congenital myasthenic syndromes

Congenital myasthenic syndromes are a rare, heterogeneous, nonimmune-mediated group of disorders of neuromuscular transmission.
Some of these disorders may be classified as channelopathies.

Congenital myasthenic syndromes are characterized by fatigable weakness with an onset typically during infancy to early childhood. Investigations are negative for circulating acetylcholine receptor antibodies (i.e., classic myasthenia gravis).

These diseases have a heterogeneous pathophysiology. They can be caused by an abnormal release of acetylcholine (presynaptic), a deficiency in acetylcholinesterase (synaptic), or a defect at the postsynaptic level (abnormal recognition of acetylcholine by nicotinic acetycholine receptors, or a reduction in acetylcholine receptors).

The latter mechanism accounts for the vast majority of cases. Approximately 10% of cases are presynaptic, about 15% are synaptic, and about 75% are postsynaptic. The majority of those that are postsynaptic are caused by an acetylcholine receptor deficiency.

Congenital myasthenic syndromes are inherited in an autosomal-recessive or, less frequently, dominant manner. Different genes encoding proteins expressed at the neuromuscular junction were found to cause congenital myasthenic syndromes.

Postsynaptic slow-channel congenital myasthenic syndrome (SCCMS)

Postsynaptic slow-channel congenital myasthenic syndrome (SCCMS) are a sybtypes of congenital myasthenic syndromes. They can be caused by mutation in the genes encoding subunits of the acetylcholine receptor (AChR):

 alpha (CHRNA1) (MIM.100690)
 beta (CHRNB1) (MIM.100710)
 delta (CHRND) (MIM.100720)
 epsilon (CHRNE) (MIM.100725)

Gain-of-function mutations are the most common cause of SCCMS.

Treatment

The treatment of congenital myasthenic syndromes varies according to subtype (e.g., slow-channel congenital myasthenic syndrome versus fast-channel congenital myasthenic syndrome).

Most patients improve on acetylcholinesterase inhibitors (e.g., pyridostigmine), with the exception of patients with endplate acetylcholinesterase deficiency (COLQ mutations) and with slow-channel congenital myasthenic syndrome, who are refractory or actually deteriorate with these drugs.

Other medications can be used, such as the potassium-channel blocker 3,4-diaminopyridine, quinidine, fluoxetine, and ephedrine with or without pyridostigmine.