Benign Familial Neonatal Convulsions Research Articles

KCNQ2 Selectivity Filter Mutations Cause Kv7.2 M-Current Dysfunction and Configuration Changes Manifesting as Epileptic Encephalopathies and Autistic Spectrum Disorders.

KCNQ2 mutations can cause benign familial neonatal convulsions (BFNCs), epileptic encephalopathy (EE), and mild-to-profound neurodevelopmental disabilities. Mutations in the KCNQ2 selectivity filter (SF) are critical to neurodevelopmental outcomes. Three patients with neonatal EE carry de novo heterozygous KCNQ2 p.Thr287Ile, p.Gly281Glu and p.Pro285Thr, and all are followed-up in our clinics. Whole-cell patch-clamp analysis with transfected mutations was performed. The Kv7.2 in three mutations demonstrated significant current changes in the homomeric-transfected cells. The conduction curves for V1/2, the K slope, and currents in 3 mutations were lower than those for the wild type (WT). The p.Gly281Glu had a worse conductance than the p.Thr287Ile and p.Pro285Thr, the patient compatible with p.Gly281Glu had a worse clinical outcome than patients with p.Thr287Ile and p.Pro285Thr. The p.Gly281Glu had more amino acid weight changes than the p.Gly281Glu and p.Pro285Thr. Among 5 BFNCs and 23 EE from mutations in the SF, the greater weight of the mutated protein compared with that of the WT was presumed to cause an obstacle to pore size, which is one of the most important factors in the phenotype and outcome. For the 35 mutations in the SF domain, using changes in amino acid weight between the WT and the KCNQ2 mutations to predict EE resulted in 80.0% sensitivity and 80% specificity, a positive prediction rate of 96.0%, and a negative prediction rate of 40.0% (p = 0.006, χ2 (1, n = 35) = 7.56; odds ratio 16.0, 95% confidence interval, 1.50 to 170.63). The findings suggest that p.Thr287Ile, p.Gly281Glu and p.Pro285Thr are pathogenic to KCNQ2 EE. In mutations in SF, a mutated protein heavier than the WT is a factor in the Kv7.2 current and outcome.

Clinical and genetic analysis of a Chinese pedigree affected with benign familial neonatal convulsion

To analyze the clinical phenotype and genetic variant in a Chinese pedigree affected with benign familial neonatal convulsion (BFNC). Clinical data and peripheral blood samples of the pedigree were obtained with informed consent. Whole exome sequencing (WES) was carried out for the proband. Candidate variants were verified by Sanger sequencing. The pedigree comprised 9 individuals, among whom 4 were affected, including 3 males and 1 female. All patients had developed seizures during the neonatal period, which had ceased in 4 to 6 months. One patient had recurrence in between 1 and 2 years old. Genetic testing has identified a novel nonsense c.810G>A (p.W270X) variant in exon 5 of the KCNQ2 gene, which has co-separated with the BFNC phenotype in the pedigree. The patients from this pedigree have conformed to the diagnosis of BFNC with good prognosis, which was in keeping with previously reported cases. The heterozygous c.810G>A (p.W270X) nonsense variant of the KCNQ2 gene probably underlay the pathogenesis of BFNC in this pedigree, which has expanded the mutational spectrum of the disease.

Heteromeric Kv7.2 current changes caused by loss-of-function of KCNQ2 mutations are correlated with long-term neurodevelopmental outcomes

Pediatric epilepsy caused by KCNQ2 mutations can manifest benign familial neonatal convulsions (BFNC) to neonatal-onset epileptic encephalopathy (EE). Patients might manifest mild to profound neurodevelopmental disabilities. We analysed c.853C > A (P285T) and three mutations that cause KCNQ2 protein changes in the 247 position: c.740C > T (S247L), c.740C > A (S247X), and c.740C > G (S247W). S247L, S247W, and P285T cause neonatal-onset EE and poor neurodevelopmental outcomes; S247X cause BFNC and normal outcome. We investigated the phenotypes correlated with human embryonic kidney 293 (HEK293) cell functional current changes. More cell-current changes and a worse conductance curve were present in the homomeric transfected S247X than in S247L, S247W, and P285T. But in the heteromeric channel, S247L, S247W and P285T had more current impairments than did S247X. The protein expressions of S247X were nonfunctional. The outcomes were most severe in S247L and S247W, and severity was correlated with heteromeric current. Current changes were more significant in cells with homomeric S247X, but currents were “rescued” after heteromeric transfection of KCNQ2 and KCNQ3. This was not the case in cells with S247L, S247W. Our findings support that homomeric current changes are common in KCNQ2 neonatal-onset EE and KCNQ2 BFNC; however, heteromeric functional current changes are correlated with long-term neurodevelopmental outcomes.

