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Amadori et al. J Transl Genet Genom 2020;4:278-84 I https://doi.org/10.20517/jtgg.2020.36 Page 281

activity [Figure 1D]. At 36 days of age, PHT blood levels were found to be inappropriately low (0.9 µg/mL,
reference range: 10-20 µg/mL) and electroclinical worsening was observed. Accordingly, the PHT dosage
was increased up to 45 mg/kg/day, in three daily administrations. Background EEG activity was replaced by
abnormal activity which included spikes and polyspikes, often followed by slow waves of medium amplitude,
which were synchronous and asynchronous in both hemispheres and more prominent in the frontal
derivations. Sometimes these abnormalities were more diffuse. Additional EEGs performed at 2 months of
life showed a significant improvement. There were rare epileptic abnormalities with multifocal expression
and predominant posterior origin.

Due to the confirmation of a heterozygous missense mutation in KCNQ2 [c.1742G>A; p.(Arg581Gln)] absent
in the parents (de novo origin), we introduced carbamazepine (CBZ) at the initial dosage of 9 mg/Kg/day,
progressively increasing up to an adequate dosage for body weight. This change in the therapeutic regimen
resulted in good seizures control. Two further EEGs (at the age of 70 and 85 days), showed a lack of
organization and multifocal epileptic abnormalities. The baby was discharged from hospital at the age of
3 months. He was seizure-free with CBZ monotherapy.

At 7 months of age, the patient experienced daily episodes of apnea and cyanosis preceded by crying.
Video-EEG showed multifocal epileptic abnormalities and confirmed the epileptic nature of these episodes.
Furthermore, the CBZ blood levels were 2.4 µg/mL (reference range: 8-12 µg/mL). The dosage was thus
increased (16.7 mg/kg/die) with subsequent good seizures control. Physical examination revealed frontal
bossing, irritability, mild hypertonia, vocalizations, and inconstant visual fixation. Psychomotor delay
was observed, as he was not able to sit unassisted. Auxological parameters were: weight of 7.2 kg (-1.64
SD), length of 64 cm (-2.05 SD), OFC 46 cm (+1.75 SD). Head ultrasound showed a 6 mm dilation of the
periencephalic spaces of the cranial vault.

DISCUSSION
KCNQ2 is located on chromosome 20q13.33 and encodes the potassium channel subunit K 7.2., that forms
v
heterotetrameric voltage-gated potassium channels together with K 7.3 subunit (encoded by KCNQ3).
v
These channels are widely expressed in the brain and transport potassium ions along their concentration
gradient, underlying the M-current. This slowly activating, non-inactivating potassium conductance inhibits
[10]
neuronal excitability . Pathogenic variants in KCNQ2 leading to loss of function cause two different
[6]
epilepsy phenotypes Truncating and missense variants, likely resulting in haploinsufficiency, are associated
with benign familial neonatal epilepsy (BFNE) whereas missense variants and small in-frame deletions,
resulting in dominant-negative effect, are associated with DEE [6,11] . Hereditary or de novo BFNE-associated
KCNQ2 variants are distributed along with the channel protein and are more common in the intracellular
[12]
domain between S2 and S3 . The mutations in KCNQ2 in encephalopathic patients are instead found in
four functionally relevant protein domains: the domain of the voltage sensor, the pore, the proximal regions
C-terminus, and calmodulin-binding helix region B [7,12] . The variant detected in our case is reported in the
ClinVar database in an individual with neonatal/infantile-onset epileptic encephalopathy (#ClinVar, variation
ID 21769, https://www.ncbi.nlm.nih.gov/clinvar/variation/21769/). This variant involves an evolutionarily
conserved amino acid located in the C-terminus domain, likely resulting in an impaired protein function.

The recognition of seizures in a new-born can be challenging as clinical manifestations may be subtle. The
EEG background plays a relevant role in the identification of patients with benign epilepsy or severe epilepsy.
Indeed, video-EEG is a powerful tool for the early recognition of distinct electro-clinical aetiology-specific
phenotypes. This is further supported by what has been observed in KCNQ2-related epilepsies, KCNT1
[13]
encephalopathy, and STXBP1 encephalopathy . In our patient, the neonatal EEG background showed
multifocal epileptic abnormalities with random attenuation alternating with burst suppression pattern.
Moreover, aEEG showed a pattern that has been recently suggested as a signature in neonates with KCNQ2-
[14]
related disorders .