Syntaxin Binding Protein 1 Related Epilepsies

2021 ◽  
Author(s):  
Alessandra Fontana ◽  
Maria Chiara Consentino ◽  
Milena Motta ◽  
Giuseppe Costanza ◽  
Manuela Lo Bianco ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Early Onset ◽  
De Novo ◽  
Binding Protein ◽  
Epileptic Encephalopathy ◽  
De Novo Mutation ◽  
Published Data ◽  
De Novo Mutations ◽  
Ohtahara Syndrome ◽  
Protein Receptors

AbstractSyntaxin binding protein 1 (STXBP1), commonly known as MUNC18–1, is a member of SEC1 family membrane trafficking proteins; their function consists in controlling the soluble N-ethylmaleimide-sensitive factor attachment protein receptors complex assembly, making them essentials regulators of vesicle fusion. The precise function and molecular mechanism through which Munc18–1 contributes to neurotransmitter releasing is not entirely understood, but several evidences suggest its probable role in exocytosis. In 2008, heterozygous de novo mutations in neuronal protein Munc18–1 were first referred as a cause of Ohtahara syndrome development. Currently, a wide examination of the published data proved that 3.1% of patients with severe epilepsy carry a pathogenic de novo mutation including STXBP1 and approximately 10.2% of early onset epileptic encephalopathy is due to an aberrant STXBP1 form codified by the mutated gene. STXBP1 mutations can be associated to a wide clinical heterogeneity. All affected individuals show developmental delay and approximately the 95% of cases have seizures and early onset epileptic encephalopathy, characterized by infantile spasms as the main consistent feature. Burst suppression pattern and hypsarrhythmia are the most frequent EEG anomalies. Other neuronal disorders include Rett syndrome and behavioral and movement disorders. Mild dysmorphic features have been detected in a small number of cases. No genotype–phenotype correlation has been reported. Management of STXBP1 encephalopathy requires a multidisciplinary approach, including epilepsy control and neurological rehabilitation. About 25% of patients are refractory to standard therapy. A single or combined antiepileptic drugs may be required. Several studies described vigabatrin, valproic acid, levetiracetam, topiramate, clobazam, and oxcarbazepine as effective in seizure control. Lamotrigine, zonisamide, and phenobarbital are also commonly used. To date, it remains unclear which therapy is the most effective. Severe morbidity and high mortality are inevitable consequences in some of these patients.

scholarly journals Germline and somatic mutations in STXBP1 with diverse neurodevelopmental phenotypes

2017 ◽  
Vol 3 (6) ◽  
pp. e199 ◽  
Author(s):  
Mohammed Uddin ◽  
Marc Woodbury-Smith ◽  
Ada Chan ◽  
Ledia Brunga ◽  
Sylvia Lamoureux ◽  
...  
Keyword(s):  
Brain Tissue ◽  
De Novo ◽  
Focal Cortical Dysplasia ◽  
Autism Spectrum ◽  
Epileptic Encephalopathy ◽  
De Novo Mutation ◽  
Chromosomal Microarray ◽  
Published Data ◽  
De Novo Mutations ◽  
Coding Region

Objective:To expand the clinical phenotype associated with STXBP1 gene mutations and to understand the effect of STXBP1 mutations in the pathogenesis of focal cortical dysplasia (FCD).Methods:Patients with STXBP1 mutations were identified in various ways: as part of a retrospective cohort study of epileptic encephalopathy; through clinical referrals of individuals (10,619) with developmental delay (DD) for chromosomal microarray; and from a collection of 5,205 individuals with autism spectrum disorder (ASD) examined by whole-genome sequencing.Results:Seven patients with heterozygous de novo mutations affecting the coding region of STXBP1 were newly identified. Three cases had radiologic evidence suggestive of FCD. One male patient with early infantile epileptic encephalopathy, DD, and ASD achieved complete seizure remission following resection of dysplastic brain tissue. Examination of excised brain tissue identified mosaicism for STXBP1, providing evidence for a somatic mechanism. Cell-type expression analysis suggested neuron-specific expression. A comprehensive analysis of the published data revealed that 3.1% of severe epilepsy cases carry a pathogenic de novo mutation within STXBP1. By contrast, ASD was rarely associated with mutations in this gene in our large cohorts.Conclusions:STXBP1 mutations are an important cause of epilepsy and are also rarely associated with ASD. In a case with histologically proven FCD, an STXBP1 somatic mutation was identified, suggesting a role in its etiology. Removing such tissue may be curative for STXBP1-related epilepsy.

