User menu

Accès à distance ? S'identifier sur le proxy UCLouvain

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

Primary tabs

download
  • Open access
  • PDF
  • 0.99 M
Panagiotakaki, Eleni De Grandis, Elisa Stagnaro, Michela Heinzen, Erin L Fons, Carmen Goubau, Christophe [UCL] International AHC Consortium

(eng) 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.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2015
Language Anglais
Journal information "Orphanet Journal of Rare Diseases" - Vol. 10, no. 1, p. 123 [1-13] (2015)
Peer reviewed yes
Publisher BioMed Central Ltd. ((United Kingdom) London)
e-issn 1750-1172
Publication status Publié
Affiliations UCL - (SLuc) Service de pédiatrie spécialisée
UCL - SSS/IREC/PEDI - Pôle de Pédiatrie
Keywords Alternating hemiplegia of childhood ; ATP1A3 ; Genotype-phenotype
Links
  1. Verret S, Steele JC. Alternating hemiplegia in childhood: a report of eight patients with complicated migraine beginning in infancy. Pediatrics. 1971;47:675–80.
  2. Dittrich J., Havlovd M., Nevsimalovd S., Paroxysmal Hemipareses in Childhood, 10.1111/j.1469-8749.1979.tb01705.x
  3. Krägeloh Ingeborg, Aicardi Jean, Alternating Hemiplegia in Infants: Report of Five Cases, 10.1111/j.1469-8749.1980.tb03746.x
  4. Aicardi J, Bourgeois M, Goutières F. Alternating hemiplegia of childhood: clinical findings and diagnostic criteria. In: Andermann F, Aicardi J, Vigevano F, editors. Alternating hemiplegia of childhood. New York: Raven; 1995. p. 3–18.
  5. Sweney M. T., Silver K., Gerard-Blanluet M., Pedespan J.-M., Renault F., Arzimanoglou A., Schlesinger-Massart M., Lewelt A. J., Reyna S. P., Swoboda K. J., Alternating Hemiplegia of Childhood: Early Characteristics and Evolution of a Neurodevelopmental Syndrome, 10.1542/peds.2008-2027
  6. Bourgeois Marle, Aicardi Jean, Goutières Françoise, Alternating hemiplegia of childhood, 10.1016/s0022-3476(06)80003-x
  7. Mikati Mohamad A, Kramer Uri, Zupanc Mary L, Shanahan Robin J, Alternating hemiplegia of childhood: clinical manifestations and long-term outcome, 10.1016/s0887-8994(00)00157-0
  8. Hoei-Hansen Christina E., Dali Christine í, Lyngbye Troels J.B., Duno Morten, Uldall Peter, Alternating hemiplegia of childhood in Denmark: Clinical manifestations and ATP1A3 mutation status, 10.1016/j.ejpn.2013.08.007
  9. Panagiotakaki Eleni, Gobbi Giuseppe, Neville Brian, Ebinger Friedrich, Campistol Jaume, Nevšímalová Soňa, Laan Laura, Casaer Paul, Spiel Georg, Giannotta Melania, Fons Carmen, Ninan Miriam, Sange Guenter, Schyns Tsveta, Vavassori Rosaria, Poncelin Dominique, Arzimanoglou Alexis, Evidence of a non-progressive course of alternating hemiplegia of childhood: study of a large cohort of children and adults, 10.1093/brain/awq295
  10. de Vries B, Stam AH, Beker F, van den Maagdenberg AMJM, Vanmolkot KRJ, Laan LAEM, Ginjaar IB, Frants RR, Lauffer H, Haan J, Haas JP, Terwindt GM, Ferrari MD, CACNA1A Mutation Linking Hemiplegic Migraine and Alternating Hemiplegia of Childhood, 10.1111/j.1468-2982.2008.01596.x
  11. Jen J. C., Wan J., Palos T. P., Howard B. D., Baloh R. W., Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures, 10.1212/01.wnl.0000172638.58172.5a
  12. Rotstein M., Doran J., Yang H., Ullner P. M., Engelstad K., De Vivo D. C., GLUT1 DEFICIENCY AND ALTERNATING HEMIPLEGIA OF CHILDHOOD, 10.1212/wnl.0b013e3181c55ebf
  13. Weller Claudia M, Leen Wilhelmina G, Neville Brian GR, Duncan John S, Vries Boukje de, Geilenkirchen Marije A, Haan Joost, Kamsteeg Erik-Jan, Ferrari Michel D, Maagdenberg Arn MJM van den, Willemsen Michèl AAP, Scheffer Hans, Terwindt Gisela M, A novel SLC2A1 mutation linking hemiplegic migraine with alternating hemiplegia of childhood, 10.1177/0333102414532379
  14. Bassi M T, A novel mutation in the ATP1A2 gene causes alternating hemiplegia of childhood, 10.1136/jmg.2003.017863
