Congenital myasthenic syndromes (CMS) are inherited disorders caused by mutations in genes encoding proteins essential for neuromuscular junction (NMJ) function. Pathogenic variants have been identified in more than 35 genes, underscoring the complexity of synaptic biology and the wide range of mechanisms that can compromise neuromuscular transmission. Among these, CMS due to mutations in AGRN, LRP4, and MUSK genes represent presynaptic and postsynaptic defects that offer valuable mechanistic insights. These mutations impair agrin/LRP4/MuSK signaling, disrupt NMJ formation and stability, and underlie phenotypes with variable clinical presentations, ranging from ptosis and fatigability to distal, bulbar, or respiratory weakness. These subtypes often show limited efficacy or even clinical worsening with acetylcholinesterase inhibitors, whereas adrenergic agonists such as salbutamol or ephedrine can provide significant benefit in selected cases. The study of these forms not only provides key insights into the molecular regulation of synapse development and maintenance, but also illustrates the challenges of establishing genotype-phenotype correlations in rare diseases, in which inter-individual variability complicates diagnosis and management. Recent advances in next-generation sequencing and functional studies have expanded the recognized mutation spectrum, uncovered novel pathogenic mechanisms, and improved the accuracy of molecular diagnosis. In this review, we provide a comprehensive overview of AGRN, LRP4, and MUSK-related CMS, integrating clinical, genetic, and mechanistic data from patients and experimental models. By highlighting diagnostic strategies, pathogenic pathways, and emerging therapeutic concepts, we show how these rare subtypes refine our understanding of NMJ biology and open the way toward personalized and mechanism-based treatments.
Villar‐Quiles et al. (Wed,) studied this question.