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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 279

INTRODUCTION
Epilepsy is one of the most common neurological disorders. It is more frequent in infancy with an incidence
[1]
of approximately 70 per 100,000 children younger than 2 years . Approximately 70%-80% of childhood
epilepsy cases are caused by one or more genetic alterations, which comprise both monogenic and polygenic
[2]
factors . While the majority of seizures occurring during the neonatal period are caused by acute brain
[3]
[4]
injury , around 13% of neonates suffer from neonatal-onset epilepsy with a specific genetic cause, usually
showing up in the first days of life.
Neonatal-onset genetic epilepsies can be classified into three large groups: genetic conditions associated with
structural brain anomaly, genetic conditions associated with metabolic disorders, and genetic conditions
[3]
resulting in functional cortical anomalies . The latter group includes disorders of cell signalling (e.g.,
CDKL5, BRAT1), disorders of synaptic transmission (e.g., STXBP1), and channelopathies (e.g., KCNQ2,
[3]
KCNT1, SCN2A) . Pathogenic variants in KCNQ2 are the most common genetic cause of neonatal seizures
[5]
among the channelopathies . Dominant mutations in this gene lead to different epileptic disorders,
[6]
including benign epilepsy and developmental and epileptic encephalopathy (KCNQ2-related DEE) . The
clinical features suggestive of KCNQ2-related DEE include seizure onset in the first week of life with severely
abnormal electroencephalography background activity, absence of structural lesions in the brain, and mild to
[6,7]
severe developmental delay .
Our understanding of the etiology and pathophysiology of DEE has considerably improved thanks to Next
[8]
Generation Sequencing (NGS). This technique has become faster and more accessible in recent years ,
[8]
allowing the development of treatments addressing the precise molecular causes of the disease . Early
genetic diagnosis is critical to avoid further potentially invasive diagnostic tests and to make appropriate
therapeutic decisions. The case of KCNQ2 related-epilepsy is paradigmatic, as supported by the importance
of the early recognition of the specific electroclinical phenotype and the use of sodium channel blockers
[9]
(SCB) in this disorder .

We describe a boy with KCNQ2-related DEE presenting with neonatal-onset seizures; the epilepsy gene-
panel revealed a de novo KCNQ2 variant: c.1742G>A; p.(Arg581Gln) (NM_172107.2). We highlight the
immediate and remarkable response to the treatment with SCB in this patient, further supporting the role of
this therapeutic approach in KCNQ2 disorders.

CASE REPORT
This 7-month-old infant was the first child from unrelated, healthy parents. Family history was negative
for epilepsies, mental retardation, and hereditary diseases, but it was positive for febrile seizures on the
maternal side. He was born at term by urgent caesarean section for deceleration of the heartbeat, after an
uneventful pregnancy. Fetal karyotype was normal. APGAR score was 8 at 1 min and 9 at 5 min. Auxological
parameters at birth were: weight 2,650 g (-2.2 Standard Deviation - SD, SGA), length 52 cm (+1.13 SD), and
occipital frontal circumference (OFC) 36 cm (+1.41 SD). Transient neonatal hypoglycemia was found, but
the perinatal course was otherwise uneventful.

At day 3, the baby presented recurrent seizures, lasting around one minute and characterized by tonic
posturing with flexion of the lower limbs, ocular retroversion, horizontal nystagmus, perioral cyanosis,
automatic sucking movements, and apnea (with SaO < 45). He was hospitalized in the Neonatal Intensive
2
Care Unit and a serial electroencephalographic (EEG) monitoring was performed. The first EEG showed
rare paroxysmal abnormalities in the left hemisphere. Due to the daily recurrence of clustered focal motor
and autonomic seizures, the patient was treated with intravenous phenobarbital (PB) at the initial dose
of 20 mg/kg up to the maintenance dose of 5 mg/kg twice daily, with no effect. At day 6, levetiracetam