Unfolding of Novel Independent Missense Mutations in VAMP2 and AGRN and Their Collective Role in Global Developmental Delay: A Case Report

Vesicle-associated membrane protein 2 (VAMP2) and Agrin (AGRN) are crucial proteins in neurotransmission. VAMP2 is a vesicular protein that facilitates the exocytosis of neurotransmitters. At the same time, AGRN plays a critical role in the maintenance and function of neuromuscular junctions. Mutations in the signaling pathway of VAMP2 and AGRN impair proper signaling between the presynaptic and postsynaptic neurons, and can result in neurodevelopmental conditions known as global developmental delay (GDD). This study highlights a presentation of GDD in a patient with concurrent mutations in VAMP2 and AGRN. A three-year-old female child presented with GDD characterized by hypotonia, intellectual disability, and dysphagia. Physical exam exhibited signs of developmental delay and severe muscle weakness. EEG findings were suggestive of a hypsarrhythmia pattern. The ophthalmological evaluation showed partial optic atrophy bilaterally. Therapeutic interventions included Keppra and Topamax, which proved ineffective. The patient’s outcome was inconclusive as care was transferred to another facility. This case study reports the novel appearance of two concurrent mutations: p.Gln76Pro associated with VAMP2 and p.Gln970Glu associated with AGRN. Mutations in VAMP2 lead to a dysfunctional SNARE complex and inhibit exocytosis of neurotransmitters into the synaptic cleft. Mutations in AGRN impair the ability to form and activate postsynaptic nicotinic acetylcholine receptors. Improper signaling between presynaptic and postsynaptic neurons is an important determinant of GDD. We hope that accounting for this mutational pattern will contribute to understanding synapse assembly and help unravel the complex interplay of factors involved in the pathology of neuromuscular disorders and GDD.