NAPB and developmental and epileptic encephalopathy: Description of the electroclinical profile associated with a novel pathogenic variant

Abstract

Developmental and epileptic encephalopathies (DEE) are a group of neurodevelopmental disorders characterized by epileptic seizures associated with developmental delay or regression. DEE are genetically heterogeneous, and the proteins involved play roles in multiple pathways such as synaptic transmission, metabolism, neuronal development or maturation, transcriptional regulation, and intracellular trafficking. We performed whole exome sequencing on a consanguineous family with three children presenting an early onset (<6 months) with clusters of seizures characterized by oculomotor and vegetative manifestations, with an occipital origin. Before 1 year of age, interictal electroencephalographic recordings were well organized and neurodevelopment was unremarkable. Then, a severe regression occurred. We identified a novel homozygous protein-truncating variant in the NAPB (N-ethylmaleimide-sensitive fusion [NSF] attachment protein beta) gene that encodes the βSNAP protein, a key regulator of NSF-adenosine triphosphatase. This enzyme is essential for synaptic transmission by disassembling and recycling proteins of the SNARE complex. Here, we describe the electroclinical profile of each patient during the disease course. Our findings strengthen the association between biallelic variants in NAPB and DEE and refine the associated phenotype. We suggest including this gene in the targeted epilepsy gene panels used for routine diagnosis of unexplained epilepsy.

Transcriptional features of low‐grade neuroepithelial tumors with the BRAF V600E mutation associated with epileptogenicity

“…Interestingly, GO terms associated with glutamate neurotransmitters were identified in downregulated DEGs, suggesting the effects of the BRAF V600E mutation in regulating the transmission of glutamate to control neural activity. The genes MAPK8IP2, SYT1, HTR2A, KMO, NAPB, STXBP1, GRM2, and GRM8 were associated with the GO terms “regulation of synaptic transmission, glutamatergic (GO:0051966)” and “synaptic transmission, glutamatergic (GO:0035249).” Notably, among these genes, NAPB, STXBP1, and GRM2 are associated with epilepsy (Keele et al, 1999; Mignon‐Ravix et al, 2023; Stamberger et al, 2016).…”

“…NAPB plays an essential role in synaptic transmission by disassembling and recycling proteins of the SNARE complex. Notably, a homozygous protein‐truncating variant in NAPB is associated with developmental and epileptic encephalopathy (Mignon‐Ravix et al, 2023). STXBP1 is known to regulate synaptic transmission by assembling the SNARE complex.…”

“…The genes MAPK8IP2, SYT1, HTR2A, KMO, NAPB, STXBP1, GRM2, and GRM8 were associated with the GO terms "regulation of synaptic transmission, glutamatergic (GO:0051966)" and "synaptic transmission, glutamatergic (GO:0035249)." Notably, among these genes, NAPB, STXBP1, and GRM2 are associated with epilepsy (Keele et al, 1999;Mignon-Ravix et al, 2023;Stamberger et al, 2016).…”

Characterization of a loss-of-function NSF attachment protein beta mutation in monozygotic triplets affected with epilepsy and autism using cortical neurons from proband-derived and CRISPR-corrected induced pluripotent stem cell lines

“…Thus, we conclude that neurons of the affected triplets express no NAPB. Previous reports have identified NAPB mutations in children with early onset epilepsy that were predicted to be protein truncating ( Conroy et al, 2016 ; Zhao et al, 2021 ; Mignon-Ravix et al, 2023 ). Here we are the first to provide experimental evidence for complete absence of NAPB in the neurons of probands carrying such genetic variants and provide experimental evidence for the role of NAPB protein in association with early onset epilepsy and autism spectrum disorders.…”

“…There is accumulating evidence that SNARE proteins and SNARE-regulatory proteins play an important role in neuronal regulation and brain development ( Wojcik and Brose, 2007 ). Protein truncating variants of NAPB have been previously identified in cases of early onset epileptic encephalopathy (EOEE) ( Conroy et al, 2016 ; Zhao et al, 2021 ; Mignon-Ravix et al, 2023 ). The novel, homozygous inherited variant we discovered in the Palestinian triplets results in the loss of splice donor site and presumably null expression of NAPB protein.…”