Potassium channel‐related epilepsy: Pathogenesis and clinical features

Abstract

Variants in potassium channel‐related genes are one of the most important mechanisms underlying abnormal neuronal excitation and disturbances in the cellular resting membrane potential. These variants can cause different forms of epilepsy, which can seriously affect the physical and mental health of patients, especially those with refractory epilepsy or status epilepticus, which are common among pediatric patients and are potentially life‐threatening. Variants in potassium ion channel‐related genes have been reported in few studies; however, to our knowledge, no systematic review has been published. This study aimed to summarize the epilepsy phenotypes, functional studies, and pharmacological advances associated with different potassium channel gene variants to assist clinical practitioners and drug development teams to develop evidence‐based medicine and guide research strategies. PubMed and Google Scholar were searched for relevant literature on potassium channel‐related epilepsy reported in the past 5–10 years. Various common potassium ion channel gene variants can lead to heterogeneous epilepsy phenotypes, and functional effects can result from gene deletions and compound effects. Administration of select anti‐seizure medications is the primary treatment for this type of epilepsy. Most patients are refractory to anti‐seizure medications, and some novel anti‐seizure medications have been found to improve seizures. Use of targeted drugs to correct aberrant channel function based on the type of potassium channel gene variant can be used as an evidence‐based pathway to achieve precise and individualized treatment for children with epilepsy.

Plain Language Summary

In this article, the pathogenesis and clinical characteristics of epilepsy caused by different types of potassium channel gene variants are reviewed in the light of the latest research literature at home and abroad, with the expectation of providing a certain theoretical basis for the diagnosis and treatment of children with this type of disease.

Key points.

• Potassium channels are ion channels that selectively allow the passage of potassium ions by a relatively complex mechanism. They are widely expressed in systems throughout the body, maintain neuronal membrane potential, regulate excitability, and participate in the repolarization process of neurons, which is closely associated with the development of neurological diseases.

• Potassium channel isoforms associated with epilepsy pathogenesis include KCa, KNa and Kv, which are encoded by a variety of genes, mainly KCNA1, KCNA2, KCNB1, KCNC1, KCNH1, KCNQ2, KCNQ3, KCNT1, KCNT2, KCNT1 and KCNMA1.

• Genetic and de novo variants in potassium channel genes can lead to alterations in the structural function or expression of potassium channels, triggering abnormal neuronal discharges leading to different forms of epileptogenesis.

• The severity of epilepsy due to variants in potassium channel genes is closely related to the type of channel dysfunction and changes at the cellular molecular level due to the genetic variant, and understanding the pathogenesis of the variant such as alterations in channel function will provide new ideas for the precise treatment of epilepsy.

1. INTRODUCTION

Epilepsy is a neurological disorder caused by abnormal neuronal discharges in the brain. ¹ There are million cases of epilepsy worldwide, ² it is estimated that 70%–80% of these cases are genetically inherited. ³ With the advancement in sequencing and diagnostic technologies in recent years, ⁴ an increasing number of epilepsy‐associated variants has been identified. Clinicians carrying out precision treatments based on genetic diagnosis results have been reported, which have revealed that variants of ion channel‐associated gene, including potassium ion channels, sodium ion channels, and others, account for 25% of inherited epilepsies. ⁵ Detailed studies on the relationship between functional type and response to drug therapy in patients with epilepsy caused by genetic factors have yielded promising results for targeted drug therapy. ⁶ , ⁷

Potassium channels play a crucial role in regulating neuronal excitability and are directly involved in seizure mechanisms. ⁸ Potassium channels are distributed on the surface of all living cells and are involved in the generation of cellular action potentials and signal transduction. ⁹ They are classified according to the different combinations of α‐ and β‐subunits and the presence of heterodimers in the inward rectifier potassium channel, Ca²⁺‐activated potassium channel (KCa), Na²⁺‐activated potassium channel (KNa), and voltage‐gated potassium channel (Kv). ¹⁰ Variants in genes encoding potassium channels cause structural and functional changes in potassium channels, which can lead to epilepsy, seizure ataxia, and other disorders. ¹¹

To our knowledge, till date, no systematic review has focused on variants in potassium ion channel‐related genes. Hence, we aimed to summarize the different types and phenotypes of epilepsy caused by variants in common potassium channel‐related genes, especially focusing on the effectiveness of drug treatment. Our findings may provide evidence‐based guidance for the drug‐based treatment of potassium channel‐associated epilepsy.

