The clarification of molecular pathology of alternating hemiplegia of childhood.

• Project/Area Number: 23791201
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Fukuoka University
• Principal Investigator: ISHII Atsushi 福岡大学, 医学部, 助手 (90568825)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 小児神経 / 遺伝子 / ATP1A3 / てんかん / 不随意運動 / エクソーム解析 / イオンチャネル / 次世代シークエンサー / 小児神経疾患 / 麻痺発作 / 発達障害 / 国際情報交換 / チャネル / 小児交互性片麻痺 / ATP１A3 / パーキンソン病 / ジストニア / 全エクソーム / 麻痺 / 不随運動

Research Abstract

Alternating hemiplegia of childhood (AHC) has an onset of an abnormal eye movement during the early years of life and paroxysmal hemiplegia in the first year and a half. In addition, AHC has associated symptoms that are epilepsy and a variety of involuntary movements. There are not specific examination findings and established treatments.
Exome sequencing was performed for the 8 patients with typical AHC to identify a responsible gene. As a result, each patient harbored a heterozygous missense ATP1A3 mutation. These mutations were not found in their parents. We elucidated that a de novo heterozygous missense mutation in the ATP1A3 gene is a cause of AHC. In addition, we found out the significant correlation between phenotype and E815K mutation.

Research Products

• [Journal Article] Effect of CYP2C19 polymorphisms on stiripentol administration in Japanese cases of Dravet syndrome (2015)
  • Author(s): Kouga T, Shimbo H, Iai M, Yamashita S, Ishii A, Ihara Y, Hirose S, Yamakawa K, Osaka H.
  • Journal Title: Brain & Development Volume: 37(2) Pages: 8-45
  • DOI: 10.1016/j.braindev.2014.04.003
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Intermediate form between alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism (2014)
  • Author(s): Sasaki M., Ishii A., Saito Y., Hirose S.
  • Journal Title: Mov Disord Volume: 29(1) Pages: 153-154
• [Journal Article] Distinct neurological disorders with ATP1A3 mutations (2014)
  • Author(s): Heinzen E. L., Arzimanoglou A., Brashear A., Clapcote S. J., Gurrieri F., Goldstein D. B., Johannesson S. H., Mikati M. A., Neville B., Nicole S., Ozelius L. J., Poulsen H., Schyns T., Sweadner K. J., van den Maagdenberg A., Vilsen B., for the A. T. P. A. Working Group
  • Journal Title: Lancet Neurol Volume: 13(5) Pages: 503-514
• [Journal Article] Association of nonsense mutation in GABRG2 with abnormal trafficking of GABAA receptors in severe epilepsy (2014)
  • Author(s): Ishii A., Kanaumi T., Sohda M., Misumi Y., Zhang B., Kakinuma N., Haga Y., Watanabe K., Takeda S., Okada M., Ueno S., Kaneko S., Takashima S., Hirose S.
  • Journal Title: Epilepsy Res Volume: 108(3) Pages: 420-432
• [Journal Article] Genotype-phenotype correlations in alternating hemiplegia of childhood (2014)
  • Author(s): S asaki 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.
  • Journal Title: Neurology Volume: 82(6) Pages: 482-490
• [Journal Article] Association of nonsense mutation in GABRG2 with abnormal trafficking of GABAA receptors in severe epilepsy (2014)
  • Author(s): Ishii, A., Kanaumi, T., Sohda, M., Misumi, Y., Zhang, B., Kakinuma, N., Haga, Y., Watanabe, K., Takeda, S., Okada, M., Ueno, S., Kaneko, S., Takashima, S., Hirose, S.
  • Journal Title: Epilepsy research Volume: 108 Pages: 420-32
  • DOI: 10.1016/j.eplepsyres.2013.12.005
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Genotype-Phenotype Correlations in Alternating Hemiplegia of Childhood. (2014)
  • Author(s): Sasaki M, Ishii A, Saito Y, (中略）, Tsuji S and Hirose S.
  • Journal Title: NEUROLOGY Volume: 82 Pages: 482-490
  • DOI: 10.1212/wnl.0000000000000102
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Inermediate Form Between Alternating Hemiplegia of Childhood and Rapid-Onset Dystonia-Parkinsonism. (2014)
