Articles on AHC September-December 2015


Written by M. Mikati


1. Kirshenbaum et al. (2015) reported that the Myshkin mice (I810N mutation) showed impairments in spatial memory, spatial habituation, locomotor habituation, object recognition, social recognition, and trace fear conditioning, as well as in the visible platform version of the Morris water maze.
Increasing the duration of training ameliorated the deficit in social recognition but not in spatial habituation.
2. Kirshenbaum et al. (2015) also reported that Myshkin mice carrying a wild-type Atp1a3 transgene that confers a 16 % increase in brain-specific total Na(+),K(+)-ATPase activity show significant phenotypic improvements compared with non-transgenic Myshkin mice.
3. Termsarasab et al. (2015) reported two cases with intermediate forms between RDP and AHC. Patient 1 initially presented with the AHC phenotype, but the RDP phenotype emerged at age 14 years. The second patient presented with levodopa-responsive paroxysmal oculogyria, a finding never before reported in ATP1A3-related disorders.
Genetic testing confirmed heterozygous changes in the ATP1A3 gene in both patients, one of them novel.
4. Panagiotakaki et al. (2015) set out to identify the spectrum of different mutations within the ATP1A3 gene and further establish any correlation with phenotype. They found that in total, 34 different ATP1A3 mutations were detected in 85 % (132/155) patients, seven of which were novel. In general, mutations were found to cluster into five different regions.
The most frequent mutations included: p.Asp801Asn (43 %; 57/132), p.Glu815Lys (16 %; 22/132), and p.Gly947Arg (11 %; 15/132). Of these, p.Glu815Lys was associated with a severe phenotype, with more severe intellectual and motor disability. p.Asp801Asn appeared to confer a milder phenotypic expression, and p.Gly947Arg appeared to correlate with the most favorable prognosis, compared to the other two frequent mutations.
Overall, the comparison of the clinical profiles suggested a gradient of severity between the three major mutations with differences in intellectual (p = 0.029) and motor (p = 0.039) disabilities being statistically significant. For patients with epilepsy, age at onset of seizures was earlier for patients with either p.Glu815Lys or p.Gly947Arg mutation, compared to those with p.Asp801Asn mutation (p < 0.001).
With regards to the five mutation clusters, some clusters appeared to correlate with certain clinical phenotypes. No statistically significant clinical correlations were found between patients with and without ATP1A3 mutations.
5. Dard et al. (2015) reported on a 34-year-old female presenting with a new ATP1A3-related entity involving a relapsing encephalopathy characterized by recurrent episodes of cerebellar ataxia and altered consciousness during febrile illnesses. The term RECA was suggested - relapsing encephalopathy with cerebellar ataxia.
The phenotype of this patient, resembling mitochondrial oxidative phosphorylation defects, emphasizes the possible role of brain energy deficiency in patients with ATP1A3 mutations. The authors suggested that rather than multiple overlapping syndromes, ATP1A3-related disorders might be seen as a phenotypic continuum
6. Shrivastava et al. (2015) demonstrated that α-synuclein assemblies form clusters within the plasma membrane of neurons and identified the α3-subunit of Na+/K+-ATPase (NKA) as a cell surface partner of α-syn assemblies. They also showed that freely diffusing α3-NKA are trapped within α-synuclein clusters resulting in α3-NKA redistribution and formation of larger nanoclusters and that this created regions within the plasma membrane with reduced local densities of α3-NKA, thereby decreasing the efficiency of Na+ extrusion following stimulus.
Thus, interactions of α3-NKA with extracellular α-synuclein assemblies reduce its pumping activity.


1. Kirshenbaum GS, Dachtler J, Roder JC and Clapcote SJ. Characterization of cognitive deficits in mice with an alternating hemiplegia-linked mutation.
Behav Neurosci. 2015 Dec;129(6):822-31. doi: 10.1037/bne0000097. Epub 2015 Oct 26.
2. Kirshenbam GS, Dachtler J, Roder JC and, Clapcote SJ(4). Transgenic rescue of phenotypic deficits in a mouse model of alternatinghemiplegia of childhood.
Neurogenetics. 2015 Oct 13. [Epub ahead of print].
3. Termsarasab P, Yang AC, Frucht SJ. Intermediate Phenotypes of ATP1A3 Mutations: Phenotype-Genotype Correlations.
Tremor Other Hyperkinet Mov (N Y). 2015 Sep 16;5:336. doi: 10.7916/D8MG7NS8.eCollection 2015.
4. Panagiotakaki E, De Grandis E, Stagnaro M, et al. Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood-a study of 155 patients
Orphanet J Rare Dis. 2015 Sep 26;10:123. doi: 10.1186/s13023-015-0335-5.
5. Dard R, Mignot C, Durr A et al. Relapsing encephalopathy with cerebellar ataxia related to an ATP1A3 mutation.
Dev Med Child Neurol. 2015 Sep 23. doi: 10.1111/dmcn.12927. [Epub ahead of print] J Biol Chem. 2015 Apr 10;290(15):9801-11. doi: 10.1074/jbc.M114.625509. Epub 2015 Feb 24.
6. Shrivastava AN, Redeker V, Fritz N, et al. α-synuclein assemblies sequester neuronal α3-Na+/K+-ATPase and impair Na+ gradient.
EMBO J. 2015 Oct 1;34(19):2408-23. doi: 10.15252/embj.201591397. Epub 2015 Aug 31.

pdf version

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