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Page 10 of 18 Orsini et al. J Transl Genet Genom 2018;2:16. I https://doi.org/10.20517/jtgg.2018.14

have been much needed to meet the high expectations regarding cannabis therapies for epilepsies, and this
[105]
trial will serve as a model for future studies, much more specific in particular in rare diseases .

One therapy that must be mentioned is that of infantile spasms. This condition requires a specific therapy
which should be carried out as early as possible to allow an adequate response to the therapy and avoid, as
often happens, some cognitive sequelaes that can be determined if treatment is started too late. The two best-
established therapies are hormonal treatments (steroids or adrenocorticotropic hormone) and vigabatrin
(second generation AED); however, little international consensus exists on which treatment to use first.
[106]
In 2017 O’Callaghan et al. published a work that reported the results of an International Collaborative
Infantile Spasms Study, the most important open-label randomized trial for the treatment of infantile
spasms carried out so far. For this multinational trial, 102 hospitals in five countries screened 766 infants
over a 7-year period, 377 of whom were recruited to the study. The children were randomly divided into
either the group in which a hormonal monotherapy was administered, or in the one in which a therapeutic
association was combined with the AEDs. The patients were free of spasms between days 14 and 42. This
outcome was achieved in 72% of infants in the combined treatment arm compared with 57% of those on
hormonal therapy alone. The response to therapy was better in patients who did not have a well-established
[106]
cause for their disease, without an identifiable etiology .

The different genetic polymorphisms can determine variations both in the pharmacokinetic field
(absorption, distribution, transport, metabolism, elimination) and in those of the pharmacodynamics
(action sites, etc.).

The genetic test is the background of an individual variation in the response to antiepileptic treatment, in
terms of efficacy and adverse reactions.

The KCNA1 mutations are associated with episodic ataxia type 1 [107,108] and homozygous Kv1.1 knockout
[109]
mice have disrupted sleep, and seizures peak during times of light . Almorexant, a dual orexin receptor
antagonist used in sleeping disorders, improves sleep and reduces seizure severity, suggesting that it may
[110]
be useful for patients with mutations in KCNA1 . Treatment of homozygous Kv1.1 knockout mice with
a ketogenic diet also reduces seizure frequency and has been shown to successfully extend life span [100] .
Finally, homozygous Kv1.1 knockout mice with partial genetic ablation of NaV1.2 exhibit reduced duration
+
of spontaneous seizures, and a significant improvement of survival rates argues that blockers of this Na
[111]
channel may have some treatment value .
Heterozygous mutations in SCN8A are associated with an epileptic encephalopathy characterized by
developmental delay, seizure onset within the first 18 months of life, and intractable epilepsy. These patients
have multiple seizure types, including infantile spasms, generalized tonic-clonic seizures, absences, and
[112]
focal seizures . Mirroring the situation with SCN1A and SCN2A, where there are both mild and severe
phenotypes, very recently there were two reports of familial benign infantile seizures, without cognitive
impairment, and some with paroxysmal dyskinesias with missense variants in SCN8A [113,114] . The research
provides a number of potential targeted therapeutic options. In particular, targeting the increased persistent
+
+
Na current makes sense. Significantly, GS967, a specific blocker of persistent Na current, extends the
survival of the NaV1.6 (N1768D/+) mouse . Riluzole, a drug known for its mild efficacy in the treatment
[115]
of amyotrophic lateral sclerosis, has proved to be an important therapeutic possibility, thanks to its
+
capability as Na current blocker. Riluzole is effective in blocking the early depolarization events seen in
[116]
CA1 pyramidal neurons , but as yet there is no published evidence of its efficacy in the NaV1.6 (N1768D/+)
[117]
mouse. Patel et al. have also demonstrated that increased persistent current of Nav1.6 mutant channels
can be preferentially reversed with cannabidiol.