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Title: Clinical profile of patients with ATP1A3 mutations in alternating hemiplegia of childhood-a study of 155 patients.
Author: Panagiotakaki, Eleni
Grandis, Elisa de
Stagnaro, Michela
Heinzen, Erin L.
Fons, Carmen
Sisodiya, Sanjay
Vries, Boukje de
Goubau, Christophe
Weckhuysen, Sarah
Kemlink, David
Scheffer, Ingrid
Lesca, Gaëtan
Rabilloud, Muriel
Klich, Amna
Ramirez-Camacho, Alia
Ulate-Campos, Adriana
Campistol Plana, Jaume
Giannotta, Melania
Moutard, Marie L.
Doummar, Diane
Hubsch-Bonneaud, Cecile
Jaffer, Fatima
Cross, Helen
Gurrieri, Fiorella
Tiziano, Danilo
Nevsimalova, Sona
Nicole, Sophie
Neville, Brian
Maagdenberg, Arn M.J.M. van den
Mikati, Mohamad
Goldstein, David B.
Vavassori, Rosaria
Arzimanoglou, Alexis
Italian IBAHC Consortium
French AHC Consortium
International AHC Consortium
Keywords: Hemiplègia
Genètica mèdica
Mutació (Biologia)
Medical genetics
Mutation (Biology)
Issue Date: 26-Sep-2015
Publisher: BioMed Central
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.
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It is part of: Orphanet Journal of Rare Diseases, 2015, vol. 10, num. 123
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ISSN: 1750-1172
Appears in Collections:Articles publicats en revistes (Cirurgia i Especialitats Medicoquirúrgiques)

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