2. K_V CHANNEL‐RELATED GENES AND EPILEPSY

2.1. Potassium voltage‐Gated channel subfamily A member 1 (KCNA1)‐related epilepsy

Variants in the KCNA1 gene, which encodes Kv1.1, can cause a variety of neurologic disorders, including Episodic ataxia type 1 (EA1), epilepsy, epileptic encephalopathy (EE), and hypomagnesemia and rare paroxysmal dyskinesia disorders. ¹² Among these, EA1 is the only disorder solely associated with variants in the KCNA1 gene. EA1 is the primary disorder caused by variants in the KCNA1 gene. More than half of the known KCNA1 variants only manifest in EA1, and the age of onset is often <20 years. Seizure symptoms include ataxia, myasthenia, dysarthria, ¹³ , ¹⁴ vertigo, ¹³ , ¹⁵ fever, exercise intolerance, mood changes, and fatigue, ¹⁴ , ¹⁶ with or without epilepsy and EE. Electrophysiologic studies have found that loss‐of‐function (LOF) variants in KCNA1 leads to EA1. ¹⁷ , ¹⁸ Acetazolamide (ACZ), phenytoin sodium (PHT), carbamazepine (CBZ), and lamotrigine (LTG) are drugs that could control seizures. ¹⁴ , ¹⁶ , ¹⁹

Both gain‐of‐function (GOF) and LOF variants in KCNA1 can lead to epilepsy and EE. GOF variants are usually associated with drug‐sensitive epilepsy without neurodevelopmental disorder, whereas LOF variants generally trigger EE, with the majority of variant sites in patients being located in the highly conserved region of Kv1.1. ²⁰ EE caused by KCNA1 variants usually presents with early onset seizures and progressively manifests as cognitive, behavioral, and language deficits. Pro‐Val‐Pro motif variants ²¹ and copy number variants in KCNA1 are likely to cause EE, and LOF variants in the gene can cause mental retardation and even sudden unexpected death in epilepsy. ²² While EE associated with variants in KCNA1 is usually refractory to treatment with medications, a case of drug‐resistant epilepsy in a patient with a GOF variant in KCNA1 has been reported in recent years. Patients whose seizures were somewhat controlled after the use of 4‐aminopyridine (4‐AP) have been reported. ²³ Verdura et al. found that oxcarbazepine (OXC) was effective in controlling seizures in a neonatal patient with EE with a LOF variant. ²⁴

2.2. Potassium voltage‐gated channel subfamily A member 2 (KCNA2)‐related epilepsy

KCNA2 variants can result in a variety of epilepsy phenotypes ranging from early‐onset epileptic encephalopathy (EOEE) to mild epilepsy. The former is often combined with mental retardation and the latter with complex hereditary spastic paraplegia, both of which are episodic ataxia. ²⁵ The mild epileptic phenotype is predominant in infancy, with generalized and focal seizures in later life without mental retardation, and individuals with this variant usually have a mixed dysfunction. ²⁶ EOEE is a group of epilepsies in which there is severe phenotypic and genetic heterogeneity, with seizures appearing at approximately 5–17 months of age. Patients subsequently exhibit global developmental delay or even developmental neurodevelopmental regression. ²⁷ Syrbe et al. reported six patients with KCNA2‐associated EOEE, four of whom had a nearly complete loss of channel function, and two of whom had GOF variants. ²⁸ A child with EOEE and mild epilepsy was found to have mixed dysfunction on diaphragm clamp testing. ²⁹ Masnada et al. reported that, among 10 patients with EE with KCNA2 gene variants, three patients with LOF variants had mild symptoms, mostly focal seizures, which could be accompanied with speech and cognitive delay; four patients with GOF variants had ataxia as the main clinical manifestation, and the epilepsy type was often generalized seizures, and cognitive deficits were more severe than those of patients with LOF variants; and the three patients with mixed dysfunction had the earliest onset of epilepsy and the most severe symptoms. ²⁷ Currently, 4‐AP is mostly used for KCNA2‐related EOEE, in which more than 80% of the children have positive treatment outcomes. ²⁹ , ³⁰ ACZ has been found to be effective in controlling seizures of this phenotype. ³¹ Seizures of this phenotype have also been controlled using valproate sodium (VPA) in combination with ethosuximide. ³²

In addition to epilepsy, KCNA2 variants have been identified in other diseases in recent years. Canafoglia et al. reported one male patient carrying a KCNA2 GOF variant who presented with only progressive myoclonus epilepsy (PME). ³³ Manole et al. reported a patient with a KCNA2 LOF variant who presented with only hereditary spastic paraplegia, mild ataxia, and dysarthria. ³⁴ Neither of the two cases exhibited an epileptic phenotype, and a observational clinical study on the cases extends the disease phenotypes associated with this gene, thereby suggesting genotypic heterogeneity. ³³ , ³⁴

2.3. Potassium voltage‐gated channel subfamily B member 1 (KCNB1)‐related epilepsy

The KCNB1 gene encodes Kv2.1, which is the main channel for delayed rectifier potassium currents in hippocampal and cortical vertebral neurons. ³⁵ Functional studies by Torkamani et al. have shown that KCNB1 gene variants have been found as a GOF effect in EE phenotypes. ³⁶ Saitsu et al. reported a child with EE caused by a KCNB1 gene variant who was sensitive to the sodium channel blocker peptide guangxitoxin‐1 (GxTX) ³⁷ and found that at the cellular level GxTX was effective in blocking Kv2.1‐mediated currents. ³⁸ Recently, a full LOF‐effect KCNB1 variant was also found in a patient with EOEE with disease onset occurring in infancy. ³⁹ The gene variant was found in a patient with a moderate EE phenotype, who presented with autism, epilepsy, and mental retardation, which was found to be a partial LOF upon functional analysis that responded well to the administration of the antiepileptic therapy sulthiame. ⁴⁰ Bar et al. reviewed 27 patients with KCNB1 variants and found that, among them, most of the patients with the severe phenotype had missense variants located on the pore domains of the potassium channels, whereas most of the patients with the moderate epilepsy phenotype had truncating variants that were located on the C‐terminal structural domains. ⁴¹ Xiong et al. similarly found that mild epilepsy phenotypes were caused by truncating variants. ⁴² Kovel et al. proposed that variants in the N‐terminal structural domain are lethal. ⁴³ This hypothesis has been proven in patients with mild epilepsy.

