KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum

被引：54

作者：

Bonardi, Claudia M. ^{[1
,2
]}

Heyne, Henrike O. ^{[3
,4
]}

Fiannacca, Martina ^{[5
]}

Fitzgerald, Mark P. ^{[6
,7
,8
]}

Gardella, Elena ^{[1
,9
]}

Gunning, Boudewijn ^{[10
]}

Olofsson, Kern ^{[11
]}

Lesca, Gaetan ^{[12
,13
]}

Verbeek, Nienke ^{[14
]}

Stamberger, Hannah ^{[15
,16
]}

Striano, Pasquale ^{[17
]}

Zara, Federico ^{[17
]}

Mancardi, Maria M. ^{[18
]}

Nava, Caroline ^{[19
]}

Syrbe, Steffen ^{[20
]}

Buono, Salvatore ^{[21
]}

Baulac, Stephanie ^{[22
]}

Coppola, Antonietta ^{[23
]}

Weckhuysen, Sarah ^{[15
,16
]}

Schoonjans, An-Sofie ^{[24
]}

Ceulemans, Berten ^{[24
]}

Sarret, Catherine ^{[25
]}

Baumgartner, Tobias ^{[26
]}

Muhle, Hiltrud ^{[27
]}

des Portes, Vincent ^{[28
]}

Toulouse, Joseph ^{[29
]}

Nougues, Marie-Christine ^{[30
]}

Rossi, Massimiliano ^{[12
,31
]}

Demarquay, Genevieve ^{[32
,33
]}

Ville, Dorothee ^{[34
]}

Hirsch, Edouard ^{[35
]}

Maurey, Helene ^{[36
]}

Willems, Marjolaine ^{[37
]}

de Bellescize, Julitta ^{[38
]}

Altuzarra, Cecilia Desmettre ^{[39
]}

Villeneuve, Nathalie ^{[40
]}

Bartolomei, Fabrice ^{[41
]}

Picard, Fabienne ^{[42
,43
]}

Hornemann, Frauke ^{[44
]}

Koolen, David A. ^{[45
]}

Kroes, Hester Y. ^{[14
]}

Reale, Chiara ^{[1
,46
]}

Fenger, Christina D. ^{[1
]}

Tan, Wen-Hann ^{[47
]}

Dibbens, Leanne ^{[48
,49
]}

Bearden, David R. ^{[50
]}

Moller, Rikke S. ^{[1
,9
]}

Rubboli, Guido ^{[1
,51
]}

机构：

[1] ERN EpiCARE, Dept Epilepsy Genet & Precis Med, Danish Epilepsy Ctr, DK-4293 Dianalund, Denmark

[2] Univ Hosp Padua, Dept Womans & Childs Hlth, I-35100 Padua, Italy

[3] Univ Helsinki, Finnish Inst Mol Med FIMM, Helsinki 00290, Finland

[4] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA

[5] Univ Genoa, Radiol Dept, I-16126 Genoa, Italy

[6] Univ Penn, Childrens Hosp Philadelphia, Div Neurol, Dept Neurol, Philadelphia, PA USA

[7] Univ Penn, Childrens Hosp Philadelphia, Dept Pediat, Div Neurol, Philadelphia, PA 19104 USA

[8] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA

[9] Univ Southern Denmark, Inst Reg Hlth Res, DK-5230 Odense, Denmark

[10] Stichting Epilepsie Instellingen Nederland, NL-8025 BV Zwolle, Netherlands

[11] Danish Epilepsy Ctr, Dept Pediat Neurol, DK-4293 Dianalund, Denmark

[12] Hosp Civils Lyon, Dept Genet, F-69002 Bron, France

[13] Univ Claude Bernard Lyon 1, Inst NeuroMyoGene, CNRS UMR 5310 INSERM U1217, F-69008 Lyon, France

[14] Univ Med Ctr, Dept Genet, NL-3584 CX Utrecht, Netherlands

[15] VIB Ctr Mol Neurol, Neurogenet Grp, B-2610 Antwerp, Belgium

[16] Univ Hosp, Dept Neurol, B-2650 Antwerp, Belgium

[17] Univ Genoa, IRCCS G Gaslini Inst, I-16147 Genoa, Italy

[18] IRCCS Ist Giannina Gaslini, Child Neuropsychiat Unit, I-16147 Genoa, Italy

[19] GH Pitie Salpetriere, AP HP, Dept Genet, F-75013 Paris, France

[20] Univ Hosp Heidelberg, Ctr Paediat & Adolescent Med, Div Pediat Epileptol, D-69120 Heidelberg, Germany

[21] Hosp Natl Relevance AORN, Neurol Div, I-80122 Naples, Italy

[22] Sorbonne Univ, Inst Cerveau, CNRS, INSERM,Paris Brain Inst ICM, F-75013 Paris, France

[23] Univ Naples Federico II, Dept Neurosci & Reprod & Odontostomatol Sci, I-80138 Naples, Italy

