Potential etiology-specific drugs (“precision medicine”) that are currently used or discussed for treatment of severe pediatric-onset epilepsies

Drugs are listed according to mutated genes. For a source of references, please refer to Wang et al. (2017) and Mesraoua et al. (2019). Note that mutations of the same gene may result in different clinical phenotypes, as recently shown for KCNQ2 mutation, in which the majority of patients have loss-of-function mutations but a small percentage have gain-of-function mutations associated with a different phenotype (Demarest and Brooks-Kayal, 2018). Except for everolimus in TSC-associated focal epilepsy and for cannabidiol and fenfluramine in Dravet syndrome, none of the treatments listed in this table have been validated in randomized controlled trials in patients with the indicated mutations, and for some of these treatments, evidence for efficacy is speculative or controversial, with most entries being anecdotal or in fact not “precision” (see comments). Clinicians should not consider this table as constituting support for treatment with these agents.

Mutated geneGene nameEncoded protein functionType of epilepsyPotentially beneficial therapyComments
CHRNA4Cholinergic receptor nicotinic alpha 4 subunitNicotinergic acetylcholine receptorNocturnal frontal lobe epilepsyZonisamide, acetazolamide, and nicotine patchesZonisamide and acetazolamide are not really “precision.” Nicotinergic agents are theoretically of possible use, but none have been proven to be of value currently
GRIN2AGlutamate ionotropic receptor N-methyl-D-aspartate (NMDA) type subunit 2AGlutamate (NMDA) receptorFocal epilepsy and speech disorder with or without mental retardationMemantineHas been proposed on the basis of two studies only, none published since 2015
KCNQ2Potassium voltage-gated channel subfamily Q member 2Potassium channelBenign familial neonatal seizures or, in infancy and childhood, EIEERetigabine/ezogabineHas in vitro evidence to support its use in gain-of-function mutants, but prospective controlled trials are still lacking
KCNT1Potassium sodium-activated channel subfamily T member 1Potassium channelEIEEQuinidineThe evidence is equivocal, with many negative reports after the initial reports of benefit
PCDH19Protocadherin 19Cell adhesion moleculeEIEEPotassium bromide, clobazamOnly anecdotal evidence. Better rationale for hormonal treatment with allopregnanolone.
PLCB1Phospholipase C beta 1EnzymeEIEEInositolNot any evidence for this in humans
PRRT2Proline-rich transmembrane protein 2UnclassifiedBenign familial infantile seizuresCarbamazepine, oxcarbazepineNot really precision (mechanism-based) treatments
SCN1ASodium voltage-gated channel alpha subunit 1Voltage-gated sodium channelDravet syndromeGABAergic drugs, fenfluramine, cannabidiolFenfluramine and cannabidiol cannot be considered precision (mechanism-based) treatments
SCN2ASodium voltage-gated channel alpha subunit 2Voltage-gated sodium channelBenign familial infantile seizures or EIEEHigh levels of phenytoin; levetiracetamNot yet clear whether levetiracetam can be considered precision (mechanism-based) treatment
SCN2ASodium voltage-gated channel alpha subunit 2Voltage-gated sodium channelEIEE, status epilepticusLidocaine, acetazolamideEvidence for precision (mechanism-based) treatment status limited
SCN8ASodium voltage-gated channel alpha subunit 8Voltage-gated sodium channelBenign familial infantile seizures or EIEEHigh levels of phenytoin or carbamazepine; amitriptyline, nilvadipine, carvedilolBased on one study for one mutation in SCN8A
SLC2A1Solute carrier family 2 member 1TransporterIdiopathic generalized epilepsyKetogenic dietBypasses the pathophysiology to provide an alternative energy supply to the brain
STXBP1Syntaxin-binding protein 1Membrane traffickingEIEELevetiracetam, folinic acid, vigabatrinOnly anecdotal evidence
TSC1 and 2TSC (tuberous sclerosis complex) subunits 1 and 2Unclassified; mutations lead to increased activity of mTORTuberous sclerosisEverolimusA precision treatment with support from clinical trials and licensed for particular uses in tuberous sclerosis complex
  • EIEE, early infantile epileptic encephalopathy.