Clinical and genetic spectrum of SCN2A-associated episodic ataxia

N. Schwarz, T. Bast, E. Gaily, G. Golla, A. Hahn, J. Hukin, M. King, C. Korff, M.J. Miranda, R.S. Møller, B. Neubauer, T. Smol, P. Striano, B. Stroud, M. Vaccarezza, G. Kluger, H. Lerche, W. Fazeli

Research output: Contribution to journalArticleScientificpeer-review

Abstract

Background Pathogenic variants in SCN2A are associated with various neurological disorders including epilepsy, autism spectrum disorder and intellectual disability. Few reports have recently described SCN2A-associated episodic ataxia (EA). Our study identifies its broader clinical and genetic spectrum, and describes pharmacological approaches. Results We report 21 patients with SCN2A-associated EA, of which 9 are unpublished cases. The large majority of patients presents with epileptic seizures (18/21, 86%), often starting within the first three months of life (12/18, 67%). In contrast, onset of episodic ataxia ranged from 10 months to 14 years of age. The frequency of EA episodes ranged from brief, daily events up to 1-2 episodes per year each lasting several weeks. Potential triggers include minor head traumas and sleep deprivation. Cognitive outcome is favorable in most patients with normal or mildly impaired cognitive development in 17/21 patients (81%). No clear genotype-phenotype correlations were identified in this cohort. However, two mutational hotspots were identified, i.e. 7/21 patients (33%) harbor the identical pathogenic variant p.A263V, whereas 5/21 (24%) carry pathogenic variants that affect the S4 segment and its cytoplasmic loop within the domain IV. In addition, we identified six novel pathogenic variants in SCN2A. While acetazolamide was previously reported as beneficial in SCN2A-associated EA in one case, our data show a conflicting response in 8 additional patients treated with acetazolamide: three of them profited from acetazolamide treatment, while 5/8 did not. Conclusions Our study describes the heterogeneous clinical spectrum of SCN2A-associated EA, identifies two mutational hotspots and shows positive effects of acetazolamide in about 50%.
Original languageEnglish
JournalEuropean Journal of Paediatric Neurology
ISSN1090-3798
DOIs
Publication statusPublished - 7 Mar 2019
MoE publication typeA1 Journal article-refereed

Fields of Science

  • Acetazolamide
  • Episodic ataxia
  • Epilepsy

Cite this

Schwarz, N. ; Bast, T. ; Gaily, E. ; Golla, G. ; Hahn, A. ; Hukin, J. ; King, M. ; Korff, C. ; Miranda, M.J. ; Møller, R.S. ; Neubauer, B. ; Smol, T. ; Striano, P. ; Stroud, B. ; Vaccarezza, M. ; Kluger, G. ; Lerche, H. ; Fazeli, W. / Clinical and genetic spectrum of SCN2A-associated episodic ataxia. In: European Journal of Paediatric Neurology. 2019.
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title = "Clinical and genetic spectrum of SCN2A-associated episodic ataxia",
abstract = "Background Pathogenic variants in SCN2A are associated with various neurological disorders including epilepsy, autism spectrum disorder and intellectual disability. Few reports have recently described SCN2A-associated episodic ataxia (EA). Our study identifies its broader clinical and genetic spectrum, and describes pharmacological approaches. Results We report 21 patients with SCN2A-associated EA, of which 9 are unpublished cases. The large majority of patients presents with epileptic seizures (18/21, 86{\%}), often starting within the first three months of life (12/18, 67{\%}). In contrast, onset of episodic ataxia ranged from 10 months to 14 years of age. The frequency of EA episodes ranged from brief, daily events up to 1-2 episodes per year each lasting several weeks. Potential triggers include minor head traumas and sleep deprivation. Cognitive outcome is favorable in most patients with normal or mildly impaired cognitive development in 17/21 patients (81{\%}). No clear genotype-phenotype correlations were identified in this cohort. However, two mutational hotspots were identified, i.e. 7/21 patients (33{\%}) harbor the identical pathogenic variant p.A263V, whereas 5/21 (24{\%}) carry pathogenic variants that affect the S4 segment and its cytoplasmic loop within the domain IV. In addition, we identified six novel pathogenic variants in SCN2A. While acetazolamide was previously reported as beneficial in SCN2A-associated EA in one case, our data show a conflicting response in 8 additional patients treated with acetazolamide: three of them profited from acetazolamide treatment, while 5/8 did not. Conclusions Our study describes the heterogeneous clinical spectrum of SCN2A-associated EA, identifies two mutational hotspots and shows positive effects of acetazolamide in about 50{\%}.",
keywords = "Acetazolamide, Episodic ataxia, Epilepsy",
author = "N. Schwarz and T. Bast and E. Gaily and G. Golla and A. Hahn and J. Hukin and M. King and C. Korff and M.J. Miranda and R.S. M{\o}ller and B. Neubauer and T. Smol and P. Striano and B. Stroud and M. Vaccarezza and G. Kluger and H. Lerche and W. Fazeli",
year = "2019",
month = "3",
day = "7",
doi = "10.1016/j.ejpn.2019.03.001",
language = "English",
journal = "European Journal of Paediatric Neurology",
issn = "1090-3798",
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Schwarz, N, Bast, T, Gaily, E, Golla, G, Hahn, A, Hukin, J, King, M, Korff, C, Miranda, MJ, Møller, RS, Neubauer, B, Smol, T, Striano, P, Stroud, B, Vaccarezza, M, Kluger, G, Lerche, H & Fazeli, W 2019, 'Clinical and genetic spectrum of SCN2A-associated episodic ataxia' European Journal of Paediatric Neurology. https://doi.org/10.1016/j.ejpn.2019.03.001

