KCNT1-Related Epilepsy: A Review

KCNT1 gene encodes the sodium-dependent potassium channel reported as a causal factor for several different epileptic disorders. The gene has been also linked with cardiac disorders and in a family to sudden unexpected death in epilepsy. KCNT1 mutations, in most cases, result in a gain of function causing a neuronal hyperpolarization with loss of inhibition. Many early-onset epileptic encephalopathies related to gain of function of KCNT1 gene have been described, most often associated with two phenotypes: malignant migrating focal seizures of infancy and familial autosomal-dominant nocturnal frontal lobe epilepsy; however, there is no clear phenotype–genotype correlation, in fact same mutations have been represented in patients with West syndrome, Ohtahara syndrome, and early myoclonic encephalopathy. Additional neurologic features include intellectual disability, psychiatric disorders, hypotonia, microcephaly, strabismus, and movement disorders. Conventional anticonvulsant, vagal stimulation, and ketogenic diet have been used in the absence of clinical benefit in individuals with KCNT1-related epilepsy; in some patients, quinidine therapy off-label has been practiced successfully. This review aims to describe the characteristics of the gene, the phenotypes related to genetic mutations with the possible genotype–phenotype correlations and the treatments proposed to date, discussing the comorbidities reported in the literature.

Neurons and mechanism of epileptic associated genes in brain network: current concepts and future perspectives.

Neurons are the basic cell structure of the nervous system and responsible for the communication between brain and body. Brain networks are formed from a single neuron to highly complexed interconnected (˷ 100 billion) neurons. Imbalances between excitation and inhibition mechanism of neuronal cells leads to altered brain network causing seizure/epileptic activity. The mechanism is known as an ictogenic mechanism. In particular, epilepsy is characterized by abnormal neuronal cells and several genetic factors are attributed for their development. CHRNA4 is the first epileptic gene discovered in an autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Since, the era of epileptic genetics has reached to peaks and still extending the branches to study in detail to solve the mysteries behind the brain and epileptic/seizure genes. However, genes such as AQP4, SESN3, ARX, NTNG1, NTNG2, TSC1 and TSC2 need more attention in epilepsy genetic studies. Therefore, this review describes brain network during epilepsy (recurrent seizure) as well as deals with recent studies on molecular genetics and identification methods of epilepsy.

Monogenic Epilepsies: Channelopathies, Synaptopathies, mTorpathies, and Otheropathies

Epilepsy has been historically defined as the recurrence of two or more seizures, together with typical electroencephalogram (EEG) changes, and significant comorbidities, including cardiac and autonomic changes, injuries, intellectual disability, permanent brain damage, and higher mortality risk. Epilepsy may be the consequence of several causes, including genetic anomalies, structural brain malformations, hypoxic–ischemic encephalopathy, brain tumors, drugs, and all contributing factors to the imbalance between excitatory and inhibitory neurons and modulatory interneurons which in turn provoke abnormal, simultaneous electric discharge(s) involving part, or all the brain. In the pregenetic, pregenomic era, in most cases, the exact cause of such neuronal/interneuronal disequilibrium remained unknown and the term “idiopathic epilepsy” was used to define all the epilepsies without cause. At the same time, some specific epileptic syndromes were indicated by the eponym of the first physician who originally described the condition (e.g., the West syndrome, Dravet syndrome, Ohtahara syndrome, and Lennox–Gastaut syndrome) or by some characteristic clinical features (e.g., nocturnal frontal lobe epilepsy, absence epilepsy, and epilepsy and mental retardation limited to females). In many of these occurrences, the distinct epileptic syndrome was defined mainly by its most relevant clinical feature (e.g., seizure semiology), associated comorbidities, and EEGs patterns. Since the identification of the first epilepsy-associated gene (i.e., CHRNA4 gene: cholinergic receptor neuronal nicotinic α polypeptide 4), one of the genes responsible for autosomal dominant nocturnal frontal lobe epilepsy (currently known as sleep-related hypermotor epilepsy) in 1995, the field of epilepsy and the history of epilepsy gene discoveries have gone through at least three different stages as follows: (1) an early stage of relentless gene discovery in monogenic familial epilepsy syndromes; (2) a relatively quiescent and disappointing period characterized by largely negative genome-wide association candidate gene studies; and (3) a genome-wide era in which large-scale molecular genetic studies have led to the identification of several novel epilepsy genes, especially in sporadic forms of epilepsy. As of 2021, more than 150 epilepsy-associated genes or loci are listed in the Online Mendelian Inheritance in Man database.

