What Is Congenital Myasthenic Syndrome?

Depending on the neuromuscular junction affected, congenital myasthenic syndrome (CMS) is grouped into three main categories:

1. Presynaptic CMS:
   • Characterized by the insufficient release of acetylcholine (ACh), which is a chemical necessary for proper muscle function.
   • It commonly manifests as CMS with episodic apnea, which has its onset in infancy and causes weakness of the facial muscles and those involved in swallowing and talking.
   • It also involves episodes of apnea (a temporary cessation of breathing).
2. Postsynaptic CMS: Can be divided into fast-channel CMS and slow-channel CMS.
   • Fast-channel CMS
     • Caused by missing or deficient ACh receptors.
     • In infants, it may cause extreme weakness, feeding and respiratory problems, and delayed motor milestones (sitting, crawling, and walking). In contrast, childhood and adult-onset cases often cause ptosis and fatigue that do not interfere with daily living.
   • Slow-channel CMS
     • Caused by ACh receptors that stay open for a longer time. 
     • Infant-onset cases may result in extreme weakness, loss of mobility, and respiratory problems in adolescence.
3. Synaptic CMS:
   • Caused by a deficiency of acetylcholinesterase, an enzyme that breaks down ACh. 
   • Symptoms include extreme weakness with feeding and respiratory difficulties since birth or early childhood.
   • Severe weakness may lead to delayed motor milestones, reduced mobility, and scoliosis (curvature of the spine).

Mutations in the CHRNE gene are responsible for more than half of all congenital myasthenic syndrome (CMS) cases. However, a large number of cases are caused by mutations in the RAPSN, CHAT, COLQ, and DOK7 genes.

These genes are responsible for providing instructions necessary for producing proteins that are involved in the normal functioning of the neuromuscular junction.

Genetic mutations cause changes in proteins, disrupting signaling between the ends of nerve cells and muscle cells, which results in an impaired ability to move skeletal muscles, muscle weakness, and delayed development of motor skills.

CMS is an inherited disease caused by defective genes in an autosomal recessive pattern, which means two copies of the defective gene, one from each parent, are needed to cause the disease.

Slow-channel CMS is inherited in an autosomal dominant manner, which means that one copy of a defective gene is sufficient to cause the disease, so an affected parent has a 50 percent risk of passing the disease to a child.

The symptoms of the congenital myasthenic syndrome (CMS) vary from mild to severe but generally include the following:

• Weakness that worsens with exertion
• Fatigue 
• Ptosis (droopy eyelids)
• Feeding difficulties or poor sucking
• Dysphagia
• Nasal regurgitation
• Dysphonia
• Poor head control
• Spinal rigidity
• A weak cry
• Nystagmus (involuntary, rapid, rhythmic eye movements)
• Delayed motor skills (crawling or walking)

In severe cases, people may experience the following:

• Episodes of breathing problems (triggered by fever, stress, or infection).
• Apnea (Short pauses in breathing).
• Cyanosis (a bluish appearance of the skin or lips due to a shortage of oxygen levels in the blood).

To diagnose congenital myasthenic syndrome (CMS), the following tests can be done:

• Medical history and physical examination
• Neurological examination
• Blood tests: To detect anti-AChR and anti-MuSK antibodies.
• Electrodiagnostic testing: To measure the electrical signals in muscles using electrodes.
• Tensilon test: A temporary increase in strength after intravenous injection of Tensilon (edrophonium), a fast-acting cholinesterase inhibitor, is consistent with CMS.

The following medications can be beneficial in the treatment of congenital myasthenic syndrome (CMS):

• Cholinesterase inhibitors or anticholinesterases
  • The drug used is Mestinon (pyridostigmine).
  • Cholinesterase inhibitors work by boosting the levels of acetylcholine (ACh), a chemical necessary for the appropriate functioning of the muscles.
• Potassium channel blockers
  • 3,4-diaminopyridine may be used to increase the release of ACh and prolong the presynaptic action potential.
• Adrenergic agonist
  • This treatment shows positive effects in different subtypes of CMS.
• Beta-2-agonist
  • It is effective in several CMS subtypes, particularly in patients with endplate acetylcholinesterase deficiency and those with DOK7 pathogenic variants.