Novel pathogenic ALG2 mutation causing congenital myasthenic syndrome: A case report

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Congenital myasthenic syndromes (CMS) are rare genetic disorders affecting neuromuscular transmission.
• Mutations in the ALG2 gene are an extremely rare cause of CMS, with limited data on clinical presentation and treatment.
• Understanding ALG2 variants is crucial for diagnosing and managing these severe conditions.

Observation:

• A neonate presented with severe truncal hypotonia, proximal muscle weakness, and feeding difficulties immediately after birth.
• Electromyography revealed neuromuscular transmission failure.
• Treatment with salbutamol and ephedrine demonstrated significant improvement in muscle strength and neuromuscular function.

Findings:

• Genetic analysis identified a likely pathogenic null variant (c.1040del, p.(Gly347Valfs*27)) and a variant of uncertain significance (c.239G>A, p.(Gly80Asp)) in the ALG2 gene.
• Functional studies confirmed the p.Gly347Valfs*27 variant acts as a null allele.
• The p.Gly80Asp variant was determined to be pathogenic by significantly reducing ALG2 expression.

Implications:

• This case underscores the importance of integrating genetic analysis with functional studies to accurately diagnose rare genetic disorders like CMS.
• The positive response to salbutamol and ephedrine suggests potential therapeutic strategies for ALG2-related CMS.
• Clarifying the pathogenicity of ALG2 variants aids in understanding disease mechanisms and developing targeted treatments for congenital myasthenic syndromes.