Childhood-onset congenital myasthenic syndrome with CHRNE c.130dup and c.344+5G > a variants diagnosed in adulthood: a case report

Introduction. Congenital myasthenic syndromes (CMS) are inherited disorders of the neuromuscular junction characterized by clinical and genetic heterogeneity. Biallelic CHRNE variants are an established cause of postsynaptic CMS and may be misdiagnosed as autoimmune myasthenia gravis, particularly when recognition is delayed until adulthood.

Case report. A 33-year-old woman developed symptoms at approximately 5 years of age, initially with dysarthria and dysphagia, followed by fatigability, ptosis, ophthalmoparesis, and fluctuating generalized weakness. Family history was negative for neuromuscular disease. She was treated for presumed myasthenia gravis with intravenous immunoglobulin, rituximab, cyclophosphamide, and thymectomy, with limited or inconsistent benefit. Anti-AChR and anti-MuSK antibodies were negative, and neurophysiologic studies supported a postsynaptic disorder of neuromuscular transmission. Exome sequencing identified two heterozygous CHRNE variants: c.130dup, p.(Glu44GlyfsTer3), classified as pathogenic and consistent with a loss-of-function mechanism, and c.344+5G > A, classified as a variant of uncertain significance (VUS). The integrated clinical, neurophysiologic, and molecular findings supported CHRNE-related CMS. Treatment with pyridostigmine followed by salbutamol was associated with a favorable clinical course.

Discussion. The coexistence of a pathogenic loss-of-function CHRNE variant and a rare intronic VUS, together with a highly concordant phenotype, supports further evaluation of c.344+5G > A as a candidate disease-associated allele. Under the ACMG/AMP framework, however, rarity and computational evidence alone are insufficient for reclassification; functional or additional genetic evidence is required.

Conclusion. CMS should be considered in patients with early-onset, long-standing myasthenic symptoms and limited or inconsistent response to immunotherapy. Integrating clinical, neurophysiologic, and molecular data can reduce diagnostic delay, prevent misclassification, and guide more appropriate management.