Articles on AHC January-April 2015


Written by M. Mikati

1. Heimer et al. (2015) reported that a novel deleterious heterozygous c.2452 G>A, p.(E818K) variant in the ATP1A3 gene in which structural analysis predicted a protein-destabilizing effect that is associated with infantile stress-induced episodic weakness, ataxia, and sensorineural hearing loss, with permanent areflexia and optic nerve pallor (designated as a CAOS syndrome due to the absence of pes cavus).
2. Holm et al. (2015) reported that the asparagine substitution of the aspartate associated with The Na+ specific binding site in the Na(+),K(+)-ATPase a substitution found in patients with rapid-onset dystonia parkinsonism or alternating hemiplegia of childhood causes a marked reduction of Na(+) affinity in the α1-, α2-, and α3-isoforms of Na(+),K(+)-ATPase. Perhaps more importantly they observed that the above dysfunction is rescued by second-site mutation of a glutamate in the extracellular part of the fourth transmembrane helix, distant to the above site. They thus hypothesize that Rescue of Na(+) affinity and Na(+) and K(+) transport by second-site mutation suggests new possibilities for treatment of neurological patients carrying Na(+),K(+)-ATPase mutations.
3. Li et al. (2015) expressed wild type, E815K, D801N and G947R ATP1A3 mutants (all cause Alternating Hemiplegia of Childhood-AHC with the E815K causing the most severe and the G947R causing the least severe phenotypes) in Xenopus laevis oocytes. They found that all the mutations caused a similar level of reduction in forward cycling and that the wild type forward cycling was reduced by coexpression with any mutant indicating a dominant negative effect. On the other hand proton transfer was impaired only in E815K. They concluded that loss of forward cycling and dominant negativity are likely necessary pathophysiological mechanisms for AHC and that additional loss of proton transport in E815K may be responsible for more severe disease.
4. Wong and Kwong (2015) reported that a Chinese girl with who had been reported before at the age of 3 years to have responded to a course of betamethasome had the D801N mutation. The doses of betamethasone was 4 mg bid (the equivalent of 2 mg/kg prednisone per day). With this therapy the attacks were completely aborted 2 days after administration, with concurrent marked improvement in EEG background and with improvement in gait and mood. Betamethasone was stopped in 4 weeks due to the cushingoid. This was associated with immediate relapse of the attacks. Steroid therapy could not be restarted because the parents’ refusal due to the marked cushingoid features.
5. Paciorkowski et al. (2015) reported two patients with catastrophic early life epilepsy, episodic prolonged apnea, choreoathetosis in one, dystonia in the other, and postnatal microcephaly, both had refractory focal onset seizures the first starting the first day of life and the second at 6 weeks of life. Two novel ATP1A3 heterozygous mutations (p.Gly358Val and p.Ile363Asn) were identified in these two children. Both mutations reduced Na,K-ATPase activity in vitro and postmortem neuropathologic specimens from one of them the one with the p.Gly358Val mutation that ATP1A3 immunofluorescence is prominently associated with interneurons in the cortex suggesting a possible underlying pathophysiological correlate for the observed symptoms.
6. Hunanyan et al. (2015) generated a knock in mouse of the most common mutations causing Alternating Hemiplegia of Childhood (D801N) and demonstrated that these mice reproduced the behavioral characteristics of the human condition including abnormal impulsivity, memory, gait, motor coordination, tremor, motor control, endogenous nociceptive response, paroxysmal hemiplegias, diplegias, dystonias, and spontaneous recurrent seizures, as well as predisposition to kindling, to flurothyl-induced seizures, and to sudden unexpected death. They also investigated the underlying pathophysiological mechanisms and found that hippocampal slices of mutants, in contrast to WT animals, showed hyperexcitable responses to 1 Hz pulse-trains of electrical stimuli delivered to the Schaffer collaterals and had significantly longer duration of K+-induced SD responses. These findings indicated that in ATP1α3 dysfunction results in abnormal short-term plasticity with increased excitability (potential mechanism for seizures) and a predisposition to more severe SD responses (potential mechanism for hemiplegias) and that addressing those mechanisms may lead to novel therapies of this disorder.
7. Talsma et al. (2015) used an unbiased genome-wide screen to find regions of the genome containing elements important for genetic modulation of ATPalpha dysfunction in Drosophila conditional mutants. They identified 64 modifier loci and 50 single gene interactions. The interacting genes coded for proteins whose function was mostly either ion homeostasis (24%) metabatropic signaling (24%) but also protein regulation (9%) cytochromes, protein synthesis, protein trafficking/degradation (7% each) or post translational modifications (5%) with the remaining of unknown function (17%). They hypothesized that knowledge of the elements of genetic modulation of ATPalpha function may provide the basis for therapies modifying diseases caused by its dysfunction.
8. Boleman et al. (2015) described a boy with topiramate-responsive alternating hemiplegia of childhood who had a mutation that had been reported to cause adult onset Rapid Onset Dystonia Parkinsonism syndrome in three previously reported patients ( the c.829 G/A; p.E277 K). They concluded that in addition to the type of gene mutation there are other undiscovered environmental, genetic, or epigenetic factors influencing the clinical phenotype in ATP1A3 related disease.
9. Wilcox et al. (2015) reported the presence of a novel, likely disease-causing, three base-pair deletion (c.443_445delGAG, p.Ser148del) in ATP1A3 in affected patients in a dystonia family from New Zealand in which only females were affected with onset of dystonia after a trigger but no parkinsonism or symptoms of AHC or CAPOS syndrome. There was one male who had the mutation but was not affected suggesting incomplete penetrance but not explaining expression in females only.


