.  Congenital myasthenic syndromes: Daniel Hantaı et al :Current Opinion in Neurology 2004, 17:539–551  Congenital myasthenic syndromes: Seminars in neurology:2004;24(1):111-123  Bradleys principles of neurology