scholarly journals Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy

Brain ◽  
2020 ◽  
Vol 143 (5) ◽  
pp. 1447-1461 ◽  
Author(s):  
Nicolas Chatron ◽  
Felicitas Becker ◽  
Heba Morsy ◽  
Miriam Schmidts ◽  
Katia Hardies ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Epileptic Encephalopathy ◽  
Allelic Loss ◽  
Loss Of Function ◽  
Seizure Onset ◽  
Joint Contractures ◽  
Epileptic Encephalopathies ◽  
Genomic Technologies ◽  
Pes Equinovarus ◽  
Modern Genomic

Abstract Developmental and epileptic encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathy caused by bi-allelic loss-of-function variants in GAD1, as presented by 11 patients from six independent consanguineous families. Seizure onset occurred in the first 2 months of life in all patients. All 10 patients, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1−/− mouse model. Four patients died before 4 years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the γ-aminobutyric acid (GABA) metabolism as it catalyses the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele.

scholarly journals Loss-of-function variants in DNM1 cause a specific form of developmental and epileptic encephalopathy only in biallelic state

2021 ◽  
pp. jmedgenet-2021-107769
Author(s):  
Gökhan Yigit ◽  
Ruth Sheffer ◽  
Muhannad Daana ◽  
Yun Li ◽  
Emrah Kaygusuz ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Clinical Symptoms ◽  
Epileptic Encephalopathy ◽  
Specific Form ◽  
Loss Of Function ◽  
Epileptic Encephalopathies ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Heterozygous Carriers ◽  
Refractory Seizures

BackgroundDevelopmental and epileptic encephalopathies (DEEs) represent a group of severe neurological disorders characterised by an onset of refractory seizures during infancy or early childhood accompanied by psychomotor developmental delay or regression. DEEs are genetically heterogeneous with, to date, more than 80 different genetic subtypes including DEE31 caused by heterozygous missense variants in DNM1.MethodsWe performed a detailed clinical characterisation of two unrelated patients with DEE and used whole-exome sequencing to identify causative variants in these individuals. The identified variants were tested for cosegregation in the respective families.ResultsWe excluded pathogenic variants in known, DEE-associated genes. We identified homozygous nonsense variants, c.97C>T; p.(Gln33*) in family 1 and c.850C>T; p.(Gln284*) in family 2, in the DNM1 gene, indicating that biallelic, loss-of-function pathogenic variants in DNM1 cause DEE.ConclusionOur finding that homozygous, loss-of-function variants in DNM1 cause DEE expands the spectrum of pathogenic variants in DNM1. All parents who were heterozygous carriers of the identified loss-of-function variants were healthy and did not show any clinical symptoms, indicating that the type of mutation in DNM1 determines the pattern of inheritance.

The Roles of Twin Studies and Modern Genomic Technologies in Integrative Health Science

2018 ◽  
pp. 34-46
Author(s):  
Robert F. Krueger ◽  
Susan C. South
Keyword(s):  
Allostatic Load ◽  
Twin Studies ◽  
Transcriptional Response ◽  
The United States ◽  
Health Science ◽  
Research Strategies ◽  
Integrative Health ◽  
Genomic Technologies ◽  
Health And Illness ◽  
Modern Genomic

This chapter focuses on genetically informative research design and strategy in integrative health science (IHS). A feature of IHS is studying individual differences in health outcomes together and in a multidisciplinary manner. The chapter focuses on the advantages of using genetically informative research strategies for IHS. Genetically informative strategies are tools to enrich inferences within the IHS paradigm. They help parse the meaning of observed associations between exposures and outcomes. Two strategies are considered for the Midlife in the United States study : (1) Gene × Environment interactions and (2) correlations between education and allostatic load. A strategy likely to be employed in IHS research involves using segments of RNA to understand mechanisms underlying health and illness, focusing on the conserved transcriptional response to adversity (CTRA). The conclusion is that IHS and genetically informative research strategies are natural allies in understanding origins of health and illness in the population at large.

scholarly journals Gain-of-function GABRB3 variants identified in vigabatrin-hypersensitive epileptic encephalopathies

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Nathan L Absalom ◽  
Vivian W Y Liao ◽  
Kavitha Kothur ◽  
Dinesh C Indurthi ◽  
Bruce Bennetts ◽  
...  
Keyword(s):  
De Novo ◽  
Drug Effects ◽  
Receptor Expression ◽  
Aminobutyric Acid ◽  
Loss Of Function ◽  
Molecular Phenotype ◽  
Gain Of Function ◽  
Gene Encoding ◽  
Epileptic Encephalopathies ◽  
Receptor Phenotype

