KCNT2-Related Disorders: Phenotypes, Functional, and Pharmacological Properties
Maria Cristina Cioclu MD
Department of Epilepsy Genetics and Personalized Medicine (member of ERN EpiCARE), Danish Epilepsy Centre, Dianalund, Denmark
Department of Biomedical, Metabolic, and Neural Science, University of Modena and Reggio Emilia, Modena, Italy
These authors contributed equally to this work.
Search for more papers by this authorIlaria Mosca PhD
Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, Campobasso, Italy
These authors contributed equally to this work.
Search for more papers by this authorPaolo Ambrosino PhD
Dept. of Science and Technology, University of Sannio, Benevento, Italy
Search for more papers by this authorDeborah Puzo MSc
Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, Campobasso, Italy
Search for more papers by this authorAllan Bayat MD, PhD
Department of Epilepsy Genetics and Personalized Medicine (member of ERN EpiCARE), Danish Epilepsy Centre, Dianalund, Denmark
Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
Search for more papers by this authorSaskia B. Wortmann MD, PhD
University Children's Hospital, Paracelsus Medical University, Salzburg, Austria
Amalia Children's Hospital, Nijmegen, The Netherlands
Search for more papers by this authorJohannes Koch MD
University Children's Hospital, Paracelsus Medical University, Salzburg, Austria
Search for more papers by this authorVincent Strehlow MD
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
Search for more papers by this authorKentaro Shirai MD
Department of Pediatrics, Tsuchiura Kyodo General Hospital, Tsuchiura, Japan
Search for more papers by this authorNaomichi Matsumoto MD, PhD
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Search for more papers by this authorStephan J. Sanders MD, PhD
Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
Institute for Human Genetics, University of California, San Francisco, CA, USA
Bakar Computational Health Sciences Institute, University of California, San Francisco, CA, USA
Search for more papers by this authorVincent Michaud MD
Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndrome Malformatifs, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
Maladies rares: Génétique et Métabolisme (MRGM), INSERM U1211, Université de Bordeaux, Bordeaux, France
Search for more papers by this authorMarine Legendre MD, PhD
Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndrome Malformatifs, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
Search for more papers by this authorAntonella Riva MD
IRCCS Istituto Giannina Gaslini, Genoa, Italy
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
Search for more papers by this authorPasquale Striano MD, PhD
IRCCS Istituto Giannina Gaslini, Genoa, Italy
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
Search for more papers by this authorHiltrud Muhle MD
Department of Neuropediatrics, University Medical Centre Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany
Search for more papers by this authorManuela Pendziwiat MSc
Department of Neuropediatrics, University Medical Centre Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
Search for more papers by this authorGaetan Lesca MD, PhD
Pathophysiology and Genetics of Neuron and Muscle (PNMG), UCBL, CNRS UMR5261—INSERM U1315, Lyon, France
Department of Medical Genetics, University Hospital of Lyon and Claude Bernard Lyon I University, Lyon, France
Search for more papers by this authorGiuseppe Donato Mangano MD
Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy
Search for more papers by this authorRosaria Nardello MD
Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties “G. D'Alessandro”, University of Palermo, Palermo, Italy
Search for more papers by this authorKCNT2-study group
Search for more papers by this authorJohannes R. Lemke MD
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
Center for Rare Diseases, University of Leipzig Medical Center, Leipzig, Germany
Search for more papers by this authorRikke S. Møller PhD
Department of Epilepsy Genetics and Personalized Medicine (member of ERN EpiCARE), Danish Epilepsy Centre, Dianalund, Denmark
Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
Search for more papers by this authorMaria Virginia Soldovieri PhD
Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, Campobasso, Italy
These authors contributed equally to this work.
Search for more papers by this authorCorresponding Author
Guido Rubboli MD
Department of Epilepsy Genetics and Personalized Medicine (member of ERN EpiCARE), Danish Epilepsy Centre, Dianalund, Denmark
University of Copenhagen, Copenhagen, Denmark
These authors contributed equally to this work.
Address correspondence to Dr Taglialatela, Department of Neuroscience, University of Naples “Federico II”, Via Pansini 5, 80131 Naples, Italy. E-mail: [email protected]; Dr Rubboli, The Danish Epilepsy Centre, Filadelfia/University of Copenhagen, Kolonivej 1, 4293 Dianalund, Denmark. E-mail: [email protected]
Search for more papers by this authorCorresponding Author
Maurizio Taglialatela MD, PhD
Department of Neuroscience, University of Naples “Federico II”, Naples, Italy
These authors contributed equally to this work.
