STXBP1 mutations cause not only Ohtahara syndrome but also West syndrome—Result of Japanese cohort study

Abstract

SUMMARYWe performed STXBP1 mutation analyses in 86 patients with various types of epilepsies, including 10 patients with OS, 43 with West syndrome, 2 with Lennox-Gastaut syndrome, 12 with symptomatic generalized epilepsy, 14 with symptomatic partial epilepsy, and 5 with other undetermined types of epilepsy. In all patients, the etiology was unknown, but ARX and CDKL5 mutations were negative in all cases. All coding exons of STXBP1 were analyzed by direct-sequencing. Two de novo nucleotide alterations of STXBP1 were identified in two patients with Ohtahara and West syndrome, respectively. No de novo or deleterious mutations in STXBP1 were found in the remaining 84 patients with various types of symptomatic epilepsies. This is the first case report showing that STXBP1 mutations caused West syndrome from the onset of epilepsy. STXBP1 analysis should be considered as an etiology of symptomatic West syndrome without explainable cause.

Unexplained Early Infantile Epileptic Encephalopathy in Han Chinese Children: Next-Generation Sequencing and Phenotype Enriching

“…(R1007) was diagnosed with Ohtahara syndrome, now at the age of one year old his DQ indicates moderate ID. Both of these patients carried the same missense variant in STXBP1 gene: (NM_003165), c.1216C > T; p.R406C, this variant was reported as a pathogenic variant in a case of Ohtahara syndrome with profound ID31, which matches our result and support the findings of previously reported studies that mutation in STXBP1 is extensively associated with severe early-onset epileptic encephalopathies including Ohtahara syndrome, West syndrome and other epileptic phenotypes with moderate to severe ID32333435.…”

The trans-SNARE-regulating function of Munc18-1 is essential to synaptic exocytosis

“…Molecules encoded by the WT STXBP1 allele are functional but their quantities are inadequate in maintaining full synaptic activities in humans ( STXBP1 haploinsufficiency). Importantly, STXBP1 haploinsufficiency impairs the inhibitory synaptic transmission more than the excitatory synaptic transmission, resulting in improper neuronal excitation observed in OS patients 49–53 .…”

“…Here, we focused on a single base pair mutation in the STXBP1 gene that results in the substitution of the cysteine 552 residue with an arginine (C552R) in the Munc18-1 protein (Fig. 6a) 53 . The cysteine 552 residue is located at the C-terminal Domain 2 of the Munc18-1 protein 25,54 .…”

West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1

“…The most frequent genetic causes of IS are mutations in TSC1 (about 9% of all IS/WS patients, OMIM#191100), CDKL5, ARX and STXBP1 genes, as well as multiple genomic imbalances, the commonest being Pallister-Killian syndrome (tetrasomy 12p; OMIM#601803) and 1p36 deletion (OMIM#607872). [7][8][9][10][11][12][13] These and other genetic causes such as genes encoding proteins involved in inborn errors of metabolism were recently reviewed in Paciorkowski et al 14 IS/WS also occur with a lower prevalence as a feature of other genetic diseases, such as Down syndrome. 14 This heterogeneity often impedes the identification of the etiology of IS/WS within the clinical practice.…”