1. Heimer G, Sadaka Y, Israelian L, Feiglin A, Ruggieri A, Marshall CR, Scherer SW, Ganelin-Cohen E, Marek-Yagel D, Tzadok M, Nissenkorn A, Anikster Y, Minassian BA, Zeev BB. CAOS-Episodic Cerebellar Ataxia, Areflexia, Optic Atrophy, and Sensorineural Hearing Loss: A Third Allelic Disorder of the ATP1A3 Gene.
J Child Neurol. 2015 Apr 20. pii: 0883073815579708. [Epub ahead of print] PubMed PMID: 25895915.
2. Holm R, Einholm AP, Andersen JP, Vilsen B. Rescue of na+ affinity in aspartate 928 mutants of na+,k+-ATPase by secondary mutation of glutamate 314.
J Biol Chem. 2015 Apr 10;290(15):9801-11. doi: 10.1074/jbc.M114.625509. Epub 2015 Feb 24. PubMed PMID: 25713066; PubMed Central PMCID: PMC4392278.
3. Li M, Jazayeri D, Corry B, McSweeney KM, Heinzen EL, Goldstein DB, Petrou S. A functional correlate of severity in alternating hemiplegia of childhood.
Neurobiol Dis. 2015 May;77:88-93. doi: 10.1016/j.nbd.2015.02.002. Epub 2015 Feb 12. PubMed PMID: 25681536.
4. Wong VC, Kwong AK. ATP1A3 mutation in a Chinese girl with alternating hemiplegia of childhood - Potential target of treatment?
Brain Dev. 2015 Feb 5. pii: S0387-7604(15)00019-4. doi: 10.1016/j.braindev.2015.01.003. [Epub ahead of print] PubMed PMID: 25662428.
5. Paciorkowski AR, McDaniel SS, Jansen LA, Tully H, Tuttle E, Ghoneim DH, Tupal S, Gunter SA, Vasta V, Zhang Q, Tran T, Liu YB, Ozelius LJ, Brashear A, Sweadner KJ, Dobyns WB, Hahn S. Novel mutations in ATP1A3 associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly.
Epilepsia. 2015 Mar;56(3):422-30. doi: 10.1111/epi.12914. Epub 2015 Feb 5. PubMed PMID: 25656163; PubMed Central PMCID: PMC4363281.
6. Hunanyan AS, Fainberg NA, Linabarger M, Arehart E, Leonard AS, Adil SM, Helseth AR, Swearingen AK, Forbes SL, Rodriguiz RM, Rhodes T, Yao X, Kibbi N, Hochman DW, Wetsel WC, Hochgeschwender U, Mikati MA. Knock-in mouse model of alternating hemiplegia of childhood: behavioral and electrophysiologic characterization.
Epilepsia. 2015 Jan;56(1):82-93. doi: 10.1111/epi.12878. Epub 2014 Dec 19. PubMed PMID: 25523819.
7. Talsma AD, Chaves JF, LaMonaca A, Wieczorek ED, Palladino MJ. Genome-wide screen for modifiers of Na + /K + ATPase alleles identifies critical genetic loci.
Mol Brain. 2014 Dec 5;7(1):89. [Epub ahead of print] PubMed PMID: 25476251; PubMed Central PMCID: PMC4302446.
8. Boelman C, Lagman-Bartolome AM, MacGregor DL, McCabe J, Logan WJ, Minassian BA. Identical ATP1A3 mutation causes alternating hemiplegia of childhood and rapid-onset dystonia parkinsonism phenotypes.
Pediatr Neurol. 2014 Dec;51(6):850-3. doi: 10.1016/j.pediatrneurol.2014.08.015. Epub 2014 Aug 29. PubMed PMID: 25439493.
9. Wilcox R, Brænne I, Brüggemann N, Winkler S, Wiegers K, Bertram L, Anderson T, Lohmann K. Genome sequencing identifies a novel mutation in ATP1A3 in a family with dystonia in females only.
J Neurol. 2015 Jan;262(1):187-93. doi: 10.1007/s00415-014-7547-9. Epub 2014 Oct 31. PubMed PMID: 25359261.

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IAHCRC - International Consortium for the Research on Alternating Hemiplegia of Childhood and other ATP1A3 related diseases