[24] Univ Antwerp, Antwerp Univ Hosp, Dept Pediat Neurol, B-2650 Edegem, Belgium

[25] CHU Clermont Ferrand, Serv Neuropediatrie, F-6310 Clermont Ferrand, France

[26] Univ Bonn, Dept Epileptol, D-53105 Bonn, Germany

[27] Univ Med Ctr Schleswig Holstein, Dept Neuropediat, D-24105 Kiel, Germany

[28] Femme Mere Enfant Hosp, Neuropaediat Dept, F-69500 Lyon, France

[29] CHU Lyon, Epileptol Sleep Disorders & Funct Pediat Neurol, F-69500 Bron, France

[30] Hosp Armand Trousseau, AP HP, Neuropaediat Dept, F-75012 Paris, France

[31] Claude Bernard Lyon 1 Univ, Lyon Neurosci Res Ctr CRNL, GENDEV Team, CNRS UMR5292,INSERM U1028, F-69675 Bron, France

[32] Neurol Hosp, Serv Neurol Fonct & Epileptol, F-69677 Bron, France

[33] Lyon Neurosci Res Ctr CRNL, NeuroPain, CNRS UMR5292, INSERM U1028, F-69677 Bron, France

[34] Lyon Univ Hosp, Pediat Neurol Dept, F-69500 Bron, France

[35] Univ Strasbourg, Hautepierre Hosp, Epilepsy Unit, F-67100 Strasbourg, France

[36] Hop Bicetre, Dept Pediat Neurol, F-94270 Paris, France

[37] Arnaud de Villeneuve Hosp, Dept Clin Genet, F-34090 Montpellier, France

[38] Hosp Civils Lyon, Dept Pediat Clin Epileptol Sleep Disorders & Func, F-69677 Lyon, France

[39] St Jacques Hosp, Dept Pediat, F-25000 Besancon, France

[40] Timone Children Hosp, Pediat Neurol Dept, F-13005 Marseille, France

[41] Aix Marseille Univ, Timone Hosp, Publ Assistance Hosp Marseille, Epileptol Dept, F-13005 Marseille, France

[42] Univ Hosp, Dept Clin Neurosci, CH-1211 Geneva, Switzerland

[43] Fac Med, CH-1211 Geneva, Switzerland

[44] Hosp Children & Adolescents, Ctr Pediat Res, D-04103 Leipzig, Germany

[45] Radboud Univ Med Ctr Radboudumc, Donders Inst Brain Cognit & Behav, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands

[46] Univ Messina, Dept Clin & Expt Med, I-98122 Messina, Italy

[47] Harvard Med Sch, Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA

[48] Univ South Australia, UniSA Clin & Hlth Sci, Epilepsy Res Grp, Adelaide, SA 5001, Australia

[49] Australian Ctr Precis Hlth, Adelaide, SA 5001, Australia

[50] Univ Rochester, Dept Neurol, Div Child Neurol, Sch Med, Rochester, NY 14642 USA

来源：

BRAIN | 2021年 / 144卷

基金：

澳大利亚国家健康与医学研究理事会; 欧洲研究理事会; 英国医学研究理事会;

关键词：

KCNT1; epileptic encephalopathies; epilepsy of infancy with migrating focal seizures; sleep-related hypermotor epilepsy; developmental and epileptic encephalopathies; MIGRATING PARTIAL SEIZURES; HYPERMOTOR EPILEPSY; POTASSIUM CHANNEL; KCNT1; MUTATIONS; ILAE COMMISSION; INFANCY; CLASSIFICATION;

D O I：

10.1093/brain/awab219

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies. This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 previously unpublished and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: (i) EIMFS (152 individuals, 33 previously unpublished); (ii) developmental and epileptic encephalopathies other than EIMFS (non-EIMFS developmental and epileptic encephalopathies) (37 individuals, 17 unpublished); (iii) autosomal dominant or sporadic sleep-related hypermotor epilepsy (53 patients, 14 unpublished); and (iv) other phenotypes (six individuals, two unpublished). In our cohort of 66 new cases, the most common phenotypic features were: (i) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; (ii) in non-EIMFS developmental and epileptic encephalopathies, possible onset with West syndrome, occurrence of atypical absences, possible evolution to developmental and epileptic encephalopathies with sleep-related hypermotor epilepsy features; one case of sudden unexplained death in epilepsy; (iii) in autosomal dominant or sporadic sleep-related hypermotor epilepsy, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in similar to 50% of the patients, sudden unexplained death in epilepsy in one individual; and (iv) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype-phenotype considerations showed many of the autosomal dominant or sporadic sleep-related hypermotor epilepsy-associated mutations to be clustered around the RCK2 domain in the C terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS developmental and epileptic encephalopathies did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset developmental and epileptic encephalopathies as well as of focal epilepsies, namely autosomal dominant or sporadic sleep-related hypermotor epilepsy.

引用

页码：3635 / 3650

页数：16

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