Potassium ion channels and epilepsy

Epilepsy is one of the commonest neurological disorder, and genetic factors play a major role in the etiology of epilepsy disorders. In recent years, more and more attention has been paid on the study of potassium channel and epilepsy. The classification of potassium channels is complex, and variants in these genes can lead to a variety of phenotypes from the severest to the mildest, from early infantile epileptic encephalopathy (EIEE) to benign familial neonatal convulsion (BFNC). Moreover, patients with mutations in the same gene may exhibit with distinctive clinical manifestations, the channel dysfunction caused by the variants is correlated with the severity of the disorder. To achieve accurate treatment, the change of channel function is needed to be studied, and more attention should be paid on the development of targeted drugs. Key words: Potassium channels; Epilepsy; Review

Benign familial neonatal convulsions: A case report

Benign familial neonatal convulsions: A case report

Epilepsies Associated with KCNQ2 Complicated by Supraventricular Tachycardia Due to a De Novo Mutation in KCNQ2

Introduction: Epilepsies associated with the KCNQ2 mutation are a spectrum of disorders, with clinical manifestations ranging from benign familial neonatal convulsion to early-onset epileptic encephalopathy, depending on the mutation type and location (such as up-stream control elements). Here, we report the case of an infant girl diagnosed with epilepsy due to a de novo mutation in KCNQ2 and more interestingly, complicated by supraventricular tachycardia. Case Presentation: An infant girl was diagnosed with epilepsy, with the following manifestations: Onset of seizures at three months; generalized tonic-clonic seizures, frequent at the beginning; status epilepticus, followed by psychomotor development retrogression; generalized spike, spike-slow, and slow waves observed during ictal electroencephalography (EEG), normal interictal EEG, and cranial magnetic resonance imaging. Seizures were controlled after administering valproic acid, and the patient exhibited normal psychomotor development eventually. Targeted next-generation sequencing identified a previously unreported de novo mutation in KCNQ2 [c.553G>A; p.(Ala185Thr)]. Interestingly, the patient also exhibited supraventricular tachycardia, confirmed by electrocardiography. Although we concluded that seizure was the convulsive syncope resulting from arrhythmia, we conceived a link between the two events, which has been called “cardiocerebral” channelopathy. Conclusions: A de novo mutation in KCNQ2 causes epilepsy and the concurrent arrhythmia may be linked with this mutation.

Levetiracetam is Less Effective than Phenobarbital in Treating Seizures Associated with KCNQ2 Variant of Benign Familial Neonatal Convulsions

AbstractBenign familial neonatal convulsions (BFNC) is an autosomal dominant disorder that presents with generalized tonic–clonic and partial seizures. Levetiracetam is becoming increasingly popular for the treatment of neonatal seizures due to a benign safety profile. Concern has arisen over possible neurotoxicity and apoptosis due to phenobarbital. A male infant with BFNC due to a KCNQ2 mutation responded to phenobarbital but not to levetiracetam. The patient's brother with the same mutation had seizures on day 4 of life; phenobarbital was administered and he became seizure free. This suggests that levetiracetam is a less effective treatment than phenobarbital for BFNC.

P 85 KCNQ-2 missense mutations and phosphatidylinositol 4,5-bisphosphate in familial epilepsy

