1. Clinical profile of patients with ATP1A3 mutations in alternating hemiplegia of childhood-a study of 155 patients
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Panagiotakaki, E., De Grandis, E., Stagnaro, M., Heinzen, E. L., Fons, C., Sisodiya, S., de Vries, B., Goubau, C., Weckhuysen, S., Kemlink, D., Scheffer, I., Lesca, G., Rabilloud, M., Klich, A., Ramirez-Camacho, A., Ulate-Campos, A., Campistol, J., Giannotta, M., Moutard, M. L., Doummar, D., Hubsch-Bonneaud, C., Jaffer, F., Cross, H., Gurrieri, F., Tiziano, D., Nevsimalova, S., Nicole, S., Neville, B., van den Maagdenberg, A. M., Mikati, M., Goldstein, D. B., Vavassori, R., Arzimanoglou, A., Italian IBAHC Consortium, French AHC Consortium, Collaborators: Bassi MT, International AHC Consortium., Borgatti, R, Cernetti, R, Di Rosa, G, Franchini, F, Gambardella, A, Giacanelli, M, Giannotta, M, Gobbi, G, Granata, T, De Grandis, E, Guerrini, R, Gurrieri, F, Incorpora, G, Nardocci, N, Neri, G, Ragona, F, Santucci, M, Sartori, S, Stagnaro, M, Tiziano, D, Vavassori, R, Veneselli, E, Vigevano, F, Zucca, C, Aicardi, J, An, I, Arbues, As, Arzimanoglou, A, Bahi- Buisson, N, Barthez, Ma, Billette de Villemeur, T, Bourgeois, M, Bru, M, Chabrol, B, Chaigne, D, Chaunu, Mp, Chiron, C, Cournelle, Am, Davoine, Cs, De St Martin, A, Deny, B, Desguerres, I, Des Portes, V, Doummar, D, Dulac, O, Dusser, A, Gerard, M, Gitiaux, C, Godet Kiesel, I, Gokben, S, Goutieres, F, Guerrin, Mh, Heron-Longe, B, Hubsch-Bonneaud, C, Hully, M, Husson, M, Ioos, Ch, Kaminska, A, Laroche, C, Lazaro, L, Lepine, A, Magy, L, Marchal, C, Michel, J, Milh, M, Motte, J, Moutard, Ml, Napuri, S, Nassogne, Mc, Neau, Jp, Nicole, S, Panagiotakaki, E, Passemard, S, Pedespan, Jm, Penniello- Valette MJ, Poncelin, D, Ponsot, G, Poulat, Al, Pouplard, F, Rabilloud, M, Riant, F, Rivier, F, Roelens, P, Roubergue, A, Sanlaville, D, Tardieu, M, Veyrieres, S, de Grandis, E, Fons, C, Sisodiya, S, de Jonghe, P, Goubeau, C, van den Maagdenberg AM, Mikati, M, Scheffer, I, Nevsimalova, S, Kemlink, D, Krepelova, A, Kolnikova, M, Sykora, P, Kaski, J, Hanna, M, Houlden, H, Ulate-Campos, A, Cancho, R, Eiris, J, López-Laso, E, Velázquez, R, Carilho, I, Ozelius, L, Suls, A, Ceulemans, B, Buyse, G, di Michele, M, Ferrari, M, Peeters-Scholte, Cm., Universitat de Barcelona, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Suls, Arvid, De Jonghe, Peter, Ceulemans, Berten, Italian IBAHC Consortium, French AHC Consortium, International AHC Consortium, UCL - (SLuc) Service de pédiatrie générale, and UCL - SSS/IREC/PEDI - Pôle de Pédiatrie
- Subjects
Male ,[SDV]Life Sciences [q-bio] ,medicine.disease_cause ,Settore MED/03 - GENETICA MEDICA ,Epilepsy ,Genètica mèdica ,0302 clinical medicine ,ATP1A3 ,inglese ,Genetics(clinical) ,Pharmacology (medical) ,Young adult ,Child ,Genetics (clinical) ,Genetics ,Medicine(all) ,0303 health sciences ,Mutation ,Medical genetics ,General Medicine ,Middle Aged ,Prognosis ,3. Good health ,Child, Preschool ,Alternating hemiplegia of childhood ,Cohort ,Hemiplègia ,Female ,Sodium-Potassium-Exchanging ATPase ,Adult ,medicine.medical_specialty ,Adolescent ,Hemiplegia ,Biology ,Genotype-phenotype ,03 medical and health sciences ,Young Adult ,Internal medicine ,medicine ,Humans ,Preschool ,Genetic Association Studies ,030304 developmental biology ,Alternating hemiplegia of childhood, ATP1A3, Genotype-phenotype ,Health Surveys ,Infant ,Research ,Mutació (Biologia) ,Mutation (Biology) ,medicine.disease ,Clinical trial ,Human medicine ,030217 neurology & neurosurgery ,Alternating hemiplegia - 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
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