SCN2A and Its Related Epileptic Phenotypes

2021 ◽  
Author(s):  
Andrea D. Praticò ◽  
Alessandro Giallongo ◽  
Marta Arrabito ◽  
Silvia D'Amico ◽  
Maria Cristina Gauci ◽  
...  
Keyword(s):  
De Novo ◽  
Wide Spectrum ◽  
Epileptic Encephalopathy ◽  
Pathogenic Variant ◽  
Channel Blockers ◽  
Epileptic Encephalopathies ◽  
Ohtahara Syndrome ◽  
Affected Parent ◽  
Environmental Causes ◽  
Almost All

AbstractEpilepsies due to SCN2A mutations can present with a broad range of phenotypes that are still not fully understood. Clinical characteristics of SNC2A-related epilepsy may vary from neonatal benign epilepsy to early-onset epileptic encephalopathy, including Ohtahara syndrome and West syndrome, and epileptic encephalopathies occurring at later ages (usually within the first 10 years of life). Some patient may present with intellectual disability and/or autism or movement disorders and without epilepsy. The heterogeneity of the phenotypes associated to such genetic mutations does not always allow the clinician to address his suspect on this gene. For this reason, diagnosis is usually made after a multiple gene panel examination through next generation sequencing (NGS) or after whole exome sequencing (WES) or whole genome sequencing (WGS). Subsequently, confirmation by Sanger sequencing can be obtained. Mutations in SCN2A are inherited as an autosomal dominant trait. Most individuals diagnosed with SCN2A–benign familial neonatal-infantile seizures (BFNIS) have an affected parent; however, hypothetically, a child may present SCN2A-BNFNIS as the result of a de novo pathogenic variant. Almost all individuals with SCN2A and severe epileptic encephalopathies have a de novo pathogenic variant. SNC2A-related epilepsies have not shown a clear genotype–phenotype correlation; in some cases, a same variant may lead to different presentations even within the same family and this could be due to other genetic factors or to environmental causes. There is no “standardized” treatment for SCN2A-related epilepsy, as it varies in relation to the clinical presentation and the phenotype of the patient, according to its own gene mutation. Treatment is based mainly on antiepileptic drugs, which include classic wide-spectrum drugs, such as valproic acid, levetiracetam, and lamotrigine. However, specific agents, which act directly modulating the sodium channels activity (phenytoin, carbamazepine, oxcarbamazepine, lamotrigine, and zonisamide), have shown positive result, as other sodium channel blockers (lidocaine and mexiletine) or even other drugs with different targets (phenobarbital).

SCN8A and Its Related Epileptic Phenotypes

2021 ◽  
Author(s):  
Andrea Praticò ◽  
Carmela Gulizia ◽  
Gloria Gangi ◽  
Claudia Oliva ◽  
Catia Romano ◽  
...  
Keyword(s):  
De Novo ◽  
Wide Spectrum ◽  
Single Gene ◽  
Great Majority ◽  
Epileptic Encephalopathy ◽  
Specific Gene ◽  
Channel Blockers ◽  
Germline Mosaicism ◽  
Pathogenic Variants ◽  
Genetic Epilepsies

AbstractSodium channelopathies are among the most common single-gene causes of epilepsy and have been considered model disorders for the study of genetic epilepsies. Epilepsies due to SCN8A pathogenic variants can present with a broad range of phenotypes varying from a severe epileptic encephalopathy with multiple types of drug-resistant seizure to neurodevelopmental delay, mental retardation, and electroencephalogram (EEG) findings of multifocal spike and waves (mostly in the temporal/parietal/occipital areas). In rare cases, benign familial infantile seizures and developmental delay with/without ataxia have been reported. A first-level, specific SCN8A Sanger's sequencing, although available, is rarely performed because the clinical phenotype is not strictly characteristic and several overlaps with other genetic epilepsies may occur. Given its indistinctive phenotype, diagnosis is usually performed through a specific gene panel for epileptic encephalopathies, early epilepsies, or genetic epilepsy in general, or through whole exome sequencing (WES) and more rarely through whole genome sequencing (WGS). Mutations in SCN8A occur as an autosomal dominant trait. The great majority of individuals diagnosed with SCN8A epilepsy do not have an affected parent, because usually SCN8A patients do not reproduce, and mutations are inherited as a “de novo” trait. In rare cases, SCN8A mutations may be inherited in the setting of parental germline mosaicism. SCN8A-related epilepsies have not shown a clear genotype–phenotype correlation, the same variants have been described with different clinical expressivity and this could be due to other genetic factors or to interacting environmental factors. There is no standardized treatment for SCN8A-related epilepsy because of the rarity of the disease and the unavailability of specific, targeted drugs. Treatment is based mainly on antiepileptic drugs which include classic wide-spectrum drugs such as valproic acid, levetiracetam, and lamotrigine. Sodium-channel blockers (phenytoin, carbamazepine, oxcarbazepine, and lamotrigine) have shown appreciable results in terms of seizure reduction, in particular, in patients presenting gain-of-function mutations. Nowadays, new potentially transformative gene therapy treatment approaches are currently being explored, allowing in the next future, a precision-based treatment directed against the gene defect and protein alterations.

