A De Novo Mutation in the Sodium-Activated Potassium Channel KCNT2 Alters Ion Selectivity and Causes Epileptic Encephalopathy

AbstractMutations in KCNQ2, encoding for subunits of potassium channels, are known to cause neonatal epileptic encephalopathy (NEE). Therapeutic options for these children are often limited. Recently, there are indications that some patients with KCNQ2 NEE show seizure response to vitamin B6 (VB6) therapy. We present a young infant with severe KCNQ2 encephalopathy resulting from a novel de novo mutation (c.1023G>C; p.(Gln341His)). In our patient, VB6 responsiveness could be demonstrated clearly by remarkable seizure-response to VB6 therapy and seizure exacerbation to discontinuation of VB6 therapy. The pathophysiology of VB6 response in potassium channel mutations is not understood. Some hypothetical mechanisms are currently in discussion. To identify the group of patients who benefits from VB6 therapy, further investigations are necessary.

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

Brain and Development ◽

10.1016/j.braindev.2016.09.009 ◽

2017 ◽

Vol 39 (3) ◽

pp. 256-260 ◽

Cited By ~ 20

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

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Case Report: Follow Up of a Patient with De Novo Mutation at Kcna2 Gene Leading to Ataxia and Epileptic Encephalopathy

Advancements in Case Studies ◽

10.31031/aics.2020.02.000545 ◽

2020 ◽

Vol 2 (4) ◽

Author(s):

Zanluchi VBS

Keyword(s):

Case Report ◽

De Novo ◽

Epileptic Encephalopathy ◽

De Novo Mutation

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Cleft Palate as Distinguishing Feature in a Patient with GABRB3 Epileptic Encephalopathy

Neuropediatrics ◽

10.1055/s-0039-1693143 ◽

2019 ◽

Vol 50 (06) ◽

pp. 378-381

Author(s):

Daniel Bamborschke ◽

Matthias Pergande ◽

Hülya Sevcan Daimagüler ◽

Elisabeth Mangold ◽

Jörg Dötsch ◽

...

Keyword(s):

Cleft Palate ◽

Gabaa Receptor ◽

Knockout Mice ◽

De Novo ◽

Index Patient ◽

Epileptic Encephalopathy ◽

De Novo Mutation ◽

Neonatal Onset ◽

Whole Exome ◽

Patients With Epilepsy

Mutations in GABAA-receptor subunit genes are associated with a heterogeneous spectrum of epilepsies. Patients with epilepsy caused by mutations in a specific GABAA-receptor (GABRA3) occasionally present with orofacial dysmorphism (e.g., cleft palates). While cleft palates have been described in Gabrb3 knockout mice and in humans with GABRB3 variants without epilepsy, the specific combination of epilepsy and cleft palate in humans with GABRB3 mutations has not yet been reported.We describe a patient with epileptic encephalopathy (EE) who presented with therapy-refractory neonatal-onset myoclonic seizures and severe developmental delay. Electroencephalogram showed burst suppression pattern at neonatal age and hypsarrhythmia at infantile age. Initial magnetic resonance imaging was unremarkable. As he additionally presented with a cleft palate, we were curious whether cleft palate and EE had the same genetic origin. Whole exome sequencing of the index patient revealed a novel pathogenic heterozygous de novo mutation in GABRB3 (c.899T > C; p.I300T). In consistency with Gabrb3 knockout mice data, this is the first report of cleft palate in a patient with GABRB3 associated EE.We suggest to add cleft palate to the phenotypic GABRB3 spectrum and to screen for mutations in GABAA-receptors in patients with EE and orofacial dysmorphism.

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

Neuropediatrics ◽

10.1055/s-0037-1603977 ◽

2017 ◽

Vol 48 (05) ◽

pp. 371-377 ◽

Cited By ~ 12

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.

