Clinical and electrophysiological features of SCN8A variants causing episodic or chronic ataxia

Hang Lyu; Christian M Boßelmann; Katrine M Johannesen; Mahmoud Koko; Juan Dario Ortigoza-Escobar; Sergio Aguilera-Albesa; Deyanira Garcia-Navas Núñez; Tarja Linnankivi; Eija Gaily; Henriette J A van Ruiten; Ruth Richardson; Cornelia Betzler; Gabriella Horvath; Eva Brilstra; Niels Geerdink; Daniele Orsucci; Alessandra Tessa; Elena Gardella; Zofia Fleszar; Ludger Schöls; Holger Lerche; Rikke S Møller; Yuanyuan Liu

doi:10.1016/j.ebiom.2023.104855

Clinical and electrophysiological features of SCN8A variants causing episodic or chronic ataxia

Hang Lyu, Christian M Boßelmann, Katrine M Johannesen, Mahmoud Koko, Juan Dario Ortigoza-Escobar, Sergio Aguilera-Albesa, Deyanira Garcia-Navas Núñez, Tarja Linnankivi, Eija Gaily, Henriette J A van Ruiten, Ruth Richardson, Cornelia Betzler, Gabriella Horvath, Eva Brilstra, Niels Geerdink, Daniele Orsucci, Alessandra Tessa, Elena Gardella, Zofia Fleszar, Ludger SchölsHolger Lerche, Rikke S Møller, Yuanyuan Liu^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

BACKGROUND: Variants in SCN8A are associated with a spectrum of epilepsies and neurodevelopmental disorders. Ataxia as a predominant symptom of SCN8A variation has not been well studied. We set out to investigate disease mechanisms and genotype-phenotype correlations of SCN8A-related ataxia.

METHODS: We collected genetic and electro-clinical data of ten individuals from nine unrelated families carrying novel SCN8A variants associated with chronic progressive or episodic ataxia. Electrophysiological characterizations of these variants were performed in ND7/23 cells and cultured neurons.

FINDINGS: Variants associated with chronic progressive ataxia either decreased Na + current densities and shifted activation curves towards more depolarized potentials (p.Asn995Asp, p.Lys1498Glu and p.Trp1266Cys) or resulted in a premature stop codon (p.Trp937Ter). Three variants (p.Arg847Gln and biallelic p.Arg191Trp/p.Asp1525Tyr) were associated with episodic ataxia causing loss-of-function by decreasing Na + current densities or a hyperpolarizing shift of the inactivation curve. Two additional episodic ataxia-associated variants caused mixed gain- and loss-of function effects in ND7/23 cells and were further examined in primary murine hippocampal neuronal cultures. Neuronal firing in excitatory neurons was increased by p.Arg1629His, but decreased by p.Glu1201Lys. Neuronal firing in inhibitory neurons was decreased for both variants. No functional effect was observed for p.Arg1913Trp. In four individuals, treatment with sodium channel blockers exacerbated symptoms.

INTERPRETATION: We identified episodic or chronic ataxia as predominant phenotypes caused by variants in SCN8A. Genotype-phenotype correlations revealed a more pronounced loss-of-function effect for variants causing chronic ataxia. Sodium channel blockers should be avoided under these conditions.

FUNDING: BMBF, DFG, the Italian Ministry of Health, University of Tuebingen.

Original language	English
Article number	104855
Number of pages	15
Journal	EBioMedicine
Volume	98
DOIs	https://doi.org/10.1016/j.ebiom.2023.104855
Publication status	Published - Dec 2023

Keywords

Animals
Ataxia/diagnosis
Codon, Nonsense
Humans
Mice
NAV1.6 Voltage-Gated Sodium Channel/genetics
Neurons
Sodium Channel Blockers

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Lyu, H., Boßelmann, C. M., Johannesen, K. M., Koko, M., Ortigoza-Escobar, J. D., Aguilera-Albesa, S., Garcia-Navas Núñez, D., Linnankivi, T., Gaily, E., van Ruiten, H. J. A., Richardson, R., Betzler, C., Horvath, G., Brilstra, E., Geerdink, N., Orsucci, D., Tessa, A., Gardella, E., Fleszar, Z., ... Liu, Y. (2023). Clinical and electrophysiological features of SCN8A variants causing episodic or chronic ataxia. EBioMedicine, 98, Article 104855. https://doi.org/10.1016/j.ebiom.2023.104855