Two children with epilepsy carrying nonsense KCNB1 variants with variant sites in the pore region and C‐terminal structural domains with mild phenotypes have been reported by Marini et al. ⁴⁴ Adrenocorticotropic hormone administration rapidly relieved the epileptic symptoms. Four children carrying missense variants had severe phenotypes; three of whom exhibited reduced seizure frequency but not complete control after a combination of medications, and medications were completely ineffective in one child. ⁴⁴ Notably, a child with epilepsy caused by a missense variant in KCNB1, for whom a combination of levetiracetam (LEV), OXC, VPA, and phenobarbital (PHB) had recently been ineffective, underwent a late ketogenic diet that was effective in reducing seizure frequency. ⁴⁵

Hence, truncating variants and nonsense variants located in the C‐terminal structural domain have a mild drug‐sensitive phenotype, whereas individuals with variants in the N‐terminal structural domain have severe symptoms and require long‐term follow‐up. Notably, anti‐seizure medications (ASMs) are usually ineffective in treating individuals with KCNB1 missense variants, and a ketogenic diet may be a potential therapeutic option.

2.4. Potassium voltage‐gated channel subfamily C member 1 (KCNC1)‐related epilepsy

KCNC1 encodes a highly conserved potassium channel subunit of the Kv3 subfamily of voltage‐gated tetrameric potassium channels. Variants in this gene can trigger PME, which is a unique epilepsy characterized by progressive neurological decline with recurrent seizures of ataxia and myoclonus. ⁴⁶ Nascimento et al. demonstrated that KCNC1 LOF variants disrupt neuronal firing, alter neurotransmitter release, and induce neuronal death. Inhibitory GABA and cerebellar neurons are among the most affected neurons, with damage to the former associated with epileptogenesis and the latter leading to cerebellar ataxia. ⁴⁷ Treatment of this group of patients with benzodiazepines (BZDs) has been shown to be effective. ⁴⁸ LOF variants in this gene have also been found in patients with developmental and epileptic encephalopathy (DEE). These patients have exhibited varying degrees of therapeutic responses to VPA; in one case, the number of seizures was <1 per 3 months after vagus nerve stimulation. ⁴⁹ In addition, variants in this gene have been reported in patients presenting with only mental retardation, malformations, and no seizures. ⁵⁰

2.5. Potassium voltage‐gated channel subfamily H member 1 (KCNH1)‐related epilepsy

KCNH1 encodes a highly conserved protein of the EAG subfamily of voltage‐gated potassium channels and is associated with a variety of neurological disorders. Variants in this gene have been found in a variety of syndromes, including deformities of facial features, hypoplasia or regenerative disorders of the nails, abnormalities of the thumbs and bones, mental retardation, and epileptic seizures. ⁵¹ , ⁵² The most common syndromes are Temple–Baraitser Syndrome and Zimmermann–Laband syndrome. ⁵² , ⁵³ The former is characterized by facial dysmorphisms, enlarged gingival size, hirsutism, absence/hypoplasia of the nails and terminal phalanges, mental retardation, and epilepsy ⁵² ; the latter is characterized by multisystemic disorders, epilepsy, and thumb and big toe nail hypoplasia. Syndromes triggered by variants in this gene may be poorly characterized, ⁵³ as in the case of one patient with no obvious gingival and nail features reported by Mucca et al. ⁵⁴ Recent studies have found a significant overlap of symptoms between the two syndromes, and it is considered that the two are a continuum of disorders. ⁵⁵ In addition to the aforementioned syndromes, the gene has recently been identified in deafness and nail dystrophy syndromes. ⁵⁶

Variants in this gene can also lead to a range of epilepsy types from benign isolated epilepsy and febrile seizures (FS) to severe EE. de novo variants in this gene, which are usually associated with EE, cluster in the transmembrane structural domains of S4 and S6, whereas somatic mosaicism or germline variants can lead to either isolated epilepsy or FS. ⁵⁷ Certain patients' epileptic symptoms can be completely controlled by medications, whereas treatment in certain patients requires a combination of multiple drugs. ⁵⁸

2.6. Potassium voltage‐gated channel subfamily Q member 2 (KCNQ2)‐related epilepsy

Sixty to seventy percent of all cases of benign familial neonatal epilepsy (BFNE) is caused by variants in KCNQ2. BFNE is an autosomal dominant epilepsy with a favorable prognosis. ⁵⁹ Seizures usually occur on the 2nd– 8th day of age and resolve after 16 months. The disorder usually begins with tonic seizures followed by a series of autonomic and motor changes that may be unilateral or bilateral or symmetrical. Seizures are brief but can occur as frequently as 30 times per day and even evolve into status epilepticus, usually accompanied by apnea. ⁵⁹ , ⁶⁰ Sodium channel blockers, such as CBZ, LTG, and OXC, have been found to control seizures in the majority of patients with BFNE. ⁶¹ The seizures may be more severe than those in BFNE.

