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Early-Onset Epilepsy in Infancy Associated with Mutations in KCNQ2 and SCN8A: A Report of Two Cases |
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Ayushi Rajeshbhai Agravat, Rishit Maheshbhai Makadia, Halak Hasmukhbhai Chauhan, Pankti Dhaivat Desai, Sunil Chandrasen Chand 1. Resident Doctor, Department of Paediatrics, Narendra Modi Medical College, Ahmedabad, Gujarat, India. 2. Resident Doctor, Department of Paediatrics, Narendra Modi Medical College, Ahmedabad, Gujarat, India. 3. Assistant Professor, Department of Paediatrics, Narendra Modi Medical College, Ahmedabad, Gujarat, India. 4. Professor, Department of Paediatrics, Narendra Modi Medical College, Ahmedabad, Gujarat, India. 5. Associate Professor, Department of Paediatrics, Narendra Modi Medical College, Ahmedabad, Gujarat, India. |
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Correspondence Address : Dr. Ayushi Rajeshbhai Agravat, Room No. 1012, PG Girls Hostel, Narendra Modi Medical College, Ahmedabad-380008, Gujarat, India. E-mail: ayushiagravat4@gmail.com |
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| ABSTRACT |  | ||||||||||||||||||||||||||
: Neonatal seizures are most commonly attributed to hypoxic-ischaemic injury, metabolic abnormalities, or central nervous system infections; however, an increasing proportion of cases are recognised to have an underlying genetic aetiology, particularly when routine investigations are non-contributory. Present report is of two neonates with early-onset seizures caused by distinct monogenic channelopathies who demonstrated markedly divergent clinical courses and outcomes. The first case was a near-term female neonate who presented on day 8 of life with recurrent tonic seizures and a significant family history of unexplained infantile death in a sibling. Comprehensive evaluation revealed no metabolic or structural abnormalities. Whole-Exome Sequencing (WES) identified a heterozygous pathogenic loss-of-function variant in the KCNQ2 gene. Seizures were controlled with phenobarbital monotherapy, and the infant remained seizure-free with age-appropriate neurodevelopment at 12 months of follow-up. The second case was a term male neonate who presented on day 11 of life with focal autonomic seizure clusters. Magnetic Resonance Imaging (MRI) brain demonstrated non-specific pachymeningeal enhancement. Despite treatment with five antiepileptic drugs (AEDs), seizures remained pharmacoresistant. Genetic analysis revealed a heterozygous variant of uncertain significance (VUS) in the SCN8A gene (c.1157C>A; p.Thr386Lys) and an additional heterozygous SCN8A variant (c.582G>T; p.Glu194Asp). By four months of age, the infant exhibited profound global developmental delay. These cases illustrate contrasting clinical trajectories in neonatal channelopathies with similar ages at seizure onset. | |||||||||||||||||||||||||||
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| Keywords : Developmental and epileptic encephalopathy, Genotype-phenotype correlation, Neonatal epilepsy, Pharmacoresistant epilepsy, Voltage-gated ion channels | |||||||||||||||||||||||||||
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DOI and Others :
DOI: 10.7860/IJNMR/2026/84829.2472
Date of Submission: Oct 10, 2025 Date of Peer Review: Dec 17, 2025 Date of Acceptance: Jan 08, 2026 Date of Publishing: Mar 31, 2026 AUTHOR DECLARATION: • Financial or Other Competing Interests: None • Was informed consent obtained from the subjects involved in the study? Yes • For any images presented appropriate consent has been obtained from the subjects. Yes PLAGIARISM CHECKING METHODS: • Plagiarism X-checker: Oct 11, 2025 • Manual Googling: Jan 02, 2026 • iThenticate Software: Jan 06, 2026 (1%) ETYMOLOGY: Author Origin EMENDATIONS: 7 |
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| Case Report |
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Case 1 A near-term female infant (36 weeks gestation, 2.4 kg) was born via emergency Lower Segment Caesarean Section (LSCS) (Table/Fig 1). On the eighth day of life, following an uneventful early phase, she presented with recurrent, unprovoked tonic seizures characterised by bilateral limb extension occurring 5-10 times per day. There was a significant family history of an elder sibling who died at one year of age following a history of seizures. Investigations including arterial blood gas, serum ammonia, lactate, electrolytes, and metabolic screening Tandem Mass Spectrometry (TMS) and Gas Chromatography-Mass Spectrometry (GCMS) were within normal limits. Genetic testing (WES) was pursued due to early-onset seizures, normal metabolic and neuroimaging evaluation, and a significant family history of epilepsy-related mortality. WES identified a heterozygous pathogenic loss-of-function variant in exon 4 of the KCNQ2 gene (Table/Fig 2). Neuroimaging via MRI was also normal (Table/Fig 3). Following this diagnosis, seizures were successfully controlled with Antiepileptic Drug (AED) monotherapy, and the infant demonstrated normal milestones at 12-month follow-up. Case 2 A full-term male (39 weeks gestation, 3.1 kg) presented on the 11th day of life with clusters of focal autonomic seizures involving eye deviation, apnoea, and desaturation. Baseline biochemical and metabolic investigations were normal. Seizures remained extremely pharmacoresistant despite the sequential use of five AEDs. There were no epileptic spasms or age-specific clinical features suggestive of West syndrome during the period of observation. Genetic testing was done in view of early-onset seizures with extreme pharmacoresistance despite appropriate antiseizure therapy. Genetic analysis identified a heterozygous SCN8A variant (c.1157C>A; p.Thr386Lys) and an additional heterozygous SLC6A1 variant (c.582G>T; p.Glu194Asp), both classified as Variants of Uncertain Significance (VUS) (Table/Fig 4). Despite aggressive polytherapy, the patient exhibited profound global developmental delay and axial hypotonia by four months of age. Brain MRI demonstrated incidental non specific pachymeningeal enhancement without evidence of structural malformation, a finding that was initially misleading (Table/Fig 5). | |||||||||||||||||||||||||||
