Central nervous system: Paediatric and neurodevelopmental disorders
Angus Clarke, Alex Murray, Julian Sampson in Harper's Practical Genetic Counselling, 2019
Some forms of primary epilepsy have a major genetic contribution but only about 1% of epilepsy is Mendelian. Specific genes have not been recognised as strongly causal in common primary, generalised, ‘idiopathic’ epilepsy, which appears to have a complex causation to which the genetic contribution is usually oligogenic rather than monogenic. In contrast, many of the relevant genes have now been identified for some of the less common Mendelian types that are proving to be due to mutation in genes encoding ion-channel components, including SCN1A in Dravet syndrome. A wide range of autosomal dominant, usually de novo, gene mutations has been identified in the infantile epileptic encephalopathies, that overlap with the genes implicated in other severe neurodevelopmental disorders and with the cortical malformations (including neuronal migration disorders). A number of CNVs apparent on chromosome microarray studies – the neurosusceptibility loci, including deletions at 15q11.2, 15q13.3 and 16p13.11 – are associated with seizures, in addition to their association with cognitive problems, autistic spectrum disorders and schizophrenia.
Antiepileptic Drugs
Sahab Uddin, Rashid Mamunur in Advances in Neuropharmacology, 2020
Stiripentol is used clinically as an add-on therapy for Dravet syndrome (refractory generalized tonic–clonic seizures in patients with severe myoclonic epilepsy in infancy) in patients where valproate and clobazam are unable to control symptoms satisfactorily (Plosker, 2012; Aneja and Sharma, 2013). It is still not approved by USFDA for Dravet syndrome because of many pharmacokinetic and pharmacodynamic drug interactions (Misty et al., 2018). Stiripentol also decreases the severity and frequency of tonic–clonic seizures as well as status epilepticus with a variety of epilepsy syndromes in infants and children (Goossens et al., 1999; Perez et al., 1999; Inoue et al., 2009).
Achieving and Sustaining Precision Effects
Betty Wedman-St Louis in Cannabis as Medicine, 2019
Sample conditions that may benefit from a chemotype III include: AcneHeart diseaseIrritable bowel diseaseMental or mood disorders DepressionPsychosisAddictionAnxieties – Post-traumatic stress disorder (PTSD)– OCDSeizure disorders Epilepsy (pediatric and adult)Dravet syndromeLennox-Gastaut syndromeTuberous sclerosis complexInfantile spasms
Safety considerations selecting antiseizure medications for the treatment of individuals with Dravet syndrome
Published in Expert Opinion on Drug Safety, 2021
Rima Nabbout, N Chemaly, C Chiron, M. Kuchenbuch
Dravet syndrome is the archetypical genetic rare epilepsy. Seizures occur in a previously healthy infant and can be misdiagnosed after the first event with febrile seizures. Seizures quickly invade the everyday life of the child and the family, as unpredictable and prolonged events often evolving to status epilepticus occur during infancy and early childhood. To limit adverse events and to improve long-term outcome, practitioners must have a knowledge of DS to establish early diagnosis and to shape their treatment strategy between indicated and contra-indicated medicines. Indeed, practitioners have to consider market authorization, known adverse events, galenic form, and drug–drug interactions to best fit their prescription to patient’s characteristics and to evaluate the best benefit risk. In general, except in urgent situations, introduction of ASM must be very progressive with a short- and long-term evaluation of efficacy and safety of each ASM.
A critical evaluation of fenfluramine hydrochloride for the treatment of Dravet syndrome
Published in Expert Review of Neurotherapeutics, 2022
An-Sofie Schoonjans, Berten Ceulemans
Dravet Syndrome is primarily caused by de novo pathogenic variants in the voltage-gated sodium channel gene SCN1A. Mutations in other genes (among which PCDH19, SCN8A, GABRA1, STXBP1) have been described in DS patients but are rare in patients with a core phenotype [8]. Heterozygous loss of function of the SCN1A gene leads to an haploinsufficiency of the voltage-gated sodium channels Nav1.1, which are mainly expressed in GABAergic interneurons [9]. Since these inhibitory interneurons rely on Nav1.1 for action potential generation and propagation, the function of these inhibitory interneurons is impeded in DS patients, leading to an elevated excitation/inhibition ratio in forebrain structures [10] and a subsequent increase in the susceptibility to develop seizures. Despite the fact that recent studies showed only a transient impairment of the excitability of these interneurons with normalization over time, the interneurons are still dysfunctional with impaired synchronization (or desynchronization) preceding seizures in DS mouse models [11,12].
Advances in genetic testing and optimization of clinical management in children and adults with epilepsy
Published in Expert Review of Neurotherapeutics, 2020
Marcello Scala, Amedeo Bianchi, Francesca Bisulli, Antonietta Coppola, Maurizio Elia, Marina Trivisano, Dario Pruna, Tommaso Pippucci, Laura Canafoglia, Simona Lattanzi, Silvana Franceschetti, Carlo Nobile, Antonio Gambardella, Roberto Michelucci, Federico Zara, Pasquale Striano
Most cases of Dravet syndrome are caused by heterozygous loss-of-function variants in SCN1A, which encodes a voltage-gated sodium channel involved in the generation and propagation of action potential [142]. In these patients, the abnormal function of SCN1A in the inhibitory neurons generates an excitation/inhibition imbalance leading to epileptogenesis [143]. According to this pathogenic model, sodium channel blocking drugs (e.g., carbamazepine, lamotrigine, oxcarbazepine, and phenytoin) should be avoided in SCN1A-associated Dravet syndrome, since these drugs are usually ineffective or can actually worsen seizures [144,145]. These patients might instead benefit from new therapeutic strategies developed in the recent years, such as antisense oligonucleotides restoring SCN1A mRNA and peptides selectively activating the Nav1.1 channel in inhibitory interneurons (e.g., Hm1) [146,147].
Related Knowledge Centers
- Febrile Seizure
- Fever
- Genetic Testing
- Autosome
- Epilepsy
- Dominance
- Genetic Disorder
- Anticonvulsant
- Seizure
- Seizure Types