Skip to main content

Advertisement

SpringerLink
Log in

Episodic ataxia type 2: phenotype characteristics of a novel CACNA1A mutation and review of the literature

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

Abstract

Episodic ataxia type 2 (EA2) is an autosomal dominant inherited neurological disorder that is characterized by paroxysmal episodes of ataxia. The causative gene for EA2 is CACNA1A which codes for the alpha 1A subunit of the voltage-gated P/Q-type calcium channel (Cav2.1). We detected a novel point mutation in the CACNA1A gene in a large Austrian family. All ten affected family members harbored a heterozygous c.3089+2T>C nucleotide exchange in intron 19. In silico modeling demonstrated a loss of the splice site of exon 19 by the mutation, which most likely results in exon skipping without frameshifting or use of an alternative splice site. Clinically, the family exhibited frequent ataxic episodes accompanied by headache in some individuals, which showed a good treatment response to acetazolamide or aminopyridine. Interictal phenotype variability was high ranging from an unremarkable clinical examination to a progressive cerebellar syndrome. Detailed cognitive testing with standardized neuropsychological tests revealed specific deficits in various domains including memory, executive functions and visual abilities. Moreover, a striking coincidence of socio-phobic behavior and anxiety disorders was detected within this family, which interfered with activities of daily living and has to be taken in consideration in EA2 patient management. We here characterize the phenotype of this novel CACNA1A mutation, review the respective literature and discuss implications on diagnosis and patient management.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Westenbroek RE, Sakurai T, Elliott EM, Hell JW, Starr TV, Snutch TP, Catterall WA (1995) Immunochemical identification and subcellular distribution of the alpha 1A subunits of brain calcium channels. J Neurosci 15:6403–6418

    CAS  PubMed  Google Scholar 

  2. Mori Y, Friedrich T, Kim MS, Mikami A, Nakai J, Ruth P, Bosse E, Hofmann F, Flockerzi V, Furuichi T et al (1991) Primary structure and functional expression from complementary DNA of a brain calcium channel. Nature 350:398–402

    Article  CAS  PubMed  Google Scholar 

  3. Mantuano E, Veneziano L, Jodice C, Frontali M (2003) Spinocerebellar ataxia type 6 and episodic ataxia type 2: differences and similarities between two allelic disorders. Cytogenet Genome Res 100:147–153

    Article  CAS  PubMed  Google Scholar 

  4. Jodice C, Mantuano E, Veneziano L, Trettel F, Sabbadini G, Calandriello L, Francia A, Spadaro M, Pierelli F, Salvi F, Ophoff RA, Frants RR, Frontali M (1997) Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p. Hum Mol Genet 6:1973–1978

    Article  CAS  PubMed  Google Scholar 

  5. Romaniello R, Zucca C, Tonelli A, Bonato S, Baschirotto C, Zanotta N, Epifanio R, Righini A, Bresolin N, Bassi MT, Borgatti R (2010) A wide spectrum of clinical, neurophysiological and neuroradiological abnormalities in a family with a novel CACNA1A mutation. J Neurol Neurosurg Psychiatry 81:840–843

    Article  PubMed  Google Scholar 

  6. Jen J, Kim GW, Baloh RW (2004) Clinical spectrum of episodic ataxia type 2. Neurology 62:17–22

    Article  CAS  PubMed  Google Scholar 

  7. Jen JC, Graves TD, Hess EJ, Hanna MG, Griggs RC, Baloh RW (2007) Primary episodic ataxias: diagnosis, pathogenesis and treatment. Brain 130:2484–2493

    Article  CAS  PubMed  Google Scholar 

  8. Griggs RC, Moxley RT 3rd, Lafrance RA, McQuillen J (1978) Hereditary paroxysmal ataxia: response to acetazolamide. Neurology 28:1259–1264

    Article  CAS  PubMed  Google Scholar 

  9. 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 62:1623–1625

    Article  CAS  PubMed  Google Scholar 

  10. 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 77:269–275

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Schmitz-Hubsch T, du Montcel ST, Baliko L, Berciano J, Boesch S, Depondt C, Giunti P, Globas C, Infante J, Kang JS, Kremer B, Mariotti C, Melegh B, Pandolfo M, Rakowicz M, Ribai P, Rola R, Schols L, Szymanski S, van de Warrenburg BP, Durr A, Klockgether T, Fancellu R (2006) Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology 66:1717–1720

