KCNT1-Related Epilepsy: A Review

Valeria Venti; Lina Ciccia; Bruna Scalia; Laura Sciuto; Carla Cimino; Simona Marino; Andrea D. Praticò; Raffaele Falsaperla

doi:10.1055/s-0041-1728688

Journal of Pediatric Neurology, Inhaltsverzeichnis

Journal of Pediatric Neurology 2023; 21(03): 197-202
DOI: 10.1055/s-0041-1728688

Review Article

KCNT1-Related Epilepsy: A Review

Authors

Valeria Venti

¹Pediatrics Postgraduate Residency Program, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
Lina Ciccia

¹Pediatrics Postgraduate Residency Program, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
Bruna Scalia

¹Pediatrics Postgraduate Residency Program, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
Laura Sciuto

¹Pediatrics Postgraduate Residency Program, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
Carla Cimino

²Unit of Pediatrics and Pediatric Emergency, University Hospital “Policlinico Rodolico-San Marco,” Catania, Italy
Simona Marino

³Unit of Neonatal Intensive Care and Neonatology, University Hospital “Policlinico Rodolico-San Marco,” Catania, Italy
Andrea D. Praticò

⁴Unit of Rare Diseases of the Nervous System in Childhood, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
Raffaele Falsaperla

²Unit of Pediatrics and Pediatric Emergency, University Hospital “Policlinico Rodolico-San Marco,” Catania, Italy

³Unit of Neonatal Intensive Care and Neonatology, University Hospital “Policlinico Rodolico-San Marco,” Catania, Italy

Abstract

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

Keywords

KCNT1 - potassium - epilepsy - autosomal-dominant nocturnal frontal lobe epilepsy - malignant migrating focal seizures of infancy - quinidine