Recently, KCNQ2 gene variants have been identified in severe phenotypes of EE and EOEE. Previous functional studies of epilepsy found that variants in this gene have predominantly been LOF variants, whereas Miceli et al. found one patient with severe EE caused by a KCNQ2 GOF variant; this functional difference may be related to the severity of the epilepsy. ⁶² Weckhuysen et al. reported that eight patients with EOEE presented with intractable epileptic tonic seizures in the first postnatal week, and the electroencephalograms showed multifocal epileptic activity with severe mental retardation and motor deficits. Seizures were frequent despite the administration of various ASMs. The age and type of seizures in this phenotype are similar to those in BFNE, but the seizures are highly treatment‐resistant. ⁵⁹ Weckhuysen et al. reported that six patients with EOEE had similar severe symptoms, but one of them responded favorably to retigabine and three responded to leung‐ho with LTG, topiramate (TPM), and zonisamide. ⁶³ Yang et al. developed a Xenopus oocyte model based on three patients carrying variants in KCNQ2, which were LOF variants determined by cellular electrophysiologic studies, and these patients showed a 90% reduction in seizures upon administration of retigabine. ⁶⁴ Recently, a novel AED, SF0034, was approved for use in the United States. Its therapeutic mechanism is similar to that of retigabine, and the efficacy of this drug is 5‐fold higher than that of retigabine; however, its side effects limit the clinical application of this drug. ⁶⁵

2.7. Potassium voltage‐gated channel subfamily Q member 3 (KCNQ3)‐related epilepsy

Variations in KCNQ3 can cause a variety of epilepsy phenotypes, ranging from BFNE and benign familial infantile epilepsy (BFIE) to EE, and also developmental disorders, such as mental retardation in isolation. ⁶⁶ BFNE and BFIE are autosomal dominant disorders, but the rate of detection of KCNQ3 variants is low due to incomplete penetrance, parental chimerism, and other factors. ⁵⁹ , ⁶⁷ KCNQ3‐associated BFNE starts 2–8 days after birth, and seizures are mostly in the form of tonicity; epilepsy resolves on its own between 1 month and 1 year of age, and development is usually normal. ⁶⁶ However, mental retardation has also been reported. ⁶⁸ The functional effect of BFNE caused by the KCNQ3 gene variant is LOF, and the sodium channel blocker PHT is most commonly used in the treatment of this disease that yields favorable results. ⁶⁹ Tulloch et al. reported that patients with BFNE respond well to LEV therapy. ⁷⁰ CBZ and OXC were also effective in controlling seizures, and CBZ was found to have no side effects with its best effects being exerted the earlier it was used. ⁷¹ Thus, BFNE caused by KCNQ3 variant is generally effectively controlled by antiepileptic therapy.

KCNQ3‐associated BFIE develops within 1 year of age and resolves on its own after 1–2 years of age, with a mostly focal form of seizures, and development is also usually normal, with complete seizure control achieved with PHB, CBZ, or VPA. ⁶⁶ Developmental deficits caused by KCNQ3, manifestations of which include EE with progressive cognitive and neuropsychological worsening or deterioration, mental retardation without epilepsy, and seizures and cortical visual impairment with mental retardation, have functional effects that can be GOF or LOF. ⁷² , ⁷³ Sands et al. reported 11 patients presenting only with global developmental delay and autism with no epileptic manifestations and functional studies confirming KCNQ3 variant as GOF. ⁷⁴ EE and intellectual decline are GOF variants, and the use of retigabine eliminates the potassium channel electro‐mechanical (E‐M) caused by current disruption induced by KCNQ3 variant, thus leading to antiepileptic therapeutic effects. ⁶⁴ However, the drug is still contraindicated in children due to its skin and retinal discoloration side effects.

3. KNa + CHANNEL‐RELATED GENES AND EPILEPSY

3.1. Potassium sodium‐activated Channel subfamily T member 1 (KCNT1)‐related epilepsy

KCNT1 encodes a sodium‐activated potassium channel that is widely expressed in the nervous system and is primarily associated with two epileptic phenotypes, epilepsy of infancy with migrating focal seizures (EIMFS) and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). EIMFS typically begins with focal seizures at 6 months of age, and can progress to continuous seizures later in life, usually with developmental regression and autonomic nervous system manifestations. ⁷⁵ Previously believed to be a GOF variant, Evely et al. recently reported a child with EIMFS, which was found to be caused by a LOF variant. ⁷⁶ ADNFLE presents with nocturnal motor seizures ranging from simple arousals to those with tonic seizure or dystonia. Cognitive comorbidities, mental, and behavioral abnormalities can be observed at a young age, as well as complications, such as pulmonary hemorrhage, among others. ⁷⁵