Beneficial effects of the ketogenic diet on drug-resistant epileptic encephalopathy associated with a de novo NBEA pathogenic variant

2021 ◽  
Vol 23 (5) ◽  
pp. 739-743
Author(s):  
Silvia Schiavoni ◽  
Carlotta Spagnoli ◽  
Susanna Rizzi ◽  
Grazia Gabriella Salerno ◽  
Daniele Frattini ◽  
...  
Keyword(s):  
Ketogenic Diet ◽  
De Novo ◽  
Epileptic Encephalopathy ◽  
Pathogenic Variant ◽  
Drug Resistant ◽  
Beneficial Effects

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 A Novel Heterozygous Missense Variant in YWHAG Gene Cause Early-Onset Epilepsy in a Chinese Family

2020 ◽  
Author(s):  
Zhi Yi ◽  
Zhenfeng Song ◽  
Jiao Xue ◽  
Chengqing Yang ◽  
Fei Li ◽  
...  
Keyword(s):  
Early Onset ◽  
Seizure Control ◽  
De Novo ◽  
Missense Variant ◽  
Epileptic Encephalopathy ◽  
Chinese Family ◽  
Gene Variants ◽  
Case Presentation ◽  
Epileptic Encephalopathies ◽  
Refractory Seizures

Abstract Background: Developmental and epileptic encephalopathies (DEE) are a heterogeneous group of severe disorders which are characterized by early-onset, refractory seizures and developmental slowing or regression. Genetic variations are significant causes for them. De novo variants in an increasing number of candidate genes have been found to be causal. YWHAG gene variants have been reported to cause developmental and epileptic encephalopathy 56 (DEE56). Case presentation: Here, we report a novel heterozygous missense variant c.170G>A (p.R57H) in YWHAG gene cause early-onset epilepsy in a Chinese family. Both the proband and his mother exhibit early onset seizures, intellectual disability, developmental delay. While the proband achieve seizure control with sodium valproate, his mother's seizures were not well controlled. Conclusions: Our report further confirming the haploinsufficiency of YWHAG results in developmental and epileptic encephalopathies.

Cyclin-Dependent Kinase-Like 5 (CDKL5) Mutation Screening in Rett Syndrome and Related Disorders

2010 ◽  
Vol 13 (2) ◽  
pp. 168-178 ◽  
Author(s):  
Rose White ◽  
Gladys Ho ◽  
Swetlana Schmidt ◽  
Ingrid E. Scheffer ◽  
Alexandra Fischer ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Early Onset ◽  
De Novo ◽  
Wide Spectrum ◽  
Neurodevelopmental Disorder ◽  
Mutation Screening ◽  
Clinical Manifestations ◽  
Epileptic Encephalopathy ◽  
Cyclin Dependent Kinase ◽  
Aicardi Syndrome

AbstractRett syndrome (RTT) is a severe neurodevelopmental disorder affecting females almost exclusively and is characterized by a wide spectrum of clinical manifestations. Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene have been found in up to 95% of classical RTT cases and a lesser proportion of atypical cases. Recently, mutations in another X-linked gene, CDKL5 (cyclin-dependent kinase-like 5) have been found to cause atypical RTT, in particular the early onset seizure (Hanefeld variant) and one female with autism. In this study we screened several cohorts of children for CDKL5 mutations, totaling 316 patients, including individuals with a clinical diagnosis of RTT but who were negative for MECP2 mutations (n = 102), males with X-linked mental retardation (n = 9), patients with West syndrome (n = 52), patients with autism (n = 59), patients with epileptic encephalopathy (n = 33), patients with Aicardi syndrome (n = 7) and other patients with intellectual disability with or without seizures (n = 54). In all, seven polymorphic variations and four de novo mutations (c.586C>T [p.S196L]; c.58G>C [p.G20R]; c.2504delC [p.P835fs]; deletion of exons 1 - 3) were identified, and in all instances of the latter the clinical phenotype was that of an epileptic encephalopathy. These results suggest that pathogenic CDKL5 mutations are unlikely to be identified in the absence of severe early-onset seizures and highlight the importance of screening for large intragenic and whole gene deletions.

