KCNQ2 and SCN8A Mutations Linked to Contrasting Neonatal Seizure Outcomes: Case Series

The case series findings were published in the Indian Journal of Neonatal Medicine and Research in March 2026 by Dr. Ayushi Rajeshbhai Agravat and a team of researchers.

Case 1: Near-Term Female Infant

A female neonate (36 weeks gestation, 2.4 kg) delivered via emergency cesarean section developed unprovoked, recurrent tonic limb seizures by her eighth day of life. Her clinical background was notable for a sibling who died from seizure complications at one year of age. Comprehensive metabolic screening and a brain MRI were entirely normal. Given her family history and early seizure onset, early genetic sequencing was performed, which uncovered a heterozygous pathogenic loss-of-function mutation in the KCNQ2 gene. Following the initiation of phenobarbital monotherapy, her seizures were completely suppressed, and she reached normal developmental milestones at her 12-month follow-up.

Case 2: Full-Term Male Infant

A male neonate (39 weeks gestation, 3.1 kg) began experiencing clusters of focal autonomic seizures—featuring apnea, desaturation, and eye deviation—on day 11 of life. Baseline metabolic tests were normal, while his brain MRI displayed non-specific pachymeningeal enhancement without structural defects. The infant's condition was extremely pharmacoresistant, with seizures persisting despite trials of five different antiseizure medications. Genetic analysis revealed two heterozygous variants of uncertain significance: one in the SCN8A gene and an additional variant in the SLC6A1 gene. Despite aggressive polytherapy, the infant demonstrated profound global developmental delay and axial hypotonia by four months of age.

Neonatal Channelopathies: Mechanistic Insights

The KCNQ2 gene encodes a potassium channel subunit that regulates neuronal excitability. Loss-of-function variants in this gene are classically associated with early-onset, self-limited epilepsy that responds rapidly to treatment, yielding favorable neurodevelopmental outcomes. Conversely, the SCN8A gene encodes a voltage-gated sodium channel vital for action potential propagation. Pathogenic variants here typically result in gain-of-function effects, causing severe neuronal hyperexcitability, profound developmental impairment, and treatment-resistant epilepsy. Additionally, the dual presence of an SLC6A1 variant (which encodes a GABA transporter) in the second case suggests an oligogenic mechanism; the simultaneous disruption of both excitatory (SCN8A) and inhibitory (SLC6A1) neural pathways likely exacerbated the extreme pharmacoresistance observed.

Implications for Clinicians

Clinicians evaluating early-onset neonatal seizures should prioritize next-generation genetic sequencing when routine metabolic and structural evaluations are unrevealing. Early genetic diagnoses are critical for accurate prognostication and for preventing the unnecessary escalation of ineffective therapies. Furthermore, practitioners should recognize that incidental neuroimaging abnormalities, such as pachymeningeal enhancement, can act as diagnostic "red herrings" in genetic channelopathies and may not correlate with the actual severity of the disorder. Integrating genetic findings with clinical seizure characteristics, family history, and treatment response remains essential for optimizing neonatal epilepsy care.

Reference

Agravat, A. R., Makadia, R. M., Chauhan, H. H., Desai, P. D., & Chand, S. C. (2026). Early-Onset Epilepsy in Infancy Associated with Mutations in KCNQ2 and SCN8A: A Report of Two Cases. Indian Journal of Neonatal Medicine and Research, 14(1), PC03-PC05