Both of these phenotypes do not respond well to standard ASMs, and the sodium channel blocker quinidine was previously used to target the GOF effect in ElMFS but had little effect. ⁷⁷ Recently, McTague et al. carried out a quinidine trial in one patient with EIMFS and two patients with ADNFLE, with one case of KCNT1 GOF EIMFS responding favorably, and the remaining two failing respond. ⁷⁸ The results of this trial are summarized in Table 7. A quinidine study on more than 20 children with KCNT1‐associated EIMFS showed that few experienced transient seizure‐free episodes, and the number of seizures was reduced by half in 20% of the patients. ⁷⁹ Recently, Poisson et al. performed a study on the responsiveness of a new drug, cannabidiol, in three patients with EIMFS, and one patient showed a significant reduction in seizure intensity with developmental progression. ⁸⁰ Datta et al. found that PHB or potassium bromide (KBr) alone were effective in controlling the EIMFS phenotype, but the positive effects were only observed with high doses of PHB. ⁸¹ The ADNFLE phenotype was well tolerated with stiripentol (STP), BZDs, LEV, and a ketogenic diet but showed limited results. ⁷⁵ A quinidine trial performed on six patients diagnosed with ADNFLE revealed that none of them responded to the treatment; however, they experienced systemic cardiac side effects. ⁸²

TABLE 7.

Clinical characteristics of KCNT1‐related phenotypes.

Phenotype	Type of variant	Mutant site	Amino acid changes	Functional effect	Drugs/Treatment effective (number of persons)	Invalid/Number of persons	Total cases
EIMFS 76 , 78 , 80 , 81	Missense	–	p.Phe932Ile	LOF	–	–	–
	Missense	c.2800G>A	A934T	–	Quinidine (1)	0	1
	Truncation	–	W476R A259D Q550del	–	Cannabidiol (3)	0	3
	Missense	c.1283G>A c.1420C>G	p.Arg428Gln p.Arg474Gly	–	PHB、KBr (2)	0	2
ANDFLE 75 , 78 , 82	–	–	–	–	STP, BZDs, LEV, ketogenic diet	–	–
	–	–	–	–	0	Quinidine (6)	6
	Missense	c.2800G>A c.862G>A	A934T G288S	–	0	Quinidine (2)	2

Abbreviations: ANDFLE, autosomal dominant nocturnal frontal lobe epilepsy; BZDs, benzodiazepines; EIMFS, infantile epilepsy with wandering focal seizures; GOF, gain of function; KBr, potassium bromide; LEV, levetiracetam; LOF, loss of function; PHB, phenobarbital; STP, stavudine.

In addition to triggering the above epilepsy types, KCNT1 variants can cause temporal lobe epilepsy, ⁸³ sleep‐related hypermotor epilepsy, ⁷⁸ and malignant migratory partial seizures of infancy. ⁸⁴

3.2. Potassium sodium‐activated Channel subfamily T member 2 (KCNT2)‐related epilepsy

KCNT2 variants can lead to different epilepsy phenotypes. Among two patients with KCNT2 GOF variants, one was diagnosed with EIMFS and other with Ohtahara syndrome followed by infantile spasms, both of which showed dysmorphic features. ⁸⁵ Recently, Mao reported two patients with EIMFS caused by KCNT2 variants, and using patch clamp electrophysiology, both were found to have reduced channel currents, which were considered to be caused by LOF variants. ⁸⁶ This is in contrast to the previously reported cases of EIMFS primarily caused by KCNT1 GOF variants. EIMFS patients are usually drug resistant, and PHB can be administered to control symptoms to a certain degree. ⁸⁶ , ⁸⁷ Ambrosino et al. reported two patients with DEE caused by variants in this gene, one of whom achieved a significant clinical outcome after the use of quinidine; thus, they hypothesized that this individual's condition may be caused by a GOF variant. ⁸⁸ The results of this study are summarized in Table 8. Notably, drug resistance is present in most KCNT2‐associated DEE phenotypes. ⁸⁷

TABLE 8.

Clinical characteristics of KCNT2‐related phenotypes.

Phenotype	Type of variant	Mutant site	Amino acid changes	Functional effect	Drugs/Treatment effective (number of persons)	Invalid/Number of persons	Total cases
EIMFS 85 , 86 , 87	1 case of code‐shift variant, 1 case of nonsense variant	–	p.L48Qfs43 p.K564*	LOF (2)	–	–	–
	Missense	c.991T>A c.592C>G	p.Tyr331Asn p.Gln198Glu	–	PHB (2)	0	2
	Missense	c.720T>A	p.Phe240Leu	–	PHB (1)	0	1
DEE 88	Missense	c.569G>C	p.Arg190Pro	GOF	Quinidine (1)	0	1

Abbreviations: EIMFS, infantile epilepsy with wandering focal seizures; GOF, gain of function; LOF, loss of function; PHB, phenobarbital.