The KCNQ2/3 channel is a slowly activating, non-inactivating voltage-gated potassium channel. It causes the M-current and sustains the resting membrane potential. Therefore, it is crucial for the regulation of neuronal plasticity. If a neuron does not reach the resting-potential after activation, excitation may spread throughout the neuronal network and a seizure may follow. In this work we study the influence of the intracellular second messenger phosphatidylinositol 4,5-bisphosphate (PIP2) on channels containing mutant KCNQ2 subunits associated with Benign Familial Neonatal Convulsions (BFNC). We hypothesize that mutations in the KCNQ2 C-terminus are characterized not only by constitutive changes, but also by changes in their modulation by second messengers. We examined the following missense-mutations: R333G, L339R, R353G, R553Q, K554N and L637Q, all located in the C-terminus of KCNQ2. Measurements were performed in whole-cell gigaseal voltage-clamp technique in HEK293t cells transfected with wildtype (WT) or mutant KCNQ2 and WT KCNQ3. We first characterized channel activation in IV curves. To examine the modulation of channels by PIP2, we perfused cells intracellularly with Neomycin by adding it to the patch pipette; the aminoglycoside-antibiotic agent acts as a PIP2 sponge and reduces PIP2 binding to KCNQ2. In addition, we activated muscarinic M1 receptors using oxotremorine, leading to PIP2 depletion through activation of phospholipase C (PLC). Our work showed. • Voltage dependence of channel activation was similar as WT for all mutants. • Two of the examined mutants have smaller currents (L339R, L637Q), four have similar currents (R333G, R553Q, K554N), and one has higher currents(R353G) as compared to the wildtype channel. • The evaluated mutants did not have a higher sensitivity to Neomycin. • Unexpectedly, activation of M1 receptors by very low agonist concentrations led to an initial, short-lasting increase in currents followed by the known decrease in current at higher concentrations. This phenomenon was observed in the wildtype and in mutants. Previous research by others described an impaired binding between Calmoduline and KCNQ2 R353G being associated with a smaller number of channels reaching the cellular membrane (Richards et al., 2004). Conversely, our results showed increased whole-cell currents with the R353G mutant. Yet we were able to confirm a hypersensibility of R353G to Oxotremorine recently described by others (Kosenko et al., 2012). These findings support the hypothesis that C-terminal missense mutations can influence channel regulation by second messengers in the absence of constitutive changes in the channel activity itself. Conceivably, the development of epileptogenic activity may even in sporadic forms of epilepsy be caused not only by structural changes, but also by alterations in intracellular second messenger pathways affecting ion channel regulation.

Epilepsies associated with KCNQ2: A spectrum of disorders

Epilepsies associated with KCNQ2 are a spectrum of disorders, and KCNQ2 mutations lead to a variety of phenotypes from the severest to the mildest, from early onset epileptic encephalopathy (EOEE) to benign familial neonatal convulsion (BFNC). The type and the position of KCNQ2 mutations may be associated with phenotypes, and provide a clue for assessing prognosis. KCNQ2 mutations lead to the reduced protein expression, abnormal distribution of potassium channels or decreased currents of potassium channels. It is the potential mechanism that KCNQ2 mutations cause different phenotypes. Recent studies have also found that KCNQ2 mutations may trigger seizures by enhancing potassium channel currents; however it needs further studies to verify. Key words: KCNQ2 potassium channel; Epilepsy; Review

Early genetic testing for neonatal epilepsy

The incidence of seizures is greatest during the neonatal period, with an estimated rate of 2–4 per 1,000 live births. Although the majority of seizures in the newborn are due to acquired brain disorders, a substantial proportion are due to metabolic and genetic disorders causing neonatal- and infantile-onset epilepsies. For decades, genetics has played a critical role in identification and treatment of seizures in the newborn and infantile period.1,2 With newborn screening, disorders such as phenylketonuria and biotinidase deficiency can be identified before patients develop seizures. Early identification and treatment prevents the development of often severe epilepsy syndromes and associated comorbidities. Detection and early treatment will continue to improve as newborn screening methods advance, whether based in genetics or clinical observation: the first channelopathy that causes epilepsy was identified in families with benign familial neonatal convulsions in the 1990s, before completion of the human genome project and modern genomics.3

Two Novel KCNQ2 Mutations in 2 Families With Benign Familial Neonatal Convulsions.

Benign familial neonatal convulsion is a rare autosomal dominant inherited epilepsy syndrome characterized by unprovoked seizures in the first few days of life, normal psychomotor development, and a positive intergenerational family history of neonatal seizures. Over 90% of the affected individuals have inherited causal mutations in KCNQ2, which encodes for the potassium voltage-gated channel subfamily Q, member 2. Mutations in KCNQ2 are also associated with a severe neonatal encephalopathy phenotype associated with poor seizure control and neurodevelopmental deficits. The authors report the clinical presentations, response to medication, and intrafamilial phenotypic variability in 2 families with benign familial neonatal convulsions, carrying previously unreported heterozygous missense mutations, c.1066C>G (p.Leu356Val) and c.1721G<A (p.Gly574Asp), in KCNQ2. The cases reported herein suggest that inherited missense mutations in KCNQ2 can be associated with an intermediate phenotype and illustrate the challenges associated with prognosis and counselling for individuals with inherited missense mutations in KCNQ2.