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Germline and somatic mutations in STXBP1 with diverse neurodevelopmental phenotypes

Neurology Genetics ◽

10.1212/nxg.0000000000000199 ◽

2017 ◽

Vol 3 (6) ◽

pp. e199 ◽

Cited By ~ 22

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.

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A Heterozygous STXBP1 Gene de novo Mutation in an Iranian Child With Epileptic Encephalopathy: Case Report

ACTA MEDICA IRANICA ◽

10.18502/acta.v57i8.2429 ◽

2020 ◽

Author(s):

Masoud Heidari ◽

Morteza d Soleyman-Neja ◽

Mohammad Hossein Taskhiri ◽

Alireza Isazadeh ◽

Manzar Bolhassani ◽

...

Keyword(s):

Neurotransmitter Release ◽

Genetic Variant ◽

De Novo ◽

Epileptic Encephalopathy ◽

Genetic Change ◽

De Novo Mutation ◽

Medical Sciences ◽

Whole Exome ◽

Iranian Child ◽

Synaptic Vesicle Fusion

The Syntaxin Binding Protein 1 (STXBP1) plays an important role in regulating neurotransmitter release and synaptic vesicle fusion through binding to syntaxin-1A (STX1A) and changing its conformation. In this study, we identified a de novo mutation (c.C1162T: p.R388X) in exon 14 of the STXBP1 gene causing an epileptic encephalopathy, early infantile, non-epileptic movement, and unclassified infantile spasms disorders in a 5-year-old boy by whole-exome sequencing. The segregation of this genetic variant was examined in the patient as well as in his parents. We found the R388X in heterozygous state in the proband but not in his parents. This genetic change could be due to de nova mutation or germlinemosaicism. © 2019 Tehran University of Medical Sciences. All rights reserved. Acta MedIran 2019;57(8):518-521.

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A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy

Neurobiology of Disease ◽

10.1016/j.nbd.2014.05.017 ◽

2014 ◽

Vol 69 ◽

pp. 117-123 ◽

Cited By ~ 56

Author(s):

Mark Estacion ◽

Janelle E. O'Brien ◽

Allison Conravey ◽

Michael F. Hammer ◽

Stephen G. Waxman ◽

...

Keyword(s):

De Novo ◽

Epileptic Encephalopathy ◽

De Novo Mutation ◽

Channel Activation

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Syntaxin Binding Protein 1 Related Epilepsies

Journal of Pediatric Neurology ◽

10.1055/s-0041-1727259 ◽

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.

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A de novo SCN8A heterozygous mutation in a child with epileptic encephalopathy: a case report

BMC Pediatrics ◽

10.1186/s12887-019-1796-9 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 1

Author(s):

Kao-Min Lin ◽

Geng Su ◽

Fengpeng Wang ◽

Xiaobin Zhang ◽

Yuanqing Wang ◽

...

Keyword(s):

Sodium Channel ◽

Exome Sequencing ◽

De Novo ◽

Intractable Epilepsy ◽

Bioinformatic Analysis ◽

Epileptic Encephalopathy ◽

De Novo Mutation ◽

Heterozygous Mutation ◽

Targeted Exome Sequencing ◽

Complex Disorder

Abstract Background Epilepsy is a complex disorder caused by various factors, including genetic aberrance. Recent studies have identified an essential role of the sodium channel Nav1.6, encoded by the gene SCN8A, in epileptic encephalopathy. Case presentation Using parent-offspring trio targeted-exome sequencing, we identified a de novo heterozygous missense mutation c.3953A > G (p.N1318S) in SCN8A in a 3-year-and-9-month Chinese female patient with early infantile epileptic encephalopathy and a normal magnetic resonance imaging of the brain. Conclusions This de novo mutation was only detected in the patient but not in her parents. Bioinformatic analysis indicates the pathogenicity of this mutation. Administration of the sodium channel blocker well controlled seizures in the patient. Therefore, we recommend trio targeted-exome sequencing as a routine method for pathogenic variant screening in patients with intractable epilepsy and a normal MRI.

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