Heterozygous mutations in the genes KCNQ2 and SCN2A cause the two other autosomal dominant seizure disorders of infancy: benign familial neonatal epilepsy and benign familial neonatal-infantile epilepsy.
Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome.
In addition, we describe, for the first time, that some mutations impair channel regulation by syntaxin-1A, highlighting a novel pathogenetic mechanism for KCNQ2-related epilepsies.
The development of severe epilepsy and cognitive decline in children carrying 5 of the 7 studied KCNQ2 mutations can be related to a dominant-negative reduction of the resulting potassium current at subthreshold membrane potentials.
(1,2) There is recent recognition of de novo KCNQ2 mutations in patients with severe neonatal-onset epilepsy with intractable seizures and severe psychomotor impairment, termed KCNQ2 encephalopathy.
Examples of that include the need to avoid specific drugs in Dravet syndrome and the ongoing investigations of the potential use of new directed therapies such as retigabine in KCNQ2-related epilepsies, quinidine in KCNT1-related epilepsies, and memantine in GRIN2A-related epilepsies.
Mutations in Kv7.2 (KCNQ2) and Kv7.3 (KCNQ3) genes, encoding for voltage-gated K(+) channel subunits underlying the neuronal M-current, have been associated with a wide spectrum of early-onset epileptic disorders ranging from benign familial neonatal seizures to severe epileptic encephalopathies.
Mutations in the KCNQ2 gene encoding for voltage-gated potassium channel subunits have been found in patients affected with early onset epilepsies with wide phenotypic heterogeneity, ranging from benign familial neonatal seizures (BFNS) to epileptic encephalopathy with cognitive impairment, drug resistance, and characteristic electroencephalography (EEG) and neuroradiologic features.
Genetic or experience-dependent reduction of KCNQ2/3 channel activity is linked with disorders that are characterized by neuronal hyperexcitability, such as epilepsy and tinnitus.
Mutations in the KCNQ2 gene encoding the voltage-dependent potassium M channel Kv7.2 subunit cause either benign epilepsy or early onset epileptic encephalopathy (EOEE).
Kv7.2/Kv7.3 dysfunction resulting from KCNQ2 mutations predominantly causes self-limited or benign epilepsy in neonates, but also causes early onset epileptic encephalopathy.
We herein provide evidence for a new phenotypic and functional profile in KCNQ2-related epilepsy: infantile spasms without prior neonatal seizures associated with a gain-of-function gene variant.
We think that KCNQ2 associated epileptic encephalopathy should be included in the differential diagnosis of childhood onset epilepsy and early onset global developmental delay, cognitive dysfunction, or ID.
The potassium voltage-gated channel subfamily Q member 2 (KCNQ2) gene has been reported to be associated with various types of epilepsy, including benign familial neonatal seizure (BFNS), early infantile epileptic encephalopathy (EIEE), and unclassified early onset encephalopathies.
Over one hundred mutations in the Kv7.2 (KCNQ2) gene encoding for phosphatidylinositol 4,5-bisphosphate (PIP<sub>2</sub>)-sensitive voltage-gated K<sup>+</sup> channel subunits have been identified in early-onset epilepsies with wide phenotypic variability.
With the advances in understanding the molecular basis of many epilepsies, targeted therapies become available, for example for KCNQ2 mutation related epilepsies, Dravet syndrome or tuberous sclerosis complex.