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Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood-a study of 155 patients

E. Panagiotakaki, E. De Grandis, M. Stagnaro, EL. Heinzen, C. Fons, S. Sisodiya, B. de Vries, C. Goubau, S. Weckhuysen, D. Kemlink, I. Scheffer, G. Lesca, M. Rabilloud, A. Klich, A. Ramirez-Camacho, A. Ulate-Campos, J. Campistol, M. Giannotta,...

. 2015 ; 10 (-) : 123. [pub] 20150926

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc16020261

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.

Associazione Italiana per la Sindrome di Emiplegia Alternante Lecco Italy

Biostatistics Department University Hospitals of Lyon and UMR 5558 Lyon France

Center for Human Genome Variation Duke University School of Medicine Durham NC USA Department of Medicine Duke University School of Medicine Durham NC USA

Child Neurology Unit Maggiore Hospital Bologna Italy

CNRS UMR 5292 Lyon France

Department of Child Neurology Armand Trousseau Hospital APHP Paris France

Department of Child Neurology Sant Joan de Déu Hospital Barcelona Spain

Department of Child Neurology University Hospitals Leuven Leuven Belgium

Department of Child Neuropsychiatry G Gaslini Hospital University of Genoa Genoa Italy

Department of Clinical and Experimental Epilepsy University College London Institute of Neurology London UK

Department of Genetics University Hospitals of Lyon CNRS UMR 5292 INSERM U1028 Lyon France

Department of Human Genetics Leiden University Medical Centre Leiden The Netherlands

Department of Human Genetics Leiden University Medical Centre Leiden The Netherlands Department of Neurology Leiden University Medical Centre Leiden The Netherlands

Department of Medicine University of Melbourne Austin Health Melbourne Australia Department of Paediatrics University of Melbourne Royal Children's Hospital Melbourne Australia

Department of Molecular Genetics Neurogenetics Group VIB Antwerp Belgium

Department of Neurology Charles University 1st Faculty of Medicine and Teaching Hospital Prague Czech Republic

Department of Neurology Pitié Salpêtrière Hospital APHP Paris France

Division of Pediatric Neurology and Department of Neurobiology Duke University School of Medicine Durham NC USA

Epilepsy Sleep and Pediatric Neurophysiology Department INSERM U1028

Epilepsy Sleep and Pediatric Neurophysiology Department Lyon France

Epilepsy Sleep and Pediatric Neurophysiology Department Lyon France Department of Child Neurology Sant Joan de Déu Hospital Barcelona Spain

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

Institute of Child Health University College London London UK

Institute of Medical Genetics University Cattolica del Sacro Cuore Policlinics A Gemelli Rome Italy

Citace poskytuje Crossref.org

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