  15. Swoboda Kathryn J., Kanavakis Emmanuel, Xaidara Athina, Johnson Justine E., Leppert Mark F., Schlesinger-Massart Mylynda B., Ptacek Louis J., Silver Kenneth, Youroukos Sotiris, Alternating hemiplegia of childhood or familial hemiplegic migraine?: A novelATP1A2 mutation, 10.1002/ana.20134
  16. Haan J, Kors EE, Terwindt GM, Vermeulen FLMG, Vergouwe MN, van den Maagdenberg AMJM, Gill DS, Pascual J, Ophoff RA, Frants RR, Ferrari MD, Alternating Hemiplegia of Childhood: No Mutations in the Familial Hemiplegic Migraine CACNA1A Gene, 10.1046/j.0333-1024.2000.00095.x
  17. de Vries B., Haan J., Stam A., Vanmolkot K., Stroink H., Laan L., Gill D., Pascual J., Frants R., van den Maagdenberg A., Ferrari M., Alternating Hemiplegia of Childhood: No Mutations in the Glutamate Transporter EAAT1, 10.1055/s-2006-924609
  18. Vuillaumier-Barrot S., Panagiotakaki E., Bizec C. Le, Baba C. El, Fontaine B., Arzimanoglou A., Seta N., Nicole S., Absence of Mutation in theSLC2A1Gene in a Cohort of Patients with Alternating Hemiplegia of Childhood (AHC), 10.1055/s-0031-1271767
  19. De Grandis Elisa, Stagnaro Michela, Biancheri Roberta, Giannotta Melania, Gobbi Giuseppe, Traverso Monica, Veneselli Edvige, Zara Federico, Lack of SLC2A1 (Glucose Transporter 1) Mutations in 30 Italian Patients With Alternating Hemiplegia of Childhood, 10.1177/0883073812452789
  20. Kors E. E., Vanmolkot K. R. J., Haan J., Kheradmand Kia S., Stroink H., Laan L. A. E. M., Gill D. S., Pascual J., van den Maagdenberg A. M. J. M., Frants R. R., Ferrari M. D., Alternating Hemiplegia of Childhood: No Mutations in the Second Familial Hemiplegic Migraine GeneATP1A2 , 10.1055/s-2004-821082
  21. Heinzen Erin L, Swoboda Kathryn J, Hitomi Yuki, Gurrieri Fiorella, Nicole Sophie, de Vries Boukje, Tiziano F Danilo, Fontaine Bertrand, Walley Nicole M, Heavin Sinéad, Panagiotakaki Eleni, Nicole Sophie, Gurrieri Fiorella, Neri Giovanni, de Vries Boukje, Koelewijn Stephany, Kamphorst Jessica, Geilenkirchen Marije, Pelzer Nadine, Laan Laura, Haan Joost, Ferrari Michel, van den Maagdenberg Arn, Zucca Claudio, Bassi Maria Teresa, Franchini Filippo, Vavassori Rosaria, Giannotta Melania, Gobbi Giuseppe, Granata Tiziana, Nardocci Nardo, De Grandis Elisa, Veneselli Edvige, Stagnaro Michela, Gurrieri Fiorella, Neri Giovanni, Vigevano Federico, Panagiotakaki Eleni, Oechsler Claudia, Arzimanoglou Alexis, Nicole Sophie, Giannotta Melania, Gobbi Giuseppe, Ninan Miriam, Neville Brian, Ebinger Friedrich, Fons Carmen, Campistol Jaume, Kemlink David, Nevsimalova Sona, Laan Laura, Peeters-Scholte Cacha, van den Maagdenberg Arn, Casaer Paul, Casari Giorgio, Sange Guenter, Spiel Georg, Boneschi Filippo Martinelli, Zucca Claudio, Bassi Maria Teresa, Schyns Tsveta, Crawley Francis, Poncelin Dominique, Vavassori Rosaria, Fiori Stefania, Abiusi Emanuela, Di Pietro Lorena, Sweney Matthew T, Newcomb Tara M, Viollet Louis, Huff Chad, Jorde Lynn B, Reyna Sandra P, Murphy Kelley J, Shianna Kevin V, Gumbs Curtis E, Little Latasha, Silver Kenneth, Ptáček Louis J, Haan Joost, Ferrari Michel D, Bye Ann M, Herkes Geoffrey K, Whitelaw Charlotte M, Webb David, Lynch Bryan J, Uldall Peter, King Mary D, Scheffer Ingrid E, Neri Giovanni, Arzimanoglou Alexis, van den Maagdenberg Arn M J M, Sisodiya Sanjay M, Mikati Mohamad A, Goldstein David B, De novo mutations in ATP1A3 cause alternating hemiplegia of childhood, 10.1038/ng.2358
  22. Rosewich Hendrik, Thiele Holger, Ohlenbusch Andreas, Maschke Ulrike, Altmüller Janine, Frommolt Peter, Zirn Birgit, Ebinger Friedrich, Siemes Hartmut, Nürnberg Peter, Brockmann Knut, Gärtner Jutta, Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study, 10.1016/s1474-4422(12)70182-5
  23. Ishii A, Saito Y, Mitsui J, Ishiura H, Yoshimura J, Arai H, et al. Identification of ATP1A3 mutations by exome sequencing as the cause of alternating hemiplegia of childhood in Japanese patients. PLoS One. 2013;8, e56120.
