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Article ; Online: CHD2 epilepsy: epigenetics and the quest for precision medicine.

Symonds, Joseph D

Developmental medicine and child neurology

2019 Volume 62, Issue 5, Page(s) 549–550

MeSH term(s)	DNA-Binding Proteins/genetics ; Epigenesis, Genetic ; Epilepsy/genetics ; Humans ; Mutation ; Phenotype ; Precision Medicine
Chemical Substances	CHD2 protein, human ; DNA-Binding Proteins
Language	English
Publishing date	2019-11-12
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	80369-8
ISSN	1469-8749 ; 0012-1622
ISSN (online)	1469-8749
ISSN	0012-1622
DOI	10.1111/dmcn.14380
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Article ; Online: Long-term predictors of developmental outcome and disease burden in

Feng, Tony / Makiello, Phoebe / Dunwoody, Benjamin / Steckler, Felix / Symonds, Joseph D / Zuberi, Sameer M / Dorris, Liam / Brunklaus, Andreas

Brain communications

2024 Volume 6, Issue 1, Page(s) fcae004

Abstract: Dravet syndrome is a severe infantile onset developmental and epileptic encephalopathy associated with mutations in the sodium channel alpha 1 subunit ... ...

Abstract	Dravet syndrome is a severe infantile onset developmental and epileptic encephalopathy associated with mutations in the sodium channel alpha 1 subunit gene
Language	English
Publishing date	2024-01-09
Publishing country	England
Document type	Journal Article
ISSN	2632-1297
ISSN (online)	2632-1297
DOI	10.1093/braincomms/fcae004
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Article ; Online: Corrigendum to "Epilepsy and developmental disorders: Next generation sequencing in the clinic" [Eur. J. Paediatr. Neurol. (2019) 15-23].

Symonds, Joseph D / McTague, Amy

European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society

2020 Volume 30, Page(s) 170

Language	English
Publishing date	2020-07-02
Publishing country	England
Document type	Published Erratum
ZDB-ID	1397146-3
ISSN	1532-2130 ; 1090-3798
ISSN (online)	1532-2130
ISSN	1090-3798
DOI	10.1016/j.ejpn.2020.06.011
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Article ; Online: Genetics update: Monogenetics, polygene disorders and the quest for modifying genes.

Symonds, Joseph D / Zuberi, Sameer M

Neuropharmacology

2017 Volume 132, Page(s) 3–19

Abstract: The genetic channelopathies are a broad collection of diseases. Many ion channel genes demonstrate wide phenotypic pleiotropy, but nonetheless concerted efforts have been made to characterise genotype-phenotype relationships. In this review we give an ... ...

Abstract	The genetic channelopathies are a broad collection of diseases. Many ion channel genes demonstrate wide phenotypic pleiotropy, but nonetheless concerted efforts have been made to characterise genotype-phenotype relationships. In this review we give an overview of the factors that influence genotype-phenotype relationships across this group of diseases as a whole, using specific individual channelopathies as examples. We suggest reasons for the limitations observed in these relationships. We discuss the role of ion channel variation in polygenic disease and highlight research that has contributed to unravelling the complex aetiological nature of these conditions. We focus specifically on the quest for modifying genes in inherited channelopathies, using the voltage-gated sodium channels as an example. Epilepsy related to genetic channelopathy is one area in which precision medicine is showing promise. We will discuss the successes and limitations of precision medicine in these conditions. This article is part of the Special Issue entitled 'Channelopathies.'
MeSH term(s)	Animals ; Channelopathies/genetics ; Channelopathies/metabolism ; Channelopathies/therapy ; Humans
Language	English
Publishing date	2017-10-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	218272-5
ISSN	1873-7064 ; 0028-3908
ISSN (online)	1873-7064
ISSN	0028-3908
DOI	10.1016/j.neuropharm.2017.10.013
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Article ; Online: WITHDRAWN: Genetics update: Monogenetics, polygene disorders and the quest for modifying genes.

Symonds, Joseph D / Zuberi, Sameer M

Neuropharmacology

2017

Abstract: The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.neuropharm.2017.10.013. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article ... ...

Abstract	The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.neuropharm.2017.10.013. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
Language	English
Publishing date	2017-07-27
Publishing country	England
Document type	Journal Article
ZDB-ID	218272-5
ISSN	1873-7064 ; 0028-3908
ISSN (online)	1873-7064
ISSN	0028-3908
DOI	10.1016/j.neuropharm.2017.07.016
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Article ; Online: Epilepsy and developmental disorders: Next generation sequencing in the clinic.