@article{3a1a8d0df51949c29d0c3c55c1b8f34b,

title = "Clinical and electrophysiological features of SCN8A variants causing episodic or chronic ataxia",

abstract = "BACKGROUND: Variants in SCN8A are associated with a spectrum of epilepsies and neurodevelopmental disorders. Ataxia as a predominant symptom of SCN8A variation has not been well studied. We set out to investigate disease mechanisms and genotype-phenotype correlations of SCN8A-related ataxia.METHODS: We collected genetic and electro-clinical data of ten individuals from nine unrelated families carrying novel SCN8A variants associated with chronic progressive or episodic ataxia. Electrophysiological characterizations of these variants were performed in ND7/23 cells and cultured neurons.FINDINGS: Variants associated with chronic progressive ataxia either decreased Na + current densities and shifted activation curves towards more depolarized potentials (p.Asn995Asp, p.Lys1498Glu and p.Trp1266Cys) or resulted in a premature stop codon (p.Trp937Ter). Three variants (p.Arg847Gln and biallelic p.Arg191Trp/p.Asp1525Tyr) were associated with episodic ataxia causing loss-of-function by decreasing Na + current densities or a hyperpolarizing shift of the inactivation curve. Two additional episodic ataxia-associated variants caused mixed gain- and loss-of function effects in ND7/23 cells and were further examined in primary murine hippocampal neuronal cultures. Neuronal firing in excitatory neurons was increased by p.Arg1629His, but decreased by p.Glu1201Lys. Neuronal firing in inhibitory neurons was decreased for both variants. No functional effect was observed for p.Arg1913Trp. In four individuals, treatment with sodium channel blockers exacerbated symptoms. INTERPRETATION: We identified episodic or chronic ataxia as predominant phenotypes caused by variants in SCN8A. Genotype-phenotype correlations revealed a more pronounced loss-of-function effect for variants causing chronic ataxia. Sodium channel blockers should be avoided under these conditions.FUNDING: BMBF, DFG, the Italian Ministry of Health, University of Tuebingen.",

keywords = "Animals, Ataxia/diagnosis, Codon, Nonsense, Humans, Mice, NAV1.6 Voltage-Gated Sodium Channel/genetics, Neurons, Sodium Channel Blockers",

author = "Hang Lyu and Bo{\ss}elmann, {Christian M} and Johannesen, {Katrine M} and Mahmoud Koko and Ortigoza-Escobar, {Juan Dario} and Sergio Aguilera-Albesa and {Garcia-Navas N{\'u}{\~n}ez}, Deyanira and Tarja Linnankivi and Eija Gaily and {van Ruiten}, {Henriette J A} and Ruth Richardson and Cornelia Betzler and Gabriella Horvath and Eva Brilstra and Niels Geerdink and Daniele Orsucci and Alessandra Tessa and Elena Gardella and Zofia Fleszar and Ludger Sch{\"o}ls and Holger Lerche and M{\o}ller, {Rikke S} and Yuanyuan Liu",

note = "Publisher Copyright: {\textcopyright} 2023",

year = "2023",

month = dec,

doi = "10.1016/j.ebiom.2023.104855",

language = "English",

volume = "98",

}

Lyu, H, Boßelmann, CM, Johannesen, KM, Koko, M, Ortigoza-Escobar, JD, Aguilera-Albesa, S, Garcia-Navas Núñez, D, Linnankivi, T, Gaily, E, van Ruiten, HJA, Richardson, R, Betzler, C, Horvath, G, Brilstra, E, Geerdink, N, Orsucci, D, Tessa, A, Gardella, E, Fleszar, Z, Schöls, L, Lerche, H, Møller, RS & Liu, Y 2023, 'Clinical and electrophysiological features of SCN8A variants causing episodic or chronic ataxia', EBioMedicine, vol. 98, 104855. https://doi.org/10.1016/j.ebiom.2023.104855

TY - JOUR

T1 - Clinical and electrophysiological features of SCN8A variants causing episodic or chronic ataxia