  24. Dobyns W. B., Ozelius L. J., Kramer P. L., Brashear A., Farlow M. R., Perry T. R., Walsh L. E., Kasarskis E. J., Butler I. J., Breakefield X. O., Rapid-onset dystonia-parkinsonism, 10.1212/wnl.43.12.2596
  25. Brashear A., DeLeon D., Bressman S. B., Thyagarajan D., Farlow M. R., Dobyns W. B., Rapid-onset dystonia-parkinsonism in a second family, 10.1212/wnl.48.4.1066
  26. de Carvalho Aguiar Patricia, Sweadner Kathleen J, Penniston John T, Zaremba Jacek, Liu Liu, Caton Marsha, Linazasoro Gurutz, Borg Michel, Tijssen Marina A.J, Bressman Susan B, Dobyns William B, Brashear Allison, Ozelius Laurie J, Mutations in the Na+/K+-ATPase α3 Gene ATP1A3 Are Associated with Rapid-Onset Dystonia Parkinsonism, 10.1016/j.neuron.2004.06.028
  27. Brashear A., Dobyns W. B., de Carvalho Aguiar P., Borg M., Frijns C. J. M., Gollamudi S., Green A., Guimaraes J., Haake B. C., Klein C., Linazasoro G., Munchau A., Raymond D., Riley D., Saunders-Pullman R., Tijssen M. A. J., Webb D., Zaremba J., Bressman S. B., Ozelius L. J., The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP1A3 gene, 10.1093/brain/awl340
  28. Demos Michelle K, van Karnebeek Clara DM, Ross Colin JD, Adam Shelin, Shen Yaoqing, Zhan Shing Hei, Shyr Casper, Horvath Gabriella, Suri Mohnish, Fryer Alan, Jones Steven JM, Friedman Jan M, , A novel recurrent mutation in ATP1A3 causes CAPOS syndrome, 10.1186/1750-1172-9-15
  29. BRASHEAR ALLISON, MINK JONATHAN W, HILL DEBORAH F, BOGGS NIKI, MCCALL W VAUGHN, STACY MARK A, SNIVELY BEVERLY, LIGHT LANEY S, SWEADNER KATHLEEN J, OZELIUS LAURIE J, MORRISON LESLIE, ATP1A3mutations in infants: a new rapid-onset dystonia-Parkinsonism phenotype characterized by motor delay and ataxia : Case Report, 10.1111/j.1469-8749.2012.04421.x
  30. Boelman Cyrus, Lagman-Bartolome Ana Marissa, MacGregor Daune L., McCabe Jane, Logan Willam J., Minassian Berge A., Identical ATP1A3 Mutation Causes Alternating Hemiplegia of Childhood and Rapid-Onset Dystonia Parkinsonism Phenotypes, 10.1016/j.pediatrneurol.2014.08.015
  31. Viollet L, Glusman G, Murphy KJ, Newcomb TM, Reyna SP, Sweney M, et al. Alternating hemiplegia of childhood: retrospective genetic study and genotype-phenotype correlations in 187 subjects from the US AHCF registry. PLoS One. 2015;10, e0127045.
  32. Kamm C., Fogel W., Wachter T., Schweitzer K., Berg D., Kruger R., Freudenstein D., Gasser T., NOVEL ATP1A3 MUTATION IN A SPORADIC RDP PATIENT WITH MINIMAL BENEFIT FROM DEEP BRAIN STIMULATION, 10.1212/01.wnl.0000310431.41036.e0
  33. Rosewich H., Ohlenbusch A., Huppke P., Schlotawa L., Baethmann M., Carrilho I., Fiori S., Lourenco C. M., Sawyer S., Steinfeld R., Gartner J., Brockmann K., The expanding clinical and genetic spectrum of ATP1A3-related disorders, 10.1212/wnl.0000000000000212
  34. Sasaki M., Ishii A., Saito Y., Morisada N., Iijima K., Takada S., Araki A., Tanabe Y., Arai H., Yamashita S., Ohashi T., Oda Y., Ichiseki H., Hirabayashi S., Yasuhara A., Kawawaki H., Kimura S., Shimono M., Narumiya S., Suzuki M., Yoshida T., Oyazato Y., Tsuneishi S., Ozasa S., Yokochi K., Dejima S., Akiyama T., Kishi N., Kira R., Ikeda T., Oguni H., Zhang B., Tsuji S., Hirose S., Genotype-phenotype correlations in alternating hemiplegia of childhood, 10.1212/wnl.0000000000000102
  35. Yang X, Gao H, Zhang J, Xu X, Liu X, Wu X, et al. ATP1A3 mutations and genotype-phenotype correlation of alternating hemiplegia of childhood in Chinese patients. PLoS One. 2014;9, e97274.
