title: Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood-a study of 155 patients.
abstract: BACKGROUND
  Mutations in the gene ATP1A3 have recently been identified to be prevalent in patients with alternating hemiplegia of childhood (AHC2). Based on a large series of patients with AHC, we set out to identify the spectrum of different mutations within the ATP1A3 gene and further establish any correlation with phenotype.
  
  
  METHODS
  Clinical data from an international cohort of 155 AHC patients (84 females, 71 males; between 3 months and 52 years) were gathered using a specifically formulated questionnaire and analysed relative to the mutational ATP1A3 gene data for each patient.
  
  
  RESULTS
  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 favourable 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.
  
  
  CONCLUSIONS
  Our results, demonstrate a highly variable clinical phenotype in patients with AHC2 that correlates with certain mutations and possibly clusters within the ATP1A3 gene. Our description of the clinical profile of patients with the most frequent mutations and the clinical picture of those with less common mutations confirms the results from previous studies, and further expands the spectrum of genotype-phenotype correlations. Our results may be useful to confirm diagnosis and may influence decisions to ensure appropriate early medical intervention in patients with AHC. They provide a stronger basis for the constitution of more homogeneous groups to be included in clinical trials.
authors.affiliation: Epilepsy, Sleep and Pediatric Neurophysiology Department (ESEFNP), University Hospitals of Lyon (HCL), Lyon, France. eleni.panagiotakaki@chu-lyon.fr.
authors.forename: Eleni
authors.initials: E
authors.lastname: Panagiotakaki
authors.affiliation: Department of Child Neuropsychiatry, G. Gaslini Hospital, University of Genoa, Genoa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: De Grandis
authors.affiliation: Department of Child Neuropsychiatry, G. Gaslini Hospital, University of Genoa, Genoa, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Stagnaro
authors.affiliation: Center for Human Genome Variation, Duke University School of Medicine, Durham, NC, USA.|Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Heinzen
authors.affiliation: Department of Child Neurology, Sant Joan de Déu Hospital, Barcelona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Fons
authors.affiliation: Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, London, UK.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Sisodiya
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Boukje
authors.initials: B
authors.lastname: de Vries
authors.affiliation: Department of Child Neurology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Goubau
authors.affiliation: Department of Molecular Genetics, Neurogenetics Group, VIB, Antwerp, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Weckhuysen
authors.affiliation: Department of Neurology, Charles University, First Faculty of Medicine and Teaching Hospital, Prague, Czech Republic.
authors.forename: David
authors.initials: D
authors.lastname: Kemlink
authors.affiliation: Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia.|Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Scheffer
authors.affiliation: Department of Genetics, University Hospitals of Lyon (HCL) and Claude Bernard Lyon I University, Lyon, France.|Lyon Neuroscience Research Center (CRNL), CNRS UMR 5292, INSERM U1028, Lyon, France.
authors.forename: Gaëtan
authors.initials: G
authors.lastname: Lesca
authors.affiliation: Biostatistics Department, University Hospitals of Lyon and UMR 5558, Lyon, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Rabilloud
authors.affiliation: Biostatistics Department, University Hospitals of Lyon and UMR 5558, Lyon, France.
authors.forename: Amna
authors.initials: A
authors.lastname: Klich
authors.affiliation: Epilepsy, Sleep and Pediatric Neurophysiology Department (ESEFNP), University Hospitals of Lyon (HCL), Lyon, France.|Department of Child Neurology, Sant Joan de Déu Hospital, Barcelona, Spain.
authors.forename: Alia
authors.initials: A
authors.lastname: Ramirez-Camacho
authors.affiliation: Department of Child Neurology, Sant Joan de Déu Hospital, Barcelona, Spain.
authors.forename: Adriana
authors.initials: A
authors.lastname: Ulate-Campos
authors.affiliation: Department of Child Neurology, Sant Joan de Déu Hospital, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Campistol
authors.affiliation: Child Neurology Unit, Maggiore Hospital, Bologna, Italy.
authors.forename: Melania
authors.initials: M
authors.lastname: Giannotta
authors.affiliation: Department of Child Neurology, Armand Trousseau Hospital, APHP, Paris, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Moutard
authors.affiliation: Department of Child Neurology, Armand Trousseau Hospital, APHP, Paris, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Doummar
authors.affiliation: Department of Neurology, Pitié-Salpêtrière Hospital, APHP, Paris, France.
authors.forename: Cecile
authors.initials: C
authors.lastname: Hubsch-Bonneaud
authors.affiliation: Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, London, UK.
authors.forename: Fatima
authors.initials: F
authors.lastname: Jaffer
authors.affiliation: Institute of Child Health, University College London, London, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Cross
authors.affiliation: Institute of Medical Genetics, University Cattolica del Sacro Cuore, Policlinics A. Gemelli, Rome, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Gurrieri
authors.affiliation: Institute of Medical Genetics, University Cattolica del Sacro Cuore, Policlinics A. Gemelli, Rome, Italy.
authors.forename: Danilo
authors.initials: D
authors.lastname: Tiziano
authors.affiliation: Department of Neurology, Charles University, First Faculty of Medicine and Teaching Hospital, Prague, Czech Republic.
authors.forename: Sona
authors.initials: S
authors.lastname: Nevsimalova
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U975, Centre de Recherche de l'Institut du Cerveau et de la Moelle, Paris, France.|Centre National de la Recherche Scientifique, UMR7225, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Nicole
authors.affiliation: Institute of Child Health, University College London, London, UK.
authors.forename: Brian
authors.initials: B
authors.lastname: Neville
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.|Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.affiliation: Division of Pediatric Neurology and Department of Neurobiology, Duke University, School of Medicine, Durham, NC, USA.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Mikati
authors.affiliation: Center for Human Genome Variation, Duke University School of Medicine, Durham, NC, USA.|Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
authors.affiliation: Associazione Italiana per la Sindrome di Emiplegia Alternante (A.I.S.EA Onlus), Lecco, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Vavassori
authors.affiliation: Epilepsy, Sleep and Pediatric Neurophysiology Department (ESEFNP), University Hospitals of Lyon (HCL), Lyon, France.|DYCOG team, Lyon Neuroscience Research Centre (CRNL), INSERM U1028; CNRS UMR 5292, Lyon, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Arzimanoglou
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D056726:Genetic Association Studies; D006306:Health Surveys; D006429:Hemiplegia / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics*; D055815:Young Adult
chemical_list: C488756:ATP1A3 protein, human; D000254:Sodium-Potassium-Exchanging ATPase