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Prefrontal Inhibitory Signaling in the Control of Social Behaviors
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
The above discussed findings from human clinical studies suggest that impaired cortical inhibition is a key regulator in the pathogenesis of psychiatric disorders with shared social deficits. In line with those clinical findings, impaired inhibition in the cerebral cortex, the mPFC in particular, is routinely found in mouse models carrying genetic modifications known to cause autism in humans. For instance, mice with heterozygous loss-of-function mutations in the SCN1A gene (Scn1a+/−) have reduced Na+ currents and impaired action potential firing in GABAergic neurons and decreased inhibitory transmission in hippocampal CA1 and prefrontal cortex (Han et al. 2012). Similarly, the frequency of spontaneous GABAergic neurotransmission is significantly reduced in the hippocampus of BTBR mice, a model of idiopathic autism (Han et al. 2014). Also, in vitro patch-clamp recordings revealed decreased neuronal excitability in mPFC PV INs of neuroligin 3 R451C knockin mice (Cao et al. 2018), and major reductions in prefrontal synaptic inhibition in neuroligin-2 conditional knockout mice (Liang et al. 2015). In addition, compared to wild-type mice, the neural activity of mPFC PV INs was directly measured using fiber photometry and was found diminished in contactin-associated protein-like 2 (CNTNAP2) knockout mice during social interaction (Selimbeyoglu et al. 2017).
Hyperkinetic Movement Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Morales-Briceno Hugo, Victor S.C. Fung, Annu Aggarwal, Philip Thompson
Epileptic encephalopathies associated with chorea:28GNAO1 mutations.SCN1A-related phenotypic.FOXG1 mutations.SCN8A mutations.SCN2A-related disorders.UBA5 mutations.DNM1 mutations.FRRS1L mutations.GRIN1/GRIN2B/GRIN2D mutations.
Central nervous system: Paediatric and neurodevelopmental disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, 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.
Current and promising therapeutic options for Dravet syndrome
Published in Expert Opinion on Pharmacotherapy, 2022
Antonella Riva, Gianluca D’Onofrio, Elisabetta Amadori, Domenico Tripodi, Ganna Balagura, Valentina Iurilli, Maria Stella Vari, Alberto Verrotti, Pasquale Striano
Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy (DEE) with recurrent prolonged, febrile and afebrile, focal clonic or generalized clonic seizures which may later evolve to other seizure types [1–4]. Although there are few epidemiological data, the reported incidence of DS ranges from 1 in 15,700 to 1 in 40,000 live births [4–6]. DS patients commonly have seizure onset within the first year of life and show normal development before seizure onset; the diagnosis can be frequently delayed, even as late as 3 years of age, because it is made when all the clinical features emerge. Patients commonly have mild to severe intellectual disability, showing development slowing after the first year of life. Pathogenic variants in the SCN1A gene, encoding the α1 pore-forming subunit of the voltage-gated sodium channel (NaV1.1), are largely the primary genetic cause of the disease [7].
Novel and emerging therapeutics for genetic epilepsies
Published in Expert Review of Neurotherapeutics, 2021
Ana Pejčić, Slobodan M. Janković, Miralem Đešević, Refet Gojak, Snežana Lukić, Nenad Marković, Miloš Milosavljević
Trazodone (EPX-300) is an antidepressant approved by the FDA in 1981 for the treatment of major depressive disorders, that is also off-label used for the treatment of other psychiatric conditions, such as anxiety disorder, substance abuse, bulimia and insomnia [127]. Trazodone is a triazolopyridine derivate with a complex mechanism of action since it inhibits serotonin transporter, serotoninergic 5-HT2 receptors, histaminergic H1 receptors and alpha-1-adrenergic receptors [127]. In a preclinical in vivo study on scn1Lab mutant zebrafish model of Dravet syndrome in 2017 [95], trazodone showed significant concentration-dependent reduction of spontaneous convulsive behavior and electrographic seizures. The exact mechanism by which trazodone achieved the anticonvulsant effect is unknown, but it is most likely the result of amplification of serotonergic transmission in the brain [88]. The case of a 25-year-old woman with highly resistant Dravet syndrome-related epilepsy with a confirmed SCN1A mutation is also encouraging [128]. Trazodone was administered for insomnia, and after 3 months a significant clinical and neurophysiology improvement, with reduction of interictal epileptiform activity, myoclonic and tonic-clonic seizures, were observed [128]. It is known that in patients with depression, trazodone can cause serious adverse effects, such as orthostatic hypotension, torsades, priapism, and an increase in suicidal thoughts [127]. Therefore, the efficacy and safety of trazodone need to be tested in a phase II, randomized clinical trial, which is under preparation [10].
Fenfluramine hydrochloride for the treatment of Dravet syndrome
Published in Expert Opinion on Orphan Drugs, 2020
Blandine Dozières-Puyravel, Stéphane Auvin
The first report on the anticonvulsant effectiveness of fenfluramine in DS was published in Epilepsia 2012 [4]. Following a Royal Decree (KB 2002/22,215), the first investigation (an open add-on retrospective study) was conducted on 12 patients with DS aged 3–35 years, seven female and five male (five of these patients were previously reported [3]). Eleven patients had a SCN1A pathogenic variant [4]. Treatment duration ranged from 1 to 19 years. Fenfluramine was prescribed at a mean dose of 0.34 (0.12–0.9) mg/kg/day. Fenfluramine was prescribed in combination with other ASMs. All patients used valproate, and nine patients received three ASMs. In this study, seizure freedom was defined as the absence of seizure a year before the final visit. Add-on fenfluramine allowed seizure freedom for at least 1 year in seven patients. The mean seizure-free period was 6 years (range, 1–19 years). Seven patients discontinued the use of fenfluramine at least once during the study, resulting in seizure recurrence in three of them. However, seizure control was achieved again with fenfluramine reintroduction. Weight loss was observed in only two patients. The mean weight of the patients was below the 50th percentile in seven of twelve patients. Two of twelve patients had heart valve thickening without clinical significance [4].