A 4-Year-Old Bahraini Girl With Developmental Delay and Epilepsy of Infancy With Migrating Focal Seizures Associated With KCNT1 Gene Mutation

Introduction

Potassium sodium-activated channel subfamily T member 1 (KCNT1)-related developmental and epileptic encephalopathy (DEE) is a rare neurological disorder caused by pathogenic heterozygous mutations in the KCNT1 gene [1]. This gene encodes a sodium-activated potassium channel that regulates neuronal activity and firing [2]. KCNT1 mutations are typically gain-of-function [3]. These mutations cause early-onset epilepsy that is resistant to treatment, as well as severe developmental delays [3,4]. The phenotype clinically presents as epilepsy of infancy with migrating focal seizures (EIMFS) or autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) [5]. Patients with KCNT1-related DEE usually develop symptoms within a few months of birth, such as multifocal migrating seizures, global developmental delay or regression, and central hypotonia [4,6]. The clinical progression is typically severe, and conventional anti-seizure medications frequently fail to offer appropriate seizure control [7]. This report describes the case of a Bahraini girl, 4 years of age at the time of this report, with developmental delay and EIMFS, an early-onset DEE associated with KCNT1 gene mutation.

Case Report

A Bahraini girl, 4 years of age at the time of this report, was born at term with normal vaginal birth to non-consanguineous parents without any perinatal or postnatal complications. She was previously healthy until 2 weeks of age when she developed her first seizure episode and was started on phenobarbitone. The seizures were characterized by abnormal movements in the form of eye rolling, left upper limb flexion, and right upper limb extension, lasting for 1 to 2 minutes, at least 2 to 3 times per day. These gradually progressed to migrating focal epilepsy. At the age of 4 months, she came with a worsening of her seizure activity. She was started on levetiracetam followed by carbamazepine, which resulted in a significant reduction in the frequency and severity of her seizures. During this time, the patient lost her social smile, visual fixation, and the ability to roll over.

Physical examination revealed a floppy infant with reduced muscle power and central hypotonia with no response to visual or auditory stimuli. No dysmorphic features nor neurocutaneous skin lesions were noticed. Electroencephalogram (EEG) showed an abnormal EEG with left parieto-temporal epileptiform spike and wave discharges along with frequent left temporo-parietal seizure activities (Figures 1, 2). All other investigations were within normal range, including brain magnetic resonance imaging (MRI), cerebrospinal fluid, amino acids and neurotransmitters, serum ammonia, lactate, organic acids, and plasma acylcarnitines.

Given the clinical presentation of developmental regression, hypotonia, and intractable migrating focal epilepsy, whole-exome sequencing was done using next-generation sequencing (NGS) technology by CENTOGENE GmbH (Rostock, Germany) within the CentoXome Solo diagnostic panel. The result confirmed a heterozygous KCNT1 variant, NM_020822.2: c.2807A>G (p.Asp936Gly), in a gene associated with autosomal dominant developmental and epileptic encephalopathy type 14 (DEE14). Due to the very specific clinical phenotype of neonatal-onset migrating focal seizures, developmental regression, and normal structural neuroimaging, the variant was interpreted as pathogenic in this patient. The molecular results supported the diagnosis of KCNT1 DEE14 (Figure 3).

Discussion

KCNT1-related DEE is a severe genetic epilepsy manifesting in the neonatal period. The clinical progression observed in our patient, characterized by early seizure onset, rapid developmental regression and genetic confirmation, highlights the significance of molecular diagnosis in infants presenting with this clinical pattern.

KCNT1-related epilepsy is considered a rare neurodevelopmental disorder based on population and case reports. According to the Danish population-based registry, which operated from 2012 to 2020, the birth incidence was lower than 1.1 per 100 000 live births. During that period, only 14 cases of KCNT1 were observed. Among those affected individuals, only 4 were diagnosed with either EIMFS or another form of DEE [8]. GeneReviews similarly describes KCNT1-related epilepsy as a rare condition with limited epidemiologic data [7]. With low incidence rates and small numbers of cases reported worldwide, KCNT1-related epilepsies are extremely rare and diverse, which emphasizes the need for early genetic testing in newborns with severe, treatment-resistant seizures [7,8].

The KCNT1 gene, which is located on chromosome 9q34.3, encodes a sodium-activated potassium channel involved in regulating neuronal excitability and action repolarization. Gain-of-function mutations enhance sodium-activated potassium (KNa1.1) currents, resulting in excessive potassium efflux during depolarization. This reduces the excitability of inhibitory interneurons relative to that of excitatory neurons, resulting in a loss of inhibitory control. This disturbed balance promotes network hyperexcitability, which contributes to the early appearance of the severe, drug-resistant seizures seen in KCNT1-related epilepsy [2,3,9].