De novo pathogenic variants in neuronal differentiation factor 2 (NEUROD2) cause a form of early infantile epileptic encephalopathy

2018 ◽  
Vol 56 (2) ◽  
pp. 113-122 ◽  
Author(s):  
Annalisa G Sega ◽  
Emily K Mis ◽  
Kristin Lindstrom ◽  
Saadet Mercimek-Andrews ◽  
Weizhen Ji ◽  
...  
Keyword(s):  
Genome Editing ◽  
Candidate Genes ◽  
Neuronal Differentiation ◽  
Protein Function ◽  
De Novo ◽  
Single Gene ◽  
Epileptic Encephalopathy ◽  
Epileptic Encephalopathies ◽  
Differentiation Factor

BackgroundEarly infantile epileptic encephalopathies are severe disorders consisting of early-onset refractory seizures accompanied often by significant developmental delay. The increasing availability of next-generation sequencing has facilitated the recognition of single gene mutations as an underlying aetiology of some forms of early infantile epileptic encephalopathies.ObjectivesThis study was designed to identify candidate genes as a potential cause of early infantile epileptic encephalopathy, and then to provide genetic and functional evidence supporting patient variants as causative.MethodsWe used whole exome sequencing to identify candidate genes. To model the disease and assess the functional effects of patient variants on candidate protein function, we used in vivo CRISPR/Cas9-mediated genome editing and protein overexpression in frog tadpoles.ResultsWe identified novel de novo variants in neuronal differentiation factor 2 (NEUROD2) in two unrelated children with early infantile epileptic encephalopathy. Depleting neurod2 with CRISPR/Cas9-mediated genome editing induced spontaneous seizures in tadpoles, mimicking the patients’ condition. Overexpression of wild-type NEUROD2 induced ectopic neurons in tadpoles; however, patient variants were markedly less effective, suggesting that both variants are dysfunctional and likely pathogenic.ConclusionThis study provides clinical and functional support for NEUROD2 variants as a cause of early infantile epileptic encephalopathy, the first evidence of human disease caused by NEUROD2 variants.

scholarly journals De novo SCN8A and inherited rare CACNA1H variants associated with severe developmental and epileptic encephalopathy

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Robin N. Stringer ◽  
Bohumila Jurkovicova-Tarabova ◽  
Ivana A. Souza ◽  
Judy Ibrahim ◽  
Tomas Vacik ◽  
...  
Keyword(s):  
Ion Channel ◽  
De Novo ◽  
Epileptic Encephalopathy ◽  
Gene Encoding ◽  
Epileptic Encephalopathies ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Whole Exome ◽  
Heterozygous Variant

AbstractDevelopmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies that are characterized by seizures and developmental delay. DEEs are primarily attributed to genetic causes and an increasing number of cases have been correlated with variants in ion channel genes. In this study, we report a child with an early severe DEE. Whole exome sequencing showed a de novo heterozygous variant (c.4873–4881 duplication) in the SCN8A gene and an inherited heterozygous variant (c.952G > A) in the CACNA1H gene encoding for Nav1.6 voltage-gated sodium and Cav3.2 voltage-gated calcium channels, respectively. In vitro functional analysis of human Nav1.6 and Cav3.2 channel variants revealed mild but significant alterations of their gating properties that were in general consistent with a gain- and loss-of-channel function, respectively. Although additional studies will be required to confirm the actual pathogenic involvement of SCN8A and CACNA1H, these findings add to the notion that rare ion channel variants may contribute to the etiology of DEEs.