Address correspondence to Dr Taglialatela, Department of Neuroscience, University of Naples “Federico II”, Via Pansini 5, 80131 Naples, Italy. E-mail: [email protected]; Dr Rubboli, The Danish Epilepsy Centre, Filadelfia/University of Copenhagen, Kolonivej 1, 4293 Dianalund, Denmark. E-mail: [email protected]
Search for more papers by this authorMaria Cristina Cioclu MD
Department of Epilepsy Genetics and Personalized Medicine (member of ERN EpiCARE), Danish Epilepsy Centre, Dianalund, Denmark
Department of Biomedical, Metabolic, and Neural Science, University of Modena and Reggio Emilia, Modena, Italy
These authors contributed equally to this work.
Search for more papers by this authorIlaria Mosca PhD
Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, Campobasso, Italy
These authors contributed equally to this work.
Search for more papers by this authorPaolo Ambrosino PhD
Dept. of Science and Technology, University of Sannio, Benevento, Italy
Search for more papers by this authorDeborah Puzo MSc
Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, Campobasso, Italy
Search for more papers by this authorAllan Bayat MD, PhD
Department of Epilepsy Genetics and Personalized Medicine (member of ERN EpiCARE), Danish Epilepsy Centre, Dianalund, Denmark
Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
Search for more papers by this authorSaskia B. Wortmann MD, PhD
University Children's Hospital, Paracelsus Medical University, Salzburg, Austria
Amalia Children's Hospital, Nijmegen, The Netherlands
Search for more papers by this authorJohannes Koch MD
University Children's Hospital, Paracelsus Medical University, Salzburg, Austria
Search for more papers by this authorVincent Strehlow MD
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
Search for more papers by this authorKentaro Shirai MD
Department of Pediatrics, Tsuchiura Kyodo General Hospital, Tsuchiura, Japan
Search for more papers by this authorNaomichi Matsumoto MD, PhD
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Search for more papers by this authorStephan J. Sanders MD, PhD
Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
Institute for Human Genetics, University of California, San Francisco, CA, USA
Bakar Computational Health Sciences Institute, University of California, San Francisco, CA, USA
Search for more papers by this authorVincent Michaud MD
Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndrome Malformatifs, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
Maladies rares: Génétique et Métabolisme (MRGM), INSERM U1211, Université de Bordeaux, Bordeaux, France
Search for more papers by this authorMarine Legendre MD, PhD
Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndrome Malformatifs, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
Search for more papers by this authorAntonella Riva MD
IRCCS Istituto Giannina Gaslini, Genoa, Italy
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
Search for more papers by this authorPasquale Striano MD, PhD
IRCCS Istituto Giannina Gaslini, Genoa, Italy
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
Search for more papers by this authorHiltrud Muhle MD
Department of Neuropediatrics, University Medical Centre Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany
Search for more papers by this authorManuela Pendziwiat MSc
Department of Neuropediatrics, University Medical Centre Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
Search for more papers by this authorGaetan Lesca MD, PhD
Pathophysiology and Genetics of Neuron and Muscle (PNMG), UCBL, CNRS UMR5261—INSERM U1315, Lyon, France
Department of Medical Genetics, University Hospital of Lyon and Claude Bernard Lyon I University, Lyon, France
Search for more papers by this authorGiuseppe Donato Mangano MD
Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy
Search for more papers by this authorRosaria Nardello MD
Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties “G. D'Alessandro”, University of Palermo, Palermo, Italy
Search for more papers by this authorKCNT2-study group
Search for more papers by this authorJohannes R. Lemke MD
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
Center for Rare Diseases, University of Leipzig Medical Center, Leipzig, Germany
Search for more papers by this authorRikke S. Møller PhD
Department of Epilepsy Genetics and Personalized Medicine (member of ERN EpiCARE), Danish Epilepsy Centre, Dianalund, Denmark
Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
Search for more papers by this authorMaria Virginia Soldovieri PhD
Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, Campobasso, Italy
These authors contributed equally to this work.
Search for more papers by this authorCorresponding Author
Guido Rubboli MD
Department of Epilepsy Genetics and Personalized Medicine (member of ERN EpiCARE), Danish Epilepsy Centre, Dianalund, Denmark
University of Copenhagen, Copenhagen, Denmark
These authors contributed equally to this work.