Symonds, Joseph D / McTague, Amy

European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society

2019 Volume 24, Page(s) 15–23

Abstract: Background: The advent of Next Generation Sequencing (NGS) has led to a redefining of the genetic landscape of the epilepsies. Hundreds of single gene epilepsies have been described. Genes associated with epilepsy involve diverse processes. Now a ... ...

Abstract	Background: The advent of Next Generation Sequencing (NGS) has led to a redefining of the genetic landscape of the epilepsies. Hundreds of single gene epilepsies have been described. Genes associated with epilepsy involve diverse processes. Now a substantial proportion of individuals with epilepsy can receive a high definition molecular genetic diagnosis. Methods: In this review we update the current genetic landscape of the epilepsies and categorise the major functional groupings of epilepsy-associated genes. We describe currently available genetic testing approaches. We perform a literature review of NGS studies and review the factors which determine yield in cohorts undergoing testing. We identify factors associated with positive genetic diagnosis and consider the utility of genetic testing in terms of treatment selection as well as more qualitative aspects of care. Findings: Epilepsy-associated genes can be grouped into five broad functional categories: ion transport; cell growth and differentiation; regulation of synaptic processes; transport and metabolism of small molecules within and between cells; and regulation of gene transcription and translation. Early onset of seizures, drug-resistance, and developmental comorbidity are associated with higher diagnostic yield. The most commonly implicated genes in NGS studies to date, in order, are SCN1A, KCNQ2, CDKL5, SCN2A, and STXBP1. In unselected infantile cohorts PRRT2, a gene associated with self-limited epilepsy, is frequently implicated. Genetic diagnosis provides utility in terms of treatment choice closing the diagnostic odyssey, avoiding unnecessary further testing, and informing future reproductive decisions. Conclusions: Genetic testing has become a first line test in epilepsy. As techniques improve and understanding advances, its utility is set to increase. Genetic diagnosis, particularly in early onset developmental and epileptic encephalopathies, influences treatment choice in a significant proportion of patients. The realistic prospect of gene therapy is a cause for optimism.
MeSH term(s)	Developmental Disabilities/complications ; Developmental Disabilities/genetics ; Epileptic Syndromes/complications ; Epileptic Syndromes/genetics ; Genetic Testing/methods ; High-Throughput Nucleotide Sequencing ; Humans ; Membrane Proteins/genetics ; Nerve Tissue Proteins/genetics
Chemical Substances	Membrane Proteins ; Nerve Tissue Proteins
Language	English
Publishing date	2019-12-18
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1397146-3
ISSN	1532-2130 ; 1090-3798
ISSN (online)	1532-2130
ISSN	1090-3798
DOI	10.1016/j.ejpn.2019.12.008
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Zs.A 4867: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 641: Show issues

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Article ; Online: Update on diagnosis and management of childhood epilepsies.

Zuberi, Sameer M / Symonds, Joseph D

Jornal de pediatria

2015 Volume 91, Issue 6 Suppl 1, Page(s) S67–77

Abstract: Objectives: To review the current evidence base for the diagnosis and management of the childhood epilepsies and to draw attention to the current gaps in this evidence base. The focus will be on therapeutic aspects. Current International League Against ... ...

Abstract	Objectives: To review the current evidence base for the diagnosis and management of the childhood epilepsies and to draw attention to the current gaps in this evidence base. The focus will be on therapeutic aspects. Current International League Against Epilepsy (ILAE) terminology will be described and used throughout the discussion. The review will draw attention to recent advances that have been made in both our understanding and treatment of the childhood epilepsies. Potential future directions for research and treatment options will be discussed. Sources: Original articles relevant to the subject were obtained from the MedLine database using pertinent MeSH terms. Relevant papers were read and assimilated. Citation searching was used. Summary of the findings: Epilepsy is a major cause of global disease burden. Childhood epilepsies are a heterogeneous group of conditions. A multi-axial diagnostic approach should be taken prior to making treatment and management decisions for any individual patient. For the majority of patients, successful control of seizures can be achieved with a single medication. However, a significant minority develops refractory disease. Epilepsy surgery can provide cure for a carefully selected group of these cases. Conclusions: There remain significant gaps the evidence base for treatment in several areas of childhood epilepsy. Concerted multi-center efforts should be made to try to close these gaps. A personalized medicine approach may help to reduce the proportion of refractory cases of childhood epilepsy in future.
MeSH term(s)	Anticonvulsants/therapeutic use ; Child ; Child, Preschool ; Electroencephalography/methods ; Epilepsy/diagnosis ; Epilepsy/drug therapy ; Evidence-Based Medicine/trends ; Humans
Chemical Substances	Anticonvulsants
Language	English
Publishing date	2015-09-04
Publishing country	Brazil
Document type	Journal Article ; Review
ZDB-ID	731324-x
ISSN	1678-4782 ; 0021-7557
ISSN (online)	1678-4782
ISSN	0021-7557
DOI	10.1016/j.jped.2015.07.003
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Article ; Online: Advances in epilepsy gene discovery and implications for epilepsy diagnosis and treatment.