    Article  CAS  PubMed  Google Scholar 

  12. Helmstaedter C, Durwen HF (1990) The verbal learning and retention test. A useful and differentiated tool in evaluating verbal memory performance. Schweiz Arch Neurol Psychiatr 141:21–30

    CAS  PubMed  Google Scholar 

  13. Meyers JE, Meyers KR (1995) Rey Complex Figure Test and Recognition Trial. PAR, Odessa

    Google Scholar 

  14. Horn W (1983) Leistungsprüfsystem L-P-S. Hogrefe, Göttingen

    Google Scholar 

  15. Jackson M, Warrington EK (1986) Arithmetic skills in patients with unilateral cerebral lesions. Cortex 22:611–620

    Article  CAS  PubMed  Google Scholar 

  16. Willmes K, Poeck K, Weniger D, Huber W (1983) Facet theory applied to the construction and validation of the Aachen Aphasia Test. Brain Lang 18:259–276

    Article  CAS  PubMed  Google Scholar 

  17. Mateer C, Kimura D (1977) Impairment of nonverbal oral movements in aphasia. Brain Lang 4:262–276

    Article  CAS  PubMed  Google Scholar 

  18. Härting C, Markowitsch HJ, Neufeld H (2000) Wechsler Gedächtnis-Test - Revidierte Fassung. Verlag Hans Huber, Bern

    Google Scholar 

  19. Zimmermann P, Fimm B (2007) Testbatterie zur Aufmerksamkeitsprüfung. Version 2.1. Psytest, Herzogenath

    Google Scholar 

  20. Aschenbrenner S, Tucha O, Lange KW (2001) Regensburger Wortflüssigkeits-Test. Hogrefe, Göttingen

    Google Scholar 

  21. Haid T, Martl C, Schubert F (2003) The Hamasch-5-Point-Test-Better Normative Data. J Int Neuropsychol Soc 4:521

    Google Scholar 

  22. Reitan RM, Wolfson D (1985) The Halstead-Reitan neuropsychological test battery. Neuropsychological Press, Tucson, AZ

    Google Scholar 

  23. Flowers KA, Robertson C (1985) The effect of Parkinson’s disease on the ability to maintain a mental set. J Neurol Neurosurg Psychiatry 48:517–529

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Kohler J (2004) Der Planungstest-Softwareprogramm zur Diagnostik von Planungsstörungen. In: EnJoiME Software (Beck & Kohler GbR). Konstanz

  25. Lehrl S, Merz J, Burkard G, Fischer B (1991) Mehrfachwahl-Wortschatz Intelligenz Test. In: Peri-Med Fachbuch. Erlangen

  26. Houdayer C, Dehainault C, Mattler C, Michaux D, Caux-Moncoutier V, Pages-Berhouet S, d’Enghien CD, Lauge A, Castera L, Gauthier-Villars M, Stoppa-Lyonnet D (2008) Evaluation of in silico splice tools for decision-making in molecular diagnosis. Hum Mutat 29:975–982

    Article  CAS  PubMed  Google Scholar 

  27. Cleves C, Parikh S, Rothner AD, Tepper SJ (2010) Link between confusional migraine, hemiplegic migraine and episodic ataxia type 2: hypothesis, family genealogy, gene typing and classification. Cephalalgia 30:740–743

    CAS  PubMed  Google Scholar 

  28. Jen J, Yue Q, Nelson SF, Yu H, Litt M, Nutt J, Baloh RW (1999) A novel nonsense mutation in CACNA1A causes episodic ataxia and hemiplegia. Neurology 53:34–37

    Article  CAS  PubMed  Google Scholar 

  29. Alonso I, Barros J, Tuna A, Coelho J, Sequeiros J, Silveira I, Coutinho P (2003) Phenotypes of spinocerebellar ataxia type 6 and familial hemiplegic migraine caused by a unique CACNA1A missense mutation in patients from a large family. Arch Neurol 60:610–614

