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

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.

Download Full-text

Altered inhibitory synapses in de novo GABRA5 and GABRA1 mutations associated with early onset epileptic encephalopathies

Brain ◽

10.1093/brain/awz123 ◽

2019 ◽

Vol 142 (7) ◽

pp. 1938-1954 ◽

Cited By ~ 2

Author(s):

Ciria C Hernandez ◽

Wenshu XiangWei ◽

Ningning Hu ◽

Dingding Shen ◽

Wangzhen Shen ◽

...

Keyword(s):

Gabaa Receptor ◽

Gabaa Receptors ◽

Early Onset ◽

De Novo ◽

Epileptic Encephalopathy ◽

Inhibitory Synapses ◽

Causative Gene ◽

Gabaergic Neurotransmission ◽

Gaba Binding ◽

Patients With Epilepsy

Abstract We performed next generation sequencing on 1696 patients with epilepsy and intellectual disability using a gene panel with 480 epilepsy-related genes including all GABAA receptor subunit genes (GABRs), and we identified six de novo GABR mutations, two novel GABRA5 mutations (c.880G>T, p.V294F and c.1238C>T, p.S413F), two novel GABRA1 mutations (c.778C>T, p.P260S and c.887T>C, p.L296S/c.944G>T, p.W315L) and two known GABRA1 mutations (c.335G>A, p.R112Q and c.343A>G, p.N115D) in six patients with intractable early onset epileptic encephalopathy. The α5(V294F and S413F) and α1(P260S and L296S/W315L) subunit residue substitutions were all in transmembrane domains, while the α1(R112Q and N115R) subunit residue substitutions were in the N-terminal GABA binding domain. Using multidisciplinary approaches, we compared effects of mutant GABAA receptor α5 and α1 subunits on the properties of recombinant α5β3γ2 and α1β3γ2 GABAA receptors in both neuronal and non-neuronal cells and characterized their effects on receptor clustering, biogenesis and channel function. GABAA receptors containing mutant α5 and α1 subunits all had reduced cell surface and total cell expression with altered endoplasmic reticulum processing, impaired synaptic clustering, reduced GABAA receptor function and decreased GABA binding potency. Our study identified GABRA5 as a causative gene for early onset epileptic encephalopathy and expands the mutant GABRA1 phenotypic spectrum, supporting growing evidence that defects in GABAergic neurotransmission contribute to early onset epileptic encephalopathy phenotypes.

Download Full-text

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.

Download Full-text

Dravet syndrome associated mutations in GABRA1, GABRB2 and GABRG2 define the genetic landscape of defects of GABAA receptors

Brain Communications ◽

10.1093/braincomms/fcab033 ◽

2021 ◽

Author(s):

Ciria C Hernandez ◽

XiaoJuan Tian ◽

Ningning Hu ◽

Wangzhen Shen ◽

Mackenzie A Catron ◽

...

Keyword(s):

Gabaa Receptor ◽

De Novo ◽

Epileptic Encephalopathy ◽

Dravet Syndrome ◽

First Year ◽

Genes Encoding ◽

Genetic Landscape ◽

Clonic Seizures ◽

Trafficking Defects ◽

First Year Of Life

Abstract Dravet syndrome is a rare, catastrophic epileptic encephalopathy that begins in the first year of life, usually with febrile or afebrile hemiclonic or generalized tonic-clonic seizures followed by status epilepticus. De novo variants in genes that mediate synaptic transmission such as SCN1A and PCDH19 are often associated with Dravet syndrome. Recently, GABAA receptor subunit genes (GABRs) encoding α1 (GABRA1), β3 (GABRB3) and γ2 (GABRG2), but not β2 (GABRB2) or β1 (GABRB1), subunits are frequently associated with Dravet syndrome or Dravet syndrome-like phenotype. We performed next generation sequencing on 870 patients with Dravet syndrome and identified nine variants in three different GABRs. Interestingly, the variants were all in genes encoding the most common GABAA receptor, the α1β2γ2 receptor. Mutations in GABRA1 (c.644T>C, p.L215P; c.640C>T, p.R214C; c.859G>A; V287I; c.641G>A, p.R214H) and GABRG2 (c.269C>G, p.T90R; c.1025C>T, p.P342L) presented as de novo cases, while in GABRB2 two variants were de novo (c.992T>C, p.F331S; c.542A>T, p.Y181F) and one was autosomal dominant and inherited from the maternal side (c.990_992del, p.330_331del). We characterized the effects of these GABR variants on GABAA receptor biogenesis and channel function. We found that defects in receptor gating were the common deficiency of GABRA1 and GABRB2 Dravet syndrome variants, while mainly trafficking defects were found with the GABRG2 (c.269C>G, p.T90R) variant. It seems that variants in α1 and β2 subunits are less tolerated than in γ2 subunits, since variant α1 and β2 subunits express well but were functionally deficient. This suggests that all of these GABR variants are all targeting GABR genes that encode the assembled α1β2γ2 receptor, and regardless of which of the three subunits are mutated, variants in genes coding for α1, β2 and γ2 receptor subunits make them candidate causative genes in the pathogenesis of Dravet syndrome.

Download Full-text

A de novo variant in CASK gene causing intellectual disability and brain hypoplasia: A Case Report and Literature Review

10.21203/rs.3.rs-317232/v1 ◽

2021 ◽

Author(s):

Ying Zhang ◽

Yanyan Nie ◽

Yu Mu ◽

Jie Zheng ◽

Xiaowei Xu ◽

...