The spectrum of disease phenotypes caused by KCNT2 variants is increasing. Inuzuka et al. identified one new phenotype of frontal lobe epilepsy caused by variants in this gene, in which patients usually have frontal lobe seizures during sleep and present with refractory stereotypic and focal motor seizures. ⁸⁹ Jackson et al. reported that two patients with a p.Arg190 missense variant in KCNT2 did not exhibit epilepsy and only presented with mental retardation and dysmorphic features. ⁹⁰ Tian et al. identified KCNT2 variants in a family with generalized epilepsy with febrile seizures plus. ⁹¹

4. KCa⁺ CHANNEL‐RELATED GENES AND EPILEPSY

4.1. Potassium Calcium‐activated channel subfamily M alpha 1 (KCNMA1)‐related epilepsy

The large‐conductance Ca²⁺‐activated K⁺ channel, also known as the BK channel, differs from other K⁺ channels in that it is activated by both intracellular Ca²⁺ ions and membrane depolarization. The BK channel plays a role in regulating cell membrane excitability and calcium signaling, and the channel prevents epilepsy by preventing excess intracellular calcium ions from triggering neuronal hyperexcitability. ⁹² The channel is composed of four α‐subunits and four optional auxiliary β‐subunits. Of these, the pore‐forming α‐subunit is encoded by KCNMA1, which generates a variety of isoforms by alternative splicing. ⁹³ , ⁹⁴ In addition to epilepsy, neurologic phenotypes of KCNMA1‐associated ion channelopathies include language and motor developmental delays, cerebellar atrophy, microcephaly, hypotonia, facial deformity, visceral malformation, and dyskinesia. ⁹⁵ In addition, KCNMA1‐associated ion channelopathies cause a number of neurologic disorders. Almost all patients with KCNMA1‐associated ion channelopathies present with paroxysmal non‐kinesigenic dyskinesia (PNKD), epilepsy, or both. ⁹⁶

Wang et al. found that the majority of patients with KCNMA1 variants had paroxysmal dyskinesias with or without epilepsy, most with mental retardation, and drug resistance. ⁹⁷ Moldenhauer et al. found that KCNMA1 variant resulting in dyskinesia combined with an epileptic phenotype was a GOF effect and that ACZ was largely ineffective, but paroxetine had a therapeutic effect. ⁹⁸ Keros et al. reported six PNKD patients who responded well to lisdexamfetamine, with a reduction in the number of seizures observed in all patients, ranging from a 10‐fold reduction to complete remission. ⁹⁹ For KCNMA1‐associated epilepsy, KCNMA1 variants that cause GOF or LOF of BK channel mechanisms have been found to be associated with seizures. Ninety‐four studies have demonstrated that the use of BK current potassium channel openers and blockers are effective in controlling epilepsy caused by this gene. ¹⁰⁰ To date, the role of BK channels in epilepsy remains controversial, and its function type requires further study with large sample sizes or modeling studies.

5. DISCUSSION

Epilepsy phenotypes due to mutations in potassium channel genes range from mild to severe, but most phenotypes are developmental epileptic encephalopathies, which can be combined with disorders such as mental retardation, language developmental disorders, and autism. In‐depth investigation of the pathogenesis of mutants and animal models such as mice and tissues and cells has yielded changes in the channel currents of some mutant‐induced phenotypes (see Figure 1 and Tables 1, 2, 3, 4, 5, 6, 7, 8, 9) as well as changes in some cell signaling molecules, and the use of drugs such as potassium or sodium channel blockers in function‐gaining mutants or animal models has yielded good results, while on the other hand, the loss‐of‐function has led to avoidance of the use of potassium channel blockers or the use of inhibitory neuropathogens in accordance with the changes in cell signaling. Cell signaling changes, drugs that promote excitation of inhibitory neurons are selected.

FIGURE 1.

Schematic diagram of the pathogenesis and channel function changes in epilepsy and epileptic syndromes due to variants in common potassium channel genes.

TABLE 1.

Clinical characteristics of the KCNA1‐related phenotype.

Phenotype	Type of variant	Mutant site	Amino acid changes	Functional effect	Drugs/treatment effective (number of persons)	Invalid/number of persons	Total cases
EA1 14 , 16 , 29	missense	–	E283K	LOF	–	–	–
	–	–	–	–	ACZ (2) CBZ (2) LTG (3)	0	7
	missense	–	Thr226Arg	–	PHT (2)	0	2
Epilepsy 16 , 20	–	–	–	GOF	–	–	–
EE 23 , 24	missense	c.888G>T	p.Leu296Phe	GOF	4‐AP (1)	0	1
	missense	c.1102G>C	p.Val368Leu	LOF	OXC (1)	0	1

Abbreviations: 4‐AP, 4‐aminopyridine; ACZ, acetazolamide; CBZ, carbamazepine; EA1, ictal ataxia type 1; EE, epileptic encephalopathy; GOF, gain of function; LOF, loss of function; LTG, lamotrigine; OXC, oxcarbazepine; PHT, phenytoin sodium.

TABLE 2.

Clinical characteristics of KCNA2‐related phenotypes.

