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

PLoS ONE. 2015;10(5):e0127045 DOI 10.1371/journal.pone.0127045


Journal Homepage

Journal Title: PLoS ONE

ISSN: 1932-6203 (Online)

Publisher: Public Library of Science (PLoS)

LCC Subject Category: Medicine | Science

Country of publisher: United States

Language of fulltext: English

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Louis Viollet
Gustavo Glusman
Kelley J Murphy
Tara M Newcomb
Sandra P Reyna
Matthew Sweney
Benjamin Nelson
Frederick Andermann
Eva Andermann
Gyula Acsadi
Richard L Barbano
Candida Brown
Mary E Brunkow
Harry T Chugani
Sarah R Cheyette
Abigail Collins
Suzanne D DeBrosse
David Galas
Jennifer Friedman
Lee Hood
Chad Huff
Lynn B Jorde
Mary D King
Bernie LaSalle
Richard J Leventer
Aga J Lewelt
Mylynda B Massart
Mario R Mérida
Louis J Ptáček
Jared C Roach
Robert S Rust
Francis Renault
Terry D Sanger
Marcio A Sotero de Menezes
Rachel Tennyson
Peter Uldall
Yue Zhang
Mary Zupanc
Winnie Xin
Kenneth Silver
Kathryn J Swoboda


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Time From Submission to Publication: 24 weeks


Abstract | Full Text

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 clusteredin exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K(26%) and 11 had G947R (8%) mutations [corrected].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.