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Title: Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood-a study of 155 patients.
Austin Authors: Panagiotakaki, Eleni;De Grandis, Elisa;Stagnaro, Michela;Heinzen, Erin L;Fons, Carmen;Sisodiya, Sanjay;de Vries, Boukje;Goubau, Christophe;Weckhuysen, Sarah;Kemlink, David;Scheffer, Ingrid E ;Lesca, Gaëtan;Rabilloud, Muriel;Klich, Amna;Ramirez-Camacho, Alia;Ulate-Campos, Adriana;Campistol, Jaume;Giannotta, Melania;Moutard, Marie-Laure;Doummar, Diane;Hubsch-Bonneaud, Cecile;Jaffer, Fatima;Cross, Helen;Gurrieri, Fiorella;Tiziano, Danilo;Nevsimalova, Sona;Nicole, Sophie;Neville, Brian;van den Maagdenberg, Arn M J M;Mikati, Mohamad;Goldstein, David B;Vavassori, Rosaria;Arzimanoglou, Alexis
Affiliation: DYCOG team, Lyon Neuroscience Research Centre (CRNL), INSERM U1028; CNRS UMR 5292, Lyon, France
Division of Pediatric Neurology and Department of Neurobiology, Duke University, School of Medicine, Durham, NC, USA
Associazione Italiana per la Sindrome di Emiplegia Alternante (A.I.S.EA Onlus), Lecco, Italy
Epilepsy, Sleep and Pediatric Neurophysiology Department (ESEFNP), University Hospitals of Lyon (HCL), Lyon, France
Department of Child Neuropsychiatry, G. Gaslini Hospital, University of Genoa, Genoa, Italy
Center for Human Genome Variation, Duke University School of Medicine, Durham, NC, USA
Department of Medicine, Duke University School of Medicine, Durham, NC, USA
Department of Child Neurology, Sant Joan de Déu Hospital, Barcelona, Spain
Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, London, UK
Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands
Department of Child Neurology, University Hospitals Leuven, Leuven, Belgium
Department of Molecular Genetics, Neurogenetics Group, VIB, Antwerp, Belgium
Department of Neurology, Charles University, First Faculty of Medicine and Teaching Hospital, Prague, Czech Republic
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia
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
Biostatistics Department, University Hospitals of Lyon and UMR 5558, Lyon, France
Child Neurology Unit, Maggiore Hospital, Bologna, Italy
Department of Child Neurology, Armand Trousseau Hospital, APHP, Paris, France
Department of Neurology, Pitié-Salpêtrière Hospital, APHP, Paris, France
Institute of Child Health, University College London, London, UK
Institute of Medical Genetics, University Cattolica del Sacro Cuore, Policlinics A. Gemelli, Rome, Italy
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
Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands
Issue Date: 26-Sep-2015 2015
Publication information: Orphanet journal of rare diseases 2015; 10: 123
Abstract: 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. 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. 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. 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.
DOI: 10.1186/s13023-015-0335-5
ORCID: 0000-0002-2311-2174
Journal: Orphanet journal of rare diseases
PubMed URL: 26410222
Type: Journal Article
Appears in Collections:Journal articles

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