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Referenzen

References
1 Lim CX, Ricos MG, Dibbens LM, Heron SE. KCNT1 mutations in seizure disorders: the phenotypic spectrum and functional effects. J Med Genet 2016; 53 (04) 217-225
2 Brancati F, Travaglini L, Zablocka D. et al; International JSRD Study Group. RPGRIP1L mutations are mainly associated with the cerebello-renal phenotype of Joubert syndrome-related disorders. Clin Genet 2008; 74 (02) 164-170
3 Salpietro V, Polizzi A, Di Rosa G. et al. Adrenal disorders and the paediatric brain: pathophysiological considerations and clinical implications. Int J Endocrinol 2014; 2014: 282489
4 Lionetti E, Francavilla R, Maiuri L. et al. Headache in pediatric patients with celiac disease and its prevalence as a diagnostic clue. J Pediatr Gastroenterol Nutr 2009; 49 (02) 202-207
5 Ranieri C, Di Tommaso S, Loconte DC. et al. In vitro efficacy of ARQ 092, an allosteric AKT inhibitor, on primary fibroblast cells derived from patients with PIK3CA-related overgrowth spectrum (PROS). Neurogenetics 2018; 19 (02) 77-91
6 Pavone P, Falsaperla R, Ruggieri M, Praticò AD, Pavone L. West syndrome treatment: new roads for an old syndrome. Front Neurol 2013; 4: 113
7 Pavone P, Briuglia S, Falsaperla R. et al. Wide spectrum of congenital anomalies including choanal atresia, malformed extremities, and brain and spinal malformations in a girl with a de novo 5.6-Mb deletion of 13q12.11-13q12.13. Am J Med Genet A 2014; 164A (07) 1734-1743
8 Matricardi S, Spalice A, Salpietro V. et al. Epilepsy in the setting of full trisomy 18: a multicenter study on 18 affected children with and without structural brain abnormalities. Am J Med Genet C Semin Med Genet 2016; 172 (03) 288-295
9 Ruggieri M. Cutis tricolor: congenital hyper- and hypopigmented lesions in a background of normal skin with and without associated systemic features: further expansion of the phenotype. Eur J Pediatr 2000; 159 (10) 745-749
10 Møller RS, Heron SE, Larsen LH. et al. Mutations in KCNT1 cause a spectrum of focal epilepsies. Epilepsia 2015; 56 (09) e114-e120
11 Nagase T, Kikuno R, Ishikawa K, Hirosawa M, Ohara O. Prediction of the coding sequences of unidentified human genes. XVII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res 2000; 7 (02) 143-150
12 Bhattacharjee A, Kaczmarek LK. For K+ channels, Na+ is the new Ca2+. Trends Neurosci 2005; 28 (08) 422-428
13 Ruggieri M, McShane MA. Parental view of epilepsy in Angelman syndrome: a questionnaire study. Arch Dis Child 1998; 79 (05) 423-426
14 Joiner WJ, Tang MD, Wang LY. et al. Formation of intermediate-conductance calcium-activated potassium channels by interaction of Slack and Slo subunits. Nat Neurosci 1998; 1 (06) 462-469
15 Chen 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 (17) 5654-5665
16 Bader CR, Bernheim L, Bertrand D. Sodium-activated potassium current in cultured avian neurones. Nature 1985; 317 (6037): 540-542
17 Franceschetti S, Lavazza T, Curia G. et al. Na+-activated K+ current contributes to postexcitatory hyperpolarization in neocortical intrinsically bursting neurons. J Neurophysiol 2003; 89 (04) 2101-2111
18 Wallén P, Robertson B, Cangiano L. et al. Sodium-dependent potassium channels of a Slack-like subtype contribute to the slow afterhyperpolarization in lamprey spinal neurons. J Physiol 2007; 585 (Pt 1): 75-90
19 Allen AS, Berkovic SF, Cossette P. et al; Epi4K Consortium, Epilepsy Phenome/Genome Project. De novo mutations in epileptic encephalopathies. Nature 2013; 501 (7466): 217-221
20 Martin HC, Kim GE, Pagnamenta AT. et al; WGS500 Consortium. Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. Hum Mol Genet 2014; 23 (12) 3200-3211
21 Rauch A, Wieczorek D, Graf E. et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 2012; 380 (9854): 1674-1682
22 McTague A, Howell KB, Cross JH, Kurian MA, Scheffer IE. The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol 2016; 15 (03) 304-316
23 Ruggieri M, Polizzi A, Pavone L, Musumeci S. Thalamic syndrome in children with measles infection and selective, reversible thalamic involvement. Pediatrics 1998; 101 (1 Pt 1): 112-119
