Dravet syndrome as part of the clinical and genetic spectrum of sodium channel epilepsies and encephalopathies

Abstract

Dravet syndrome is the most studied form of genetic epilepsy. It has now been clarified that the clinical spectrum of the syndrome does not have firmly established boundaries. The core phenotype is characterized by intractable, mainly clonic, seizures precipitated by increased body temperature with onset in the first year of life and subsequent appearance of multiple seizures types still precipitated by, but not confined to, hyperthermia. Cognitive impairment is invariably present when the full syndrome is manifested. This complex of symptoms is related to mutations in the SCN1A gene, which are often de novo and constitutional but can also be inherited from a parent with less severe clinical manifestations or be present as somatic mosaicism. Inheritance from less severely affected individuals, at times only having experienced a few febrile seizures, and differences in severity, even within the same family, with a subset of patients only showing fragments of the syndrome, testify to a remarkable phenotypic heterogeneity as far as severity, but less so clinical phenomenology, are concerned. This characteristic, together with underascertainment of SCN1A mutations due to human errors or technical limitations in uncovering alternative pathogenic molecular mechanisms, such as genomic rearrangements or poison exons, has contributed to making clinicians and geneticists suspicious that Dravet syndrome may be caused by more than one gene. This opinion has been further amplified by the description of other genetic disorders, such as PCDH19-or CHD2-related epilepsy, whose phenotypes have included fragments of the Dravet phenotypic spectrum, and by the suboptimal characterization of phenotypes associated with mutations in SCN1B, HCN1, KCN2A, GABRA1, GABRG2, and STXBP1.

Developmentally-regulated impairment of parvalbumin interneuron synaptic transmission in an experimental model of Dravet syndrome

“…It is possible -and perhaps likely -that mice remaining alive represent a nonrandom subset of the initial population. It is well known that there is a spectrum of disease severity in Scn1a+/mice , similar to that observed in humans [Harkin et al, 2007, Mei et al, 2019, the basis of which is unclear but may involve genetic modifiers , Calhoun et al, 2017. This concern may pertain to any study involving an experimental animal model of a neurodevelopmental disorder associated with mortality.…”

Dravet Syndrome—The Polish Family’s Perspective Study

“…Over 150 mutations in the SCN1A gene have been described. Another form of epilepsy connected with SCN1A mutations, apart from DS, is epilepsy with febrile seizures plus and epilepsy of infancy with migrating focal seizures [ 1 , 2 , 3 , 4 ]. Familial hemiplegic migraine also may be caused by abnormalities within SCN1A gene [ 1 , 2 , 3 , 4 ].…”

“…About 75–85% of individuals affected by DS have loss-of-function mutations in the SCN1A gene encoding the sodium channel alpha subunit [ 2 ]. In SCN1A mutation negative patients with clinical similarity to DS, different genetic background is found, particularly the following gene mutations: PCDH19 , CHD2 , STXBP1 , HCN1 , GABRG2 , GABRA1 , and SCN1B [ 3 ].…”

Novel treatments in Epilepsy guided by Genetic Diagnosis

“…Precision medicine: novel treatment strategies developed from pathophysiological knowledge 3. Precision medicine: aetiology-based preventive treatments and in progress treatments Clinical-based evidence of known ASM modifying -either worsening or improving -seizure frequency One of the first and best example of how the identification of the underling genetic aetiology guides treatment is that of Dravet Syndrome (DS) the most renowned and studied developmental and epileptic encephalopathy (DEE) (Mei et al 2019). Well before the genetic cause was identified, some clinical reports indicated that sodium channel blockers including lamotrigine (LTG) and carbamazepine (CBZ) should be avoided in patients with DS since they have the potential to determine an increase in seizure frequency evolving to status epilepticus in some patients (Guerrini et al, 1998;de Lange et al 2018).…”

“…Well before the genetic cause was identified, some clinical reports indicated that sodium channel blockers including lamotrigine (LTG) and carbamazepine (CBZ) should be avoided in patients with DS since they have the potential to determine an increase in seizure frequency evolving to status epilepticus in some patients (Guerrini et al, 1998;de Lange et al 2018). Following the discovery that DS is associated to mutations of the alpha1 subunit of the sodium channel (SCN1A) possibly causing loss of channel function, the clinical evidence that the administration of sodium channel blockers made seizure worse was partly explained (Claes et al 2001;Mantegazza, Marini 2010;Mei et al 2019). Although complete seizure control is rarely attainable, clinical studies have shown that the combination of valproic acid (VPA), clobazam (CLB) and stiripentol (STP) is the most effective in preventing seizures especially avoiding the evolution into status epilepticus, frequently observed in infants with DS (Ceulemans et al 2004;Wirrel et al 2018, Wirrel andNabbout 2019).…”