- Meeting abstract
- Open Access
- Published:
Alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism are both ATP1A3-related disorders
Molecular and Cellular Pediatrics volume 1, Article number: A15 (2014)
Alternating hemiplegia of childhood (AHC) was first described as a distinctive disease in 1971 [1]. The disease is characterised by early-onset episodes of hemiplegia, dystonia, numerous paroxysmal symptoms, and developmental impairment [2]. Almost all cases of AHC are sporadic.
To identify de-novo mutations associated with this disease 40 clinically well-characterized patients were recruited from September 2004 till April 2013. Whole-exome sequencing was performed in three proband-parent trios. Informative genes were evaluated in the 37 remaining patients and ATP1A3 emerged as the gene associated with AHC [3]. Interestingly, this gene was already known to be associated with another movement disorder with later onset namely rapid-onset dystonia-parkinsonism (RDP) [4]. We then thoroughly analysed clinical and molecular findings of AHC and RDP to evaluate the phenotypic and genotypic spectrum. In addition, we started to analyse the functional consequences of the encoded Na+,K+ alpha 3 subunit for different ATP1A3 mutations associated with either AHC or RDP applying cell survival assays and two-electrode voltage clamp techniques.
39 of 40 patients with a characteristic AHC/RDP phenotype displayed a de-novo mutation in ATP1A3. Our study first showed that AHC and RDP are not two distinct diseases but rather constitute a clinical continuum of one disorder with AHC at the severe end of the spectrum and RDP as a milder variant. Clinically overlapping features are abrupt onset of triggered dystonic episodes, a rostrocaudal gradient of involvement as well as brainstem dysfunction; clearly differentiating characteristics are fixed dystonia in RDP and episodic hemiplegia in AHC. Further, mutations affecting functional and transmembrane protein domains tend to be associated with an AHC phenotype and the majority of ATP1A3 mutations are located in only four exons [5]. To further elucidate the pathomechanisms of ATP1A3 related disorders in vitro studies on selected mutations are ongoing.
References
- 1.
Verret S, Steele JC: Alternating hemiplegia in childhood: a report of eight patients with complicated migraine beginning in infancy. Pediatrics 1971,47(4):675–80.
- 2.
Bourgeois M, Aicardi J, Goutieres F: Alternating hemiplegia of childhood. J Pediatr 1993,122(5 Pt 1):673–9.
- 3.
Rosewich H, Thiele H, Ohlenbusch A, Maschke U, Altmuller J, Frommolt P, et al.: Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study. Lancet Neurol 2012,11(9):764–73. 10.1016/S1474-4422(12)70182-5
- 4.
de Carvalho Aguiar P, Sweadner KJ, Penniston JT, Zaremba J, Liu L, Caton M, et al.: Mutations in the Na+/K+ -ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism. Neuron 2004,43(2):169–75. 10.1016/j.neuron.2004.06.028
- 5.
Rosewich H, Ohlenbusch A, Huppke P, Schlotwa L, Baethmann M, Carrilho I, Fiori S, Lourenço CM, Sawyer S, Steinfeld R, Gärtner J, Brockmann K: Neurology. 2014, in press.
Author information
Affiliations
Corresponding author
Correspondence to Hendrik Rosewich.
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
About this article
Published
DOI
Keywords
- Dystonia
- Hemiplegia
- Clinical Continuum
- Voltage Clamp Technique
- Cell Survival Assay