    Article  PubMed  Google Scholar 

  30. Jen J, Wan J, Graves M, Yu H, Mock AF, Coulin CJ, Kim G, Yue Q, Papazian DM, Baloh RW (2001) Loss-of-function EA2 mutations are associated with impaired neuromuscular transmission. Neurology 57:1843–1848

    Article  CAS  PubMed  Google Scholar 

  31. Baloh RW, Yue Q, Furman JM, Nelson SF (1997) Familial episodic ataxia: clinical heterogeneity in four families linked to chromosome 19p. Ann Neurol 41:8–16

    Article  CAS  PubMed  Google Scholar 

  32. Scoggan KA, Chandra T, Nelson R, Hahn AF, Bulman DE (2001) Identification of two novel mutations in the CACNA1A gene responsible for episodic ataxia type 2. J Med Genet 38:249–253

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Kaunisto MA, Harno H, Kallela M, Somer H, Sallinen R, Hamalainen E, Miettinen PJ, Vesa J, Orpana A, Palotie A, Farkkila M, Wessman M (2004) Novel splice site CACNA1A mutation causing episodic ataxia type 2. Neurogenetics 5:69–73

    Article  CAS  PubMed  Google Scholar 

  34. Denier C, Ducros A, Durr A, Eymard B, Chassande B, Tournier-Lasserve E (2001) Missense CACNA1A mutation causing episodic ataxia type 2. Arch Neurol 58:292–295

    Article  CAS  PubMed  Google Scholar 

  35. Self J, Mercer C, Boon EM, Murugavel M, Shawkat F, Hammans S, Hodgkins P, Griffiths H, Lotery A (2009) Infantile nystagmus and late onset ataxia associated with a CACNA1A mutation in the intracellular loop between s4 and s5 of domain 3. Eye (Lond) 23:2251–2255

    Article  CAS  Google Scholar 

  36. Kim JM, Kim JS, Ki CS, Jeon BS (2006) Episodic ataxia type 2 due to a deletion mutation in the CACNA1A gene in a Korean family. J Clin Neurol 2:268–271

    Article  PubMed Central  PubMed  Google Scholar 

  37. Spacey SD, Materek LA, Szczygielski BI, Bird TD (2005) Two novel CACNA1A gene mutations associated with episodic ataxia type 2 and interictal dystonia. Arch Neurol 62:314–316

    Article  PubMed  Google Scholar 

  38. Riant F, Mourtada R, Saugier-Veber P, Tournier-Lasserve E (2008) Large CACNA1A deletion in a family with episodic ataxia type 2. Arch Neurol 65:817–820

    Article  PubMed  Google Scholar 

  39. van den Maagdenberg AM, Kors EE, Brunt ER, van Paesschen W, Pascual J, Ravine D, Keeling S, Vanmolkot KR, Vermeulen FL, Terwindt GM, Haan J, Frants RR, Ferrari MD (2002) Episodic ataxia type 2. Three novel truncating mutations and one novel missense mutation in the CACNA1A gene. J Neurol 249:1515–1519

    Article  PubMed  Google Scholar 

  40. Jung J, Testard H, Tournier-Lasserve E, Riant F, Vallet AE, Berroir S, Broussolle E (2010) Phenotypic variability of episodic ataxia type 2 mutations: a family study. Eur Neurol 64:114–116

    Article  CAS  PubMed  Google Scholar 

  41. Guida S, Trettel F, Pagnutti S, Mantuano E, Tottene A, Veneziano L, Fellin T, Spadaro M, Stauderman K, Williams M, Volsen S, Ophoff R, Frants R, Jodice C, Frontali M, Pietrobon D (2001) Complete loss of P/Q calcium channel activity caused by a CACNA1A missense mutation carried by patients with episodic ataxia type 2. Am J Hum Genet 68:759–764

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Choi KD, Yook JW, Kim MJ, Kim HS, Park YE, Kim JS, Choi JH, Shin JH, Kim DS (2013) Possible anticipation associated with a novel splice site mutation in episodic ataxia type 2. Neurol Sci

  43. Krishnan AV, Bostock H, Ip J, Hayes M, Watson S, Kiernan MC (2008) Axonal function in a family with episodic ataxia type 2 due to a novel mutation. J Neurol 255:750–755