Address correspondence to Dr Taglialatela, Department of Neuroscience, University of Naples “Federico II”, Via Pansini 5, 80131 Naples, Italy. E-mail: [email protected]; Dr Rubboli, The Danish Epilepsy Centre, Filadelfia/University of Copenhagen, Kolonivej 1, 4293 Dianalund, Denmark. E-mail: [email protected]
Search for more papers by this authorCorresponding Author
Maurizio Taglialatela MD, PhD
Department of Neuroscience, University of Naples “Federico II”, Naples, Italy
These authors contributed equally to this work.
Address correspondence to Dr Taglialatela, Department of Neuroscience, University of Naples “Federico II”, Via Pansini 5, 80131 Naples, Italy. E-mail: [email protected]; Dr Rubboli, The Danish Epilepsy Centre, Filadelfia/University of Copenhagen, Kolonivej 1, 4293 Dianalund, Denmark. E-mail: [email protected]
Search for more papers by this authorAbstract
Objective
Pathogenic variants in KCNT2 are rare causes of developmental epileptic encephalopathy (DEE). We herein describe the phenotypic and genetic features of patients with KCNT2-related DEE, and the in vitro functional and pharmacological properties of KCNT2 channels carrying 14 novel or previously untested variants.
Methods
Twenty-five patients harboring KCNT2 variants were investigated: 12 were identified through an international collaborative network, 13 were retrieved from the literature. Clinical data were collected and included in a standardized phenotyping sheet. Novel variants were detected using exome sequencing and classified using ACMG criteria. Functional and pharmacological studies were performed by whole-cell electrophysiology in HEK-293 and SH-SY5Y cells.
Results
The phenotypic spectrum encompassed: (a) intellectual disability/developmental delay (21/22 individuals with available information), ranging from mild to severe/profound; (b) epilepsy (15/25); (c) neurological impairment, with altered muscle tone (14/22); (d) dysmorphisms (13/20). Nineteen pathogenic KCNT2 variants were found (9 new, 10 reported previously): 16 missense, 1 in-frame deletion of a single amino acid, 1 nonsense, and 1 frameshift. Among tested variants, 8 showed gain-of-function (GoF), and 6 loss-of-function (LoF) features when expressed heterologously in vitro. Quinidine and fluoxetine blocked all GoF variants, whereas loxapine and riluzole activated some LoF variants while blocking others.
Interpretation
We expanded the phenotypic and genotypic spectrum of KCNT2-related disorders, highlighting novel genotype–phenotype associations. Pathogenic KCNT2 variants cause GoF or LoF in vitro phenotypes, and each shows a unique pharmacological profile, suggesting the need for in vitro functional and pharmacological investigation to enable targeted therapies based on the molecular phenotype. ANN NEUROL 2023;94:332–349
Potential Conflicts of Interest
The authors report no competing interests. S.J.S. receives research support from BioMarin Pharmaceuticals.
Open Research
Data Availability Statement
All main results of this study are available within the article and its Supplementary material. Further inquiries can be directed to the corresponding authors.
Supporting Information
| Filename | Description |
|---|---|
| ana26662-sup-0001-FigureS1.tifimage/tif, 4.9 MB | Figure S1. |
| ana26662-sup-0002-Tables.docxWord 2007 document , 45.5 KB | Table S1. KCNT2 study group members and affiliations. Table S2. Literature cohort Table S3. Inter- and intra-subunit interactions identified for each of the indicated residues in the closed and open configurations of KCNT2 subunits. Top: interactions identified when the respective position is occupied by the amino acid occurring in the wild-type KCNT2 channel. Bottom: interactions identified when the respective position is occupied by the amino acid substituted in each KCNT2 variant. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Aldrich R, Chandy KG, Grissmer S, et al. Calcium- and sodium-activated potassium channels (KCa, KNa) in GtoPdb v.2021.3. IUPHARBPS Guide Pharmacol CITE 2021; 2021.
- 2Salkoff L, Butler A, Ferreira G, et al. High-conductance potassium channels of the SLO family. Nat Rev Neurosci 2006; 7: 921–931.
- 3Chen H, Kronengold J, Yan Y, et al. The N-terminal domain of slack determines the formation and trafficking of slick/slack heteromeric sodium-activated potassium channels. J Neurosci 2009; 29: 5654–5665.
- 4Yang B, Desai R, Kaczmarek LK. Slack and slick KNa channels regulate the accuracy of timing of auditory neurons. J Neurosci 2007; 27: 2617–2627.
