Biological Sciences Division
Published May 21, 2015 | Version v1
Journal article Open

Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry

Creators

  • 1. University of Utah
  • 2. Institute for Systems Biology
  • 3. McGill University
  • 4. University of Connecticut
  • 5. University of Rochester
  • 6. Stanford Health Alliance
  • 7. Wayne State University
  • 8. Palo Alto Medical Foundation
  • 9. University of Colorado Hospital
  • 10. Case Western Reserve University
  • 11. Pacific Northwest Diabetes Research Institute
  • 12. University of California San Diego
  • 13. University of Chicago

Description

Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers' questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clustered in exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K (26%) and 11 had G937R (8%) mutations. Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.

Data availability

All relevant data are within the paper and its Supporting Information files.

Files

journal.pone.0127045.pdf

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Additional details

Identifiers

DOI
10.1371/journal.pone.0127045
Other
oai:uchicago.tind.io:9589

Funding

Alternating Hemiplegia of Childhood Foundation
Genetique Actions
University of Luxembourg
Institute for Systems Biology Strategic Partnership
Luxembourg Centre for Systems Biomedicine
National Institute of General Medical Sciences
Center for Systems Biology

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Neurology, Pediatrics