Childhood Rapid-Onset Ataxia: Expanding the Phenotypic Spectrum of ATP1A3 Mutations

Abstract

ATP1A3 mutations are related to a wide spectrum of clinical conditions, including several defined syndromes as rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), together with many other intermediate phenotypes. Ataxia is always more increasingly reported, either as accessory or prominent sign, in ATP1A3-related conditions, being thus considered as a peculiar feature of this spectrum. Here, we report three cases of childhood rapid-onset ataxia due to two different ATP1A3 variants. Interestingly, two patients (mother and son) showed a variant c.2266C>T (p.R756C), while the third carried the c.2452G>A (p.E818K) variant, commonly described in association with CAPOS syndrome. Our report contributes to extent the phenotypic spectrum of ATP1A3 mutations, remarking childhood rapid-onset ataxia as an additional clinical presentation of ATP1A3-related conditions. Finally, we discussed this phenomenology in the light of translational evidence from a RDP animal model.

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

Fig. 1

References

  1. 1.

    Heinzen EL, Arzimanoglou A, Brashear A, Clapcote SJ, Gurrieri F, Goldstein DB, et al. Distinct neurological disorders with ATP1A3 mutations. Lancet Neurol. 2014;13(5):503–14. https://doi.org/10.1016/S1474-4422(14)70011-0.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Holm TH, Lykke-Hartmann K. Insights into the pathology of the α3 Na+/K+-ATPase ion pump in neurological disorders; lessons from animal models. Front Physiol. 2016;7(209) https://doi.org/10.3389/fphys.2016.00209.

  3. 3.

    Sweney MT, Newcomb TM, Swoboda KJ. The expanding spectrum of neurological phenotypes in children with ATP1A3 mutations, alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism, CAPOS and beyond. Pediatr Neurol. 2015;52(1):56–64. https://doi.org/10.1016/j.pediatrneurol.2014.09.015.

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Brashear A, Mink JW, Hill DF, Boggs N, McCall WV, Stacy MA, et al. ATP1A3 mutations in infants: a new rapid-onset dystonia-Parkinsonism phenotype characterized by motor delay and ataxia. Dev Med Child Neurol. 2012;54(11):1065–7. https://doi.org/10.1111/j.1469-8749.2012.04421.x.

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Sweadner KJ, Toro C, Whitlow CT, Snively BM, Cook JF, Ozelius LJ, et al. ATP1A3 mutation in adult rapid-onset ataxia. LeDoux MS, editor. PLoS One. 2016;11(3):e0151429. https://doi.org/10.1371/journal.pone.0151429.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Fornarino S, Stagnaro M, Rinelli M, Tiziano D, Mancardi MM, Traverso M, et al. Paroxysmal features responding to flunarizine in a child with rapid-onset dystonia-parkinsonism. Neurology. 2014;82(22):2037–8. https://doi.org/10.1212/WNL.0000000000000473.

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Nicita F, Travaglini L, Sabatini S, Garavaglia B, Panteghini C, Valeriani M, et al. Childhood-onset ATP1A3-related conditions: report of two new cases of phenotypic spectrum. Parkinsonism Relat Disord. 2016;30:81–2. https://doi.org/10.1016/j.parkreldis.2016.05.029.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Yano ST, Silver K, Young R, DeBrosse SD, Ebel RS, Swoboda KJ, et al. Fever-induced paroxysmal weakness and encephalopathy, a new phenotype of ATP1A3 mutation. Pediatr Neurol. 2017;73:101–5. https://doi.org/10.1016/j.pediatrneurol.2017.04.022.

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Heimer G, Sadaka Y, Israelian L, Feiglin A, Ruggieri A, Marshall CR, et al. CAOS—episodic cerebellar ataxia, areflexia, optic atrophy, and sensorineural hearing loss: a third allelic disorder of the ATP1A3 gene. J Child Neurol. 2015;30(13):1749–56. https://doi.org/10.1177/0883073815579708.

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Demos MK, van Karnebeek CD, Ross CJ, Adam S, Shen Y, Zhan SH, et al. A novel recurrent mutation in ATP1A3 causes CAPOS syndrome. Orphanet J Rare Dis. 2014;9(1):15. https://doi.org/10.1186/1750-1172-9-15.

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Sasaki M, Ishii A, Saito Y, Morisada N, Iijima K, Takada S, et al. Genotype-phenotype correlations in alternating hemiplegia of childhood. Neurology. 2014;82(6):482–90. https://doi.org/10.1212/WNL.0000000000000102.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Bøttger P, Tracz Z, Heuck A, Nissen P, Romero-Ramos M, Lykke-Hartmann K. Distribution of Na/K-ATPase alpha 3 isoform, a sodium-potassium P-type pump associated with rapid-onset of dystonia parkinsonism (RDP) in the adult mouse brain. J Comp Neurol. 2011;519(2):376–404. https://doi.org/10.1002/cne.22524.

    CAS  Article  Google Scholar 

  13. 13.

    Calderon DP, Fremont R, Kraenzlin F, Khodakhah K. The neural substrates of rapid-onset dystonia-parkinsonism. Nat Neurosci. 2011;14(3):357–65. https://doi.org/10.1038/nn.2753.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Alessandro Capuano.

Ethics declarations

All the procedures described in the text have been conducted in accordance with ethical principles.

Conflict of Interest

The authors declare that they have no conflict of interests.

Electronic Supplementary Material

ESM 1

(DOCX 62 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Schirinzi, T., Graziola, F., Nicita, F. et al. Childhood Rapid-Onset Ataxia: Expanding the Phenotypic Spectrum of ATP1A3 Mutations. Cerebellum 17, 489–493 (2018). https://doi.org/10.1007/s12311-018-0920-y

Download citation

Keywords

  • ATP1A3
  • Ataxia
  • Cerebellum
  • Rapid-onset dystonia-parkinsonism
  • AHC