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Page 282 Amadori et al. J Transl Genet Genom 2020;4:278-84 I https://doi.org/10.20517/jtgg.2020.36

Deep phenotypic characterization played a relevant role in the choice of the most appropriate genetic test
in our case. Genetic testing should be performed as early as possible, especially in patients showing some
[15]
specific electro-clinical phenotypes (e.g., KCNQ2 or KCNT1), to recognize potentially treatable disorders .
In our patient, genetic testing was performed within the first month of life and the results were obtained at
age 2 months, revealing the de novo missense mutation in KCNQ2 and allowing a “targeted” treatment.

The role of a precision medicine approach in neonatal seizures with known etiology is becoming more
and more relevant in recent years [13,16] . In consideration of the good electro-clinical response to SCB, our
suspicion was focused on SCN2A, SCN8A, and KCNQ2.

Voltage-gated sodium channels and KCNQ potassium channels co-localize at the neuronal membrane
[17]
and a modulating effect of SCB on both channels has been suggested . The use of broad-spectrum anti-
[9]
epileptic drugs in KCNQ2-related epilepsy has been suggested . The most common drug used in “benign”
[9]
phenotypes was PB, followed by SCB . In general, patients with a mutation in KCNQ2 suffering from B(F)
NE become seizure-free spontaneously in the first month of life or between the 6 months and 1 year of age.
Accordingly, the International League Against Epilepsy recommends the use of the term “self-limiting”
[18]
instead of “benign” . Therefore, the large use of PB is most likely explained by the common use of this
[9]
drug as standard therapy in neonatal seizures . CBZ and PHT are instead considered appropriate as first-
[9]
line treatment in KCNQ2-related encephalopathy, regardless of the underlying pathogenic variant . Also,
[9]
lacosamide improved seizures frequency in the early-onset epileptic encephalopathy . However, functional
studies and additional clinical observations are required before it can be considered a possible target
[19]
therapy .
The finding that retigabine opens the K 7 potassium channel sparked the interest in its use in patients with a
v
KCNQ2 mutation and it was considered the first specific anti-seizure drug for KCNQ-related epilepsy. Despite
preliminary promising results, especially when the drug was administered during early development (such
[12]
as improvement of seizure frequency and development in patients treated before the age of 6 months) ,
its prescription was questioned because long-term treatment was characterized by several side effects (e.g.,
[20]
blue discolouration of skin and retina) .

Another possible drug in patients with abnormal KCNQ function is pyridoxine. Indeed, some patients
with KCNQ2-encephalopathy respond to this vitamin but the pathophysiology of mechanisms behind this
,
[21]
response to pyridoxine is not completely understood .
In our patient, we switched to CBZ after the dramatic effect of PHT treatment on seizure control because
of the safer drug profile of CBZ within the SCB group. Indeed, other SCBs present several disadvantages,
as shown by the adverse event profile of PHT (purple glove syndrome, cerebellar toxicity, and cardiac
[9]
arrhythmias) or long-lasting dose increments of lamotrigine .
Current treatments in KCNQ2-related epilepsy mainly focus on seizure control, but the early genetic
diagnosis will be more and more relevant in the choice of the most appropriate therapeutic regimen,
especially considering the progressive introduction of new therapies.

Advances in the knowledge of the genetic basis of early-onset epilepsies have opened the way for precision
medicine approaches in this category, which had been long considered as a single entity. In KCNQ2-
[18]
related encephalopathy, seizures may remit, but mild to profound global developmental delay may occur .
Therefore, it is mandatory that in the future, clinicians will consider to run genetic testing as part of
the initial workup, with higher priority for neonates, so that the results can be incorporated in the early