Clinical and genetic spectrum of SCN2A-associated episodic ataxia

N. Schwarz, T. Bast, E. Gaily, G. Golla, K. M. Gorman, L. R. Griffiths, A. Hahn, J. Hukin, M. King, C. Korff, M. J. Miranda, R. S. Møller, B. Neubauer, R. A. Smith, T. Smol, P. Striano, B. Stroud, M. Vaccarezza, G. Kluger, H. Lerche & 1 andre W. Fazeli*

*Kontaktforfatter for dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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 Results: We report 21 patients with SCN2A-associated EA, of which 9 are unpublished cases.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 present 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%.

OriginalsprogEngelsk
TidsskriftEuropean Journal of Paediatric Neurology
Vol/bind23
Udgave nummer3
Sider (fra-til)438-447
ISSN1090-3798
DOI
StatusUdgivet - 1. maj 2019

Fingeraftryk

Acetazolamide
Sleep Deprivation
Nervous System Diseases
Craniocerebral Trauma

Citer dette

Schwarz, N., Bast, T., Gaily, E., Golla, G., Gorman, K. M., Griffiths, L. R., ... Fazeli, W. (2019). Clinical and genetic spectrum of SCN2A-associated episodic ataxia. European Journal of Paediatric Neurology, 23(3), 438-447. https://doi.org/10.1016/j.ejpn.2019.03.001
Schwarz, N. ; Bast, T. ; Gaily, E. ; Golla, G. ; Gorman, K. M. ; Griffiths, L. R. ; Hahn, A. ; Hukin, J. ; King, M. ; Korff, C. ; Miranda, M. J. ; Møller, R. S. ; Neubauer, B. ; Smith, R. A. ; Smol, T. ; Striano, P. ; Stroud, B. ; Vaccarezza, M. ; Kluger, G. ; Lerche, H. ; Fazeli, W. / Clinical and genetic spectrum of SCN2A-associated episodic ataxia. I: European Journal of Paediatric Neurology. 2019 ; Bind 23, Nr. 3. s. 438-447.
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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 present 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, Epilepsy, Episodic ataxia, SCN2A",
author = "N. Schwarz and T. Bast and E. Gaily and G. Golla and Gorman, {K. M.} and Griffiths, {L. R.} and A. Hahn and J. Hukin and M. King and C. Korff and Miranda, {M. J.} and M{\o}ller, {R. S.} and B. Neubauer and Smith, {R. A.} and T. Smol and P. Striano and B. Stroud and M. Vaccarezza and G. Kluger and H. Lerche and W. Fazeli",
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month = "5",
day = "1",
doi = "10.1016/j.ejpn.2019.03.001",
language = "English",
volume = "23",
pages = "438--447",
journal = "European Journal of Paediatric Neurology",
issn = "1090-3798",
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Schwarz, N, Bast, T, Gaily, E, Golla, G, Gorman, KM, Griffiths, LR, Hahn, A, Hukin, J, King, M, Korff, C, Miranda, MJ, Møller, RS, Neubauer, B, Smith, RA, 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, bind 23, nr. 3, s. 438-447. 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.; Gorman, K. M.; Griffiths, L. R.; Hahn, A.; Hukin, J.; King, M.; Korff, C.; Miranda, M. J.; Møller, R. S.; Neubauer, B.; Smith, R. A.; Smol, T.; Striano, P.; Stroud, B.; Vaccarezza, M.; Kluger, G.; Lerche, H.; Fazeli, W.

I: European Journal of Paediatric Neurology, Bind 23, Nr. 3, 01.05.2019, s. 438-447.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer 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 - Gorman, K. M.

AU - Griffiths, L. R.

AU - Hahn, A.

AU - Hukin, J.

AU - King, M.

AU - Korff, C.

AU - Miranda, M. J.

AU - Møller, R. S.

AU - Neubauer, B.

AU - Smith, R. A.

AU - Smol, T.

AU - Striano, P.

AU - Stroud, B.

AU - Vaccarezza, M.

AU - Kluger, G.

AU - Lerche, H.

AU - Fazeli, W.

PY - 2019/5/1

Y1 - 2019/5/1

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 present 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 present 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 - Epilepsy

KW - Episodic ataxia

KW - SCN2A

U2 - 10.1016/j.ejpn.2019.03.001

DO - 10.1016/j.ejpn.2019.03.001

M3 - Journal article

VL - 23

SP - 438

EP - 447

JO - European Journal of Paediatric Neurology

JF - European Journal of Paediatric Neurology

SN - 1090-3798

IS - 3

ER -

Schwarz N, Bast T, Gaily E, Golla G, Gorman KM, Griffiths LR et al. Clinical and genetic spectrum of SCN2A-associated episodic ataxia. European Journal of Paediatric Neurology. 2019 maj 1;23(3):438-447. https://doi.org/10.1016/j.ejpn.2019.03.001