[Congenital myasthenic syndromes]

Area of Science:

• Neuromuscular disorders
• Genetic basis of disease
• Synaptic biology

Context:

• Congenital myasthenic syndromes (CMS) are a heterogeneous group of inherited disorders affecting neuromuscular junction (NMJ) transmission.
• Mutations in 15 genes encoding 11 NMJ molecules cause CMS, leading to diverse clinical presentations.
• Understanding these genetic defects is crucial for diagnosis and therapeutic development.

Purpose:

• To review the genetic basis and clinical classification of congenital myasthenic syndromes.
• To highlight recent advances in therapeutic strategies, including protein-anchoring therapy.
• To report on the prevalence and genetic landscape of CMS in Japan.

Summary:

• CMS are classified into four categories based on affected NMJ molecules: acetylcholine receptor (AChR) channelopathies, endplate AChR deficiency, endplate acetylcholinesterase (AChE) deficiency, and CMS with episodic apnea.
• A novel protein-anchoring therapy using an exogenously administered AChE/ColQ complex, targeted to the NMJ via ColQ's synaptic basal lamina signal, shows potential for treating extracellular matrix defects.
• In Japan, 15 CMS cases were diagnosed, with 12 patients harboring unique mutations, suggesting a significant number of undiagnosed cases.

Impact:

• Provides a comprehensive overview of CMS genetics and classification.
• Introduces a promising therapeutic avenue for CMS targeting extracellular matrix defects.
• Highlights the need for increased awareness and diagnosis of CMS, particularly in the Japanese population.