Hostname: page-component-586b7cd67f-2brh9 Total loading time: 0 Render date: 2024-11-27T13:51:52.809Z Has data issue: false hasContentIssue false
  • English
  • Français

CACNA1A Mutation in a EA-2 Patient Responsive to Acetazolamide and Valproic Acid

Published online by Cambridge University Press:  02 December 2014

Kylie A. Scoggan ,
Joseph H. Friedman  and
Dennis E. Bulman
Kylie A. Scoggan
Affiliation:
Ottawa Health Research Institute, Ottawa, ON, Canada Nutrition Research Division, Health Canada, Ottawa, ON, Canada
Joseph H. Friedman
Affiliation:
Division of Neurology, Brown University, Ottawa, ON, Canada NeuroHealth Parkinson's Disease and Movement Disorders Center 227, Warwich, RI, USA
Dennis E. Bulman*
Affiliation:
Ottawa Health Research Institute, Ottawa, ON, Canada Division of Neurology, University of Ottawa, Ottawa, ON, Canada
*
Ottawa Health Research Institute, 501 Smyth Road, Ottawa, Ontario, K1H 8L6, Canada.
Rights & Permissions [Opens in a new window]

Abstract:

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.
Background:

Episodic ataxia type-2 (EA-2) is an autosomal dominant neurological disorder that has been shown to result from mutations in the CACNA1A gene encoding the P/Q-type calcium channel. Affected individuals experience episodes of cerebellar ataxia usually associated with migraine symptoms, interictal nystagmus, mild residual and in some cases a progressive cerebellar incoordination and respond to acetazolamide treatment. We identified a patient with a positive family history for episodic ataxia, who was originally diagnosed with epilepsy and treated with valproic acid. Subsequent examination revealed that the symptoms were consistent with a diagnosis of EA-2. The patient responded positively to a combination of acetazolamide and valproic acid. Molecular genetic analysis of the CACNA1A gene was performed in order to confirm a diagnosis of EA-2.

Methods:

The CACNA1A gene was evaluated for mutations using single strand conformational polymorphism analysis and direct DNA sequencing. Allele specific oligo hybridization was used to confirm that the mutation was segregating with only affected family members and was not present in the control group.

Results:

In this study we identified a new missense mutation in exon 12 of the CACNA1A gene from a patient with EA-2 whose symptoms could be controlled with a combination of acetazolamide and valproic acid. This G to A transition changes a highly conserved glutamic acid residue to a lysine residue in domain II S2 of the P/Q-type calcium channel α1A subunit.

Conclusions:

The use of valproic acid in treating patients with EA-2 is not well documented. Here we describe a patient with a novel mutation in the CACNA1A gene who responded positively to a combination of acetazolamide and valproic acid.

Résumé

RÉSUMÉ Contexte:

L'ataxie épisodique de type 2 (AE-2) est une maladie neurologique de transmission autosomique dominante qui est due à des mutations du gène CACNA1A codant le canal calcique de type P/Q. Les individus atteints présentent des épisodes d'ataxie cérébelleuse habituellement associés à des symptômes migraineux, un nystagmus intercritique, une légère incoordination cérébelleuse résiduelle qui est progressive chez certains patients et répond au traitement par l'acétazolamide. Nous avons identifié un patient ayant une histoire familiale d'ataxie épisodique, chez qui un diagnostic d'épilepsie avait été posé et qui avait été traité par l'acide valproïque. Un nouvel examen du patient a permis de déterminer que ses symptômes étaient suggestifs d'une AE-2. Le patient a bien répondu à une association médicamenteuse, soit l'acétazolamide administré avec l'acide valproïque. L'analyse du gène CACNA1A a été effectuée pour confirmer le diagnostic d'AE-2.

Méthodes:

Des mutations du gène CACNA1A ont été recherchées par la technique de détection des polymorphismes de conformation monocaténaires (single-strand conformation polymorphism - SSCP) et par séquençage direct de l'ADN. L'hybridation d'un oligo allèle spécifique a confirmé que la mutation ségrégait seulement chez les membres atteints de la famille et n'était pas présente chez le groupe témoin.