Symonds, Joseph D / Zuberi, Sameer M / Johnson, Michael R

Current opinion in neurology

2017 Volume 30, Issue 2, Page(s) 193–199

Abstract: Purpose of review: Epilepsy genetics is shifting from the academic pursuit of gene discovery to a clinical discipline based on molecular diagnosis and stratified medicine. We consider the latest developments in epilepsy genetics and review how gene ... ...

Abstract	Purpose of review: Epilepsy genetics is shifting from the academic pursuit of gene discovery to a clinical discipline based on molecular diagnosis and stratified medicine. We consider the latest developments in epilepsy genetics and review how gene discovery in epilepsy is influencing the clinical classification of epilepsy and informing new therapeutic approaches and drug discovery. Recent findings: Recent studies highlighting the importance of mutation in GABA receptors, NMDA receptors, potassium channels, G-protein coupled receptors, mammalian target of rapamycin pathway and chromatin remodeling are discussed. Examples of precision medicine in epilepsy targeting gain-of-function mutations in KCNT1, GRIN2A, GRIN2D and SCN8A are presented. Potential reasons for the paucity of examples of precision medicine for loss-of-function mutations or in non-ion channel epilepsy genes are explored. We highlight how systems genetics and gene network analyses have suggested that pathways disrupted in epilepsy overlap with those of other neurodevelopmental traits including human cognition. We review how network-based computational approaches are now being applied to epilepsy drug discovery. Summary: We are living in an unparalleled era of epilepsy gene discovery. Advances in clinical care from this progress are already materializing through improved clinical diagnosis and stratified medicine. The application of targeted drug repurposing based on single gene defects has shown promise for epilepsy arising from gain-of-function mutations in ion-channel subunit genes, but important barriers remain to translating these approaches to non-ion channel epilepsy genes and loss-of-function mutations. Gene network analysis offers opportunities to discover new pathways for epilepsy, to decipher epilepsy's relationship to other neurodevelopmental traits and to frame a new approach to epilepsy drug discovery.
Language	English
Publishing date	2017-04
Publishing country	England
Document type	Journal Article
ZDB-ID	1182686-1
ISSN	1473-6551 ; 1350-7540
ISSN (online)	1473-6551
ISSN	1350-7540
DOI	10.1097/WCO.0000000000000433
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Article ; Online: Genotype-phenotype associations in 1018 individuals with SCN1A-related epilepsies.

Epilepsia

2024 Volume 65, Issue 4, Page(s) 1046–1059

Abstract: Objective: SCN1A variants are associated with epilepsy syndromes ranging from mild genetic epilepsy with febrile seizures plus (GEFS+) to severe Dravet syndrome (DS). Many variants are de novo, making early phenotype prediction difficult, and genotype- ... ...

