Page 64 - Read Online

Page 8 of 18 Orsini et al. J Transl Genet Genom 2018;2:16. I https://doi.org/10.20517/jtgg.2018.14
[47]
lopathy early onset . Recent in vitro experiments have shown that retigabine opens Kv7 potassium channels
[51]
and restores normal channel function in KCNQ2-related encephalopathy mutations .

Regarding the treatment of GRIN2A-related epileptic disorder, new strategies are based on the use of
[57]
N-methyl-D-aspartate (NMDA) receptor antagonists : memantine, an NMDA receptor antagonist
approved by the Food and Drug Administration, has shown the ability to reduce the frequency and onset of
seizures in some types of encephalopathies affecting children defined early-onset epileptic encephalopathy,
associated with a de novo missense mutation in GRIN2A (p.Leu812Met). However, the same drug was not
effective in another case-report in which the authors demonstrated a different mutation (p.Asn615Lys) in the
[85]
same gene, but with a completely different effect on the function of the protein .
Quinidine, a well-known anti-arrhythmic drug, has been used to restore in vitro the hyperactivity of the
[86]
KCNT1 mutant potassium channel in Xenopus oocytes . A recent clinical case presented a child in whom
oral administration of this drug led to an improvement in epilepsy and psychomotor skills which he suffered
[87]
from because of focal epileptic seizures due to a lack of the protein product of KCNT1 . However, the same
drug had no efficacy in another patient with KCNT1 mutation and with severe secondarily generalized focal
seizures. Therefore, we must use a great deal of attention and experience, in using quinidine, in patients with
[88]
such genetic dysfunction . The serious side effects on the liver of patients using valproate and presenting a
POLG gene mutation are well known .
[89]
Some papers have shown a strong correlation between the genetic polymorphisms that affect microsomal
epoxide hydrolase (EPHX1) gene and pharmacokinetics of carbamazepine in Chinese patients suffering from
[90]
some forms of epilepsy and in Kosovan people of Albanian ethnicity with epilepsy .
A study demonstrated that in patients with SCN1A, ABCC2 and UGT2B7 genetic polymorphisms there is the
possibility of making important changes to oxcarbazepine maintenance doses .
[91]

In an Indian population the genetic contribution of CYP1A1 alleles on treatment outcome in people with
epilepsy was studied. In particular, it has been demonstrated, through a study carried out on a population of
Indian women with epilepsy, that the mutation in the variant rs2606345, which consists in a reduction of the
CYP1A1 expression, determines a lack of response to the first line treatment with most used AEDs [92,93] .

Rapamycin (sirolimus) has been shown to decrease cortical dysplasia and tuber growth in patients with
tuberosis sclerosis, also decreasing epileptic symptoms; moreover, the same drug is useful in patients
with hemimegalencephaly. One possible explanation is that sirolimus blocks the mTOR complex, whose
overexpression causes dysplasia in various organs and the formation of glial bands, subependymal nodules,
[2]
tumors during both the fetal phase and subsequent central nervouse system development . Another clinical
trial was performed to understand the effects of everolimus (a derivative of sirolimus) on subependymal
giant cell astrocytoma growth and showed a sustained effect on tumor reduction over ≥ 5 years of treatment,
[94]
with no safety concerns .
Very recently we learned that some forms of epilepsy listed below are associated with Dishevelled, Egl-10
and Pleckstrin domain containing protein 5 (DEPDC5) loss-of-function mutations, including autosomal
dominant nocturnal frontal lobe epilepsy, familial focal epilepsy with variable foci, 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. It has recently been demonstrated that mutations
of DEPDC5 are associated with increased production activity of the mTOR signal cascade factors, because
of the capability of DEPDC5 to reduce the mTOR activity. In global DEPDC5 knockout rats, in which the
therapy was performed during the prenatal period, with rescued growth delay and embryonic lethality,