In five prospectively diagnosed patients with relapsing post-herpes
simplex encephalitis (HSE), NMDAR-antibodies were identified. Antibody synthesis
started 1–4 weeks post-HSE, preceding the neurological relapse. Three of
five patients improved post-immunotherapy, one spontaneously, and one has
started to improve. Two additional patients with NMDAR-antibodies, 9 with
unknown neuronal surface-antibodies, and one with NMDAR and unknown antibodies
were identified during retrospective assessment of 34 HSE-patients; the
frequency of autoantibodies increased over time (serum p=0.004, CSF
p=0.04). The three retrospectively identified NMDAR-antibody positive
patients also had evidence of relapsing post-HSE. Overall, these findings
indicate that HSE triggers NMDAR-antibodies and potentially other brain
autoimmunity.
AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by
GRIA1-4
genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca
2+
-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous
de novo GRIA2
mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most
GRIA2
mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that
de-novo
variants in
GRIA2
can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.
VAMP2
encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2). Together with its partners syntaxin-1A and synaptosomal-associated protein 25 (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release neurotransmitters. VAMP2 is essential for vesicular exocytosis and activity-dependent neurotransmitter release. Here, we report five heterozygous
de novo
mutations in
VAMP2
in unrelated individuals presenting with a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. In total, we identified two single-amino-acid deletions and three non-synonymous variants affecting conserved residues within the C terminus of the VAMP2 SNARE motif. Affected individuals carrying
de novo
non-synonymous variants involving the C-terminal region presented a more severe phenotype with additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. Reconstituted fusion involving a lipid-mixing assay indicated impairment in vesicle fusion as one of the possible associated disease mechanisms. The genetic synaptopathy caused by
VAMP2 de novo
mutations highlights the key roles of this gene in human brain development and function.
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