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Page 6 of 18 Orsini et al. J Transl Genet Genom 2018;2:16. I https://doi.org/10.20517/jtgg.2018.14

treatment is still largely empirical and rational prescribing based on the mechanism of action in an
individual patient is not generally possible. A fundamental problem is that the main mechanisms of action
and biochemical effects of drugs are not yet known in depth or not completely clear. This is in part due to
the fact that the exact molecular targets of current AEDs are largely unidentified. Therefore, drug discovery
is not targeted and instead relies on developments using in vivo seizure models. Further, as a consequence
of these models, the common antiepileptic therapies are limited to controlling the epileptic symptoms but
not to preventing the epileptogenic events. It seems likely that we will need to understand epileptogenesis
in order to devise novel therapeutic interventions. Accordingly, research is rather oriented towards the
[69]
mechanisms of action and the complex molecular processes to which diseases are subjected .

Genetic confirmation through the use of specific molecular diagnostic techniques in epileptic syndrome
can provide an important contribution in establishing a more precise prognosis and in the evaluation of
recurrence of epileptic seizures [70,71] .

Furthermore, it offers an excellent opportunity to obtain better information on targeted treatments and the
development of targeted drugs. The impact of increased knowledge is of paramount importance in particular
in patients with epileptic encephalopathies, a group of neurodevelopmental disorders characterized by
marked epileptic activity associated with regression of neurological development [72,73] .

Current drugs directly reduce neuronal excitability mainly by modulating ion channels and neurotransmitter
receptors. Recent acquisitions have revealed further pathways that show different mechanisms such as
synaptic vesicle traffic, mammalian target of rapamycin (mTOR) signaling, chromatin remodeling and
transcription, thus offering new therapies [74,75] .

The genetics of epilepsy is still very complex, mutations of different genes can cause the same syndrome or
even mutations in a single gene (for example, SCN1A) can be associated with a wide range of phenotypes,
[76]
ranging from feverish convulsions to severe epileptic encephalopathies .

It is also important to underline that there is a wide individual variability of response to antiepileptic
treatment and the genetic differences between patients are most likely implicated in this variation [Table 3].

Drug use
On the basis of a particular form of epilepsy we can explain, in whole or in part, the answer, both positive
and negative (paradoxical) to certain AEDs. For instance, the clinical picture of Dravet syndrome can
be worsened by the use of carbamazepine and phenytoin, since the disease is caused by mutations in the
sodium channel gene (SCN1A) and these drugs interfere on the mechanism of action mentioned blocking
the channel [4,69,77] . In contrast, sodium channel blocking is considered the first choice therapy for the epileptic
syndrome associated with mutations in SCN8A (another sodium channel gene) and KCNQ2 genes [4,49] .

LTG is a known blocker of the sodium channel and N-type calcium channels and its use has sparked
controversy. Some works claimed it as a factor in exacerbation of seizures, therefore research has led to the
avoidance of its use in patients with Dravet syndrome. On the other hand, other studies assert a positive
effect in some patients with Dravet syndrome. This beneficial effect could be explained by the mechanism
involving the cyclic-nucleotide channels activated by hyperpolarization processes [47,51] .

At present, approved therapy for Dravet syndrome includes the use of three drugs in a polytherapy that
are valproate, clobazam and often stiripentol. As regards stiripentol, this is the only drug used in Dravet
syndrome for which an important randomized controlled trial has been performed (when combined with
valproate and clobazam); but it is widely known that the use of stiripentol, valproate and clobazam can cause