A case of early onset epileptic encephalopathy with de novo mutation in SLC35A2: Clinical features and treatment for epilepsy

2017 ◽  
Vol 39 (3) ◽  
pp. 256-260 ◽  
Author(s):  
Tomokazu Kimizu ◽  
Yukitoshi Takahashi ◽  
Taikan Oboshi ◽  
Asako Horino ◽  
Takayoshi Koike ◽  
...  
Keyword(s):  
Clinical Features ◽  
Early Onset ◽  
De Novo ◽  
Epileptic Encephalopathy ◽  
De Novo Mutation

De Novo Mutations inSLC35A2Encoding a UDP-Galactose Transporter Cause Early-Onset Epileptic Encephalopathy

2013 ◽  
Vol 34 (12) ◽  
pp. 1708-1714 ◽  
Author(s):  
Hirofumi Kodera ◽  
Kazuyuki Nakamura ◽  
Hitoshi Osaka ◽  
Yoshihiro Maegaki ◽  
Kazuhiro Haginoya ◽  
...  
Keyword(s):  
Early Onset ◽  
De Novo ◽  
Epileptic Encephalopathy ◽  
De Novo Mutations

Expanding Phenotype of De Novo Mutations in GNAO1: Four New Cases and Review of Literature

2017 ◽  
Vol 48 (05) ◽  
pp. 371-377 ◽  
Author(s):  
Tobias Dietel ◽  
Christina Evers ◽  
Katrin Hinderhofer ◽  
Rudolf Korinthenberg ◽  
Daniel Ezzo ◽  
...  
Keyword(s):  
De Novo ◽  
Involuntary Movement ◽  
Epileptic Encephalopathy ◽  
De Novo Mutation ◽  
Guanine Nucleotide ◽  
Review Of Literature ◽  
De Novo Mutations ◽  
Guanine Nucleotide Binding Protein ◽  
Guanine Nucleotide Binding ◽  
Severe Epilepsy

AbstractMutations in GNAO1 (guanine nucleotide-binding protein, alpha-activating activity polypeptide O) were recently identified as being causative for early epileptic encephalopathy. Since then approximately 27 patients with severe developmental delay and different neurological phenotypes for epilepsy and involuntary movement disorder have been reported. We report four additional patients with mutations in GNAO1 including a report of siblings of different sex harboring the same de novo mutation (c.736G > A, p.Glu246Lys) but showing differences in phenotype with pronounced dystonia in the boy and epilepsy in his sister. Another de novo mutation in GNAO1 (c.607G > A, p.Gly203Arg) was identified in two unrelated girls with severe epilepsy. Both girls later also developed severe dystonia with severe nonepileptic spasms. An extensive review of published cases revealed that epilepsy was reported in only one male patient so far. Thus it appears possible that epilepsy is a sex-dependent phenotypic feature of GNAO1-related diseases.

De novo mutations of STXBP1 in Chinese children with early onset epileptic encephalopathy

2018 ◽  
Vol 17 (8) ◽  
pp. e12492 ◽  
Author(s):  
T. Li ◽  
M. Cheng ◽  
J. Wang ◽  
S. Hong ◽  
M. Li ◽  
...  
Keyword(s):  
Early Onset ◽  
De Novo ◽  
Epileptic Encephalopathy ◽  
Chinese Children ◽  
De Novo Mutations

scholarly journals Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Tianyun Wang ◽  
◽  
Kendra Hoekzema ◽  
Davide Vecchio ◽  
Huidan Wu ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Large Scale ◽  
De Novo ◽  
Targeted Sequencing ◽  
Published Data ◽  
De Novo Mutations ◽  
Risk Genes ◽  
Mutation Burden ◽  
Number Of Patients ◽  
Significant Burden

Abstract Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E−06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E−07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype–genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.

scholarly journals A Novel Heterozygous Missense Variant in YWHAG Gene Cause Early-Onset Epilepsy in a Chinese Family

2020 ◽  
Author(s):  
Zhi Yi ◽  
Zhenfeng Song ◽  
Jiao Xue ◽  
Chengqing Yang ◽  
Fei Li ◽  
...  
Keyword(s):  
Early Onset ◽  
Seizure Control ◽  
De Novo ◽  
Missense Variant ◽  
Epileptic Encephalopathy ◽  
Chinese Family ◽  
Gene Variants ◽  
Case Presentation ◽  
Epileptic Encephalopathies ◽  
Refractory Seizures

Abstract Background: Developmental and epileptic encephalopathies (DEE) are a heterogeneous group of severe disorders which are characterized by early-onset, refractory seizures and developmental slowing or regression. Genetic variations are significant causes for them. De novo variants in an increasing number of candidate genes have been found to be causal. YWHAG gene variants have been reported to cause developmental and epileptic encephalopathy 56 (DEE56). Case presentation: Here, we report a novel heterozygous missense variant c.170G>A (p.R57H) in YWHAG gene cause early-onset epilepsy in a Chinese family. Both the proband and his mother exhibit early onset seizures, intellectual disability, developmental delay. While the proband achieve seizure control with sodium valproate, his mother's seizures were not well controlled. Conclusions: Our report further confirming the haploinsufficiency of YWHAG results in developmental and epileptic encephalopathies.

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