A multi-disciplinary clinic for SCN8A-related epilepsy

Schreiber, John M.; Tochen, Laura; Brown, Mackenzie; Evans, Sarah Helen; Ball, Laura J.; Bumbut, Adrian; Thewamit, Rapeepat; Whitehead, Matthew T.; Black, Chelsea L.; Boutzoukas, Emanuel M.; Fanto, Eleanor J.; Suslovic, William; Berl, Madison M.; Hammer, Michael F.; Gaillard, William D.

doi:10.1016/j.eplepsyres.2019.106261

Cited by 24 publications

(53 citation statements)

References 46 publications

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“…A total of 49 studies on 27 genes satisfied the inclusion criteria. We identified more than one paper for eight genes: ATP1A3 (one case series [13], one case report [14]); GNAO1 (four original articles [15][16][17][18], one case report [19]); KCNQ2 (two original articles [20,21], one case series [22], two case reports [23,24]); SCN8A (three original articles [6,25,26], two case reports [27,28]); SLC13A5 (two original articles [29,30]); STXBP1 (two original articles [31,32], one case series [33], one case report [34]); SCN2A (three original articles [35][36][37] and two case reports [38,39]); and SYNJ1 (one original article [40] and one case report [41]).…”

Section: Genetic Resultsmentioning

confidence: 99%

“…The main seizure types at onset include "focal" (30 patients, 14 with clonic seizures), tonic (24), epileptic spasms (ES) (14), and myoclonic (10) [6,15,[17][18][19]22,[25][26][27][28][31][32][33][34][35]39,[42][43][44][45][46][47][48][49][50][51][52][53][54][55][56]. Thirteen patients had tonic-clonic seizures [6,15,16,26,33,54,56,57], twelve had subtle seizures [19,29,30,36,38,39,41,44,46,54,…”

Section: Genetic Resultsmentioning

confidence: 99%

“…SCN8A (sodium channel, voltage-gated, type VIII, alpha subunit): Neonatal-onset epilepsy with associated MD was reported in 1/22 [6], 1/19 [25] and 2/17 [26] cases, respectively. Seizure types are described as tonic with/without apnea, spasms, but also focal clonic.…”

Section: Channelopathiesmentioning

confidence: 99%

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Genetic Neonatal-Onset Epilepsies and Developmental/Epileptic Encephalopathies with Movement Disorders: A Systematic Review

Spagnoli

Fusco

Leuzzi

et al. 2021

IJMS

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Despite expanding next generation sequencing technologies and increasing clinical interest into complex neurologic phenotypes associating epilepsies and developmental/epileptic encephalopathies (DE/EE) with movement disorders (MD), these monogenic conditions have been less extensively investigated in the neonatal period compared to infancy. We reviewed the medical literature in the study period 2000–2020 to report on monogenic conditions characterized by neonatal onset epilepsy and/or DE/EE and development of an MD, and described their electroclinical, genetic and neuroimaging spectra. In accordance with a PRISMA statement, we created a data collection sheet and a protocol specifying inclusion and exclusion criteria. A total of 28 different genes (from 49 papers) leading to neonatal-onset DE/EE with multiple seizure types, mainly featuring tonic and myoclonic, but also focal motor seizures and a hyperkinetic MD in 89% of conditions, with neonatal onset in 22%, were identified. Neonatal seizure semiology, or MD age of onset, were not always available. The rate of hypokinetic MD was low, and was described from the neonatal period only, with WW domain containing oxidoreductase (WWOX) pathogenic variants. The outcome is characterized by high rates of associated neurodevelopmental disorders and microcephaly. Brain MRI findings are either normal or nonspecific in most conditions, but serial imaging can be necessary in order to detect progressive abnormalities. We found high genetic heterogeneity and low numbers of described patients. Neurological phenotypes are complex, reflecting the involvement of genes necessary for early brain development. Future studies should focus on accurate neonatal epileptic phenotyping, and detailed description of semiology and time-course, of the associated MD, especially for the rarest conditions.

