title: Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry.
abstract: 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.
authors.affiliation: Pediatric Motor Disorders Research Program, Departments of Neurology and Pediatrics, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Louis
authors.initials: L
authors.lastname: Viollet
authors.affiliation: Institute for Systems Biology, Seattle, Washington, United States of America.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Glusman
authors.affiliation: Pediatric Motor Disorders Research Program, Departments of Neurology and Pediatrics, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Kelley J
authors.initials: KJ
authors.lastname: Murphy
authors.affiliation: Pediatric Motor Disorders Research Program, Departments of Neurology and Pediatrics, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Tara M
authors.initials: TM
authors.lastname: Newcomb
authors.affiliation: Pediatric Motor Disorders Research Program, Departments of Neurology and Pediatrics, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Sandra P
authors.initials: SP
authors.lastname: Reyna
authors.affiliation: Pediatric Motor Disorders Research Program, Departments of Neurology and Pediatrics, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Matthew
authors.initials: M
authors.lastname: Sweney
authors.affiliation: Pediatric Motor Disorders Research Program, Departments of Neurology and Pediatrics, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Nelson
authors.affiliation: Neurogenetics Unit, Montreal Neurologic Institute and Hospital, McGill University, Montreal Quebec, Canada.
authors.forename: Frederick
authors.initials: F
authors.lastname: Andermann
authors.affiliation: Neurogenetics Unit, Montreal Neurologic Institute and Hospital, McGill University, Montreal Quebec, Canada.
authors.forename: Eva
authors.initials: E
authors.lastname: Andermann
authors.affiliation: Departments of Pediatrics and Neurology, Connecticut Children's Medical Center and University of Connecticut School of Medicine, Hartford, CT, United States of America.
authors.forename: Gyula
authors.initials: G
authors.lastname: Acsadi
authors.affiliation: Department of Neurology, University of Rochester School of Medicine, Rochester, New York, United States of America.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Barbano
authors.affiliation: Diablo Valley Child Neurology, an affiliate of Stanford Health Alliance, Pleasant Hill, California, United States of America.
authors.forename: Candida
authors.initials: C
authors.lastname: Brown
authors.affiliation: Institute for Systems Biology, Seattle, Washington, United States of America.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Brunkow
authors.affiliation: Division of Pediatric Neurology, Children's Hospital of Michigan, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Harry T
authors.initials: HT
authors.lastname: Chugani
authors.affiliation: Department of Child Neurology, Palo Alto Medical Foundation Redwood City Clinic, Redwood City, California, United States of America.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Cheyette
authors.affiliation: Department of Pediatric Neurology, Children's Hospital Colorado, University of Colorado Hospital, Aurora, Colorado, United States of America.
authors.forename: Abigail
authors.initials: A
authors.lastname: Collins
authors.affiliation: Departments of Genetics and Genome Sciences, Pediatrics, and Neurology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: DeBrosse
authors.affiliation: Pacific Northwest Diabetes Research Institute, Seattle, Washington, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Galas
authors.affiliation: Departments of Neuroscience and Pediatrics, University of California San Diego, San Diego, California, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Friedman
authors.affiliation: Institute for Systems Biology, Seattle, Washington, United States of America.
authors.forename: Lee
authors.initials: L
authors.lastname: Hood
authors.affiliation: Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Chad
authors.initials: C
authors.lastname: Huff
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Lynn B
authors.initials: LB
authors.lastname: Jorde
authors.affiliation: Departments of Pediatrics and Neurology, University College Dublin School of Medicine and Medical Science, Dublin, Ireland.
authors.forename: Mary D
authors.initials: MD
authors.lastname: King
authors.affiliation: Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
authors.forename: Bernie
authors.initials: B
authors.lastname: LaSalle
authors.affiliation: Children's Neuroscience Centre, Murdoch Childrens Research Institute, University of Melbourne Department of Paediatrics, The Royal Children's Hospital Melbourne, Parkville Victoria, Australia.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Leventer
authors.affiliation: Department of Pediatrics, College of Medicine Jacksonville, University of Florida, Jacksonville, Florida, United States of America.
authors.forename: Aga J
authors.initials: AJ
authors.lastname: Lewelt
authors.affiliation: Department of Family Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Mylynda B
authors.initials: MB
authors.lastname: Massart
authors.affiliation: Stevens Henager College, Salt Lake City, Utah, United States of America.
authors.forename: Mario R
authors.initials: MR
authors.lastname: Mérida
authors.affiliation: Department of Neurology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Ptáček
authors.affiliation: Institute for Systems Biology, Seattle, Washington, United States of America.
authors.forename: Jared C
authors.initials: JC
authors.lastname: Roach
authors.affiliation: Center for Medical Ethics and Humanities in Medicine, University Of Virginia UVA health system, Charlottesville, Virginia, United States of America.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Rust
authors.affiliation: Departement de Neurophysiologie. Hopital Armand Trousseau APHP, Paris, France.
authors.forename: Francis
authors.initials: F
authors.lastname: Renault
authors.affiliation: Department of Biomedical Engineering, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Terry D
authors.initials: TD
authors.lastname: Sanger
authors.affiliation: Swedish Neuroscience Institute, Swedish Medical Center, Seattle, Washington, United States of America.
authors.forename: Marcio A
authors.initials: MA
authors.lastname: Sotero de Menezes
authors.affiliation: Pediatric Motor Disorders Research Program, Departments of Neurology and Pediatrics, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Rachel
authors.initials: R
authors.lastname: Tennyson
authors.affiliation: Department of Paediatrics and Adolescent Medicine, Juliane Marie Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Uldall
authors.affiliation: Study Design and Biostatistics Center, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Children's Hospital Orange County, and Department of Pediatrics, University of California, Orange, California, United States of America.
authors.forename: Mary
authors.initials: M
authors.lastname: Zupanc
authors.affiliation: Center for Human Genetic Research, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Winnie
authors.initials: W
authors.lastname: Xin
authors.affiliation: Departments of Pediatrics and Neurology, University of Chicago and Comer Children's Hospital, Chicago, Illinois, United States of America.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Silver
authors.affiliation: Pediatric Motor Disorders Research Program, Departments of Neurology and Pediatrics, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Swoboda
mesh_terms: D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D006429:Hemiplegia / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D007223:Infant; D008297:Male; D012042:Registries; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics*
chemical_list: C488756:ATP1A3 protein, human; D000254:Sodium-Potassium-Exchanging ATPase