24 Pavone P, Praticò AD, Falsaperla R. et al. Congenital generalized hypertrichosis: the skin as a clue to complex malformation syndromes. Ital J Pediatr 2015; 41: 55
25 Coppola G, Plouin P, Chiron C, Robain O, Dulac O. Migrating partial seizures in infancy: a malignant disorder with developmental arrest. Epilepsia 1995; 36 (10) 1017-1024
26 Barcia 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 (11) 1255-1259
27 McTague A, Appleton R, Avula S. et al. Migrating partial seizures of infancy: expansion of the electroclinical, radiological and pathological disease spectrum. Brain 2013; 136 (Pt 5): 1578-1591
28 Kim GE, Kronengold J, Barcia G. et al. Human slack potassium channel mutations increase positive cooperativity between individual channels. Cell Rep 2014; 9 (05) 1661-1672
29 Møller RS, Heron SE, Larsen LHG. et al. Mutations in KCNT1 cause a spectrum of focal epilepsies. Epilepsia 2015; 56 (09) e114-e120
30 Ohba C, Kato M, Takahashi N. et al. De novo KCNT1 mutations in early-onset epileptic encephalopathy. Epilepsia 2015; 56 (09) e121-e128
31 De Filippo MR, Rizzo F, Marchese G. et al. Lack of pathogenic mutations in six patients with MMPSI. Epilepsy Res 2014; 108 (02) 340-344
32 Ruggieri M, Praticò AD, Caltabiano R, Polizzi A. Rediagnosing one of Smith's patients (John McCann) with “neuromas tumours” (1849). Neurol Sci 2017; 38 (03) 493-499
33 Ruggieri M, Praticò AD, Scuderi A, Sorge G, Polizzi A. The multiple faces of artwork diagnoses. Lancet Neurol 2017; 16 (06) 417-418
34 Ruggieri M, Tigano G, Mazzone D, Tiné A, Pavone L. Involvement of the white matter in hypomelanosis of Ito (incontinentia pigmenti achromiens). Neurology 1996; 46 (02) 485-492
35 Salpietro V, Polizzi A, Bertè LF. et al. Idiopathic intracranial hypertension: a unifying neuroendocrine hypothesis through the adrenal-brain axis. Neuroendocrinol Lett 2012; 33 (06) 569-573
36 Pavone P, Falsaperla R, Ruggieri M. et al. Clinical course of N-methyl-D-aspartate receptor encephalitis and the effectiveness of cyclophosphamide treatment. J Pediatr Neurol 2017; 15 (02) 84-89
37 Kuchenbuch M, Benquet P, Kaminska A. et al. Quantitative analysis and EEG markers of KCNT1 epilepsy of infancy with migrating focal seizures. Epilepsia 2019; 60 (01) 20-32
38 Mikati MA, Jiang YH, Carboni M. et al. Quinidine in the treatment of KCNT1-positive epilepsies. Ann Neurol 2015; 78 (06) 995-999
39 O'Connor KC, Lopez-Amaya C, Gagne D. et al. Anti-myelin antibodies modulate clinical expression of childhood multiple sclerosis. J Neuroimmunol 2010; 223 (1-2): 92-99
40 Pavone V, Signorelli SS, Praticò AD. et al. Total hemi-overgrowth in pigmentary mosaicism of the (hypomelanosis of) ito type: eight case reports. Medicine (Baltimore) 2016; 95 (10) e2705
41 Ruggieri M, Polizzi A, Marceca GP, Catanzaro S, Praticò AD, Di Rocco C. Introduction to phacomatoses (neurocutaneous disorders) in childhood. Childs Nerv Syst 2020; 36 (10) 2229-2268
42 Ruggieri M, Pavone P, Polizzi A. et al. Ophthalmological manifestations in segmental neurofibromatosis type 1. Br J Ophthalmol 2004; 88 (11) 1429-1433
43 Ruggieri M. Mosaic (segmental) neurofibromatosis type 1 (NF1) and type 2 (NF2): no longer neurofibromatosis type 5 (NF5). Am J Med Genet 2001; 101 (02) 178-180
44 Ruggieri M, Polizzi A, Spalice A. et al. The natural history of spinal neurofibromatosis: a critical review of clinical and genetic features. Clin Genet 2015; 87 (05) 401-410
45 Ruggieri M, Polizzi A. Segmental neurofibromatosis. J Neurosurg 2000; 93 (03) 530-532
46 Carranza Rojo D, Hamiwka L, McMahon JM. et al. De novo SCN1A mutations in migrating partial seizures of infancy. Neurology 2011; 77 (04) 380-383
47 Poduri A, Chopra SS, Neilan EG. et al. Homozygous PLCB1 deletion associated with malignant migrating partial seizures in infancy. Epilepsia 2012; 53 (08) e146-e150
48 Praticò AD, Falsaperla R, Ruggieri M, Corsello G, Pavone P. Prognostic challenges of SCN1A genetic mutations: report on two children with mild features. J Pediatr Neurol 2016; 14 (02) 82-88