| Discussion |
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Neonatal seizures represent a significant diagnostic challenge, with causes ranging from hypoxic–ischaemic injury and infection to metabolic and structural abnormalities. However, an increasing proportion of early-onset seizures are now attributed to monogenic aetiologies, particularly ion channelopathies, when routine investigations are unrevealing (1). Prospective population-based studies have demonstrated that single-gene epilepsies account for a substantial proportion of childhood-onset epilepsy, with an estimated incidence of approximately 1 per 2,000 live births (2). Advances in next-generation sequencing have markedly improved recognition of neonatal developmental and epileptic encephalopathies. Among potassium channelopathies, KCNQ2 -related disorders represent a well-established cause of neonatal epilepsy. KCNQ2 encodes the Kv7.2 subunit of voltage-gated potassium channels, which regulate neuronal membrane excitability. Pathogenic variants in KCNQ2 have been described across a phenotypic spectrum ranging from self-limited familial neonatal epilepsy to severe neonatal-onset developmental and epileptic encephalopathy (3). Foundational work by Singh NA et al., first identified KCNQ2 mutations in benign familial neonatal seizures, establishing potassium channel dysfunction as a mechanism for neonatal epilepsy (4). Subsequent cohort studies have demonstrated that loss-of-function variants are frequently associated with early seizure onset and favourable neurodevelopmental outcomes, particularly when seizures respond promptly to antiseizure therapy (3),(5). In Case 1, early-onset tonic seizures, absence of metabolic or structural abnormalities, and a positive family history were consistent with the classical KCNQ2 self-limited phenotype. The favourable seizure control with phenobarbital monotherapy and normal neurodevelopment at 12 months parallel observations from multicentre cohorts demonstrating good prognosis in non encephalopathic KCNQ2 variants (3),(5). These findings reinforce the importance of early genetic diagnosis in guiding prognostication and preventing unnecessary therapeutic escalation. In contrast, I#ISCN8AI?I-related disorders are typically associated with more severe phenotypes. SCN8A encodes the Nav1.6 voltage-gated sodium channel, critical for action potential initiation and propagation. Pathogenic variants often result in gain-of-function effects, leading to neuronal hyperexcitability and pharmacoresistant epilepsy (6),(7),(9). Large genotype-phenotype correlation studies have demonstrated that I#ISCN8AI?I-related developmental and epileptic encephalopathy commonly presents within the first six months of life and is frequently associated with significant developmental impairment and treatment resistance (6),(9). International consensus statements and GeneReviews summaries similarly emphasise early pharmacoresistance and adverse neurodevelopmental outcomes in affected individuals (6),(10). Case 2 demonstrated seizure onset in the neonatal period, failure of five antiseizure medications, and early global developmental delay, consistent with the severe end of the SCN8A phenotypic spectrum described in published cohorts (6),(9). Notably, brain MRI demonstrated non specific pachymeningeal enhancement without structural malformation. Neuroimaging abnormalities in genetic epilepsies may be incidental and potentially misleading, acting as a diagnostic “red herring,” particularly when infection and inflammation have been excluded. This underscores the need for early genetic evaluation when seizures are pharmacoresistant and metabolic studies are normal. An additional complexity in Case 2 was the presence of a heterozygous SLC6A1 variant. SLC6A1 encodes the GABA transporter-1 (GAT-1), and pathogenic variants have been associated with developmental delay, epilepsy, hypotonia, and neurobehavioural impairment (11). Although both SCN8A and SLC6A1 variants were classified as variants of uncertain significance, the co-existence of two variants affecting excitatory and inhibitory pathways raises the possibility of oligogenic contribution. Emerging literature suggests that dual-variant or “multiple-hit” genetic mechanisms may modulate phenotypic severity in developmental epilepsies (12). While functional validation was not available in index case, the extreme pharmacoresistance observed may reflect cumulative disruption of neuronal excitability. The direct comparison of these two neonates highlights the marked heterogeneity of neonatal channelopathies. As summarised in (Table/Fig 1), both infants presented within the second week of life and had normal metabolic evaluations; however, their clinical trajectories diverged substantially. Case 1 followed a self-limited course consistent with milder KCNQ2 phenotypes, whereas Case 2 demonstrated early pharmacoresistance and developmental impairment characteristic of severe SCN8A-related encephalopathy. | |||||||||||||||||||||||||||
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Case report
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