The voltage-gated potassium channel subfamily KQT member 2 gene (KCNQ2) is a potassium channel gene located on chromosome 20q13.3. It is found to be mainly expressed in the brain. Since it plays a crucial role in neuronal firing, KCNQ2-related disorders represent a broad continuum of neonatal epileptic phenotypes. It range from Benign Familial Neonatal Epilepsy (BFNE) with a relatively good prognosis, to Neonatal Epileptic Encephalopathy (NEE), which is usually associated with a poorer neurodevelopmental outcome. Other rarer phenotypes have been reported as well, including myokymia , benign familial infantile seizures (BFIS) and infantile spasms [1-3].

KCNQ2 related disorders comprise both benign seizure disorders and early onset epileptic encephalopathies. Especially within the latter group, patients suffer from refractory seizures to standard antiepileptic drugs and developmental delay. Besides the hope of personalized medical approaches to treat the recently unraveled large amount of genetic channelopathies, there are sparse case reports and systematic data on treatment responses in KCNQ2 related epilepsy.

Analogies between benign familial neonatal convulsions and other channelopathies of skeletal and cardiac muscle, including periodic paralysis, myotonia and the long QT syndrome, provide clues about the nature of epilepsy-susceptibility genes and about the fundamental basis of epilepsy as an episodic disorder. A few reports on patients with a KCNQ2 mutation with a more severe outcome exist like refractory epilepsy developmental or epileptic encephalopathy but a definite relationship has not been established [4,5].

It now appears that the KCNQ2/KCNQ3 K⁺ channels that are mutated in benign as well as refractory neonatal epileptic disorders represent an important new target for anti-epileptic drugs. In the future, the identification of ion channel defects as predisposing factors in the common epilepsies could herald a new era of genotype-specific therapies. 

In this case report, we present a neonate with seizures who was refractory to most of the known drugs. On genetic investigation was found to have KCNQ2mutation.

A 5 month old male infant was born by full term normal vaginal delivery at a tertiary care hospital of North India, IGMC, Shimla Himachal Pradesh to healthy non consanguineous parents. Birth weight of the baby was 2.5 kg and there was no significant birth history and the baby was discharged on 3^rd day of life. The baby presented to us at the age of 5 months with a history of gross development delay with a developmental quotient of 40% in all 4 domains, along with fever, with decreased feed acceptance with abnormal body movements in the form of vacant stare. Child was vaccinated (pentavalent 2^nd dose) 1 day prior to onset of illness. He was admitted to IGMC, Shimla with above complaints. Initial possibility of adverse event following immunization or sepsis or metabolic seizure was kept. Patient at admission vitals were HR =188, RR 80/mint, Capillary Refill Time 4-5 sec, SPO2 = 90% on room air, blood pressure was below 3^rd centile. On central nervous system examination child was lethargic with GCS of 7/15. Cry, tone and activity was depressed, anterior fontanelle was leveled, head control was absent. Rest of the systemic examination was normal. There was no neurocutaneous marker. In view of shock with severe metabolic acidosis with poor GCS, child was intubated and started on mechanical ventilation. After fluid resuscitation with NS, total of 60 ml/kg started on ionotropic support, adrenaline infusion at the rate of 0.1 µg/kg/mint which gradually hiked upto 0.5 µg/kg/mint and also started on ceftriaxone 100 mg/kg/day in two divided dose which was omitted after culture sensitivity report came sterile. Investigation revealed hypocalcemia with ionized calcium 0.6, as meningitis was ruled out so hypocalcemia was kept as a cause for seizure. Child was given calcium correction as per guideline. Child remained seizure free for 6 days so in view of clinical improvement, weaned off from ventilator, ionotropes gradually and started on CPAP.

