Abstract
Myasthenia gravis (MG) results from structural and functional defects in neuromuscular transmission at the neuromuscular junction, leading to a wide spectrum of clinical manifestations. The most common form is autoimmune myasthenia gravis, in which an abnormal immune response targets components of the neuromuscular junction, impairing the ability of the muscle membrane to recognize neurotransmitters. The most extensively studied pathogenic mechanism involves autoantibodies against the acetylcholine receptor (AChR). Congenital myasthenic syndromes (CMS) differ from autoimmune myasthenia gravis in that impaired neuromuscular transmission is caused by genetic defects rather than autoantibodies. First described in 1937, CMS has since been recognized as a heterogeneous group of disorders that continue to expand with advances in molecular genetics. Based on the site of the underlying defect, CMS can be classified into four major categories: presynaptic, synaptic, postsynaptic, and glycosylation-related disorders. Collectively, these defects result in transient or persistent weakness of the ocular, facial, bulbar, and limb muscles, with clinical severity ranging from mild weakness that does not interfere with daily activities to permanent disability, respiratory failure, or death. Symptoms typically present during the neonatal or infancy period, although a small proportion of patients may first develop symptoms in adulthood. The diagnosis of congenital myasthenic syndromes is based on a combination of clinical evaluation, electrophysiological studies, and genetic testing to identify pathogenic variants. Treatment is primarily symptomatic and may involve monotherapy or combination therapy with acetylcholinesterase inhibitors, 3,4-diaminopyridine (3,4-DAP), albuterol, ephedrine, fluoxetine, or quinidine, depending on the underlying genetic subtype. Gene therapy and other targeted therapeutic approaches are currently under investigation. Prognosis depends on the causative genetic mutation, the muscle groups involved, and the age at symptom onset. Infants with respiratory, feeding, or swallowing difficulties are at increased risk of pneumonia, respiratory failure, and poor survival. In many other cases, however, muscle weakness remains stable without progressive deterioration and may even improve over time.
