KCNQ2 variants in neonatal onset of self-limiting epilepsy

Introduction

Seizures are the most common neurological emergency in the newborn, occurring in between one and five per 1,000 live births [1]. The majority of seizures in the neonatal period occur in the context of an acute illness (“acute provoked” seizures, previously called “acute symptomatic”), but in some cases the seizures may be the first manifestation of early infantile epilepsy. The self-limited epilepsies with onset in neonates or infants (SeLNE), formerly called benign familial neonatal and/or infantile epilepsies, are autosomal dominant disorders and account for three percent of all cases of neonatal seizures. Over 80 % of SeLNE cases are due to pathogenic variants in the Potassium Voltage-Gated Channel Subfamily Q Member 2 (KCNQ2) gene and less commonly in SCN2A and KCNQ3 [2].

Although seizures in infants with SeLNE often start between three and seven days after birth and become increasingly frequent, they subsequently remit spontaneously by around four to six months of age. About 90 % of patients with SeLNE have a normal neurodevelopment prognosis [1].

Sodium channel blocking anti-seizure medications, such as phenytoin, carbamazepine (CBZ), oxcarbazepine and lacosamide have been proven effective in neonates with channel-related epilepsy that may be refractory to other therapy [3], 4]. Approximately 80 % of KCNQ2 and SCN2A related epilepsies have a full response to sodium channel blockers [5].

We report the clinical presentation and response to medication in two cases of self-limiting KCNQ2-related epilepsy.

Case presentation

Discussion

We report two cases with the same pathogenic nonsense variant in KCNQ2 associated with a self-limited neonatal epilepsy phenotype. Both the cases experienced episodes of multifocal tonic seizures that responded to carbamazepine treatment.

The Potassium Voltage-Gated Channel Subfamily Q Member 2 (KCNQ2) gene is located on chromosome 20q13.33 and encodes the voltage-gated potassium channel subunit Kv7.2. The M channel is a heteromeric tetramer consisting of Kv7.2 and Kv7.3 subunits. When expressed individually, each subunit creates low-functioning channels. However, when both subunits are co-expressed, they generate functional channels that enhance the M-current by 10–50 times. This interaction would explain why pathogenic variants in either the KCNQ2 or KCNQ3 genes produce similar symptoms [10]. In situ hybridisation reveals that KCNQ2 is predominantly found in the cerebellar cortex, the neocortex, and the hippocampal formation, including the dentate gyrus. This is noteworthy because these three structures display different susceptibility to epileptic seizures. KCNQ3 is also localised to these areas in the mouse brain. However, the expression of KCNQ2 occurs earlier than that of KCNQ3 and increases rapidly during the first week of life. KCNQ3 is expressed in very low amounts at birth, while KCNQ2 is already expressed significantly [10]. This indicates that associations of KCNQ2 and KCNQ3 are likely to change as development progresses. The seizure remission is likely attributed to a compensation mechanism for KCNQ2/KCNQ3 channel defects by other types of potassium channels that emerge after birth [11].

The phenotypes of KCNQ2-related disorders range from self-limited neonatal epilepsy to neurodevelopmental impairment or severe conditions, including developmental epileptic encephalopathy (DEE). Variability in phenotype may be associated with the location and type of variant. Other genetic or environmental factors may be involved in the disorder. Nearly 200 different variants have been identified in patients with SeLNE and DEE. SeLNE is thought to result from haploinsufficiency of KCNQ2 and is predominantly caused by nonsense, frameshift and splicing variants, often inherited from a parent. On the other hand, KCNQ2 variants associated with DEE are usually de novo and are often missense or in-frame insertions or deletions thought to act via a dominant-negative mechanism [3]. The clinical features indicating SeLNE include the absence of abnormality on brain MRI, normal interictal neurologic examination, normal early development, and remission of seizures by 12 months of age. On the other hand, the suspicion of KCNQ2 DEE is based on the absence of structural lesions in the brain, severe abnormality on EEG background activity, poor response to epileptic medications, and developmental impairment [3].

The neurophysiological evaluation and monitoring by conventional EEG and aEEG (amplitude integrated encephalography) has become an integral part of clinical practice. The identification of a typical sequential seizure pattern with a prominent tonic onset on video-EEG in a neonate without structural brain damage or acute cause is a marker of genetic epilepsy due to KCNQ2/KCNQ3/SCN2A channelopathies. Most recent studies have found that patients with SeLNE typically have normal interictal EEG [4].

Various treatments, including sodium channel blockers (carbamazepine, oxcarbazepine, and phenytoin), and vitamin B6 have been found to treat seizures in SeLNE. When channelopathy is suspected as the cause of neonatal seizures, the ILAE (International League Against Epilepsy) task force recommends treatment with carbamazepine and phenytoin, with a high level of agreement among experts. However, there is insufficient evidence to recommend the use of any particular medication for the treatment of SeLNE. Further randomised controlled studies are needed to determine an optimal treatment [12], 13].

In case one, phenobarbital, phenytoin and levetiracetam were administered following local guidelines, but carbamazepine was commenced when a review of the case and the seizure semiology led to the diagnosis of SeLNE. In case two, carbamazepine treatment was started immediately because of the suspected likely diagnosis, and seizure control was achieved early, reducing the need for hospital stay.

Conclusions

KCNQ2 related self-limiting neonatal epilepsy is a genetic condition causing early onset seizures that typically resolve within a few months, with generally favourable prognosis and normal development. Rapid genome sequencing to identify the underlying genetic cause can aid prognostication, inform appropriate selection of anti-epileptic treatment and guide genetic counselling for the family, including recurrence risk in future offspring.

Learning points

1. Pathogenic variants in KCNQ2 are responsible for around 80 % of cases of self-limited familial neonatal epilepsies, underscoring the importance of genetic testing.

2. When self-limited familial epilepsy is suspected, antiseizure medication treatment with sodium channel blockers should be considered.

3. Prognosis for self-limited familial epilepsy is favourable, with seizures typically disappearing between the first and twelfth month of life.