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Orsini et al. J Transl Genet Genom 2018;2:16. I https://doi.org/10.20517/jtgg.2018.14 Page 5 of 18
[55]
the HLA-B*1502 allele were previously identified and carbamazepine was thus avoided as a therapy . The
frequency of this allele in the specific population is in the order of 1%-8% in residents of China and most
[56]
South Asian countries , with peaks as high as 15%-21% among Indonesians and 34% among Filipinos ,
[52]
while instead the frequency of the HLA-B*15:02 allele is very low (< 0.5%) in people of European, or North
[57]
East Asian (Korean and Japanese) ancestry . For these reasons regulatory agencies and guidelines (like the
Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA-B genotype and carbamazepine
dosing) recommend that patients from Han Chinese and other South Asian ethnic groups be routinely
genotyped for HLA-B*15:02 before starting treatment with carbamazepine, and that carbamazepine be
avoided if possible in carriers of the allele [56,58] . The HLA-B*15:02 allele has also been associated with an
increased risk of SJS and TEN after therapy with other AEDs, including phenytoin (first generation AED)
[59]
[60]
and, to a lesser extent, lamotrigine , and oxcarbazepine (second generation AED) . In fact, these AEDs
have an aromatic ring just as carbamazepine (CBZ) does.
In addition, another allele, the HLA-A*31:01 has been linked with increased risk of carbamazepine-induced
hypersensitivity reactions, such as maculopapular exanthema, SJS/TEN and also drug reaction with
eosinophilia and systemic symptoms (DRESS) [61,62] . HLA-A*31:01 is frequent in many ethnic groups, both
[63]
in Europeans and Orientals . A recent meta-analysis confirmed a significant association of HLA-A*31:01
with carbamazepine-induced DRESS but a weaker association with CBZ-SJS/TEN, thus suggesting that
[64]
HLA-A*31:01 is a genetic predictor for CBZ-DRESS but not for CBZ-SJS/TEN . Studies have been made to
find if, apart from a clinical benefit, genotyping for HLA-A*31:01, which reduces the incidence of cutaneous
adverse drug reactions, could be economically convenient and the results show that this routine practice
[65]
would be cost-effective .
The HLA-B*15:02 allele belongs to the HLA-B75 serotype, and other alleles belonging to the same serotype,
such as HLAB*15:08, HLA-B*15:11 and HLA-B*15:18, have been associated with an increased risk of
[52]
carbamazepine-induced SJS/TEN . By contrast, some HLA alleles have been reported to be potentially
protective against the risk of carbamazepine-induced SJS/TEN, such as HLA-B*40:01, HLA-B*07:02, HLAB*
58:01, HLA-A*33:03, HLA-B*4001, HLA-B*4601 and HLA-DRB1*03:01 [66,67] .

In conclusion, to date, there is limited evidence regarding the value of genotyping in predicting AED response.
The best example of a useful pharmacogenetic variant in epilepsy is testing for HLAB*15:02 to prevent
serious adverse cutaneous reactions in individuals from South Asian ethnic groups in whom initiation of
carbamazepine therapy is considered. Unfortunately, there is no widely applicable genetic test to predict
response to AED treatment in patients with the most common forms of epilepsy. However, we believe
that genetic testing will help in preventing adverse drug reactions or to prescribe the correct dose of AED.
Furthermore, it will help researchers better understand epilepsy genetics and approach new precision medicine.

PRECISION THERAPY
The treatment of epilepsy is still largely based on empirical science and the prescription of drugs for epileptic
patients cannot be based on the mechanisms of action of these. The performance of a personalized therapy
is limited by the broad clinical phenotypic spectrum and the underlying heterogeneous aetiology. However,
recent scientific acquisitions about genetics mechanisms, studies of neuroimaging and epilepsy neurobiology
are providing many indications about the choice between the drugs of the past or the newest ones, thus
laying the foundations for a new era in the treatment of epilepsy, in which patients will benefit from
therapies based on the etiological cause of diseases .
[68]

The newest AEDs offer many therapeutic advantages compared to traditional and older generation therapies,
in fact they have a lower risk profile of side effects and have by far fewer drug interactions. Despite this,