New trends in neonatal seizures

Seizures are very frequent in neonatal period. A seizure is an abrupt alteration in neurological function of the newborn and it can be due to many different causes. There are new pathogenetic hypothesis that try to clarify the mechanism of neonatal sizures. Leaving aside new four classical types of neonatal seizures (subtle, clonic, tonic, myoclonic), new clinical forms have been recently identified: benign idiopathic neonatal convulsion (fifth day fist), benign familial neonatal convulsion, early epileptic encephalopathy with suppression burst (Ohtahara syndrome); early myoclonic epileptic encephalopathy. Finally, there are some open issues about the treatment and the prognosis of neonatal seizures. This review summarizes current knowledge regarding pathophysiology, treatment and prognosis of neonatal seizures. (J Pediatr Neurol 2004; 2(4): 191-197).

Common pediatric epilepsy syndromes.

Benign rolandic epilepsy (BRE), childhood idiopathic occipital epilepsy (CIOE), childhood absence epilepsy (CAE), and juvenile myoclonic epilepsy (JME) are some of the common epilepsy syndromes in the pediatric age group. Among the four, BRE is the most commonly encountered. BRE remits by age 16 years with many children requiring no treatment. Seizures in CAE also remit at the rate of approximately 80%; whereas, JME is considered a lifelong condition even with the use of antiepileptic drugs (AEDs). Neonates and infants may also present with seizures that are self-limited with no associated psychomotor disturbances. Benign familial neonatal convulsions caused by a channelopathy, and inherited in an autosomal dominant manner, have a favorable outcome with spontaneous resolution. Benign idiopathic neonatal seizures, also referred to as "fifth-day fits," are an example of another epilepsy syndrome in infants that carries a good prognosis. BRE, CIOE, benign familial neonatal convulsions, benign idiopathic neonatal seizures, and benign myoclonic epilepsy in infancy are characterized as "benign" idiopathic age-related epilepsies as they have favorable implications, no structural brain abnormality, are sensitive to AEDs, have a high remission rate, and have no associated psychomotor disturbances. However, sometimes selected patients may have associated comorbidities such as cognitive and language delay for which the term "benign" may not be appropriate.

The Human Ether-A-Go-Go–Related Gene Activator NS1643 Enhances Epilepsy-Associated KCNQ Channels

Human ether-a-go-go-related gene (hERG) and KCNQ channels are two classes of voltage-gated potassium channels. Specific mutations have been identified that are causal for type II long QT (LQT2) syndrome, neonatal epilepsy, and benign familial neonatal convulsions. Increasing evidence from clinical studies suggests that LQT2 and epilepsy coexist in some patients. Therefore, an integral approach to investigating and treating the two diseases is likely more effective. In the current study, we found that NS1643 [1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea], a previously reported hERG activator, is also an activator of KCNQ channels. It potentiates the neuronal KCNQ2, KCNQ4, and KCNQ2/Q3 channels, but not the cardiac KCNQ1. The effects of NS1643 on the KCNQ2 channel include left shifting of voltage for reaching 50% of the maximum conductance and slowing of deactivation. Analysis of the dose-response curve of NS1643 revealed an EC50 value of 2.44 ± 0.25 μM. A hydrophobic phenylalanine (F137) located at the middle region of the voltage-sensing domain was identified as critical for NS1643 activity on KCNQ2. When testing NS1643 effects in rescuing LQT2 hERG mutants and the KCNQ2 BFNC mutants, we found it is particularly efficacious in some cases. Considering the substantial relationship between LQT2 and epilepsy, these findings reveal that NS1643 is a useful compound to elucidate the causal connection of LQT2 and epilepsy. More generally, this may provide a strategy in the development of therapeutics for LQT2 and epilepsy.

Polarized axonal surface expression of neuronal KCNQ potassium channels is regulated by calmodulin interaction with KCNQ2 subunit.

