Skip to main content

Advertisement

Log in

Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia

  • Original Communication
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Mutations in SCN2A cause epilepsy syndromes of variable severity including neonatal-infantile seizures. In one case, we previously described additional childhood-onset episodic ataxia. Here, we corroborate and detail the latter phenotype in three further cases. We describe the clinical characteristics, identify the causative SCN2A mutations and determine their functional consequences using whole-cell patch-clamping in mammalian cells. In total, four probands presented with neonatal-onset seizures remitting after five to 13 months. In early childhood, they started to experience repeated episodes of ataxia, accompanied in part by headache or back pain lasting minutes to several hours. In two of the new cases, we detected the novel mutation p.Arg1882Gly. While this mutation occurred de novo in both patients, one of them carries an additional known variant on the same SCN2A allele, inherited from the unaffected father (p.Gly1522Ala). Whereas p.Arg1882Gly alone shifted the activation curve by −4 mV, the combination of both variants did not affect activation, but caused a depolarizing shift of voltage-dependent inactivation, and a significant increase in Na+ current density and protein production. p.Gly1522Ala alone did not change channel gating. The third new proband carries the same de novo SCN2A gain-of-function mutation as our first published case (p.Ala263Val). Our findings broaden the clinical spectrum observed with SCN2A gain-of-function mutations, showing that fairly different biophysical mechanisms can cause a convergent clinical phenotype of neonatal seizures and later onset episodic ataxia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Lerche H, Shah M, Beck H, Noebels J, Johnston D, Vincent A (2013) Ion channels in genetic and acquired forms of epilepsy. J Physiol 591(Pt 4):753–764. doi:10.1113/jphysiol.2012.240606

    Article  CAS  PubMed  Google Scholar 

  2. Russell JF, Fu Y-H, Ptácek LJ (2013) Episodic neurologic disorders: syndromes, genes, and mechanisms. Ann Rev Neurosci 36:25–50

    Article  CAS  PubMed  Google Scholar 

  3. Liao Y, Anttonen AK, Liukkonen E, Gaily E, Maljevic S, Schubert S, Bellan-Koch A, Petrou S, Ahonen VE, Lerche H, Lehesjoki AE (2010) SCN2A mutation associated with neonatal epilepsy, late-onset episodic ataxia, myoclonus, and pain. Neurology 75(16):1454–1458. doi:10.1212/WNL.0b013e3181f8812e

    Article  CAS  PubMed  Google Scholar 

  4. Kasteleijn-Nolst Trenite D, Parisi P (2012) Migraine in the borderland of epilepsy: “migralepsy” an overlapping syndrome of children and adults? Epilepsia 53(Suppl 7):20–25. doi:10.1111/j.1528-1167.2012.03711.x

    Article  PubMed  Google Scholar 

  5. Berg AT, Plioplys S (2012) Epilepsy and autism: is there a special relationship? Epilep Behav E&B 23(3):193–198. doi:10.1016/j.yebeh.2012.01.015

    Article  Google Scholar 

  6. Berkovic SF, Heron SE, Giordano L, Marini C, Guerrini R, Kaplan RE, Gambardella A, Steinlein OK, Grinton BE, Dean JT, Bordo L, Hodgson BL, Yamamoto T, Mulley JC, Zara F, Scheffer IE (2004) Benign familial neonatal-infantile seizures: characterization of a new sodium channelopathy. Ann Neurol 55(4):550–557. doi:10.1002/ana.20029

    Article  CAS  PubMed  Google Scholar 

  7. Liao Y, Deprez L, Maljevic S, Pitsch J, Claes L, Hristova D, Jordanova A, Ala-Mello S, Bellan-Koch A, Blazevic D, Schubert S, Thomas EA, Petrou S, Becker AJ, De Jonghe P, Lerche H (2010) Molecular correlates of age-dependent seizures in an inherited neonatal-infantile epilepsy. Brain J Neurol 133(Pt 5):1403–1414. doi:10.1093/brain/awq057

    Article  Google Scholar 

  8. Scalmani P, Rusconi R, Armatura E, Zara F, Avanzini G, Franceschetti S, Mantegazza M (2006) Effects in neocortical neurons of mutations of the NaV1. 2 Na+ channel causing benign familial neonatal-infantile seizures. J Neurosci 26(40):10100–10109

    Article  CAS  PubMed  Google Scholar 

  9. Ogiwara I, Ito K, Sawaishi Y, Osaka H, Mazaki E, Inoue I, Montal M, Hashikawa T, Shike T, Fujiwara T (2009) De novo mutations of voltage-gated sodium channel αII gene SCN2A in intractable epilepsies. Neurology 73(13):1046–1053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kobayashi K, Ohzono H, Shinohara M, Saitoh M, Ohmori I, Ohtsuka Y, Mizuguchi M (2012) Acute encephalopathy with a novel point mutation in the SCN2A gene. Epilepsy Res 102(1–2):109–112. doi:10.1016/j.eplepsyres.2012.04.016