- 5Barcia G, Fleming MR, Deligniere A, et al. De novo gain of function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat Genet 2012; 44: 1255–1259.
- 6Heron SE, Smith KR, Bahlo M, et al. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 2012; 44: 1188–1190.
- 7Evely K, Pryce K, Bhattacharjee A. The Phe932Ile mutation in KCNT1 channels associated with severe epilepsy, delayed myelination and leukoencephalopathy produces a loss-of-function channel phenotype. Neuroscience 2017; 351: 65–70.
- 8Gertler T, Bearden D, Bhattacharjee A, Carvill G. KCNT1-related epilepsy. In: MP Adam, HH Ardinger, RA Pagon, et al., eds. GeneReviews®. Seattle: University of Washington, 2018. Accessed May 15, 2022. http://www.ncbi.nlm.nih.gov/books/NBK525917/.
- 9Bearden D, Strong A, Ehnot J, et al. Targeted treatment of migrating partial seizures of infancy with quinidine. Ann Neurol 2014; 76: 457–461.
- 10Cole BA, Johnson RM, Dejakaisaya H, et al. Structure-based identification and characterization of inhibitors of the epilepsy-associated KNa1.1 (KCNT1) Potassium Channel. iScience 2020; 23:101100.
- 11Spitznagel BD, Mishra NM, Qunies AM, et al. VU0606170, a selective slack channels inhibitor, decreases calcium oscillations in cultured cortical neurons. ACS Chem Nerosci 2020; 11: 3658–3671.
- 12Burbano LE, Li M, Jancovski N, et al. Antisense oligonucleotide therapy for KCNT1 encephalopathy. JCI Insight 2022; 7:e146090.
- 13Alagoz M, Kherad N, Bozkurt S, Yuksel A. New mutations in KCNT2 gene causing early infantile epileptic encephalopathy type 57: case study and literature review. Acta Biochim Pol 2020; 67: 431–434.
- 14Ambrosino P, Soldovieri MV, Bast T, et al. De novo gain-of-function variants in KCNT2 as a novel cause of developmental and epileptic encephalopathy. Ann Neurol 2018; 83: 1198–1204.
- 15Gong P, Jiao X, Yu D, Yang Z. Case report: causative De novo variants of KCNT2 for developmental and epileptic encephalopathy. Front Genet Wwwfrontiersinorg 2021; 12: 12.
- 16Gururaj S, Palmer EE, Sheehan GD, et al. A De novo mutation in the sodium-activated Potassium Channel KCNT2 alters ion selectivity and causes epileptic encephalopathy. Cell Rep 2017; 21: 926–933.
- 17Inuzuka LM, Macedo-Souza LI, Della-Ripa B, et al. Additional observation of a de novo pathogenic variant in KCNT2 leading to epileptic encephalopathy with clinical features of frontal lobe epilepsy. Brain Dev 2020; 42: 691–695.
- 18Jackson A, Banka S, Stewart H, et al. Recurrent KCNT2 missense variants affecting p.Arg190 result in a recognizable phenotype. Am J Med Genet A 2021; 185: 3083–3091.
- 19Mao X, Bruneau N, Gao Q, et al. The epilepsy of infancy with migrating focal seizures: identification of de novo mutations of the KCNT2 gene that exert inhibitory effects on the corresponding heteromeric KNa1.1/KNa1.2 Potassium Channel. Front Cell Neurosci 2020; 14: 1–12.
- 20Álvarez-Mora MI, Sánchez A, Rodríguez-Revenga L, et al. Diagnostic yield of next-generation sequencing in 87 families with neurodevelopmental disorders. Orphanet J Rare Dis 2022; 17: 60.
- 21Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the international league against epilepsy: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017; 58: 522–530.
- 22Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17: 405–424.
- 23Karczewski KJ, Francioli LC, Tiao G, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 2020; 581: 434–443.
- 24Rizzo F, Ambrosino P, Guacci A, et al. Characterization of two de novo KCNT1 mutations in children with malignant migrating partial seizures in infancy. Mol Cell Neurosci 2016; 72: 54–63.
- 25Xicoy H, Wieringa B, Martens GJ. The SH-SY5Y cell line in Parkinson's disease research: a systematic review. Mol Neurodegener 2017; 12: 10.
- 26Hite RK, MacKinnon R. Structural titration of Slo2.2, a Na+−dependent K+ channel. Cell 2017; 168: 390–399.e11.