AU - Lyu, Hang

AU - Boßelmann, Christian M

AU - Johannesen, Katrine M

AU - Koko, Mahmoud

AU - Ortigoza-Escobar, Juan Dario

AU - Aguilera-Albesa, Sergio

AU - Garcia-Navas Núñez, Deyanira

AU - Linnankivi, Tarja

AU - Gaily, Eija

AU - van Ruiten, Henriette J A

AU - Richardson, Ruth

AU - Betzler, Cornelia

AU - Horvath, Gabriella

AU - Brilstra, Eva

AU - Geerdink, Niels

AU - Orsucci, Daniele

AU - Tessa, Alessandra

AU - Gardella, Elena

AU - Fleszar, Zofia

AU - Schöls, Ludger

AU - Lerche, Holger

AU - Møller, Rikke S

AU - Liu, Yuanyuan

PY - 2023/12

Y1 - 2023/12

N2 - BACKGROUND: Variants in SCN8A are associated with a spectrum of epilepsies and neurodevelopmental disorders. Ataxia as a predominant symptom of SCN8A variation has not been well studied. We set out to investigate disease mechanisms and genotype-phenotype correlations of SCN8A-related ataxia.METHODS: We collected genetic and electro-clinical data of ten individuals from nine unrelated families carrying novel SCN8A variants associated with chronic progressive or episodic ataxia. Electrophysiological characterizations of these variants were performed in ND7/23 cells and cultured neurons.FINDINGS: Variants associated with chronic progressive ataxia either decreased Na + current densities and shifted activation curves towards more depolarized potentials (p.Asn995Asp, p.Lys1498Glu and p.Trp1266Cys) or resulted in a premature stop codon (p.Trp937Ter). Three variants (p.Arg847Gln and biallelic p.Arg191Trp/p.Asp1525Tyr) were associated with episodic ataxia causing loss-of-function by decreasing Na + current densities or a hyperpolarizing shift of the inactivation curve. Two additional episodic ataxia-associated variants caused mixed gain- and loss-of function effects in ND7/23 cells and were further examined in primary murine hippocampal neuronal cultures. Neuronal firing in excitatory neurons was increased by p.Arg1629His, but decreased by p.Glu1201Lys. Neuronal firing in inhibitory neurons was decreased for both variants. No functional effect was observed for p.Arg1913Trp. In four individuals, treatment with sodium channel blockers exacerbated symptoms. INTERPRETATION: We identified episodic or chronic ataxia as predominant phenotypes caused by variants in SCN8A. Genotype-phenotype correlations revealed a more pronounced loss-of-function effect for variants causing chronic ataxia. Sodium channel blockers should be avoided under these conditions.FUNDING: BMBF, DFG, the Italian Ministry of Health, University of Tuebingen.

AB - BACKGROUND: Variants in SCN8A are associated with a spectrum of epilepsies and neurodevelopmental disorders. Ataxia as a predominant symptom of SCN8A variation has not been well studied. We set out to investigate disease mechanisms and genotype-phenotype correlations of SCN8A-related ataxia.METHODS: We collected genetic and electro-clinical data of ten individuals from nine unrelated families carrying novel SCN8A variants associated with chronic progressive or episodic ataxia. Electrophysiological characterizations of these variants were performed in ND7/23 cells and cultured neurons.FINDINGS: Variants associated with chronic progressive ataxia either decreased Na + current densities and shifted activation curves towards more depolarized potentials (p.Asn995Asp, p.Lys1498Glu and p.Trp1266Cys) or resulted in a premature stop codon (p.Trp937Ter). Three variants (p.Arg847Gln and biallelic p.Arg191Trp/p.Asp1525Tyr) were associated with episodic ataxia causing loss-of-function by decreasing Na + current densities or a hyperpolarizing shift of the inactivation curve. Two additional episodic ataxia-associated variants caused mixed gain- and loss-of function effects in ND7/23 cells and were further examined in primary murine hippocampal neuronal cultures. Neuronal firing in excitatory neurons was increased by p.Arg1629His, but decreased by p.Glu1201Lys. Neuronal firing in inhibitory neurons was decreased for both variants. No functional effect was observed for p.Arg1913Trp. In four individuals, treatment with sodium channel blockers exacerbated symptoms. INTERPRETATION: We identified episodic or chronic ataxia as predominant phenotypes caused by variants in SCN8A. Genotype-phenotype correlations revealed a more pronounced loss-of-function effect for variants causing chronic ataxia. Sodium channel blockers should be avoided under these conditions.FUNDING: BMBF, DFG, the Italian Ministry of Health, University of Tuebingen.

KW - Animals

KW - Ataxia/diagnosis

KW - Codon, Nonsense

KW - Humans

KW - Mice

KW - NAV1.6 Voltage-Gated Sodium Channel/genetics

KW - Neurons

KW - Sodium Channel Blockers

UR - http://www.scopus.com/inward/record.url?scp=85175099333&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2023.104855

DO - 10.1016/j.ebiom.2023.104855

M3 - Article

C2 - 38251463

SN - 2352-3964

VL - 98

JO - EBioMedicine

JF - EBioMedicine

M1 - 104855

ER -

Clinical and electrophysiological features of SCN8A variants causing episodic or chronic ataxia

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