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Section: Genetic Resultsmentioning

confidence: 99%

Section: Genetic Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Genetic Neonatal-Onset Epilepsies and Developmental/Epileptic Encephalopathies with Movement Disorders: A Systematic Review

Spagnoli

Fusco

Leuzzi

et al. 2021

IJMS

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“…This (Vanoye et al, 2014) *Non genetic origin mutations reported: Mutations described through clinical diagnosis, but the mutation type (Mendelian or de novo) were not reported, mainly due to the lack of parents to perform genotyping and difficulty in contacting the family. DII (S1) Missense NR (Butler et al, 2017b;Hewson et al, 2018;Lindy et al, 2018;Costain et al, 2019;Johannesen et al, 2019) T767I DII (S1) Missense Decreased current density Increased current amplitude provokes by voltage ramp protocol (Estacion et al, 2014;Gardella et al, 2018;Lindy et al, (Fung et al, 2015;Zhang et al, 2015;Lindy et al, 2018;Kim et al, 2019;Tsang et al, 2019;Pan and Cummins, 2020;Schreiber et al, DIII (S6)-DIV (S1) Missense NR (Pons et al, 2018;Denis et al, 2019) G1475R DIII (S6)-DIV (S1) Missense Enhanced persistent current (Hussain et al, 2016;Ortiz Madinaveitia et al, 2017;Parrini et al, 2017;Wang et al, 2017a;Gardella et al, 2018;Lindy et al, 2018;Xiao et al, 2018;Kim et al, 2019;Trivisano et al, 2019;Zaman et al, 2019;Ranza et al, 2020;Schreiber et al, 2020) G1476S DIII (S6)-DIV (S1) Missense NR (Lindy et al, 2018) I1479V DIII (S6)-DIV (S1) Missense NR (Larsen et al, 2015;Lindy et al, 2018;Schreiber et al, 2020) E1483K DIII (S6)-DIV (S1) Missense NR (Johannesen et al, 20...…”

Section: Nav16mentioning

confidence: 99%

Epilepsy-Related Voltage-Gated Sodium Channelopathies: A Review

et al. 2020

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Epilepsy is a disease characterized by abnormal brain activity and a predisposition to generate epileptic seizures, leading to neurobiological, cognitive, psychological, social, and economic impacts for the patient. There are several known causes for epilepsy; one of them is the malfunction of ion channels, resulting from mutations. Voltage-gated sodium channels (NaV) play an essential role in the generation and propagation of action potential, and malfunction caused by mutations can induce irregular neuronal activity. That said, several genetic variations in NaV channels have been described and associated with epilepsy. These mutations can affect channel kinetics, modifying channel activation, inactivation, recovery from inactivation, and/or the current window. Among the NaV subtypes related to epilepsy, NaV1.1 is doubtless the most relevant, with more than 1500 mutations described. Truncation and missense mutations are the most observed alterations. In addition, several studies have already related mutated NaV channels with the electrophysiological functioning of the channel, aiming to correlate with the epilepsy phenotype. The present review provides an overview of studies on epilepsy-associated mutated human NaV1.1, NaV1.2, NaV1.3, NaV1.6, and NaV1.7.

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“…Loss-of-function mutations have been associated with intellectual disability and ataxia in humans. [16][17][18] Studies in larger populations affected by SCN8A-related disorders 9,19 have shown that mutations can be found in any part of the gene and they were found in the cytoplasmic loos, extracellular loops, and 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 precisionbased treatment directed against the gene defect and protein alterations.…”

Section: Geneticsmentioning

confidence: 99%

SCN8A and Its Related Epileptic Phenotypes

Praticò

Gulizia

Gangi

et al. 2021

Journal of Pediatric Neurology

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Sodium 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.

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A multi-disciplinary clinic for SCN8A-related epilepsy

Cited by 24 publications

References 46 publications

Genetic Neonatal-Onset Epilepsies and Developmental/Epileptic Encephalopathies with Movement Disorders: A Systematic Review

Genetic Neonatal-Onset Epilepsies and Developmental/Epileptic Encephalopathies with Movement Disorders: A Systematic Review

Epilepsy-Related Voltage-Gated Sodium Channelopathies: A Review

SCN8A and Its Related Epileptic Phenotypes

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