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What are the congenital myasthenic syndromes?
The congenital myasthenic syndromes are a group of extremely rare disorders typically caused by genetic mutations affecting the structure and/or function of the Neuromuscular Junction.
They manifest as extraocular, facial, bulbar, and/or limb weakness and fatigability beginning in early life and persisting into adulthood.
These syndromes have been characterized by site of dysfunction within the Neuromuscular Junction and are the subject of ongoing investigation, with new syndromes described each year.
Patients with these disorders do not respond to thymectomy or other immunotherapies.
The presynaptic disorders involve defective release or synthesis of ACh and account for 8% of the congenital syndromes.
The synaptic basal lamina disorders are due to mutations in the collagen tail of AChE, and account for 16%.
The postsynaptic disorders are caused primarily by mutations in various AChR subunits, altering receptor number and/or receptor ion channel kinetics.
They account for the majority of cases (76%)
The Congenital Myasthenic Syndromes
| Presynaptic | Familial infantile congenital MG + episodic apnea |
| Decreased synaptic vesicles and reduced ACh quantal release | |
| Congenital Lambert–Eaton-like episodic ataxia 2 | |
| Reduced quantal release | |
| Synaptic basal lamina defects | AChE deficiency at NMJs |
| Postsynaptic | |
| Kinetic AChR abnormalities | Reduced numbers of AChRs at NMJs |
| Slow AChR channel syndromes with increased response to ACh | |
| Fast-channel syndromes with reduced response to ACh | |
| Normal numbers of AChRs at NMJs with reduced response to ACh | |
| Fast-channel syndrome: AChR ε subunit dysfunction | |
| Fast-channel syndrome: AChR α subunit dysfunction | |
| High conductance and fast closure of AChRs | |
| Increased numbers of AChRs at NMJs | |
| Slow-channel syndrome: AChR β subunit dysfunction | |
| Nonkinetic AChR abnormalities | Reduced numbers of AChRs at NMJs due to AChR mutations |
| Usually ε subunit abnormality | |
| Rarely, α, β, ε subunit abnormalities | |
| Other postsynaptic defects | Rapsyn mutations causing reduced numbers of AChRs at NMJs |
| Plectin deficiency | |
| Weakness + episodic apnea, and bulbar dysfunction |
ACh , acetylcholine; AChR , acetylcholine receptor; AChE , acetylcholinesterase; MG , myasthenia gravis; NMJ , neuromuscular junction.
From Nogajski JH, Kiernan MC, Ouvrier RA, Andrews PI: Congenital myasthenic syndromes. J Clin Neurosci 16:1-11, 2009.
Washington University Neuromuscular Online Reference: http://www.neuro.wustl.edu/neuromuscular/synmg.html
Sources
Cizeron-Clairac G, LePense R, Frenkian-Cuvelier M, et al.: Thymus and myasthenia gravis. J Neuroimmunol 201:57-63, 2008.
Magg L, Andreetta F, Antozzi C, et al.: Thymoma-associated myasthenia gravis: Outcome, clinical and pathological correlations in 197 patients on a 20 year experience. J Neuroimmunol 201:237-244, 2008.