49 Milh M, Falace A, Villeneuve N. et al. Novel compound heterozygous mutations in TBC1D24 cause familial malignant migrating partial seizures of infancy. Hum Mutat 2013; 34 (06) 869-872
50 Rizzo F, Ambrosino P, Guacci A. et al. Characterization of two de novoKCNT1 mutations in children with malignant migrating partial seizures in infancy. Mol Cell Neurosci 2016; 72: 54-63
51 Falsaperla R, Perciavalle V, Pavone P. et al. Unilateral eye blinking arising from the ictal ipsilateral occipital area. Clin EEG Neurosci 2016; 47 (03) 243-246
52 Incorpora G, Pavone P, Castellano-Chiodo D, Praticò AD, Ruggieri M, Pavone L. Gelastic seizures due to hypothalamic hamartoma: rapid resolution after endoscopic tumor disconnection. Neurocase 2013; 19 (05) 458-461
53 Pavone P, Praticò AD, Pavone V. et al. Ataxia in children: early recognition and clinical evaluation. Ital J Pediatr 2017; 43 (01) 6
54 Pavone P, Praticò AD, Ruggieri M. et al. Acquired peripheral neuropathy: a report on 20 children. Int J Immunopathol Pharmacol 2012; 25 (02) 513-517
55 Ruggieri M, Praticò AD, Evans DG. Diagnosis, management, and new therapeutic options in childhood neurofibromatosis type 2 and related forms. Semin Pediatr Neurol 2015; 22 (04) 240-258
56 Ruggieri M, Huson SM. The neurofibromatoses. An overview. Ital J Neurol Sci 1999; 20 (02) 89-108
57 Salpietro V, Mankad K, Kinali M. et al. Pediatric idiopathic intracranial hypertension and the underlying endocrine-metabolic dysfunction: a pilot study. J Pediatr Endocrinol Metab 2014; 27 (1-2): 107-115
58 Scheffer IE, Bhatia KP, Lopes-Cendes I. et al. Autosomal dominant nocturnal frontal lobe epilepsy. A distinctive clinical disorder. Brain 1995; 118 (Pt 1): 61-73
59 Steinlein OK, Mulley JC, Propping P. et al. A missense mutation in the neuronal nicotinic acetylcholine receptor α 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 1995; 11 (02) 201-203
60 Aridon P, Marini C, Di Resta C. et al. Increased sensitivity of the neuronal nicotinic receptor α 2 subunit causes familial epilepsy with nocturnal wandering and ictal fear. Am J Hum Genet 2006; 79 (02) 342-350
61 Tinuper P, Bisulli F, Cross JH. et al. Definition and diagnostic criteria of sleep-related hypermotor epilepsy. Neurology 2016; 86 (19) 1834-1842
62 Parrino L, De Paolis F, Milioli G. et al. Distinctive polysomnographic traits in nocturnal frontal lobe epilepsy. Epilepsia 2012; 53 (07) 1178-1184
63 Tassinari CA, Cantalupo G, Högl B. et al. Neuroethological approach to frontolimbic epileptic seizures and parasomnias: the same central pattern generators for the same behaviours. Rev Neurol (Paris) 2009; 165 (10) 762-768
64 Ruggieri M, Pavone V, De Luca D, Franzò A, Tiné A, Pavone L. Congenital bone malformations in patients with neurofibromatosis type 1 (Nf1). J Pediatr Orthop 1999; 19 (03) 301-305
65 Juang JMJ, Lu TP, Lai LC. et al. Disease-targeted sequencing of ion channel genes identifies de novo mutations in patients with non-familial Brugada syndrome. Sci Rep 2014; 4: 6733
66 Parisi P, Oliva A, Coll Vidal M. et al. Coexistence of epilepsy and Brugada syndrome in a family with SCN5A mutation. Epilepsy Res 2013; 105 (03) 415-418
67 Ruggieri M, Gabriele AL, Polizzi A. et al. Natural history of neurofibromatosis type 2 with onset before the age of 1 year. Neurogenetics 2013; 14 (02) 89-98
68 Heron 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 (11) 1188-1190
69 Ishii A, Shioda M, Okumura A. et al. A recurrent KCNT1 mutation in two sporadic cases with malignant migrating partial seizures in infancy. Gene 2013; 531 (02) 467-471
70 Caltabiano R, Magro G, Polizzi A. et al. A mosaic pattern of INI1/SMARCB1 protein expression distinguishes schwannomatosis and NF2-associated peripheral schwannomas from solitary peripheral schwannomas and NF2-associated vestibular schwannomas. Childs Nerv Syst 2017; 33 (06) 933-940
71 Barbagallo M, Ruggieri M, Incorpora G. et al. Infantile spasms in the setting of Sturge-Weber syndrome. Childs Nerv Syst 2009; 25 (01) 111-118