Résultats:

Nous avons identifié une nouvelle mutation faux-sens dans l'exon 12 du gène CACNA1A de ce patient atteint d'AE-2 dont les symptômes étaient contrôlés par une association médicamenteuse, soit l'acétazolamide et l'acide valproïque. La substitution d'un A à un G change un acide glutamique hautement conservé en une lysine dans le domaine II S2 de la sous-unité α1A du canal calcique de type P/Q.

Conclusions:

Il existe peu de données sur l'utilisation de l'acide valproïque pour traiter les patients atteints d'AE-2. Nous décrivons un patient porteur d'une nouvelle mutation du gène CACNA1A qui a bien répondu à une association médicamenteuse, l'acétazolamide et l'acide valproïque.

Type
Original Article
Information
Canadian Journal of Neurological Sciences , Volume 33 , Issue 1 , February 2006 , pp. 68 - 72
Copyright
Copyright © The Canadian Journal of Neurological 2006

References

1. Brandt, T, Strupp, M. Episodic ataxia type 1 and 2 (familial periodicataxia/vertigo). Audiol Neurootol. 1997;2(6):373–83.Google Scholar
2. Bulman, DE. Phenotype variation and newcomers in ion channeldisorders. Hum Mol Genet. 1997;6(10):1679–85.Google Scholar
3. Wagner, S, Lerche, H, Mitrovic, N, Heine, R, George, AL, Lehmann-Horn, F. A novel sodium channel mutation causing a hyperkalemic paralytic and paramyotonic syndrome with variable clinical expressivity. Neurology. 1997;49(4):1018–25.Google Scholar
4. Ophoff, RA, Terwindt, GM, Vergouwe, MN, van Eijk, R, Oefner, PJ, Hoffman, SM, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel geneCACNL1A4. Cell. 1996;87(3):543–52.Google Scholar
5. Guida, S, Trettel, F, Pagnutti, S, Mantuano, E, Tottene, A, Veneziano, L,et al. Complete loss of P/Q calcium channel activity caused by a CACNA1A missense mutation carried by patients with episodicataxia type 2. Am J Hum Genet. 2001;68(3):759–64.Google Scholar
6. Denier, C, Ducros, A, Vahedi, K, Joutel, A, Thierry, P, Ritz, A, et al. Highprevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2. Neurology. 1999;52(9):1816–21.CrossRefGoogle Scholar
7. Friend, KL, Crimmins, D, Phan, TG, Sue, CM, Colley, A, Fung, VS, et al. Detection of a novel missense mutation and second recurrent mutation in the CACNA1A gene in individuals with EA-2 and FHM. Hum Genet. 1999;105(3):261–5.Google Scholar
8. Mantuano, E, Veneziano, L, Spadaro, M, Giunti, P, Guida, S, Leggio, MG, et al. Clusters of non-truncating mutations of P/Q type Ca2+ channel subunit Ca(v)2.1 causing episodic ataxia 2. J Med Genet. 2004;41(6):e82.Google Scholar
9. Spacey, SD, Hildebrand, ME, Materek, LA, Bird, TD, Snutch, TP. Functional implications of a novel EA2 mutation in the P/Q-type calcium channel. Ann Neurol. 2004;56(2):213–20.Google Scholar
10. Jodice, C, Mantuano, E, Veneziano, L, Trettel, F, Sabbadini, G,Calandriello, L, et al. 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. 1997;6(11):1973–8.Google Scholar
11. Yue, Q, Jen, JC, Nelson, SF, Baloh, RW. Progressive ataxia due to amissense mutation in a calcium-channel gene. Am J Hum Genet. 1997;61(5):1078–87.Google Scholar
12. Gillard, SE, Volsen, SG, Smith, W, Beattie, RE, Bleakman, D, Lodge, D. Identification of pore-forming subunit of P-type calcium channels: an antisense study on rat cerebellar Purkinje cells in culture. Neuropharmacology. 1997;36(3):405–9.Google Scholar