    Article  PubMed  Google Scholar 

  44. Cricchi F, Di Lorenzo C, Grieco GS, Rengo C, Cardinale A, Racaniello M, Santorelli FM, Nappi G, Pierelli F, Casali C (2007) Early-onset progressive ataxia associated with the first CACNA1A mutation identified within the I-II loop. J Neurol Sci 254:69–71

    Article  CAS  PubMed  Google Scholar 

  45. Robbins MS, Lipton RB, Laureta EC, Grosberg BM (2009) CACNA1A nonsense mutation is associated with basilar-type migraine and episodic ataxia type 2. Headache 49:1042–1046

    Article  PubMed  Google Scholar 

  46. Glasscock E, Qian J, Yoo JW, Noebels JL (2007) Masking epilepsy by combining two epilepsy genes. Nat Neurosci 10:1554–1558

    Article  CAS  PubMed  Google Scholar 

  47. Gargus JJ (2006) Ion channel functional candidate genes in multigenic neuropsychiatric disease. Biol Psychiatry 60:177–185

    Article  CAS  PubMed  Google Scholar 

  48. Jouvenceau A, Eunson LH, Spauschus A, Ramesh V, Zuberi SM, Kullmann DM, Hanna MG (2001) Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel. Lancet 358:801–807

    Article  CAS  PubMed  Google Scholar 

  49. Guerin AA, Feigenbaum A, Donner EJ, Yoon G (2008) Stepwise developmental regression associated with novel CACNA1A mutation. Pediatr Neurol 39:363–364

    Article  PubMed  Google Scholar 

  50. Bertholon P, Chabrier S, Riant F, Tournier-Lasserve E, Peyron R (2009) Episodic ataxia type 2: unusual aspects in clinical and genetic presentation. Special emphasis in childhood. J Neurol Neurosurg Psychiatry 80:1289–1292

    Article  CAS  PubMed  Google Scholar 

  51. Mantuano E, Romano S, Veneziano L, Gellera C, Castellotti B, Caimi S, Testa D, Estienne M, Zorzi G, Bugiani M, Rajabally YA, Barcina MJ, Servidei S, Panico A, Frontali M, Mariotti C (2010) Identification of novel and recurrent CACNA1A gene mutations in fifteen patients with episodic ataxia type 2. J Neurol Sci 291:30–36

    Article  CAS  PubMed  Google Scholar 

  52. Karner E, Nachbauer W, Bodner T, Benke T, Boesch S, Delazer M (2012) Long-term outcome of cognitive functions, emotional behavior, and quality of life in a family with familial hemiplegic migraine. Cogn Behav Neurol 25:85–92

    Article  PubMed  Google Scholar 

  53. Eunson LH, Graves TD, Hanna MG (2005) New calcium channel mutations predict aberrant RNA splicing in episodic ataxia. Neurology 65:308–310

    Article  CAS  PubMed  Google Scholar 

  54. Wan J, Carr JR, Baloh RW, Jen JC (2005) Nonconsensus intronic mutations cause episodic ataxia. Ann Neurol 57:131–135

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to acknowledge Andreas Janecke for his advice and support in genetic counselling.

Conflicts of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Neurology, Medical University Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria

    Wolfgang Nachbauer, Michael Nocker, Elfriede Karner, Iris Unterberger, Andreas Eigentler, Werner Poewe, Margarete Delazer & Sylvia Boesch

  2. Department of Neurology, University of Belgrade, Belgrade, Serbia

    Iva Stankovic

  3. Department of Biochemistry, Leopold-Franzens-University Innsbruck, Innsbruck, Austria

    Rainer Schneider

Authors
  1. Wolfgang Nachbauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Nocker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elfriede Karner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Iva Stankovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Iris Unterberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andreas Eigentler
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rainer Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Werner Poewe
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Margarete Delazer
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sylvia Boesch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sylvia Boesch.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 22 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nachbauer, W., Nocker, M., Karner, E. et al. Episodic ataxia type 2: phenotype characteristics of a novel CACNA1A mutation and review of the literature. J Neurol 261, 983–991 (2014). https://doi.org/10.1007/s00415-014-7310-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-014-7310-2

Keywords

Search

Navigation