    Article  CAS  PubMed  Google Scholar 

  11. Carvill GL, Heavin SB, Yendle SC, McMahon JM, O’Roak BJ, Cook J, Khan A, Dorschner MO, Weaver M, Calvert S (2013) Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet 45(7):825–830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Nakamura K, Kato M, Osaka H, Yamashita S, Nakagawa E, Haginoya K, Tohyama J, Okuda M, Wada T, Shimakawa S, Imai K, Takeshita S, Ishiwata H, Lev D, Lerman-Sagie T, Cervantes-Barragan DE, Villarroel CE, Ohfu M, Writzl K, Gnidovec Strazisar B, Hirabayashi S, Chitayat D, Myles Reid D, Nishiyama K, Kodera H, Nakashima M, Tsurusaki Y, Miyake N, Hayasaka K, Matsumoto N, Saitsu H (2013) Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome. Neurology 81(11):992–998. doi:10.1212/WNL.0b013e3182a43e57

    Article  CAS  PubMed  Google Scholar 

  13. Baasch AL, Hüning I, Gilissen C, Klepper J, Veltman JA, Gillessen-Kaesbach G, Hoischen A, Lohmann K (2014) Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures, severe intellectual disability, optic atrophy, muscular hypotonia, and brain abnormalities. Epilepsia 55(4):e25–e29

    Article  CAS  PubMed  Google Scholar 

  14. Matalon D, Goldberg E, Medne L, Marsh ED (2014) Confirming an expanded spectrum of SCN2A mutations: a case series. Epileptic Disorders 16(1):13–18

    PubMed  Google Scholar 

  15. Kamiya K, Kaneda M, Sugawara T, Mazaki E, Okamura N, Montal M, Makita N, Tanaka M, Fukushima K, Fujiwara T, Inoue Y, Yamakawa K (2004) A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline. J Neurosci Off J Soc Neurosci 24(11):2690–2698. doi:10.1523/JNEUROSCI.3089-03.2004

    Article  CAS  Google Scholar 

  16. Lemke JR, Riesch E, Scheurenbrand T, Schubach M, Wilhelm C, Steiner I, Hansen J, Courage C, Gallati S, Burki S, Strozzi S, Simonetti BG, Grunt S, Steinlin M, Alber M, Wolff M, Klopstock T, Prott EC, Lorenz R, Spaich C, Rona S, Lakshminarasimhan M, Kroll J, Dorn T, Kramer G, Synofzik M, Becker F, Weber YG, Lerche H, Bohm D, Biskup S (2012) Targeted next generation sequencing as a diagnostic tool in epileptic disorders. Epilepsia 53(8):1387–1398. doi:10.1111/j.1528-1167.2012.03516.x

    Article  CAS  PubMed  Google Scholar 

  17. Lauxmann S, Boutry-Kryza N, Rivier C, Mueller S, Hedrich UB, Maljevic S, Szepetowski P, Lerche H, Lesca G (2013) An SCN2A mutation in a family with infantile seizures from Madagascar reveals an increased subthreshold Na+ current. Epilepsia 54(9):e117–e121. doi:10.1111/epi.12241

    Article  CAS  PubMed  Google Scholar 

  18. Du W, Bautista JF, Yang H, Diez-Sampedro A, You SA, Wang L, Kotagal P, Luders HO, Shi J, Cui J, Richerson GB, Wang QK (2005) Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder. Nat Genet 37(7):733–738. doi:10.1038/ng1585

    Article  CAS  PubMed  Google Scholar 

  19. Guerrini R, Sanchez-Carpintero R, Deonna T, Santucci M, Bhatia KP, Moreno T, Parmeggiani L, Bernardina BD (2002) Early-onset absence epilepsy and paroxysmal dyskinesia. Epilepsia 43(10):1224–1229

    Article  PubMed  Google Scholar 

  20. Marini C, Conti V, Mei D, Battaglia D, Lettori D, Losito E, Bruccini G, Tortorella G, Guerrini R (2012) PRRT2 mutations in familial infantile seizures, paroxysmal dyskinesia, and hemiplegic migraine. Neurology 79(21):2109–2114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zuberi S, Eunson L, Spauschus A, De Silva R, Tolmie J, Wood N, McWilliam R, Stephenson J, Kullmann D, Hanna M (1999) A novel mutation in the human voltage-gated potassium channel gene (Kv1. 1) associates with episodic ataxia type 1 and sometimes with partial epilepsy. Brain J Neurol 122(5):817–825

