SYT1-associated neurodevelopmental disorder: a case series.

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Synaptotagmin 1 (SYT1) is essential for calcium-dependent neurotransmitter release and synaptic vesicle endocytosis.
• Understanding SYT1's role is crucial for deciphering synaptic function and related neurological disorders.

Observation:

• Eleven patients presented with de novo heterozygous missense mutations in SYT1, affecting conserved residues in the C2B domain.
• Clinical features included infantile hypotonia, ophthalmic abnormalities, hyperkinetic movement disorders, motor stereotypies, and variable developmental delay.
• EEG showed universal disturbance with intermittent low-frequency, high-amplitude oscillations, while MRI was unremarkable.

Findings:

• Five specific SYT1 mutations (M303K, D304G, D366E, I368T, N371K) were functionally assessed in mouse models.
• Mutations D304G and D366E impaired SYT1 relocalization after stimulation, indicating defects in endocytic retrieval.
• All tested variants slowed the exocytic rate following sustained stimulation, impacting synaptic vesicle kinetics.

Implications:

• De novo dominant SYT1 mutations are linked to a distinct neurodevelopmental syndrome.
• The severity of synaptic vesicle dysfunction directly correlates with the phenotype's severity, highlighting SYT1's critical role in cognitive development.
• This study provides diagnostic criteria including clinical features, EEG patterns, and mutation analysis for SYT1-associated neurodevelopmental disorder.