KCNQ potassium channels composed of KCNQ2 and KCNQ3 subunits give rise to the M-current, a slow-activating and non-inactivating voltage-dependent potassium current that limits repetitive firing of action potentials. KCNQ channels are enriched at the surface of axons and axonal initial segments, the sites for action potential generation and modulation. Their enrichment at the axonal surface is impaired by mutations in KCNQ2 carboxy-terminal tail that cause benign familial neonatal convulsion and myokymia, suggesting that their correct surface distribution and density at the axon is crucial for control of neuronal excitability. However, the molecular mechanisms responsible for regulating enrichment of KCNQ channels at the neuronal axon remain elusive. Here, we show that enrichment of KCNQ channels at the axonal surface of dissociated rat hippocampal cultured neurons is regulated by ubiquitous calcium sensor calmodulin. Using immunocytochemistry and the cluster of differentiation 4 (CD4) membrane protein as a trafficking reporter, we demonstrate that fusion of KCNQ2 carboxy-terminal tail is sufficient to target CD4 protein to the axonal surface whereas inhibition of calmodulin binding to KCNQ2 abolishes axonal surface expression of CD4 fusion proteins by retaining them in the endoplasmic reticulum. Disruption of calmodulin binding to KCNQ2 also impairs enrichment of heteromeric KCNQ2/KCNQ3 channels at the axonal surface by blocking their trafficking from the endoplasmic reticulum to the axon. Consistently, hippocampal neuronal excitability is dampened by transient expression of wild-type KCNQ2 but not mutant KCNQ2 deficient in calmodulin binding. Furthermore, coexpression of mutant calmodulin, which can interact with KCNQ2/KCNQ3 channels but not calcium, reduces but does not abolish their enrichment at the axonal surface, suggesting that apo calmodulin but not calcium-bound calmodulin is necessary for their preferential targeting to the axonal surface. These findings collectively reveal calmodulin as a critical player that modulates trafficking and enrichment of KCNQ channels at the neuronal axon.

Role of calmodulin in neuronal Kv7/KCNQ potassium channels and epilepsy

Neuronal Kv7/KCNQ channels are critical regulators of neuronal excitability since they potently suppress repetitive firing of action potentials. These voltage-dependent potassium channels are composed mostly of Kv7.2 / KCNQ2 and Kv7.3 / KCNQ3 subunits that show overlapping distribution throughout the brain and in the peripheral nervous system. They are also called ‘M-channels’ since their inhibition by muscarinic agonists leads to a profound increase in action potential firing. Consistent with their ability to suppress seizures and attenuate chronic inflammatory and neuropathic pain, mutations in the KCNQ2 and KCNQ3 genes are associated with benign familial neonatal convulsions, a dominantly-inherited epilepsy in infancy. Recently, de novo mutations in the KCNQ2 gene have been linked to early onset epileptic encephalopathy. Notably, some of these mutations are clustered in a region of the intracellular cytoplasmic tail of Kv7.2 that interacts with a ubiquitous calcium sensor, calmodulin. In this review, we highlight the recent advances in understanding the role of calmodulin in modulating physiological function of neuronal Kv7 channels including their biophysical properties, assembly, and trafficking. We also summarize recent studies that have investigated functional impact of epilepsy-associated mutations localized to the calmodulin binding domains of Kv7.2.

Kcnq 1-5 (Kv7.1-5) potassium channel expression in the adult zebrafish

BackgroundKCNQx genes encode slowly activating-inactivating K+ channels, are linked to physiological signal transduction pathways, and mutations in them underlie diseases such as long QT syndrome (KCNQ1), epilepsy in adults (KCNQ2/3), benign familial neonatal convulsions in children (KCNQ3), and hearing loss or tinnitus in humans (KCNQ4, but not KCNQ5). Identification of kcnqx potassium channel transcripts in zebrafish (Danio rerio) remains to be fully characterized although some genes have been mapped to the genome. Using zebrafish genome resources as the source of putative kcnq sequences, we investigated the expression of kcnq1-5 in heart, brain and ear tissues.ResultsOverall expression of the kcnqx channel transcripts is similar to that found in mammals. We found that kcnq1 expression was highest in the heart, and also present in the ear and brain. kcnq2 was lowest in the heart, while kcnq3 was highly expressed in the brain, heart and ear. kcnq5 expression was highest in the ear. We analyzed zebrafish genomic clones containing putative kcnq4 sequences to identify transcripts and protein for this highly conserved member of the Kcnq channel family. The zebrafish appears to have two kcnq4 genes that produce distinct mRNA species in brain, ear, and heart tissues.ConclusionsWe conclude that the zebrafish is an attractive model for the study of the KCNQ (Kv7) superfamily of genes, and are important to processes involved in neuronal excitability, cardiac anomalies, epileptic seizures, and hearing loss or tinnitus.