Keyword(s):

Intellectual Disability ◽

Mental Disorders ◽

De Novo ◽

Clinical Symptoms ◽

Clinical Manifestations ◽

De Novo Mutation ◽

Loss Of Function ◽

Bioinformatics Analyses ◽

Whole Exome ◽

De Novo Variant

Abstract Background：The pathogenic variation of CASK gene can cause CASK related mental disorders. The main clinical manifestations are microcephaly with pontine and cerebellar hypoplasia, X-linked mental disorders with or without nystagmus and FG syndrome. The main pathogenic mechanism is the loss of function of related protein caused by mutation. We reported a Chinese male newborn with a de novo variant in CASK gene. Case presentation：We present an 18-day-old baby with intellectual disability and brain hypoplasia. Whole-exome sequencing was performed, which detected a hemizygous missense mutation c.764G>A of CASK gene. The mutation changed the 255th amino acid from Arg to His. Software based bioinformatics analyses were conducted to infer its functional effect.Conclusions：In this paper, a de novo mutation of CASK gene was reported. Moreover, a detailed description of all the cases described in the literature is reported.CASK mutations cause a variety of clinical phenotypes. Its diagnosis is difficult due to the lack of typical clinical symptoms. Genetic testing should be performed as early as possible if this disease is suspected. This case provides an important reference for the diagnosis and treatment of future cases.

Download Full-text

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

Download Full-text

Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106373 ◽

2019 ◽

Vol 57 (2) ◽

pp. 132-137 ◽

Cited By ~ 9

Author(s):

Edgard Verdura ◽

Carme Fons ◽

Agatha Schlüter ◽

Montserrat Ruiz ◽

Stéphane Fourcade ◽

...

Keyword(s):

De Novo ◽

Epileptic Encephalopathy ◽

Dominant Mode ◽

Wild Type ◽

Adequate Treatment ◽

Cellular Assays ◽

Disease Spectrum ◽

Whole Exome ◽

Pore Domain ◽

Mode Of Inheritance

BackgroundSince 1994, over 50 families affected by the episodic ataxia type 1 disease spectrum have been described with mutations in KCNA1, encoding the voltage-gated K+ channel subunit Kv1.1. All of these mutations are either transmitted in an autosomal-dominant mode or found as de novo events.MethodsA patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy was sequenced by whole-exome sequencing (WES). A candidate variant was tested using cellular assays and patch-clamp recordings.ResultsWES revealed a homozygous variant (p.Val368Leu) in KCNA1, involving a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG). Functional analysis showed that mutant protein alone failed to produce functional channels in homozygous state, while coexpression with wild-type produced no effects on K+ currents, similar to wild-type protein alone. Treatment with oxcarbazepine, a sodium channel blocker, proved effective in controlling seizures.ConclusionThis newly identified variant is the first to be reported to act in a recessive mode of inheritance in KCNA1. These findings serve as a cautionary tale for the diagnosis of channelopathies, in which an unreported phenotypic presentation or mode of inheritance for the variant of interest can hinder the identification of causative variants and adequate treatment choice.

Download Full-text

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

Cell Reports ◽

10.1016/j.celrep.2017.09.088 ◽

2017 ◽

Vol 21 (4) ◽

pp. 926-933 ◽

Cited By ~ 11

Author(s):

Sushmitha Gururaj ◽

Elizabeth Emma Palmer ◽

Garrett D. Sheehan ◽

Tejaswi Kandula ◽

Rebecca Macintosh ◽

...

Keyword(s):

Potassium Channel ◽

De Novo ◽

Ion Selectivity ◽

Epileptic Encephalopathy ◽

De Novo Mutation

Download Full-text

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

Download Full-text

Genotypes and Phenotypes of MEF2C Haploinsufficiency Syndrome: New Cases and Novel Point Mutations

Frontiers in Pediatrics ◽

10.3389/fped.2021.664449 ◽

2021 ◽

Vol 9 ◽

Author(s):

Lin Wan ◽

Xinting Liu ◽

Linyan Hu ◽

Huimin Chen ◽

Yulin Sun ◽

...

Keyword(s):

De Novo ◽

Neurodevelopmental Disorder ◽

Point Mutations ◽

Clinical Manifestations ◽

Poor Performance ◽

Genetic Alterations ◽

Mendelian Inheritance ◽

Whole Exome ◽

Patients With Epilepsy ◽

Free Status

Aim: MEF2C haploinsufficiency syndrome (MCHS) is a severe neurodevelopmental disorder. We describe the clinical phenotypes and genotypes of seven patients with MCHS to enhance the understanding of clinical manifestations and genetic alterations associated with MCHS.Method: Seven patients (6 females and 1 male, aged between 2 years 5 months and 6 years) who had MEF2C mutations, and their parents underwent trio-based whole-exome sequencing; subsequently, their clinical features were assessed. A literature review of patients with MCHS was performed by searching the PubMed and Online Mendelian Inheritance in Man databases.Results: Seven mutations were identified, of which six were unreported in the past; of the reported cases, five patients had de novo mutations but two had an undefined inheritance pattern. All patients presented delays in developmental milestones, severe intellectual disabilities and lack of speech. Six patients exhibited infantile hypotonia, five patients experienced stereotypic movements and were unable to walk, four patients exhibited poor eye contact indicative of autism and two showed poor performance. While six patients experienced seizure, five among them became seizure free after receiving anti-seizure medicine. Three patients showed a regression in their development, whereas the mothers of two patients exhibited mosaicism but were healthy without any abovementioned symptoms.Interpretation: Regression was not a common phenomenon but occurred in MCHS. The prognosis of MCHS patients with epilepsy was good, but most patients can achieve a seizure-free status. Healthy people may have low-level mosaicism and carry a pathogenic MEF2C mutation.

Download Full-text