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Orsini et al. J Transl Genet Genom 2018;2:16. I https://doi.org/10.20517/jtgg.2018.14 Page 7 of 18

Table 3. Precision therapy
Gene Pathology Therapy
SCN1A Dravet Syndrome Valproate, clobazam, stiripentol, fenfluramine
Recommended avoidance carbamazepine and phenytoin
Controversial recommendations: lamotrigine
SCN8A E KCNQ2 From benign familial seizures to severe form of Carbamazepine and phenytoin
epileptic encephalopathy early onset
KCNQ2-5 Retigabine
GRIN2A Early onset epileptic encephalopathy Memantine
KCNT1 Focal epileptic seizures Quinidine
POLG-epilepsies Recommended avoidance Valproate
Kosovan people of Albanian ethnicity and Chinese Affected carbamazepine pharmacokinetic
EPHX1
people with epilepsy
SCN1A, ABCC2, UGT2B7 Han Chinese people with epilepsy Affected maintenance dose of oxcarbazepine
Dysplasia, tuber growth and epileptic symptoms in tuberosis sclerosis Rapamycine (sirolimus)
hemimegalencephaly
DEPD5 Familial focal epilepsy with variable foci, Rapamycine (sirolimus)
autosomal dominant nocturnal frontal lobe
epilepsy, familial temporal lobe epilepsy, rolandic
epilepsy and other non-lesional focal childhood
epilepsies and focal epilepsy associated with focal
cortical dysplasia, both familial and sporadic
GATOR1 Focal epilepsy with cortical malformation m-TOR inhibitors
Prickle mutations epilepsy Inhibitors of USP9X
Glut1 deficiency syndrome and mutations in SLC2A1 Use of ketogenic diet
ALDH7A Vit. B6-dependent epilepsy Pyridoxine (vit. B6)
Resistant epilepsy, Dravet syndrome Cannabidiol
Epileptic spasms in infancy Steroids or ACTH and vigabatrin
KCN1A Episodic ataxia type 1 Almorexant, ketogenic diet
SCN8A, SCN1A SCN2A Epileptic encephalopathy Low evidences about Na-channels blockers: amiodarone,
bepridil, aprindine, cibenzolin, riluzole
KCNA2 Early infantile epileptic encephalopathy 4-aminopyrimidine and acetazolamide
CACNA1A Infantile spasms, West syndrome Ethosuximide
HCN1 Early infantile epileptic encephalopathy Ivabradine, propofol, isoflurane, ketamine, lamotrigine,
gabapentin
CHRNA4, CHRNB2 (nAChR) Epileptic encephalopathy nAChR antagonists
m-TOR: mammalian target of rapamycin; USP9X: ubiquitin-specific peptidase 9 X-linked; ACTH: Adrenocorticotropic Hormone; nAChRs:
nicotinic acetylcholine receptors

serious side effects and, as is well known, it is capable of reducing the number of critical episodes but not
[77]
completely eliminating them .
New and effective treatment strategies with possibly novel mechanisms are therefore needed.

Many studies confirm the efficacy of fenfluramine in Dravet syndrome [78,79] . This drug was initially developed
as an appetite suppressant, but withdrawn from the market due to serious adverse effects, including cardiac
and pulmonary problems such as valvular heart disease and pulmonary hypertension [80,81] . Fenfluramine
[82]
has the ability to act on the serotoninergic cascade , but unfortunately the specific mechanisms by which it
carries out its anti-epileptic actions still need to be discovered. More recent works affirm that fenfluramine
significantly reduced epileptiform discharges in SCN1A knock-out morphants [83,84] .

Retigabine (or ezogabine) (third generation AED), most often used in adult patients, is a drug that primarily
acts as a positive allosteric modulator of KCNQ2-5 ion channels (Kv7.2-7.5) and is the first drug used to treat
[47]
epilepsy, which exploits its action on the potassium channels of neuronal cells . In vitro studies show that
the most potent action of this drug is on the KCNQ2/3 heteromeric channels, which has been closely related
to numerous forms of epileptic disorders from benign familial seizures to a severe form of epileptic encepha-