  36. Svetel Marina, Ozelius Laurie J., Buckley Amber, Lohmann Katja, Brajković Lela, Klein Christine, Kostić Vladimir S., Rapid-onset dystonia-parkinsonism: case report, 10.1007/s00415-009-5385-y
  37. Rosewich H., Weise D., Ohlenbusch A., Gartner J., Brockmann K., Phenotypic overlap of alternating hemiplegia of childhood and CAPOS syndrome, 10.1212/wnl.0000000000000735
  38. Rosewich Hendrik, Baethmann Martina, Ohlenbusch Andreas, Gärtner Jutta, Brockmann Knut, A novel ATP1A3 mutation with unique clinical presentation, 10.1016/j.jns.2014.03.034
  39. Anselm I. A., Sweadner K. J., Gollamudi S., Ozelius L. J., Darras B. T., RAPID-ONSET DYSTONIA-PARKINSONISM IN A CHILD WITH A NOVEL ATP1A3 GENE MUTATION, 10.1212/wnl.0b013e3181b04acd
  40. Roubergue Anne, Roze Emmanuel, Vuillaumier-Barrot Sandrine, Fontenille Marie-Joséphine, Méneret Aurélie, Vidailhet Marie, Fontaine Bertrand, Doummar Diane, Philibert Bertrand, Riant Florence, Nicole Sophie, The multiple faces of theATP1A3-related dystonic movement disorder, 10.1002/mds.25396
  41. Blanco-Arias P., Einholm A. P., Mamsa H., Concheiro C., Gutierrez-de-Teran H., Romero J., Toustrup-Jensen M. S., Carracedo A., Jen J. C., Vilsen B., Sobrido M.-J., A C-terminal mutation of ATP1A3 underscores the crucial role of sodium affinity in the pathophysiology of rapid-onset dystonia-parkinsonism, 10.1093/hmg/ddp170
  42. European Network for Research on Alternating Hemiplegia. Accessed 9 September 2015. [ http://www.enrah.net ]
  43. European Network for Rare Paediatric Neurological Diseases (nEUroped). Accessed 9 September 2015. [ http://www.eurordis.org/content/european-network-rare-paediatric-neurological-diseases-neuroped ]
  44. IAHCRC International Consortium research and care for the ATP1A3 diseases. Accessed 9 September 2015. [ http://www.iahcrc.net ]
  45. Yekutieli Daniel, Benjamini Yoav, under dependency, 10.1214/aos/1013699998
  46. Weigand KM, Messchaert M, Swarts HG, Russel FG, Koenderink JB. Alternating hemiplegia of childhood mutations have a differential effect on Na (+), K (+) -ATPase activity and ouabain binding. Biochim Biophys Acta. 1842;2014:1010–6.
  47. Li Melody, Jazayeri Dana, Corry Ben, McSweeney K. Melodi, Heinzen Erin L., Goldstein David B., Petrou Steven, A functional correlate of severity in alternating hemiplegia of childhood, 10.1016/j.nbd.2015.02.002
  48. Heinzen Erin L, Arzimanoglou Alexis, Brashear Allison, Clapcote Steven J, Gurrieri Fiorella, Goldstein David B, Jóhannesson Sigurður H, Mikati Mohamad A, Neville Brian, Nicole Sophie, Ozelius Laurie J, Poulsen Hanne, Schyns Tsveta, Sweadner Kathleen J, van den Maagdenberg Arn, Vilsen Bente, Distinct neurological disorders with ATP1A3 mutations, 10.1016/s1474-4422(14)70011-0
Bibliographic reference Panagiotakaki, Eleni ; De Grandis, Elisa ; Stagnaro, Michela ; Heinzen, Erin L ; Fons, Carmen ; et. al. Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood-a study of 155 patients.. In: Orphanet Journal of Rare Diseases, Vol. 10, no. 1, p. 123 [1-13] (2015)
Permanent URL http://hdl.handle.net/2078.1/172203