Increased susceptibility to acetylcholine in the entorhinal cortex of pilocarpine-treated rats involves alterations in KCNQ channels

In models of temporal lobe epilepsy, in-vitro exposure of the entorhinal cortex (EC) to low concentrations of acetylcholine (ACh) induces muscarinic-dependent seizure-like events. Potassium channels from the KCNQ/Kv7 family, which close upon activation of muscarinic receptors, are mutated in several epileptic syndromes such as benign familial neonatal convulsions (KCNQ2/KCNQ3) and sudden unexplained death in epilepsy (KCNQ1). Therefore, we tested the hypothesis whether the ictogenic effect of ACh involves alterations of KCNQ channels. In horizontal temporo-hippocampal slices from pilocarpine-treated chronically epileptic rats, field potential recordings of epileptiform activity were performed in response to the application of ACh, the KCNQ blocker linopirdine, and KCNQ agonists. In the EC of control rats, ACh (20 and 50μM) induced nested fast activity in the range of 15–20Hz riding on <1Hz slow oscillations. By contrast, in slices from pilocarpine-treated rats, 5μM ACh was sufficient to induce interictal discharges that frequently transformed to epileptiform events at 20μM ACh. While the non-specific KCNQ/Kv7 channel blocker linopirdine (20 and 50μM) had no effect in control animals, in slices from epileptic rats it induced interictal discharges or seizure-like events. These could be blocked by the unspecific KCNQ/Kv7 agonist retigabine and attenuated by the Kv7.1 agonist L364–373. Immunohistochemistry revealed reduced expression of KCNQ2 and KCNQ3 in the EC and of KCNQ3-positive dendrites in the subiculum of epileptic rats. These results indicate that channels of the KCNQ family are key regulators of seizure susceptibility and their decreased availability in the epileptic tissue may reduce seizure threshold and contribute to ictogenesis.

KCNQ channels show conserved ethanol block and function in ethanol behaviour.

In humans, KCNQ2/3 channels form an M-current that regulates neuronal excitability, with mutations in these channels causing benign neonatal familial convulsions. The M-current is important in mechanisms of neural plasticity underlying associative memory and in the response to ethanol, with KCNQ controlling the release of dopamine after ethanol exposure. We show that dKCNQ is broadly expressed in the nervous system, with targeted reduction in neuronal KCNQ increasing neural excitability and KCNQ overexpression decreasing excitability and calcium signalling, consistent with KCNQ regulating the resting membrane potential and neural release as in mammalian neurons. We show that the single KCNQ channel in Drosophila (dKCNQ) has similar electrophysiological properties to neuronal KCNQ2/3, including conserved acute sensitivity to ethanol block, with the fly channel (IC50 = 19.8 mM) being more sensitive than its mammalian ortholog (IC50 = 42.1 mM). This suggests that the role of KCNQ in alcohol behaviour can be determined for the first time by using Drosophila. We present evidence that loss of KCNQ function in Drosophila increased sensitivity and tolerance to the sedative effects of ethanol. Acute activation of dopaminergic neurons by heat-activated TRP channel or KCNQ-RNAi expression produced ethanol hypersensitivity, suggesting that both act via a common mechanism involving membrane depolarisation and increased dopamine signalling leading to ethanol sedation.

Role of KCNQ2 and KCNQ3 genes in juvenile idiopathic epilepsy in Arabian foals

Juvenile idiopathic epilepsy (JIE) in Arabian foals resembles benign-familial neonatal convulsion (BFNC) syndrome, a rare idiopathic epilepsy of new-born humans. BFNC syndrome exhibits genetic heterogeneity, as has been hypothesised to occur in Arabian foals, and is known to be caused by mutations in the voltage-gated potassium channel subunit KCNQ2 and KCNQ3 genes. The close phenotypic characteristics of both Arabian foals and children suggest these epileptic syndromes are caused by the same genetic disorder. In horses, the KCNQ2 and KCNQ3 genes are located on the terminal region of chromosomes 22 and 9, respectively, essentially homologous to their location on chromosomes 20q13.3 and 8q24 in humans.Gene trees for the KCNQ2 and KCNQ3 genes between horses and other mammals, particularly humans and mice, were constructed and compared to widely accepted mammalian phylogenetic trees. The KCNQ2 gene tree exhibited close clustering between horses and humans, relative to horses and mice, in contrast to the evolutionary trees of other mammals. Distance values between the horse and human groups were lower as opposed to those found between the horse and mouse groups. The similarity between the horse and the human, especially for the KCNQ2 gene, where the majority of mutations causing BFNC have been found, supports the hypothesis of similar heritable and genetic patterns of the disease in both species and suggests that contrary to the classic mouse-model concept, humans may be a more suitable model for the study of JIE in Arabian foals.