The most common and severe clinical presentation of KCNT1-related epilepsy is EIMFS, a genetically heterogenous condition in which KCNT1 is one of the most frequently identified pathogenic genes. This condition typically arises within the first 6 months of life, often in the first few weeks. The seizures in KCNT1-related epilepsy show a variety of clinical symptoms. Typically, focal motor seizures occur first, and then as the disease progresses, patients may experience tonic, clonic, myoclonic, and epileptic spasms, demonstrating the complexity of this disease. It is often very severe and resistant to antiepileptic medications. By the age of 6 to 9 months, seizures may progress to a near-continuous pattern. In addition, patients may present with apnea, perioral cyanosis, and flushing. Other symptoms that may be observed include central hypotonia, microcephaly, marked developmental delay, and mobility problems. ADNFLE, on the other hand, affects fewer patients, is usually inherited, and usually presents as seizures associated with behavioral and mental health issues, as well as cognitive impairment [4,6,7,10].

Subsequent case series published in the literature have also helped to refine genotype-phenotype correlations in KCNT1-related epilepsy. Large-scale studies have shown that KCNT1 is responsible for a significant number of genetically proven EIMFS cases, although the clinical severity is highly variable among affected subjects [10]. Barcia et al have identified mutation hotspots in the KCNT1 gene that show a high degree of phenotypic variability even among subjects with similar mutations [11]. Their results confirmed that KCNT1 mutations are strongly linked with early-onset, treatment-resistant EIMFS and are often associated with severe developmental delay and poor prognosis.

Our patient’s symptoms began with neonatal-onset focal seizures, which progressed rapidly to migrating focal epilepsy and then to early developmental regression in the first few months of life. This clinical presentation is very similar to the malignant phenotypes reported in previous series, in which the onset of seizures is in the neonatal period, the seizures become intractable to conventional antiepileptic therapy, and the seizures are accompanied by progressive developmental regression [10,11]. As in the series reported by Barcia et al, our patient had early-onset severe epilepsy without structural brain lesions, which is consistent with the idea that KCNT1-related EIMFS is a form of genetic encephalopathy rather than a structural epilepsy syndrome [12]. The identified KCNT1 heterozygous mutation in our patient is also consistent with the molecular data reported in these series.

The diagnosis of KCNT1-related epilepsy in infancy relies on recognizing the clinical symptoms and neurological findings and confirming them with molecular testing. In this condition, the EEG will show multifocal seizures that shift across the brain, accompanied by generalized background attenuation. These findings suggest an underlying genetic cause. To confirm the diagnosis, next-generation sequencing (NGS) or whole-exome sequencing is needed to find the harmful KCNT1 variant. Therefore, combining the EEG with genetic testing is vital for the diagnosis of KCNT1-related epilepsy [4,7,12].

The management of KCNT1-related epilepsy still remains challenging, as the seizures are often unresponsive to standard anti-seizure drugs [7]. According to GeneReviews, there is limited and often incomplete response to standard therapies, including sodium channel blockers, as most patients continue to experience refractory seizures despite polytherapy [7]. Targeted therapy with quinidine has been investigated based on its ability to block KCNT1 channels, but the response has been variable in selected patients [13]. The use of the drug is often associated with inconsistent therapeutic response, which may be limited by adverse effects and the need for close cardiac monitoring [13]. Early genetic diagnosis is, therefore, crucial for management and accurate counseling, as it also opens the way for the development of precision therapies [7].

The prognosis of KCNT1-related EIMFS is usually poor. Mortality is high; in 2019, Kuchenbuch et al reported a mortality rate of around 47%. The median age of death was approximately 3 years old. Survivors often face severe and lasting neurodevelopmental issues and continue to have seizures that do not respond to medication. Prolonged periods without seizures are extremely unusual. Early genetic testing and more focused therapy are urgently needed because of this severe and limiting illness [14].

Conclusions

KCNT1-related DEE is a rare, severe neurological disease. This condition, which is associated with neurodevelopmental regression, is linked to the onset of seizures that are refractory to antiepileptic drugs, at a young age. This case report stresses the importance of continued research working on therapies that target this particular disease, to improve patient outcomes. This case report also stresses the importance of early genetic analysis in newborn patients with refractory epilepsy, and the need for more research being conducted on KCNT1-targeted therapies.