72 Ruggieri M, Praticò AD, Caltabiano R, Polizzi A. Early history of the different forms of neurofibromatosis from ancient Egypt to the British Empire and beyond: first descriptions, medical curiosities, misconceptions, landmarks, and the persons behind the syndromes. Am J Med Genet A 2018; 176 (03) 515-550
73 Ruggieri M, Praticò AD, Serra A. et al. Early history of neurofibromatosis type 2 and related forms: earliest descriptions of acoustic neuromas, medical curiosities, misconceptions, landmarks and the pioneers behind the eponyms. Childs Nerv Syst 2017; 33 (04) 549-560
74 Hmaimess G, Kadhim H, Nassogne MC, Bonnier C, van Rijckevorsel K. Levetiracetam in a neonate with malignant migrating partial seizures. Pediatr Neurol 2006; 34 (01) 55-59
75 Caraballo RH, Fontana E, Darra F. et al. Migrating focal seizures in infancy: analysis of the electroclinical patterns in 17 patients. J Child Neurol 2008; 23 (05) 497-506
76 Cilio MR, Bianchi R, Balestri M. et al. Intravenous levetiracetam terminates refractory status epilepticus in two patients with migrating partial seizures in infancy. Epilepsy Res 2009; 86 (01) 66-71
77 McTague A, Nair U, Malhotra S. et al. Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy. Neurology 2018; 90 (01) e55-e66
78 Falsaperla R, D'Angelo G, Praticò AD. et al. Ketogenic diet for infants with epilepsy: A literature review. Epilepsy Behav 2020; 112: 107361
79 Praticò AD, Pavone P, Scuderi MG. et al. Symptomatic hypocalcemia in an epileptic child treated with valproic acid plus lamotrigine: a case report. Cases J 2009; 2: 7394
80 Pratico AD, Ruggieri M, Falsaperla R, Pavone P. A probable topiramate-induced limbs paraesthesia and rigid fingers flexion. Curr Drug Saf 2018; 13 (02) 131-136
81 Pratico AD, Longo L, Mansueto S. et al. Off-label use of drugs and adverse drug reactions in pediatric units: a prospective, multicenter study. Curr Drug Saf 2018; 13 (03) 200-207
82 Zamponi N, Rychlicki F, Corpaci L, Cesaroni E, Trignani R. Vagus nerve stimulation (VNS) is effective in treating catastrophic 1 epilepsy in very young children. Neurosurg Rev 2008; 31 (03) 291-297
83 Bhattacharjee A, Joiner WJ, Wu M, Yang Y, Sigworth FJ, Kaczmarek LK. Slick (Slo2.1), a rapidly-gating sodium-activated potassium channel inhibited by ATP. J Neurosci 2003; 23 (37) 11681-11691
84 Yang B, Gribkoff VK, Pan J. et al. Pharmacological activation and inhibition of Slack (Slo2.2) channels. Neuropharmacology 2006; 51 (04) 896-906
85 Sweetman SC. ed. Martindale: The Complete Drug Reference. 37th ed.. London, UK: Pharmaceutical Press; 2011
86 Ueda CT, Hirschfeld DS, Scheinman MM, Rowland M, Williamson BJ, Dzindzio BS. Disposition kinetics of quinidine. Clin Pharmacol Ther 1976; 19 (01) 30-36
87 Bearden D, Strong A, Ehnot J, DiGiovine M, Dlugos D, Goldberg EM. Targeted treatment of migrating partial seizures of infancy with quinidine. Ann Neurol 2014; 76 (03) 457-461
88 Mullen SA, Carney PW, Roten A. et al. Precision therapy for epilepsy due to KCNT1 mutations: a randomized trial of oral quinidine. Neurology 2018; 90 (01) e67-e72
89 Liu L, Collier AC, Link JM. et al. Modulation of P-glycoprotein at the human blood-brain barrier by quinidine or rifampin treatment: a positron emission tomography imaging study. Drug Metab Dispos 2015; 43 (11) 1795-1804
90 Ochs HR, Greenblatt DJ, Lloyd BL, Woo E, Sonntag M, Smith TW. Entry of quinidine into cerebrospinal fluid. Am Heart J 1980; 100 (03) 341-346
91 Westerhout J, Smeets J, Danhof M, de Lange EC. The impact of P-gp functionality on non-steady state relationships between CSF and brain extracellular fluid. J Pharmacokinet Pharmacodyn 2013; 40 (03) 327-342
92 Abdelnour E, Gallentine W, McDonald M, Sachdev M, Jiang YH, Mikati MA. Does age affect response to quinidine in patients with KCNT1 mutations? Report of three new cases and review of the literature. Seizure 2018; 55: 1-3
93 Arai-Ichinoi N, Uematsu M, Sato R. et al. Genetic heterogeneity in 26 infants with a hypomyelinating leukodystrophy. Hum Genet 2016; 135 (01) 89-98