Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications
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Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications. / Johannesen, Katrine M.; Liu, Yuanyuan; Koko, Mahmoud; Gjerulfsen, Cathrine E.; Sonnenberg, Lukas; Schubert, Julian; Fenger, Christina D.; Eltokhi, Ahmed; Rannap, Maert; Koch, Nils A.; Lauxmann, Stephan; Krüger, Johanna; Kegele, Josua; Canafoglia, Laura; Franceschetti, Silvana; Mayer, Thomas; Rebstock, Johannes; Zacher, Pia; Ruf, Susanne; Alber, Michael; Sterbova, Katalin; Lassuthová, Petra; Vlckova, Marketa; Lemke, Johannes R.; Platzer, Konrad; Krey, Ilona; Heine, Constanze; Wieczorek, Dagmar; Kroell-Seger, Judith; Lund, Caroline; Klein, Karl Martin; Au, P. Y.Billie; Rho, Jong M.; Ho, Alice W.; Masnada, Silvia; Veggiotti, Pierangelo; Giordano, Lucio; Accorsi, Patrizia; Hoei-Hansen, Christina E.; Striano, Pasquale; Zara, Federico; Verhelst, Helene; Verhoeven, Judith S.; Braakman, Hilde M.H.; van der Zwaag, Bert; Harder, Aster V.E.; Brilstra, Eva; Pendziwiat, Manuela; Lebon, Sebastian; Vaccarezza, Maria; Le, Ngoc Minh; Christensen, Jakob; Grønborg, Sabine; Scherer, Stephen W.; Howe, Jennifer; Fazeli, Walid; Howell, Katherine B.; Leventer, Richard; Stutterd, Chloe; Walsh, Sonja; Gerard, Marion; Gerard, Bénédicte; Matricardi, Sara; Bonardi, Claudia M.; Sartori, Stefano; Berger, Andrea; Hoffman-Zacharska, Dorota; Mastrangelo, Massimo; Darra, Francesca; Vøllo, Arve; Motazacker, M. Mahdi; Lakeman, Phillis; Nizon, Mathilde; Betzler, Cornelia; Altuzarra, Cecilia; Caume, Roseline; Roubertie, Agathe; Gélisse, Philippe; Marini, Carla; Guerrini, Renzo; Bilan, Frederic; Tibussek, Daniel; Koch-Hogrebe, Margarete; Perry, M. Scott; Ichikawa, Shoji; Dadali, Elena; Sharkov, Artem; Mishina, Irina; Abramov, Mikhail; Kanivets, Ilya; Korostelev, Sergey; Kutsev, Sergey; Wain, Karen E.; Eisenhauer, Nancy; Wagner, Monisa; Savatt, Juliann M.; Müller-Schlüter, Karen; Bassan, Haim; Borovikov, Artem; Nassogne, Marie Cecile; Destrée, Anne; Schoonjans, An Sofie; Meuwissen, Marije; Buzatu, Marga; Jansen, Anna; Scalais, Emmanuel; Srivastava, Siddharth; Tan, Wen Hann; Olson, Heather E.; Loddenkemper, Tobias; Poduri, Annapurna; Helbig, Katherine L.; Helbig, Ingo; Fitzgerald, Mark P.; Goldberg, Ethan M.; Roser, Timo; Borggraefe, Ingo; Brünger, Tobias; May, Patrick; Lal, Dennis; Lederer, Damien; Rubboli, Guido; Heyne, Henrike O.; Lesca, Gaetan; Hedrich, Ulrike B.S.; Benda, Jan; Gardella, Elena; Lerche, Holger; Møller, Rikke S.
In: Brain, Vol. 145, No. 9, 2022, p. 2991-3009.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications
AU - Johannesen, Katrine M.
AU - Liu, Yuanyuan
AU - Koko, Mahmoud
AU - Gjerulfsen, Cathrine E.
AU - Sonnenberg, Lukas
AU - Schubert, Julian
AU - Fenger, Christina D.
AU - Eltokhi, Ahmed
AU - Rannap, Maert
AU - Koch, Nils A.
AU - Lauxmann, Stephan
AU - Krüger, Johanna
AU - Kegele, Josua
AU - Canafoglia, Laura
AU - Franceschetti, Silvana
AU - Mayer, Thomas
AU - Rebstock, Johannes
AU - Zacher, Pia
AU - Ruf, Susanne
AU - Alber, Michael
AU - Sterbova, Katalin
AU - Lassuthová, Petra
AU - Vlckova, Marketa
AU - Lemke, Johannes R.