Abstract Variants in the GABRB3 gene encoding the β3-subunit of the γ-aminobutyric acid type A ( receptor are associated with various developmental and epileptic encephalopathies. Typically, these variants cause a loss-of-function molecular phenotype whereby γ-aminobutyric acid has reduced inhibitory effectiveness leading to seizures. Drugs that potentiate inhibitory GABAergic activity, such as nitrazepam, phenobarbital or vigabatrin, are expected to compensate for this and thereby reduce seizure frequency. However, vigabatrin, a drug that inhibits γ-aminobutyric acid transaminase to increase tonic γ-aminobutyric acid currents, has mixed success in treating seizures in patients with GABRB3 variants: some patients experience seizure cessation, but there is hypersensitivity in some patients associated with hypotonia, sedation and respiratory suppression. A GABRB3 variant that responds well to vigabatrin involves a truncation variant (p.Arg194*) resulting in a clear loss-of-function. We hypothesized that patients with a hypersensitive response to vigabatrin may exhibit a different γ-aminobutyric acid A receptor phenotype. To test this hypothesis, we evaluated the phenotype of de novo variants in GABRB3 (p.Glu77Lys and p.Thr287Ile) associated with patients who are clinically hypersensitive to vigabatrin. We introduced the GABRB3 p.Glu77Lys and p.Thr287Ile variants into a concatenated synaptic and extrasynaptic γ-aminobutyric acid A receptor construct, to resemble the γ-aminobutyric acid A receptor expression by a patient heterozygous for the GABRB3 variant. The mRNA of these constructs was injected into Xenopus oocytes and activation properties of each receptor measured by two-electrode voltage clamp electrophysiology. Results showed an atypical gain-of-function molecular phenotype in the GABRB3 p.Glu77Lys and p.Thr287Ile variants characterized by increased potency of γ-aminobutyric acid A without change to the estimated maximum open channel probability, deactivation kinetics or absolute currents. Modelling of the activation properties of the receptors indicated that either variant caused increased chloride flux in response to low concentrations of γ-aminobutyric acid that mediate tonic currents. We therefore propose that the hypersensitivity reaction to vigabatrin is a result of GABRB3 variants that exacerbate GABAergic tonic currents and caution is required when prescribing vigabatrin. In contrast, drug strategies increasing tonic currents in loss-of-function variants are likely to be a safe and effective therapy. This study demonstrates that functional genomics can explain beneficial and adverse anti-epileptic drug effects, and propose that vigabatrin should be considered in patients with clear loss-of-function GABRB3 variants.

scholarly journals Correction: Bi-allelic loss of function variants in SLC30A5 as cause of perinatal lethal cardiomyopathy

2021 ◽  
Author(s):  
Johann Kaspar Lieberwirth ◽  
Pascal Joset ◽  
Anja Heinze ◽  
Julia Hentschel ◽  
Anja Stein ◽  
...  
Keyword(s):  
Allelic Loss ◽  
Loss Of Function

scholarly journals Bi-allelic loss-of-function variants in BCAS3 cause a syndromic neurodevelopmental disorder

2021 ◽  
Author(s):  
Holger Hengel ◽  
Shabab B. Hannan ◽  
Sarah Dyack ◽  
Sara B. MacKay ◽  
Ulrich Schatz ◽  
...  
Keyword(s):  
Neurodevelopmental Disorder ◽  
Allelic Loss ◽  
Loss Of Function

scholarly journals Epileptic Encephalopathies: An Overview

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Sonia Khan ◽  
Raidah Al Baradie
Keyword(s):  
Slow Wave Sleep ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
Management Options ◽  
Epileptic Encephalopathies ◽  
Age Related ◽  
Ohtahara Syndrome ◽  
Cerebral Dysfunction ◽  
Epileptic Syndromes