- 27Bhattacharjee A, Joiner WJ, Wu M, et al. Slick (Slo2.1), a rapidly-gating sodium-activated Potassium Channel inhibited by ATP. J Neurosci 2003; 23: 11681–11691.
- 28Şahin M, Öncü G, Yılmaz MA, et al. Transformation of SH-SY5Y cell line into neuron-like cells: investigation of electrophysiological and biomechanical changes. Neurosci Lett 2021; 745:135628.
- 29Niday Z, Tzingounis AV. Potassium channel gain of function in epilepsy: an unresolved paradox. Neuroscientist 2018; 24: 368–380.
- 30Yeung SY, Millar JA, Mathie A. Inhibition of neuronal KV potassium currents by the antidepressant drug, fluoxetine. Br J Pharmacol 1999; 128: 1609–1615.
- 31Biton B, Sethuramanujam S, Picchione KE, et al. The antipsychotic drug loxapine is an opener of the sodium- activated potassium channel slack (Slo2.2). J Pharmacol Exp Ther 2012; 340: 706–715.
- 32Ziegler A, Colin E, Goudenège D, Bonneau D. A snapshot of some pLI score pitfalls. Hum Mutat 2019; 40: 839–841.
- 33Nappi P, Miceli F, Soldovieri MV, et al. Epileptic channelopathies caused by neuronal Kv7 (KCNQ) channel dysfunction. Pflugers Arch 2020; 472: 881–898.
- 34Martinez-Espinosa PL, Wu J, Yang C, et al. Knockout of Slo2.2 enhances itch, abolishes KNa current, and increases action potential firing frequency in DRG neurons. Elife 2015; 4:e10013.
- 35Tomasello DL, Hurley E, Wrabetz L, Bhattacharjee A. Slick (Kcnt2) sodium-activated potassium channels limit Peptidergic nociceptor excitability and hyperalgesia. J Exp Neurosci 2017 Sep; 14: 1179069517726996.
10.1177/1179069517726996 Google Scholar
- 36Quraishi IH, Mercier MR, McClure H, et al. Impaired motor skill learning and altered seizure susceptibility in mice with loss or gain of function of the Kcnt1 gene encoding slack (KNa1.1) Na+−activated K+ channels. Sci Rep 2020; 10: 3213.
- 37Bauer CK, Calligari P, Radio FC, et al. Mutations in KCNK4 that affect gating cause a recognizable neurodevelopmental syndrome. Am J Hum Genet 2018; 103: 621–630.
- 38Hamilton MJ, Suri M. “Electrifying dysmorphology”: potassium channelopathies causing dysmorphic syndromes. Adv Genet 2020; 105: 137–174.
- 39Dilena R, DiFrancesco JC, Soldovieri MV, et al. Early treatment with quinidine in 2 patients with epilepsy of infancy with migrating focal seizures (EIMFS) due to gain-of-function KCNT1 mutations: functional studies, clinical responses, and critical issues for personalized therapy. Neurotherapeutics 2018; 15: 1112–1126.
- 40Numis AL, Nair U, Datta AN, et al. Lack of response to quinidine in KCNT1-related neonatal epilepsy. Epilepsia 2018; 59: 1889–1898.
- 41Goldberg EM. Rational small molecule treatment for genetic epilepsies. Neurotherapeutics 2021; 18: 1490–1499.
- 42Motlagh HN, Hilser VJ. Agonism/antagonism switching in allosteric ensembles. Proc Natl Acad Sci U S A 2012; 109: 4134–4139.
- 43Vanoye CG, Desai RR, Ji Z, et al. High-throughput evaluation of epilepsy-associated KCNQ2 variants reveals functional and pharmacological heterogeneity. JCI Insight 2022; 7:e156314.
- 44Barrese V, Miceli F, Soldovieri MV, et al. Neuronal potassium channel openers in the management of epilepsy: role and potential of retigabine. Clin Pharmacol 2010; 2: 225–236.
- 45Kang SK, Vanoye CG, Misra SN, et al. Spectrum of KV2.1 dysfunction in KCNB1-associated neurodevelopmental disorders. Ann Neurol 2019; 86: 899–912.
- 46Bonardi CM, Heyne HO, Fiannacca M, et al. KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum. Brain 2021; 11: 3635–3650.
- 47Fitzgerald MP, Fiannacca M, Smith DM, et al. Treatment responsiveness in KCNT1-related epilepsy. Neurotherapeutics 2019; 16: 848–857.
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