Myasthenic Syndrome, Congenital, 4A, Slow-Channel

Alternative Names

  • CMS4A
  • CMS
  • Congenital Myasthenic Syndrome Type Ia1
  • CMS Ia1
  • CMS1A1
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WHO-ICD-10 version:2010

Diseases of the nervous system

Diseases of myoneural junction and muscle

OMIM Number

605809

Mode of Inheritance

Autosomal recessive and autosomal dominant

Gene Map Locus

17p13.2

Description

Congenital Myasthenic Syndrome (CMS) is a group of rare disorders of the neuromuscular junction characterized by early onset progressive muscle weakness. CMS4A is a slow channel CMS caused by mutations in the CHRNE gene. CMS4A has an early onset and symptoms can vary in intensity from minor fatigue to complete loss of mobility. Ptosis, opthalmoparesis, dysphagia, feeding problems, hypotonia, bulbar muscle weakness and respiratory problems are commonly seen. 

Diagnosis of CMS based solely on clinical evaluation can be difficult and patients can sometimes be mistaken to have myasthenia gravis or other similar disorders. Genetic tests for underlying mutations can help confirm a CMS diagnosis. Identification of the exact form of CMS and the underlying mutation is also essential for administering treatment because unlike other forms of CMS, slow channel CMS is not treated with cholinesterase inhibitors but with quinidine and fluoxetine.

Molecular Genetics

CMS4A has been found to follow an autosomal dominant pattern of inheritance with incomplete penetrance but autosomal recessive cases have also been reported. 

The disorder is caused by mutations in the CHRNE gene which encodes the epsilon subunit of the acetylcholine receptor. Mutations in CHRNE produce a prolonged opening of the acetylcholine receptor channel resulting in slowed decay of end plate currents, calcium overload of the synaptic region and ultimately myopathy of the endplate and postsynaptic membrane.

Epidemiology in the Arab World

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Other Reports

Saudi Arabia

Saleh et al. (2011) described 3 male siblings of a consanguineous family with CMS. All three patients were born from normal pregnancies and had shown normal movements in utero. By 2-3 months of age, the oldest sibling showed signs of bilateral ptosis, choking, decreased feeding and failure to thrive and had several episodes of respiratory failure. Symptoms in the younger two siblings were milder and surfaced by 4 months of age. All patients started pyridostigmine by 5 months of age. The patients, aged 21, 17 and 13 years, showed normal development and their cognitive function was intact. Patients were found to have bilateral ptosis, reduced eye movements, extremely slow and hypometric saccades with weak orbicularis ocular muscle. The patients also had Cogan lid twitch sign, and administration of an ice pack test greatly improved ptosis. Patients were found to have a homozygous duplication 123-127dupCTCAC in exon 2 of the CHRNE gene which was not found in 50 ethnically matched controls. Both parents were found to be heterozygous for the mutation. The authors emphasized the value of the ice pack test as an important diagnostic tool for CMS.

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