13. Pinto, A, Gillard, S, Moss, F, Whyte, K, Brust, P, Williams, M, et al. Human autoantibodies specific for the alpha1A calcium channel subunit reduce both P-type and Q-type calcium currents in cerebellar neurons. Proc Natl Acad Sci USA. 1998;95(14):8328–33.Google Scholar
14. Catterall, WA. Structure and function of neuronal Ca2+ channels andtheir role in neurotransmitter release. Cell Calcium. 1998;24(5-6):307–23.Google Scholar
15. Mori, Y, Friedrich, T, Kim, MS, Mikami, A, Nakai, J, Ruth, P, et al. Primary structure and functional expression from complementary DNA of a brain calcium channel. Nature. 1991;350(6317):398–402.Google Scholar
16. Starr, TV, Prystay, W, Snutch, TP. Primary structure of a calciumchannel that is highly expressed in the rat cerebellum. Proc Natl Acad Sci USA. 1991;88(13):5621–5.Google Scholar
17. Westenbroek, RE, Sakurai, T, Elliott, EM, Hell, JW, Starr, TV, Snutch, TP, et al. Immunochemical identification and subcellular distribution of the alpha 1A subunits of brain calcium channels. J Neurosci. 1995;15(10):6403–18.Google Scholar
18. Catterall, WA. Structure and function of voltage-gated ion channels. Annu Rev Biochem. 1995;64:493–531.Google Scholar
19. Fletcher, CF, Lutz, CM, O’Sullivan, TN, Shaughnessy, JD Jr., Hawkes, R, Frankel, WN, et al. Absence epilepsy in tottering mutant mice is associated with calcium channel defects. Cell. 1996;87(4):607–17.Google Scholar
20. Letts, VA, Felix, R, Biddlecome, GH, Arikkath, J, Mahaffey, CL, Valenzuela, A, et al. The mouse stargazer gene encodes a neuronalCa2+-channel gamma subunit. Nat Genet. 1998;19(4):340–7.Google Scholar
21. Burgess, DL, Jones, JM, Meisler, MH, Noebels, JL. Mutation of theCa2+ channel beta subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (lh) mouse. Cell. 1997;88(3):385–92.CrossRefGoogle ScholarPubMed
22. Escayg, A, De Waard, M, Lee, DD, Bichet, D, Wolf, P, Mayer, T, et al. Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. Am J Hum Genet.2000;66(5):1531–9.Google Scholar
23. Jouvenceau, A, Eunson, LH, Spauschus, A, Ramesh, V, Zuberi, SM, Kullmann, DM, et al. Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel. Lancet.2001;358(9284):801–7.Google Scholar
24. Imbrici, P, Jaffe, SL, Eunson, LH, Davies, NP, Herd, C, Robertson, R, et al. Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia. Brain. 2004;127(12):2682–92.Google Scholar
25. Jen, J, Kim, GW, Baloh, RW. Clinical spectrum of episodic ataxia type 2. Neurology. 2004;62(1):17–22.Google Scholar
26. Strupp, M, Kalla, R, Dichgans, M, Freilinger, T, Glasauer, S, Brandt, T. Treatment of episodic ataxia type 2 with the potassium channel blocker 4-aminopyridine. Neurology. 2004;62(9):1623–5.Google Scholar
27. Hanna, MG, Graves, TD, Jaffe, S, Imbrici, P, Kullmann, DM, on behalfof the authors. Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia-authors’ response. Brain. 2005;128(6):E33.CrossRefGoogle Scholar
28. Scoggan, KA, Chandra, T, Nelson, R, Hahn, AF, Bulman, DE. Identification of two novel mutations in the CACNA1A gene responsiblefor episodicataxia type 2.JMed Genet.2001;38(4):249–53 Google Scholar
29. Trettel, F, Mantuano, E, Calabresi, V, Veneziano, L, Olsen, AS,Georgescu, A, et al. A fine physical map of the CACNA1A gene region on 19p13.1-p13.2 chromosome. Gene. 2000;241(1):45–50.Google Scholar