Phenotype	Type of variant	Mutant site	Amino acid changes	Functional effect	Drugs/Treatment effective (number of persons)	Invalid/Number of persons	Total cases
EOEE 27 , 28 , 29	Missense	c.1214C>T c.788T>C c.1214C>T c.1214C>T c.894G>T c.890G>A	p.Pro405Leu p.Ile263Thr p.Pro405Leu p.Pro405Leu p.Leu298Phe p.Arg297Gln	GOF GOF GOF GOF LOF LOF	6	0	6
	missense	c.706G>A	p.E236K	GOF and LOF	1	0	1
	Truncated variant 1 case, 9 cases of missense variation	c.637C>T c.1192G>T c.1214C>T c.469G>A c.469G>A c.469G>A c.890G>A c.878T>A c.982T>G c.1120A>G	p.Gln213* p.Gly398Cys p.Pro405Leu p.Glu157Lys p.Glu157Lys p.Glu157Lys p.Arg297Gln p.Leu293His p.Leu328Val p.Thr374Ala	3 cases of LOF 4 cases of GOF 3 cases of GOF and LOF	10	0	10
Epilepsy phenotype (mild phenotype) 33	Missense	c.890G>A	p.Arg297Gln	GOF和LOF	VPA + ESM (1)	0	1
PME 32	Missense	c.890G>A	p.Arg297Gln	GOF	–	–	–
	Missense	c.890C>A	p.Arg297Gln	–	ACZ (1)	0	1

Abbreviations: ACZ, acetazolamide; EOEE, early onset epileptic encephalopathy; ESM, ethosuximide; GOF, gain of function; LOF, loss of function; PME, progressive myoclonus; VPA, sodium valproate.

TABLE 3.

Clinical characteristics of KCNB1‐related phenotypes.

Phenotype	Type of variant	Mutant site	Amino acid changes	Functional effect	Drugs/Treatment effective (number of persons)	Invalid/Number of persons	Total cases
EE	Missense	c.916C>T	p.R306C	GOF	GxTx (1)	0	1
Mild phenotype (autism, epilepsy, mental retardation) 39	Missense	c.595A>T	p.Ile199Phe	Partial LOF	Sulthiame (1)	0	1
Epilepsy (mild phenotype) 44	No Sense	c.1108G>A c.1747C>T	p.Trp370* p.Arg583*	–	ACTH (2)	0	2
EOEE 40	Code shift	–	p. Arg583*	Full LOF	–	–	–
Epilepsy (severe phenotype) 42 , 44 , 45	17 missense variants, 1 truncation variant	c.128A>G c.629C>G c.934C>T c.968C>T c.984C>G c.1001T>C c.1045G>T c.1105T>C c.1115C>T c.1130C>A c.1132G>T c.1139A>G c.1144G>A c.1180G>A c.1183G>A c.1226T>C c.1489G>T c.857del	–p.A192Pfs* 1	–	–	–	18
	Missense	c.586A>T c.829C>T c.1045G>T c.916C>T	p.Ile370Phe p.Thr210Met p.Val349Phe p.Arg306Cys	–	VPA, ESM, CLN (1) LTG (1) VPA、RFN (1)	1	4
	Missense	c.990G>C	p.Glu330Asp	–	LEV, VPA, OXC, PHB, ketogenic diet (1)	0	1

Abbreviations: ACTH, adrenocorticotropic hormone; CLN (Clonazepam), clonazepam; EE, epileptic encephalopathy; ESM, ethosuximide; GOF, gain of function; GxTx, sodium channel blocker peptide guangxitoxin‐1; LEV, levetiracetam; LOF, loss of function; LTG, lamotrigine; EOEE, early onset epileptic encephalopathy; OXC, oxcarbazepine; PHB, phenobarbital; RFN (Rufinamid), lufenamide; VPA, valproate sodium.

TABLE 4.

Clinical characteristics of KCNC1‐related phenotypes.

Phenotype	Type of variant	Mutant site	Amino acid changes	Functional effect	Drugs/Treatment effective (number of persons)	Invalid/Number of persons	Total cases
PME 48	Missense	c.1262C>T c.1262C>T c.623G>A c.1196C>T c.1262C>T	p.Ala421Val p.Ala421Val p.Cys208Tyr p.Thr399Met p.Ala421Val	–	Chlorpazan, TPM (1) VPA, CLN (1)	3	5
DEE 49	Missense	c.1262C>T c.1538C>T	p.Ala421Val p.Ala513Val	LOF	VPA, VNS (2)	0	2
Mental retardation, malformations, no epilepsy 50	No Sense	c.1015C>T	p.R339*	–	–	–	–

Abbreviations: CLN, clonazepam; DEE, developmental epileptic encephalopathy; GOF, gain of function; LOF, loss of function; PME, progressive myoclonus; TPM (Topiramate), topiramate; VNS, vagus nerve stimulation; VPA, sodium valproate.

TABLE 5.

Clinical characteristics of KCNQ2‐related phenotypes.

Phenotype	Type of variant	Mutant site	Amino acid changes	Functional effect	Drugs/Treatment effective (number of persons)	Invalid/Number of persons	Total cases
BFNE 61	–	–	–	–	CBZ, LTG, OXC (1)	0	1
eoee 59 , 62 , 63 , 64	Missense	c.638G>A c.821C>T c.613A>G c.1678C>T c.793G>C c.1636A>G c.869G>A c.869G>A	p.Arg213Gln p.Thr274Met p.Ile205Val p.Arg560Trp p.Ala265Pro p.Met546Val p.Gly290Asp p.Gly290Asp	–	–	–	–
	–	–	–	–	Retigabine (1) LTG, TPM, ZNS (3)	0	4
	Missense	–	p.V175L	GOF	–	–	1
	Missense	–	Y237C I238V F304S	LOF	–	–	3
EE 62	–	–	–	LOF	–	–	–

Abbreviations: BFNE, benign familial neonatal epilepsy; CBZ, carbamazepine; EE, epileptic encephalopathy; EOEE, early onset epileptic encephalopathy; GOF, gain of function; LOF, loss of function; LTG, lamotrigine; OXC, oxcarbazepine; TPM, topiramate; ZNS, zonisamide.

