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Congenital myasthenic syndromes

Orpha number ORPHA590
Synonym(s) -
Prevalence 1-9 / 1 000 000
Inheritance
  • Autosomal dominant
  • Autosomal recessive
Age of onset Neonatal/infancy
ICD-10
  • G70.2
OMIM
UMLS
  • C0751882
MeSH
  • D020294
MedDRA -
SNOMED CT -

Summary

Congenital myasthenic syndromes (CMS) are a group of genetic disorders of neuromuscular transmission. Prevalence is estimated at 1-2/500,000. Clinical manifestations usually become apparent during the neonatal period, but onset may occur later during childhood, adolescence or even adulthood. The syndromes are characterised by muscle weakness affecting the axial and limb muscles (with hypotonia in early-onset forms), the ocular muscles (leading to ptosis and ophthalmoplegia), and the facial and bulbar musculature (affecting sucking and swallowing, and leading to dysphonia). The symptoms fluctuate and worsen with physical effort. Fetal manifestations (hydramnios and arthrogryposis) are sometimes present. Severe forms are associated with respiratory disease. The CMS identified for mutated genes (representing 50% of cases) can be divided into three subtypes. The most frequent forms are postsynaptic CMS, which are caused by mutations leading to reduced amount, or more rarely, kinetic anomalies of the acetylcholine receptor (slow-channel syndrome and fast-channel syndrome), mutations in the RAPSN, MuSK, Dok7 genes and mutations in the SCN4A sodium channel gene. Synaptic CMS are caused by acetylcholinesterase deficiency associated with mutations affecting the collagen-like tail subunit of the enzyme. Presynaptic CMS are rarer forms of the disease caused mainly by mutations in the gene encoding choline acetyltransferase. The most frequent CMS are caused by mutations within genes coding for epsilon AChR subunit, rapsyn and Dok7. Transmission of the CMS is autosomal recessive, except in the case of slow-channel syndrome, which is inherited as an autosomal dominant trait. The diagnostic strategy involves two steps: 1) establishing the diagnosis of a CMS based on its familial occurrence and early onset; 2) identifying the physiopathological type of disease on the basis of the mode of transmission, by detecting a repetitive CMAP after single stimulation upon electromyogram (characteristic of acetylcholinesterase deficiency and slow-channel syndrome), the response to anticholinesterases, studies of endplate morphology and molecular analysis. The differential diagnosis should include the congenital myopathies for early-onset forms and autoimmune seronegative myasthenia (absence of anti-acetylcholine receptor and anti-MuSK antibodies) for the later-onset forms. Genetic counselling is useful for defining the mode of transmission and for prenatal diagnosis. When a CMS has been identified through molecular analysis, prenatal diagnosis may be offered in case of a family history of a severe form of the disease. Anticholinesterases are effective against all CMS, except slow-channel syndrome and CMS due to acetylcholinesterase deficiency or most of Dok7 mutations. 3,4-diaminopyridine can be used in combination with acetylcholinesterase therapy or alone in the treatment of most CMS. Paroxetine and quinidine are recommended for slow-channel syndrome. Ephedrine may be beneficial in several cases of acetylcholinesterase deficiency and Dok7 related CMS. The prognosis is difficult to evaluate whatever the involved CMS gene.

Expert reviewer(s)

  • Pr Bruno EYMARD

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Detailed information

Summary information
Clinical genetics review
  • EN (2012)
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