SLC25A22 and Its Related Epileptic Encephalopathies

2021 ◽  
Author(s):  
Francesca Patanè ◽  
Elisa Pasquetti ◽  
Federica Sullo ◽  
Monica Tosto ◽  
Laura Sciuto ◽  
...  
Keyword(s):  
Epileptic Encephalopathy ◽  
Epileptic Encephalopathies ◽  
Psychomotor Delay ◽  
Brain Functions ◽  
Ohtahara Syndrome ◽  
Inherited Metabolic Disorders ◽  
Solute Carrier ◽  
Disease Modifying Treatment ◽  
Myoclonic Encephalopathy ◽  
Migrating Partial Seizures

AbstractEpileptic encephalopathy is a condition in which seizures, electroencephalographic epileptiform abnormalities lead to a progressive deterioration of brain functions causing a significant psychomotor delay. One of the typical features of this heterogeneous and large group of severe disorders is the extremely early onset of seizures. The main causes of the epileptic encephalopathies include structural brain defects, inherited metabolic disorders; in this aspect, more than 100 genetic defects, including mutations in the solute carrier family 25 (SLC25A22) gene which encodes a mitochondrial glutamate carrier. To date, the main clinical phenotypes related to mutations of this gene are Ohtahara syndrome (or early infantile epileptic encephalopathy), early myoclonic encephalopathy and migrating partial seizures in infancy. In all the cases, prognosis is poor and no disease-modifying treatment is available in the present days.

scholarly journals Case Report: Causative De novo Variants of KCNT2 for Developmental and Epileptic Encephalopathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Pan Gong ◽  
Xianru Jiao ◽  
Dan Yu ◽  
Zhixian Yang
Keyword(s):  
De Novo ◽  
Gene Mutations ◽  
Epileptic Encephalopathy ◽  
Infantile Spasms ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Dysmorphic Features ◽  
Pathogenic Variants ◽  
Ohtahara Syndrome ◽  
Whole Exome

Objective:KCNT2 gene mutations had been described to cause developmental and epileptic encephalopathies (DEEs). In this study, we presented the detailed clinical features and genetic analysis of two unrelated patients carrying two de novo variants in KCNT2 and reviewed eight different cases available in publications.Methods: Likely pathogenic variants were identified by whole exome sequencing; clinical data of the patients were retrospectively collected and analyzed.Results: Our two unrelated patients were diagnosed with Ohtahara syndrome followed by infantile spasms (IS) and possibly the epilepsy of infancy with migrating focal seizures (EIMFS), respectively. They both manifested dysmorphic features with hirsute arms, thick hair, prominent eyebrows, long and thick eyelashes, a broad nasal tip, and short and smooth philtrum. In the eight patients reported previously, two was diagnosed with IS carrying a ‘change-of-function' mutation and a gain-of-function mutation, respectively, two with EIMFS-like carrying a gain-of-function mutation and a loss-of-function mutation, respectively, one with EIMFS carrying a loss-of-function mutation, three with DEE without functional analysis. Among them, two patients with gain-of-function mutations both exhibited dysmorphic features and presented epilepsy phenotype, which was similar to our patients.Conclusion: Overall, the most common phenotypes associated with KCNT2 mutation were IS and EIMFS. Epilepsy phenotype associated with gain- and loss-of-function mutations could overlap. Additional KCNT2 cases will help to make genotype-phenotype correlations clearer.

scholarly journals Heterozygous variants in KMT2E cause a spectrum of neurodevelopmental disorders and epilepsy

2019 ◽  
Author(s):  
Anne H O'Donnell-Luria ◽  
Lynn S Pais ◽  
Victor Faundes ◽  
Jordan C Wood ◽  
Abigail Sveden ◽  
...  
Keyword(s):  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Epileptic Encephalopathy ◽  
Dominant Negative ◽  
Mild Intellectual Disability ◽  
Negative Effects ◽  
Missense Variants ◽  
Neurodevelopmental Abnormalities ◽  
Almost All ◽  
Gastrointestinal Abnormalities

We delineate a KMT2E gene-related neurodevelopmental disorder based on 38 individuals in 36 families. This includes 31 distinct heterozygous variants in the KMT2E gene (28 ascertained from Matchmaker Exchange and 3 previously reported), and 4 individuals with chromosome 7q22.2-22.23 microdeletions encompassing the KMT2E gene (1 previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants, and was responsive to treatment with anti-epileptic medications in almost all. Over 70% of the individuals were male and expressivity was variable by sex, with epilepsy more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant negative effects specific to these missense variants in KMT2E may explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

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