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


Peer review

Editorial Board

Instructions for authors

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.