A novel KCNT1 mutation in a Chinese family with severe autosomal-dominant nocturnal frontal lobe epilepsy

We describe a Chinese family with severe autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) and psychiatric problems in whom whole-exome family trio sequencing identified a heterozygous mutation in the potassium channel subfamily T, member 1 (KCNT1), a sodium-gated potassium channel gene, which was a novel missense mutation c.2153A>T (p. Asp718Val). The typical characteristics of the three patients in the family were refractory epilepsy, acquired cognitive impairment, and psychiatric problems, which include hallucinations and suicidal thoughts and behaviors. The age at onset was found to be earlier in son and daughter of the proband than that of the proband, as proven by the proband’s history of an epileptic seizure at the age of 16 years and her son’s and daughter’s history of seizures at the age of 8 years. Magnetic resonance imaging findings were negative for any abnormalities. Because of psychiatric symptoms, these three patients were administered risperidone at different times during their illness. The protestor’s son had tried fenofibrate treatment, but clinical remission was unclear. In summary, our findings broadened the mutation database in relation to KCNT1 and implicated the sodium-gated potassium channel complex in ADNFLE, more broadly, in the pathogenesis of focal epilepsies.

Convolutional Neural Network for Seizure Detection of Nocturnal Frontal Lobe Epilepsy

The Nocturnal Frontal Lobe Epilepsy (NFLE) is a form of epilepsy in which seizures occur predominantly during sleep. In other forms of epilepsy, the commonly used clinical approach mainly involves manual inspection of encephalography (EEG) signals, a laborious and time-consuming process which often requires the contribution of more than one experienced neurologist. In the last decades, numerous approaches to automate this detection have been proposed and, more recently, machine learning has shown very promising performance. In this paper, an original Convolutional Neural Network (CNN) architecture is proposed to develop patient-specific seizure detection models for three patients affected by NFLE. The performances, in terms of accuracy, sensitivity, and specificity, exceed by several percentage points those in the most recent literature. The capability of the patient-specific models has been also tested to compare the obtained seizure onset times with those provided by the neurologists, with encouraging results. Moreover, the same CNN architecture has been used to develop a cross-patient seizure detection system, resorting to the transfer-learning paradigm. Starting from a patient-specific model, few data from a new patient are enough to customize his model. This contribution aims to alleviate the task of neurologists, who may have a robust indication to corroborate their clinical conclusions.

Sleep-Related Movement Disorders

Some movement disorders and behavioral disorders appear specifically during sleep or in relation to sleep. These are rapid eye movement (REM) sleep behavior disorders (RBD); restless legs syndrome; periodic limb movement in sleep (PLMS); cataplexy, which manifests itself as sudden falling, head dropping, or jaw dropping due to sudden loss of muscle tone triggered by emotions (laughing in particular); hypnic jerks or hypnagogic myoclonus; fragmentary myoclonus in children; autosomal dominant nocturnal frontal lobe epilepsy; sleep walking and sleep terrors; head banging, and bruxism (grinding of the teeth). Careful history taking or reviewing a home video provides valuable clues, but the gold standard remains video polysomnography (PSG). Some sleep-related movements do not represent “disorders” as such but are harmless, physiological motor phenomena, and are discussed because of their frequency and relevance in differential diagnostic considerations.

Epilepsy with migrating focal seizures

ObjectiveTo report new sporadic cases and 1 family with epilepsy of infancy with migrating focal seizures (EIMFSs) due to KCNT1 gain-of-function and to assess therapies' efficacy including quinidine.MethodsWe reviewed the clinical, EEG, and molecular data of 17 new patients with EIMFS and KCNT1 mutations, in collaboration with the network of the French reference center for rare epilepsies.ResultsThe mean seizure onset age was 1 month (range: 1 hour to 4 months), and all children had focal motor seizures with autonomic signs and migrating ictal pattern on EEG. Three children also had infantile spasms and hypsarrhythmia. The identified KCNT1 variants clustered as “hot spots” on the C-terminal domain, and all mutations occurred de novo except the p.R398Q mutation inherited from the father with nocturnal frontal lobe epilepsy, present in 2 paternal uncles, one being asymptomatic and the other with single tonic-clonic seizure. In 1 patient with EIMFS, we identified the p.R1106Q mutation associated with Brugada syndrome and saw no abnormality in cardiac rhythm. Quinidine was well tolerated when administered to 2 and 4-year-old patients but did not reduce seizure frequency.ConclusionsThe majority of the KCNT1 mutations appear to cluster in hot spots essential for the channel activity. A same mutation can be linked to a spectrum of conditions ranging from EMFSI to asymptomatic carrier, even in the same family. None of the antiepileptic therapies displayed clinical efficacy, including quinidine in 2 patients.

Infantile refractory seizures due to de novo KCNT 1 mutation

We describe a term female infant who presented with multiple seizures early in infancy. The clinical and electrical seizures were refractory to traditional antiepileptic medications. After extensive workup, seizure panel testing revealed KCNT1 gene mutation, which is associated with nocturnal frontal lobe epilepsy and epilepsy of infancy with migrating focal seizures. The infant’s condition improved with the combination of traditional as well non-traditional antiepileptic therapy.