Abstract	Objective: SCN1A variants are associated with epilepsy syndromes ranging from mild genetic epilepsy with febrile seizures plus (GEFS+) to severe Dravet syndrome (DS). Many variants are de novo, making early phenotype prediction difficult, and genotype-phenotype associations remain poorly understood. Methods: We assessed data from a retrospective cohort of 1018 individuals with SCN1A-related epilepsies. We explored relationships between variant characteristics (position, in silico prediction scores: Combined Annotation Dependent Depletion (CADD), Rare Exome Variant Ensemble Learner (REVEL), SCN1A genetic score), seizure characteristics, and epilepsy phenotype. Results: DS had earlier seizure onset than other GEFS+ phenotypes (5.3 vs. 12.0 months, p < .001). In silico variant scores were higher in DS versus GEFS+ (p < .001). Patients with missense variants in functionally important regions (conserved N-terminus, S4-S6) exhibited earlier seizure onset (6.0 vs. 7.0 months, p = .003) and were more likely to have DS (280/340); those with missense variants in nonconserved regions had later onset (10.0 vs. 7.0 months, p = .036) and were more likely to have GEFS+ (15/29, χ Significance: Understanding genotype-phenotype associations in SCN1A-related epilepsies is critical for early diagnosis and management. We demonstrate an earlier disease onset in patients with missense variants in important functional regions, the occurrence of GEFS+ truncating variants, and the value of in silico prediction scores. Status epilepticus as initial seizure type is a highly specific, but not sensitive, early feature of DS.
MeSH term(s)	Humans ; Retrospective Studies ; NAV1.1 Voltage-Gated Sodium Channel/genetics ; Epilepsy/genetics ; Epilepsy/diagnosis ; Epilepsies, Myoclonic/genetics ; Seizures, Febrile/genetics ; Phenotype ; Genetic Association Studies ; Status Epilepticus ; Mutation/genetics
Chemical Substances	NAV1.1 Voltage-Gated Sodium Channel ; SCN1A protein, human
Language	English
Publishing date	2024-02-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	216382-2
ISSN	1528-1167 ; 0013-9580
ISSN (online)	1528-1167
ISSN	0013-9580
DOI	10.1111/epi.17882
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Article ; Online: Dravet syndrome and its mimics: Beyond SCN1A.

Steel, Dora / Symonds, Joseph D / Zuberi, Sameer M / Brunklaus, Andreas

Epilepsia

2017 Volume 58, Issue 11, Page(s) 1807–1816

Abstract: Objective: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by the onset of prolonged febrile and afebrile seizures in infancy, and evolving to drug-resistant epilepsy with accompanying cognitive, behavioral, and ...

Abstract	Objective: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by the onset of prolonged febrile and afebrile seizures in infancy, and evolving to drug-resistant epilepsy with accompanying cognitive, behavioral, and motor impairment. Most cases are now known to be caused by pathogenic variants in the sodium channel gene SCN1A, but several other genes have also been implicated. This review examines current understanding of the role of non-SCN1A genes in DS, and what is known about phenotypic similarities and differences. We discuss whether these are best thought of as minority causes of DS, or as similar but distinct conditions. Methods: Based on a review of literature, a list of genes linked to DS was compiled and PubMed was searched for reports of DS-like phenotypes arising from variants in each. Online Mendelian Inheritance in Man (OMIM) was used to identify further reports relevant to each gene. Results: Genes that have been reported to cause DS-like phenotypes include SCN2A, SCN8A, SCN9A, SCN1B, PCDH19, GABRA1, GABRG2, STXBP1, HCN1, CHD2, and KCNA2. Many of these genes, however, appear to be associated with their own, different, clinical picture. Other candidate genes for DS have been reported, but there is currently an insufficient body of literature to support their causative role. Significance: Although most cases of DS arise from SCN1A variants, numerous other genes cause encephalopathies that are clinically similar. Increasingly, a tendency is noted to define newly described epileptic disorders primarily in genetic terms, with clinical features being linked to genotypes. As genetic diagnosis becomes more readily available, its potential to guide pathophysiologic understanding and therapeutic strategy cannot be ignored. Clinical assessment remains essential; the challenge now is to develop a gene-based taxonomy that complements traditional syndromic classifications, allowing elements of both to inform new approaches to treatment.
MeSH term(s)	Epilepsies, Myoclonic/diagnosis ; Epilepsies, Myoclonic/genetics ; Humans ; Mutation/genetics ; NAV1.1 Voltage-Gated Sodium Channel/genetics ; NAV1.2 Voltage-Gated Sodium Channel/genetics ; NAV1.6 Voltage-Gated Sodium Channel/genetics ; Phenotype ; Receptors, GABA-A/genetics
Chemical Substances	GABRA1 protein, human ; NAV1.1 Voltage-Gated Sodium Channel ; NAV1.2 Voltage-Gated Sodium Channel ; NAV1.6 Voltage-Gated Sodium Channel ; Receptors, GABA-A ; SCN1A protein, human ; SCN2A protein, human ; SCN8A protein, human
Language	English
Publishing date	2017-11
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	216382-2
ISSN	1528-1167 ; 0013-9580
ISSN (online)	1528-1167
ISSN	0013-9580
DOI	10.1111/epi.13889
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