    Article  Google Scholar 

  22. Scholl UI, Choi M, Liu T, Ramaekers VT, Häusler MG, Grimmer J, Tobe SW, Farhi A, Nelson-Williams C, Lifton RP (2009) Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10. Proc Natl Acad Sci 106(14):5842–5847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Escayg A, De Waard M, Lee DD, Bichet D, Wolf P, Mayer T, Johnston J, Baloh R, Sander T, Meisler MH (2000) Coding and noncoding variation of the human calcium-channel β 4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. Am J Hum Genet 66(5):1531–1539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Specchio N, Vigevano F (2006) The spectrum of benign infantile seizures. Epilepsy Res 70:156–167

    Article  Google Scholar 

  25. Strupp M, Kalla R, Claassen J, Adrion C, Mansmann U, Klopstock T, Freilinger T, Neugebauer H, Spiegel R, Dichgans M, Lehmann-Horn F, Jurkat-Rott K, Brandt T, Jen JC, Jahn K (2011) A randomized trial of 4-aminopyridine in EA2 and related familial episodic ataxias. Neurology 77(3):269–275. doi:10.1212/WNL.0b013e318225ab07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Strupp M, Kalla R, Dichgans M, Freilinger T, Glasauer S, Brandt T (2004) Treatment of episodic ataxia type 2 with the potassium channel blocker 4-aminopyridine. Neurology 62(9):1623–1625

    Article  CAS  PubMed  Google Scholar 

  27. Dreissen YE, Tijssen MA (2012) The startle syndromes: physiology and treatment. Epilepsia 53(Suppl 7):3–11. doi:10.1111/j.1528-1167.2012.03709.x

    Article  PubMed  Google Scholar 

  28. Jen JC, Graves TD, Hess EJ, Hanna MG, Griggs RC, Baloh RW, Investigators C (2007) Primary episodic ataxias: diagnosis, pathogenesis and treatment. Brain J Neurol 130(Pt 10):2484–2493. doi:10.1093/brain/awm126

    Article  CAS  Google Scholar 

  29. Tan SV, Wraige E, Lascelles K, Bostock H (2013) Episodic ataxia type 1 without episodic ataxia: the diagnostic utility of nerve excitability studies in individuals with KCNA1 mutations. Dev Med Child Neurol 55(10):959–962. doi:10.1111/dmcn.12236

    Article  PubMed  Google Scholar 

  30. Wolff M, Loddenkemper T, Jillella D, Docker M, Wong-Kisiel LC, Møller RS, Weckhuysen S, Ceulemans B, Klepper J, Baumeister FA, Koolen DA, Kluger G (2014) SCN2A-related epileptic encephalopathies: extended phenotype and response to sodium channel blockers. Paper presented at the 11th European Congress on Epileptology, Stockholm, 02.07.2014

  31. Pothmann L, Muller C, Averkin RG, Bellistri E, Miklitz C, Uebachs M, Remy S, Menendez de la Prida L, Beck H (2014) Function of inhibitory micronetworks is spared by Na+ channel-acting anticonvulsant drugs. J Neurosci Off J Soc Neurosci 34(29):9720–9735. doi:10.1523/JNEUROSCI.2395-13.2014

    Article  Google Scholar 

  32. Misra SN, Kahlig KM, George AL Jr (2008) Impaired NaV1.2 function and reduced cell surface expression in benign familial neonatal-infantile seizures. Epilepsia 49(9):1535–1545. doi:10.1111/j.1528-1167.2008.01619.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Schaller KL, Caldwell JH (2003) Expression and distribution of voltage-gated sodium channels in the cerebellum. Cerebellum 2(1):2–9. doi:10.1080/14734220309424

    Article  CAS  PubMed  Google Scholar 

  34. Touma M, Joshi M, Connolly MC, Ellen Grant P, Hansen AR, Khwaja O, Berry GT, Kinney HC, Poduri A, Agrawal PB (2013) Whole genome sequencing identifies SCN2A mutation in monozygotic twins with Ohtahara syndrome and unique neuropathologic findings. Epilepsia 54(5):e81–e85

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors thank all patients and their parents for participating in this study. We thank Markus Lommi, Ann-Liz Träskelin and Paula Hakala for technical assistance, Dr. Julian Schubert and Stefanie Garkisch for their help with analysis of genetic data. This work was supported by the German Research Foundation (DFG Le1030/10-2, Le1030/11-1 to HL, 416/5-1 to BAN) and the Folkhälsan Research Foundation (A-EL), partly in the frame of the EuroEPINOMICS programme of the European Science foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to H. Lerche.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical standards

Informed consent was obtained from the parents of all four patients. All procedures were in accordance with the Declaration of Helsinki and were approved by the local ethical review boards.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 97 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schwarz, N., Hahn, A., Bast, T. et al. Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia. J Neurol 263, 334–343 (2016). https://doi.org/10.1007/s00415-015-7984-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-015-7984-0

Keywords

Navigation