Genetics of epilepsy

Nolan, Danielle; Fink, John K.

doi:10.1016/b978-0-444-64076-5.00030-2

Cited by 33 publications

(25 citation statements)

References 133 publications

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“…Voltage‐gated sodium channels play a critical role in the production of action potentials and neuronal excitability in the brain, heart, and muscle; hence, deleterious gene variants encoding the subunits of these sodium channels are well known to cause epilepsy, in addition to Brugada syndrome and other cardiac conduction defects (Nolan & Fink, ; Watanabe et al, ). Voltage‐gated sodium channels are comprised of one alpha pore‐forming main subunit and one or two beta accessory subunits (Brackenbury, Djamgoz, & Isom, ; Catterall, ).…”

Section: Introductionmentioning

confidence: 99%

Developmental and epileptic encephalopathy in two siblings with a novel, homozygous missense variant in SCN1B

Darras

Rego

et al. 2019

American J of Med Genetics Pt A

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Developmental and epileptic encephalopathies are genetic disorders in which both the developmental disability and the frequent epileptic activity are the effect of a specific gene variant. While heterozygous variants in SCN1B have been described in families with generalized epilepsy with febrile seizures plus, Type 1, only three cases of homozygous, missense variants in SCN1B have been reported in association with autosomal recessive inheritance of a severe developmental and epileptic encephalopathy. We present two siblings who are homozygous for a novel, missense variant in SCN1B, c.265C>T, predicting p.Arg89Cys. The proband is an 11-year-old female with infantile-onset, fever-induced, intractable generalized tonic-clonic seizures, myoclonic seizures, and developmental slowing and autism spectrum disorder occurring later in the course of the disease. Her 4-year-old brother had a similar epilepsy phenotype, but still displays normal development. This variant has not been previously reported in the homozygous state in control databases. The variant was predicted to be damaging and occurred in the vicinity of other epileptic encephalopathy-associated missense variants that are biallelic and located in the extracellular immunoglobulin loop domain of the protein, which mediates interaction of the beta-1 subunit with cellular adhesion molecules. Our report is the first set of siblings with homozygosity for the p.Arg89Cys variant in SCN1B and further implicates biallelic mutations in this gene as a cause of epileptic encephalopathy mimicking Dravet syndrome. Interestingly, the phenotype we observed was milder compared to that previously described in patients with recessive SCN1B mutations. K E Y W O R D S developmental and epileptic encephalopathy, Dravet syndrome, SCN1B

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Section: Introductionmentioning

confidence: 99%

Developmental and epileptic encephalopathy in two siblings with a novel, homozygous missense variant in SCN1B

Darras

Rego

et al. 2019

American J of Med Genetics Pt A

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“…In the present study, we enrolled 141 pediatric epilepsy patients after excluding those affected by specific non‐genetic factors and used a targeted panel consisting of 480 genes known to be associated with epilepsy to identify causative variants. This gene panel used in this study included nearly 200 potential and suspected epilepsy‐associated genes that are currently not present in the Online Mendelian Inheritance in Man (OMIM) database but that have been reported in recent publications . Increasing our knowledge of these genes could broaden our understanding of the mechanisms underlying epilepsy and provide potential value for functional research and further verification studies.…”

Section: Introductionmentioning

confidence: 99%

“…This gene panel used in this study included nearly 200 potential and suspected epilepsy-associated genes that are currently not present in the Online Mendelian Inheritance in Man (OMIM) database but that have been reported in recent publications. 11,12 Increasing our knowledge of these genes could broaden our understanding of the mechanisms underlying epilepsy and provide potential value for functional research and further verification studies. We evaluated genotype-phenotype correlations and performed a follow-up study to explore the therapeutic effects and adjustments.…”

Section: Introductionmentioning

confidence: 99%

Genotype and phenotype analysis using an epilepsy‐associated gene panel in Chinese pediatric epilepsy patients

et al. 2018

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Epilepsy is a common and genetically heterogeneous disorder among children. Advances in next-generation sequencing have revealed that numerous epilepsy genes, helped us improve the understanding of mechanisms underlying epileptogenesis, and guided the development of treatments. We identified 39 candidate variants in 21 genes, including 37 that were pathogenic or likely pathogenic variants according to the American College of Medical Genetics and Genomics scoring system and two variants of uncertain significance that were considered causative after they were associated with clinical characteristics. Thirty were de novo variants (76.9%), and 20 variants had not previously been reported (51.3%). We obtained a diagnosis in 39 of the 141 probands (27.7%). The most frequently mutated gene was SCN1A; KCNQ2, KCNT1, PCDH19, STXBP1, SCN2A, TSC2, and PRRT2 were mutated in more than one individual; ANKRD11, CDKL5, DCX, DEPDC5, GABRB3, GRIN2A, IQSEC2, KCNA2, KCNB1, KCNJ6, TSC1, SCN9A, and SCN1B were mutated in a single individual. In addition, we detected a nonsense variant in a candidate gene KCND1 and considered it as a new candidate epilepsy gene, which needed further functional study. Consequently, large number of unreported variants were detected, diverse phenotypes were associated with known epilepsy genes. Changes in clinical management beyond genetic counseling were suggested.

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“…In some cases, the link between clinical manifestations and defective electrical properties is direct. In epilepsy, the prototypical ion channel-related disease (or "channelopathy"), mutations in specific classes of voltage-gated ion channels cause elevated spike probability at single neuron level and the occurrence of hypersynchronous activity [5]. Neurodegeneration may appear in advanced stages of the disease as a long-term consequence of exceeding glutamate release and N-methyl-D-aspartate (NMDA) receptor-mediated Ca 2+ overload on postsynaptic neurons, a phenomenon known as "excitotoxicity".…”

Section: Terminal Cell Death Mechanisms Activated By Ims-related Pathmentioning

confidence: 99%

Harnessing ionic mechanisms to achieve disease modification in neurodegenerative disorders

Masi

Narducci

Mannaioni

2019

Pharmacological Research

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Progressive neuronal death is the key pathogenic event leading to clinical symptoms in neurodegenerative disorders (NDDs). Neuroprotective treatments are virtually unavailable, partly because of the marked internal heterogeneity of the mechanisms underlying pathology. Targeted neuroprotection would require deep mechanistic knowledge across the entire aetiological spectrum of each NDD and the development of tailored treatments. Although ideal, this strategy appears challenging, as it would require a degree of characterization of both the disease and the patient that is currently unavailable. The alternate strategy is to search for commonalities across molecularly distinct NDD forms and exploit these for the development of drugs with broad-spectrum efficacy. In this view, mounting evidence points to ionic mechanisms (IMs) as targets with potential therapeutic efficacy across distinct NDD subtypes. The scope of this review is to present clinical and preclinical evidence supporting the link between disruption of IMs and neuronal death in specific NDDs and to critically revise past and ongoing attempts of harnessing IMs for the development of neuroprotective treatments.

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Genetics of epilepsy

Cited by 33 publications

References 133 publications

Developmental and epileptic encephalopathy in two siblings with a novel, homozygous missense variant in SCN1B

Developmental and epileptic encephalopathy in two siblings with a novel, homozygous missense variant in SCN1B

Genotype and phenotype analysis using an epilepsy‐associated gene panel in Chinese pediatric epilepsy patients

Harnessing ionic mechanisms to achieve disease modification in neurodegenerative disorders

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