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Orsini et al. J Transl Genet Genom 2018;2:16. I https://doi.org/10.20517/jtgg.2018.14 Page 9 of 18
[95]
prevented enhanced cell size and dysmorphism of neurons . Numerous studies show that the reduction of
the mTOR signaling pathway is certainly a basic mechanism underlying the pathophysiology of epilepsy in
[96]
rodents and humans .
GATOR1 complex gene mutations leading to mTORC1 pathway upregulation are closely related to the
onset of focal epilepsy with cortical malformations. However, unfortunately, there is not enough scientific
evidence to be able to state that treatment with mTOR inhibitors in patients with gene mutations affecting
[97]
the GATOR1 complex subunit is efficacious .

Mutations in the PRICKLE genes are associated with seizures in humans, zebrafish, mice, and flies, offering
a seizure-suppression pathway that may be evolutionarily conserved. This path has never been studied in the
past by the researchers who deal with antiepileptic therapy. The inhibition of ubiquitin-specific peptidase 9
X-linked (USP9X) can arrest PRICKLE-mediated seizures, so USP9X molecules may be evaluated as a new
[98]
class of anti-seizure therapy .

There are various associations between specific genetic mutations and non-pharmacological and rational
therapeutic decisions. The benefits of using a ketogenic diet in patients with Glut1 deficiency syndrome
due to mutations in SLC2A1 are widely known. The clinical spectrum of this condition is heterogeneous
and includes a group of epileptic syndromes ranging from mild cases with no epilepsy to severe cases
characterized by intractable epilepsy, infantile spasms and developmental delay. The treatment of first choice
to resolve the symptoms due to neuroglycopenia consists in providing an alternative fuel to the brain through
[99]
the ketones; this may be achieved through the use of a ketogenic diet . It is of fundamental importance
to start a ketogenic diet as early as possible, and therefore to make an early diagnosis to provide brain
[100]
[101]
nourishment and control seizures . However, the benefits on neurodevelopment seem controversial .
Biallelic mutations of the ALDH7A1 gene cause a deficit of antiquitin and these mutations underlie
pyridoxine (vitamin B6)-dependent epilepsy. The seizures are due to the fact that the lack of antiquininit
is determined to accumulate 1-piperideine-6-carboxylate condenses with pyridoxal 5’-phosphate and
inactivates this enzyme cofactor, essential component for the metabolism of the central nervous system and
in specific neurotransmitters. The simple therapy using pyridoxine in most cases can lead to full control
of convulsive episodes. ALDH7A1 analysis of gene could also be used for prenatal diagnosis of pyridoxine-
[102]
dependent epilepsy .
Cannabis sativa was the first plant cultivated by humans for purposes other than food or other useful
purposes. For thousands of years, extracts of the plant have been used for a variety of therapeutic conditions,
including the treatment of epilepsy. In recent times, with the power of the new social media, the general
population have been more and more interested in and approached the topics concerning the use of cannabis-
based therapies and in particular their effectiveness as a therapy in drug-resistant epilepsy, demonstrating
significant benefits for the therapeutic indication. The research has also been very much addressed in its use
for a severe epileptic encephalopathy of childhood called Dravet syndrome. Given the low number of studies
and research on the use of cannabidiol as a drug for the therapy of variable symptoms including epileptic
ones, recently the research has been oriented with more attention in this regard. For example, some children
were recruited to whom cannabidiol was administered in particular formulations, a botanically-derived
pharmaceutical, with compassionate use programs and were placed in an open-label trial [103,104] .

In 2017 the results of a double-blind, placebo-controlled trial of cannabidiol in children with Dravet syndrome
were published. The percentage of patients who had a greater than 50% reduction in convulsive seizure
frequency was 43% with cannabidiol and 27% with placebo (OR 2.00, 95% CI 0.93-4.30, P = 0.08). These results