On 7^th day of illness patient had multiple episodes of seizure in the form of tonic posturing of bilateral upper and lower limb at interval of half an hour. MRI was done which revealed linear and serpiginoous blooming foci in bilateral parieto-occipital and right frontal lobes with mild generalized cerebral atrophy. He received phenobarbitone (maximum 60 mg/kg), levetiracetam (60 mg/kg) and phenytoin (60 mg/kg) but frequency of seizure was not affected by any of the above mentioned drugs. So child was reintubated in view of refractory seizures and started on mechanical ventilation and intravenous antiepileptic midazolam infusion which gradually hiked 18 µg/kg/min but seizure was still persistent. Propofol was added and received for 48 hours but child not responded and ketamine added. Seizure frequency decreased gradually to 1-2 episodes per day.

On 12^th day of illness in view of super refractory seizures following immunization possibility of Dravet syndrome was kept and phenytoin was tapered off gradually as it can intensify the symptoms in Dravet. Whole genome sequencing was sent and IVIG was given to child and started on valproate and clobazam. Other possibility of metabolic disease was kept and was started on mitochondrial cocktail. Tandem mass spectrometery was sent and was normal. Seizures relieved on 26^th day of illness, midazolam and other antiepileptics gradually tapered off except for maintenance of valproate 20 mg/kg/day and phenobabrbione dose 8 mg/kg/day and child gradually weaned from ventilator to CPAP recieved for 2 days and then shifted to prongs till 50 days of admission. Whole genome sequencing report came positive for KCQN2 gene mutation, which was suggestive of developmental and epileptic encephalopathy. MRI suggestive of generalized cerebral atrophy with bilateral parieto-occipital and right more than left frontal lobe subacute to chronic hemorrhage. Patient discharged after 53 days on sodium valproate and phenobarbitone.

KCNQ2-related neonatal epileptic encephalopathy (KCNQ2-NEE) is a rare condition starting to be increasingly recognized and reported in recent years due to its relatively severe phenotype.

Multiple daily seizures with onset in first week of life characterize KCNQ2-NEE. Tonic seizures along with motor and autonomic features and refractory to most antiepileptic drugs, is the common finding. Patients usually present with profound intellectual and/or psychomotor developmental impairment later on in childhood, although seizures cease within a few years of age. EEGs in the first week of life show a burst suppression pattern and multifocal epileptiform activity usually develop later in the course but may eventually return to normal after seizure control [6]. 

Our patient presented with gross developmental delay at 5 months of age. Intractable seizures soon after birth, not attributable to structural, electrolyte or metabolic etiologies were the findings. He had neurodevelopmental delay and genetic test results came back with a de novo mutation in KCNQ2, which is a known pathogenic mutation first reported by Saitsu et al. [7]. In a case of early infantile epileptic encephalopathy. The mutation resulted in an ala265-to-val (A265V) substitution and the patient Saitsu et al. [7] reported had very similar presentations as our patient. Therefore, we find his epileptic encephalopathy attributable to this mutation.

KCNQ1, as KCNQ2, is a member of the potassium voltage gated channel subfamily. While KCNQ1 is expressed more in cardiomyocytes, it has also been found to be expressed in the brain. The most prominent expressing site for KCNQ2 is brain. Few researchers have done animal experiments to under the mutations of this gene in detail. Niday et al. [8] found KCNQ2 ablation in mice which led to enhanced neuronal excitability of neocortical layer, two-third pyramidal neurons as well as a larger action potential amplitude. This can be a possible explanation for epileptogenesis due to KCNQ2 mutation. In the heart, very low levels of KCNQ2 expression have been discovered as well [9]. But in theory, if the mutation had a functional impact on action potential in the cardiomyocyte, it is possible for patients carrying certain mutations in KCNQ2 to present with both epilepsy and arrhythmia. After thorough literature search, it can be said that no study has found evidence of KCNQ2 impacting cardiac action potentials.

KCNQ2 mutations are found in a substantial proportion of patients with a neonatal epileptic encephalopathy with a potentially recognizable electroclinical and radiological phenotype. This suggests that KCNQ2 screening should be included in the diagnostic workup of refractory neonatal seizures of unknown origin.

Acknowledgment

We are grateful to the patient and his parents for their consent to report this case.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethical Statement

We have obtained a written consent from the patient’s parents for the publication of this case report.

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