Page 67 - Read Online

Orsini et al. J Transl Genet Genom 2018;2:16. I https://doi.org/10.20517/jtgg.2018.14 Page 11 of 18

A further mechanism involving ionic channels has been extensively studied, is the one concerned with
[116]
+
2+
blocking the Na /Ca exchanger which is implicated in the disease mechanism .
+
2+
It is known that some drugs capable of blocking the Na /Ca exchanger (amiodarone [118] , bepridil [119] ,
[121]
[120]
aprindine and cibenzoline ) are considered important therapeutic options also in epilepsies.
De novo mutations in KCNA2 have been identified in cases of early infantile epileptic encephalopathy. In this
pathology the onset of seizures is between 5 and 17 months, with a phenotypic spectrum including febrile
and afebrile, hemiclonic, myoclonic, myoclonic-atonic, absence, focal dyscognitive, focal, and generalized
[122]
seizures; mild to moderate intellectual disability; delayed speech development; severe ataxia . The KCNA2
spectrum also encompasses milder familial epilepsy [123] . Some treatment options have been taken into
+
consideration. The 4-aminopyridine is an approved K blocker already being trialed in patients carrying
[124]
gain-of function mutations. Xie et al. have tested a non-targeted approach and reported that the carbonic
anhydrase inhibitor, acetazolamide, is capable of rescuing the motor incoordination in Pingu mice.

Early evidence supported the idea that CACNA1A mutations were associated with genetic generalized
epilepsies [125,126] . Micro-deletions that encompass CACNA1A and a single truncating mutation have been
associated with severe epileptic encephalopathies that include infantile spasms and West syndrome. De novo
missense mutations have been convincingly shown to cause severe epileptic encephalopathies with seizure
types that typically include focal, tonic, and tonic-clonic seizures, severe intellectual disability and motor
impairment [127,128] . It is known that acetazolamide and 4-aminopyridine are able to decrease, in tottering
mice, the high-power low-frequency oscillations, which are thought to be a marker of cortical excitability,
so these drugs are evaluated as treatment options for episodic ataxia 2 [129] . Spontaneous seizures in the
[130]
CACNA1A knockout mouse can be abolished by knocking out CACNA1G . This suggests that T-type Ca
2+
[131]
channel blockers, including ethosuximide, may be good therapeutic options .
Numerous studies of literature on animal models have shown concrete evidence regarding the transcriptional
changes of hyperpolarization-activated cyclic nucleotide-gate (HCN) channels in correlation with excitability,
but there remains little evidence on the association between epilepsy and genetic change correlated to the
mentioned channels. A study by Nava et al. [132] showed that HCN1 missense mutations were associated
with the development of early infantile epileptic encephalopathy. In addition, these patients had symptoms
associated with Dravet syndrome with intellectual impairment and autism. In gain-of-function disease,
HCN1 blockers may be useful. Ivabradine is a use-dependent broad-spectrum blocker of HCN channels
approved for use in angina pectoris. It is an important drug because it is well tolerated by most patients,
[133]
however, its capacity is not known, nor is the timing to overcome the encephalic barrier . The hypnotics
propofol and ketamine, as well as the anesthetic isoflurane, are reported to inhibit HCN1 channels [134-136] .
Finally, the AEDs, lamotrigine and gabapentin (second generation AED), have both been reported to enhance
HCN currents [137,138] , potentially benefiting in particular patients with loss-of-function mutations.

In patients with mutation of the receptor for nACh, even if the type of mutation has been known for a long
time, numerous precision therapy options have not yet been found. Only carbamazepine proved to be useful
in patients with nicotinic acetylcholine receptors mutations with approximately 70% showing remission on
low doses. Molecular and cellular studies argue that drugs that block nAChR should be effective in disease
caused by mutations in CHRNA4, CHRNB2, and CHRNA2c [139,140] [Table 4].

In conclusion, cost-effectiveness of precision medicine was considered in this review. An interesting and
recent study investigating the cost-effectiveness of a whole exome sequencing (WES)-based gene panel
(targeted WES) in patients with severe epilepsies of infancy found that early targeted WES had lower total