TABLE 6.

Clinical characteristics of KCNQ3‐related phenotypes.

Phenotype	Type of variant	Mutant site	Amino acid changes	Functional effect	Drugs/treatment effective (number of persons)	Invalid/Number of persons	Total cases
BFNE 69 , 71	–	‐	–	–	PHT (1)	0	1
	–	–	–	–	CBZ, OXC (1)	0	1
BFIE 66	7 cases of missense variants, 3 cases of deletion variants	c.333_334delGT c.1888delG c.333_334delGT c.619 C>T c.1057C>G c.1057 C>G c.587 A>T c.587 A>T c.1700T>A c.807G>A	p.Ser113HisfsX6 p.Val630SerfsX12 p.Ser113HisfsX6 p.Arg207Trp p.Arg353Gly p.Arg353Gly p.Ala196Va p.Ala196Val p.Val567Asp p.Trp269Ter	–	PHB, CBZ, VPA (10)	0	10
Mental retardation 74	Missense	c.689G>A c.688C>A c.689G>A c.688C>T c.688C>T c.688C>T c.689G>A c.688C>T c.688C>T c.680G>A c.680G>A	p.R230H p.R230S p.R230H* p.R230C p.R230C p.R230C p.R230H p.R230C p.R230C p.R227Q p.R227Q	LOF	–	–	11

Abbreviations: BFIE, benign familial infantile epilepsy; BFNE, benign familial neonatal epilepsy; CBZ, carbamazepine; CBZ, carbamazepine; GOF, gain of function; LOF, loss of function; OXC, oxcarbazepine; PHB, phenobarbital; PHT, phenytoin sodium; VPA, valproate sodium.

TABLE 9.

Clinical characteristics of KCNMA1‐related phenotypes.

Phenotype	Type of variant	Mutant site	Amino acid changes	Functional effect	Drugs/Treatment effective (number of persons)	Invalid/Number of persons	Total cases
PNKD 99	Missense	c.2984 A>G c.2984 A>G c.2984 A>G – – c.2984 A>G	N999S N999S N999S N999S/R1128W N999S/R1128W N999S	–	Amphetamine (6)	0	6
Epilepsy combined with movement disorders 98	Missense	–	N999S D434G N999S/R1128W	–	Paroxetine (3)	ACZ (3)	3

Abbreviations: ACZ, acetazolamide; GOF, gain of function; LOF, loss of function; PNKD, episodic nonkinesis‐induced movement disorder.

Therapeutically, KCNA1 gene variant‐associated epilepsy is phenotypically mild and can be self‐resolving in most individuals, and can be effectively controlled in severe individuals by administration of 4‐AP and OXC medications; the administration of 4‐AP, VPA, and ACZ was found to be effective in controlling epilepsy in KCNA2 gene variant‐associated epilepsy; and KCNB1 gene variant‐associated epilepsy exhibits a majority of resistance to medications, and it is recommended that the use of sultiame, a ketogenic dietary approaches to reduce the number of seizures; KCNC1 gene variant‐associated epilepsy is effectively treated with clobazam, clonazepam, TPM, and VPA; KCNH1‐associated epilepsy has a high degree of individual variability in the treatment of epilepsy, with some epilepsy being completely controlled, and some epilepsy being ineffectively treated with multidrug combinations; and for the treatment of epilepsy associated with the KCNQ2 and KCNQ3 gene variations, drugs such as CBZ, LTG, and OXC have shown to be effective in the treatment of the epilepsies. In addition, BZDs and quinidine can be used for KCNT1 and KCNT2 gene variant‐associated epilepsy; KBr, STP and LEV can be given for KCNT1 gene variant‐associated epilepsy; amphetamine and paroxetine are recommended for KCNMA1 gene variant‐associated seizures. However, it still needs to be pointed out that the association between gene phenotype and drug specificity is still greatly affected by individual variability.

By summarizing the various potassium channel‐related gene phenotypes, functional studies, and therapeutic regimens and searching out the associations, we hope to provide some theoretical help for the precise and individualized treatment of epilepsy caused by potassium channel‐related gene mutations.

AUTHOR CONTRIBUTIONS

Zhao Tong was responsible for reviewing relevant literature, organizing the content of the literature and writing the paper; Wang Le was responsible for reading relevant literature and writing and revising the paper; Chen Fang was responsible for revising the paper, quality control and reviewing the manuscript, as well as overall supervision and management of the article.

CONFLICT OF INTEREST STATEMENT

We declare no competing interests. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Zhao T, Wang L, Chen F. Potassium channel‐related epilepsy: Pathogenesis and clinical features. Epilepsia Open. 2024;9:891–905. 10.1002/epi4.12934