AU - Platzer, Konrad
AU - Krey, Ilona
AU - Heine, Constanze
AU - Wieczorek, Dagmar
AU - Kroell-Seger, Judith
AU - Lund, Caroline
AU - Klein, Karl Martin
AU - Au, P. Y.Billie
AU - Rho, Jong M.
AU - Ho, Alice W.
AU - Masnada, Silvia
AU - Veggiotti, Pierangelo
AU - Giordano, Lucio
AU - Accorsi, Patrizia
AU - Hoei-Hansen, Christina E.
AU - Striano, Pasquale
AU - Zara, Federico
AU - Verhelst, Helene
AU - Verhoeven, Judith S.
AU - Braakman, Hilde M.H.
AU - van der Zwaag, Bert
AU - Harder, Aster V.E.
AU - Brilstra, Eva
AU - Pendziwiat, Manuela
AU - Lebon, Sebastian
AU - Vaccarezza, Maria
AU - Le, Ngoc Minh
AU - Christensen, Jakob
AU - Grønborg, Sabine
AU - Scherer, Stephen W.
AU - Howe, Jennifer
AU - Fazeli, Walid
AU - Howell, Katherine B.
AU - Leventer, Richard
AU - Stutterd, Chloe
AU - Walsh, Sonja
AU - Gerard, Marion
AU - Gerard, Bénédicte
AU - Matricardi, Sara
AU - Bonardi, Claudia M.
AU - Sartori, Stefano
AU - Berger, Andrea
AU - Hoffman-Zacharska, Dorota
AU - Mastrangelo, Massimo
AU - Darra, Francesca
AU - Vøllo, Arve
AU - Motazacker, M. Mahdi
AU - Lakeman, Phillis
AU - Nizon, Mathilde
AU - Betzler, Cornelia
AU - Altuzarra, Cecilia
AU - Caume, Roseline
AU - Roubertie, Agathe
AU - Gélisse, Philippe
AU - Marini, Carla
AU - Guerrini, Renzo
AU - Bilan, Frederic
AU - Tibussek, Daniel
AU - Koch-Hogrebe, Margarete
AU - Perry, M. Scott
AU - Ichikawa, Shoji
AU - Dadali, Elena
AU - Sharkov, Artem
AU - Mishina, Irina
AU - Abramov, Mikhail
AU - Kanivets, Ilya
AU - Korostelev, Sergey
AU - Kutsev, Sergey
AU - Wain, Karen E.
AU - Eisenhauer, Nancy
AU - Wagner, Monisa
AU - Savatt, Juliann M.
AU - Müller-Schlüter, Karen
AU - Bassan, Haim
AU - Borovikov, Artem
AU - Nassogne, Marie Cecile
AU - Destrée, Anne
AU - Schoonjans, An Sofie
AU - Meuwissen, Marije
AU - Buzatu, Marga
AU - Jansen, Anna
AU - Scalais, Emmanuel
AU - Srivastava, Siddharth
AU - Tan, Wen Hann
AU - Olson, Heather E.
AU - Loddenkemper, Tobias
AU - Poduri, Annapurna
AU - Helbig, Katherine L.
AU - Helbig, Ingo
AU - Fitzgerald, Mark P.
AU - Goldberg, Ethan M.
AU - Roser, Timo
AU - Borggraefe, Ingo
AU - Brünger, Tobias
AU - May, Patrick
AU - Lal, Dennis
AU - Lederer, Damien
AU - Rubboli, Guido
AU - Heyne, Henrike O.
AU - Lesca, Gaetan
AU - Hedrich, Ulrike B.S.
AU - Benda, Jan
AU - Gardella, Elena
AU - Lerche, Holger
AU - Møller, Rikke S.
N1 - Publisher Copyright: © The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.
PY - 2022
Y1 - 2022
N2 - We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1-3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1-3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1-3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.
AB - We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1-3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1-3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1-3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.
KW - epilepsy
KW - genetics
KW - personalized medicine
KW - SCN8A
U2 - 10.1093/brain/awab321
DO - 10.1093/brain/awab321
M3 - Journal article
C2 - 34431999
AN - SCOPUS:85138447351
VL - 145
SP - 2991
EP - 3009
JO - Brain
JF - Brain
SN - 0006-8950
IS - 9
ER -
ID: 321954257