Epileptic encephalopathies are an epileptic condition characterized by epileptiform abnormalities associated with progressive cerebral dysfunction. In the classification of the International League Against Epilepsy eight age-related epileptic encephalopathy syndromes are recognized. These syndromes include early myoclonic encephalopathy and Ohtahara syndrome in the neonatal period, West syndrome and Dravet syndrome in infancy, myoclonic status in nonprogressive encephalopathies, and Lennox-Gastaut syndrome, Landau-Kleffner syndrome, and epilepsy with continuous spike waves during slow wave sleep in childhood and adolescences. Other epileptic syndromes such as migrating partial seizures in infancy and severe epilepsy with multiple independent spike foci may be reasonably added. In this paper, we provide an overview of epileptic encephalopathies including clinical neurophysiological features, cognitive deterioration, and management options especially that these conditions are generally refractory to standard antiepileptic drugs.

scholarly journals Bi-allelic Loss-of-Function Mutations in the NPR-C Receptor Result in Enhanced Growth and Connective Tissue Abnormalities

2018 ◽  
Vol 103 (2) ◽  
pp. 288-295 ◽  
Author(s):  
Eveline Boudin ◽  
Tjeerd R. de Jong ◽  
Tim C.R. Prickett ◽  
Bruno Lapauw ◽  
Kaatje Toye ◽  
...  
Keyword(s):  
Connective Tissue ◽  
Allelic Loss ◽  
Loss Of Function ◽  
Tissue Abnormalities

scholarly journals Role of Legal Principles in Eliminating and Minimizing the Risks of Genomic Technologies

Lex Russica ◽  
2019 ◽  
pp. 121-128 ◽  
Author(s):  
M. N. Maleina
Keyword(s):  
Genetic Information ◽  
Personal Data ◽  
Negative Consequences ◽  
Genetic Characteristics ◽  
Legal Principles ◽  
Genomic Technologies ◽  
Preventive Actions ◽  
The Individual ◽  
Modern Genomic

The use of modern genomic technologies, along with the benefits to the man and society, can lead to negative consequences. Such risks exist both in the process and after the production, isolation, modification, storage of DNA. Prior to detailed legislative regulation of relations regarding the use of genomic technologies for medicinal purposes and not for medical reasons, legal principles become vital.The paper formulates the following basic legal principles of genomic technologies application: the principle of preventive actions of the state to protect citizens from the risks of using genomic technologies; the principle of preserving the human genome as a special species; the principle of guaranteeing the inviolability of the individual of every citizen when using genomic technologies; the principle of priority of life and health of citizens over the interests of science and society; the principle of equality of citizens regardless of genetic characteristics; the principle of protection of genetic information of every citizen as part of personal data; the principle of guaranteeing access to the citizen’s own genetic information. Legal principles can be used to resolve a dispute by analogy of law.

scholarly journals Experience of using modern genomic technologies to study microorganisms and their communities

2021 ◽  
pp. 159-167
Author(s):  
E. V. Voropaev ◽  
I. O. Stoma ◽  
D. V. Tapalski
Keyword(s):  
Risk Groups ◽  
Metagenomic Analysis ◽  
Minimal Amount ◽  
Genomic Technologies ◽  
Bacterial Microbiome ◽  
Genomic Studies ◽  
H Pylori ◽  
Sequencing Platforms ◽  
Modern Genomic ◽  
Medical University

Objective. The aim of this work was to review the main results of genomic studies of microorganisms and their communities performed on the base of the Research Laboratory of Gomel State Medical University.Materials and methods. Genomic, transcriptomic and metagenomic analysis of the microorganisms of the stomach and respiratory tract.Results. The capabilities of modern next-generation sequencing platforms have been analyzed, and the authors` own results of the use of genomic, transcriptomic and metagenomic analysis of the microbiota in patients with various gastric and respiratory pathologies have been described.Conclusion. The analysis of the obtained data has revealed peculiarities of the structure of the microbial communities of the stomach of the patients infected with H. pylori with different gastric pathology: the proportion participation of H. pylori in the metagenome of the samples with different forms of gastric cancer did not exceed 25 %, of gastritis — 6 %, of peptic ulcer — 1 %. At the same time, the minimal amount of H. pylori in all the cases could reach 0.1 %. A signifcant degree of CagA and CagY loci variability of H. pylori was detected. Streptoccocus genus bacteria dominated (36 %) in the bacterial microbiome of a patient diagnosed with the coronavirus disease, and in the viral microbiome, SARS-CoV-2 constituted 59 % of the total number of viruses in the material. The analysis of 13 strains of Klebsiella pneumoniae with multiple and extreme resistance to antibiotics has found that the studied strains belong to fve MLST-types, three of which are classifed as high epidemic risk groups.

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