Clinical and genetic spectrum of SCN2A-associated episodic ataxia. / Schwarz, N.; Bast, T.; Gaily, E.; Golla, G.; Hahn, A.; Hukin, J.; King, M.; Korff, C.; Miranda, M.J.; Møller, R.S.; Neubauer, B.; Smol, T.; Striano, P.; Stroud, B.; Vaccarezza, M.; Kluger, G.; Lerche, H.; Fazeli, W.

In: European Journal of Paediatric Neurology, 07.03.2019.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Clinical and genetic spectrum of SCN2A-associated episodic ataxia

AU - Schwarz, N.

AU - Bast, T.

AU - Gaily, E.

AU - Golla, G.

AU - Hahn, A.

AU - Hukin, J.

AU - King, M.

AU - Korff, C.

AU - Miranda, M.J.

AU - Møller, R.S.

AU - Neubauer, B.

AU - Smol, T.

AU - Striano, P.

AU - Stroud, B.

AU - Vaccarezza, M.

AU - Kluger, G.

AU - Lerche, H.

AU - Fazeli, W.

PY - 2019/3/7

Y1 - 2019/3/7

N2 - Background Pathogenic variants in SCN2A are associated with various neurological disorders including epilepsy, autism spectrum disorder and intellectual disability. Few reports have recently described SCN2A-associated episodic ataxia (EA). Our study identifies its broader clinical and genetic spectrum, and describes pharmacological approaches. Results We report 21 patients with SCN2A-associated EA, of which 9 are unpublished cases. The large majority of patients presents with epileptic seizures (18/21, 86%), often starting within the first three months of life (12/18, 67%). In contrast, onset of episodic ataxia ranged from 10 months to 14 years of age. The frequency of EA episodes ranged from brief, daily events up to 1-2 episodes per year each lasting several weeks. Potential triggers include minor head traumas and sleep deprivation. Cognitive outcome is favorable in most patients with normal or mildly impaired cognitive development in 17/21 patients (81%). No clear genotype-phenotype correlations were identified in this cohort. However, two mutational hotspots were identified, i.e. 7/21 patients (33%) harbor the identical pathogenic variant p.A263V, whereas 5/21 (24%) carry pathogenic variants that affect the S4 segment and its cytoplasmic loop within the domain IV. In addition, we identified six novel pathogenic variants in SCN2A. While acetazolamide was previously reported as beneficial in SCN2A-associated EA in one case, our data show a conflicting response in 8 additional patients treated with acetazolamide: three of them profited from acetazolamide treatment, while 5/8 did not. Conclusions Our study describes the heterogeneous clinical spectrum of SCN2A-associated EA, identifies two mutational hotspots and shows positive effects of acetazolamide in about 50%.

AB - Background Pathogenic variants in SCN2A are associated with various neurological disorders including epilepsy, autism spectrum disorder and intellectual disability. Few reports have recently described SCN2A-associated episodic ataxia (EA). Our study identifies its broader clinical and genetic spectrum, and describes pharmacological approaches. Results We report 21 patients with SCN2A-associated EA, of which 9 are unpublished cases. The large majority of patients presents with epileptic seizures (18/21, 86%), often starting within the first three months of life (12/18, 67%). In contrast, onset of episodic ataxia ranged from 10 months to 14 years of age. The frequency of EA episodes ranged from brief, daily events up to 1-2 episodes per year each lasting several weeks. Potential triggers include minor head traumas and sleep deprivation. Cognitive outcome is favorable in most patients with normal or mildly impaired cognitive development in 17/21 patients (81%). No clear genotype-phenotype correlations were identified in this cohort. However, two mutational hotspots were identified, i.e. 7/21 patients (33%) harbor the identical pathogenic variant p.A263V, whereas 5/21 (24%) carry pathogenic variants that affect the S4 segment and its cytoplasmic loop within the domain IV. In addition, we identified six novel pathogenic variants in SCN2A. While acetazolamide was previously reported as beneficial in SCN2A-associated EA in one case, our data show a conflicting response in 8 additional patients treated with acetazolamide: three of them profited from acetazolamide treatment, while 5/8 did not. Conclusions Our study describes the heterogeneous clinical spectrum of SCN2A-associated EA, identifies two mutational hotspots and shows positive effects of acetazolamide in about 50%.

KW - Acetazolamide

KW - Episodic ataxia

KW - Epilepsy

U2 - 10.1016/j.ejpn.2019.03.001

DO - 10.1016/j.ejpn.2019.03.001

M3 - Article

JO - European Journal of Paediatric Neurology

JF - European Journal of Paediatric Neurology

SN - 1090-3798

ER -