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 gene | Gene name | Encoded protein function | Type of epilepsy | Potentially beneficial therapy | Comments |
|---|---|---|---|---|---|
| CHRNA4 | Cholinergic receptor nicotinic alpha 4 subunit | Nicotinergic acetylcholine receptor | Nocturnal frontal lobe epilepsy | Zonisamide, acetazolamide, and nicotine patches | Zonisamide and acetazolamide are not really “precision.” Nicotinergic agents are theoretically of possible use, but none have been proven to be of value currently |
| GRIN2A | Glutamate ionotropic receptor N-methyl-D-aspartate (NMDA) type subunit 2A | Glutamate (NMDA) receptor | Focal epilepsy and speech disorder with or without mental retardation | Memantine | Has been proposed on the basis of two studies only, none published since 2015 |
| KCNQ2 | Potassium voltage-gated channel subfamily Q member 2 | Potassium channel | Benign familial neonatal seizures or, in infancy and childhood, EIEE | Retigabine/ezogabine | Has in vitro evidence to support its use in gain-of-function mutants, but prospective controlled trials are still lacking |
| KCNT1 | Potassium sodium-activated channel subfamily T member 1 | Potassium channel | EIEE | Quinidine | The evidence is equivocal, with many negative reports after the initial reports of benefit |
| PCDH19 | Protocadherin 19 | Cell adhesion molecule | EIEE | Potassium bromide, clobazam | Only anecdotal evidence. Better rationale for hormonal treatment with allopregnanolone. |
| PLCB1 | Phospholipase C beta 1 | Enzyme | EIEE | Inositol | Not any evidence for this in humans |
| PRRT2 | Proline-rich transmembrane protein 2 | Unclassified | Benign familial infantile seizures | Carbamazepine, oxcarbazepine | Not really precision (mechanism-based) treatments |
| SCN1A | Sodium voltage-gated channel alpha subunit 1 | Voltage-gated sodium channel | Dravet syndrome | GABAergic drugs, fenfluramine, cannabidiol | Fenfluramine and cannabidiol cannot be considered precision (mechanism-based) treatments |
| SCN2A | Sodium voltage-gated channel alpha subunit 2 | Voltage-gated sodium channel | Benign familial infantile seizures or EIEE | High levels of phenytoin; levetiracetam | Not yet clear whether levetiracetam can be considered precision (mechanism-based) treatment |
| SCN2A | Sodium voltage-gated channel alpha subunit 2 | Voltage-gated sodium channel | EIEE, status epilepticus | Lidocaine, acetazolamide | Evidence for precision (mechanism-based) treatment status limited |
| SCN8A | Sodium voltage-gated channel alpha subunit 8 | Voltage-gated sodium channel | Benign familial infantile seizures or EIEE | High levels of phenytoin or carbamazepine; amitriptyline, nilvadipine, carvedilol | Based on one study for one mutation in SCN8A |
| SLC2A1 | Solute carrier family 2 member 1 | Transporter | Idiopathic generalized epilepsy | Ketogenic diet | Bypasses the pathophysiology to provide an alternative energy supply to the brain |
| STXBP1 | Syntaxin-binding protein 1 | Membrane trafficking | EIEE | Levetiracetam, folinic acid, vigabatrin | Only anecdotal evidence |
| TSC1 and 2 | TSC (tuberous sclerosis complex) subunits 1 and 2 | Unclassified; mutations lead to increased activity of mTOR | Tuberous sclerosis | Everolimus | A precision treatment with support from clinical trials and licensed for particular uses in tuberous sclerosis complex |
EIEE, early infantile epileptic encephalopathy.