  • Author(s): Sasaki M, Ishii A, Saito Y, Hirose S.
  • Journal Title: Movement Disorders Volume: 29 Pages: 153-154
  • DOI: 10.1002/mds.25659
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Distinct neurologocal disorders with ATP1A3 mutations. (2014)
  • Author(s): Heinzen, E.L.*, Arzimanoglou, A., Brashear, A., Clapcote, S.J., Gurrieri, F., Goldstein, D.B., Johannesson, S.H., Mikati, M.A., Neville, B., Nicole, S., Ozelius, L.J., Poulsen, H., Schyns, T., Sweadner, K.J., van den Maagdenberg, A., Vilsen, B., the ATP1A3 Working Group (included Ikeda, K.).
  • Journal Title: Lancent Neurol. Volume: 13 Pages: 503-14
  • DOI: 10.1016/s1474-4422(14)70011-0
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pancreatic Solid Pseudo-Papillary Tumor Detected After Abdominal Injury (2013)
  • Author(s): Ishii A., Yoshimura K., Ideguchi .h, Hirose S.
  • Journal Title: Gastroenterology Research Volume: 6(2) Pages: 67-70
• [Journal Article] Identification of ATP1A3 mutations by exome sequencing as the cause of alternating hemiplegia of childhood in Japanese patients (2013)
  • Author(s): Ishii A., Saito Y., Mitsui J., Ishiura H., Yoshimura J., Arai H., Yamashita S., Kimura S., Oguni H., Morishita S., Tsuji S., Sasaki M., Hirose S.
  • Journal Title: PLOS ONE Volume: 8(2)
• [Journal Article] Genetic analysis of PRRT2 for benign infantile epilepsy, infantile convulsions with choreoathetosis syndrome, and benign convulsions with mild gastroenteritis (2013)
  • Author(s): Ishii A., Yasumoto S., Ihara Y., Inoue T., Fujita T., Nakamura N., Ohfu M., Yamashita Y., Takatsuka H., Taga T., Miyata R., Ito M., Tsuchiya H., Matsuoka T., Kitao T., Murakami K., Lee W. T., Kaneko S., Hirose S.
  • Journal Title: Brain Dev Volume: 35(6) Pages: 524-530
• [Journal Article] A recurrent KCNT1 mutation in two sporadic cases with malignant migrating partial seizures in infancy (2013)
  • Author(s): Ishii A., Shioda M., Okumura A., Kidokoro H., Sakauchi M., Shimada S., Shimizu T., Osawa M., Hirose S., Yamamoto T.
  • Journal Title: Gene Volume: 531(2) Pages: 467-471
• [Journal Article] Newborn screening for Fabry disease in Japan : prevalence and genotypes of Fabry disease in a pilot study (2013)
  • Author(s): Inoue T., Hattori K., Ihara K., Ishii A., Nakamura K., Hirose S.
  • Journal Title: J Hum Genet Volume: 58(8) Pages: 548-552
• [Journal Article] 小児神経学の新たな展開ゲノム科学による病因不明・難治性小児神経疾患の病態解明への戦略 (2013)
  • Author(s): 石井敦士,廣瀬伸一
  • Journal Title: 日本小児科学会雑誌 Volume: 117(9) Pages: 1383-1388
• [Journal Article] Genetic analysis of PRRT2 for benign infantile epilepsy, infantile convulsions with choreoathetosis syndrome, and benign convulsions with mild gastroenteritis (2013)
  • Author(s): Ishii A, et al
  • Journal Title: Brain & development. Volume: 35 Pages: 524-30
  • DOI: 10.1016/j.braindev.2012.09.006
  • Peer Reviewed
• [Journal Article] A recurrent KCNT1 mutation in two sporadic cases with malignant migrating partial seizures in infancy (2013)
  • Author(s): Ishii A, Shioda M, Okumura A, Kidokoro H, Sakauchi M, Shimada S, Shimizu T, Osawa M, Hirose S, Yamamoto T.
  • Journal Title: Gene Volume: 531 Pages: 467-471
  • DOI: 10.1016/j.gene.2013.08.096
  • Peer Reviewed
• [Journal Article] Newborn screening for Fabry disease in Japan: prevalence and genotypes of Fabry disease in a pilot study. (2013)
  • Author(s): Inoue T, Hattori K, Ihara K, Ishii A, Nakamura K, Hirose S
  • Journal Title: Journal of Human Genetics Volume: 58 Pages: 548-52
  • DOI: 10.1038/jhg.2013.48
  • Peer Reviewed
• [Journal Article] Identification of ATP1A3 mutations by exome sequencing as the cause of alternating hemiplegia of childhood in Japanese patients. (2013)
  • Author(s): Ishii A, Saito Y, Mitsui J, Ishiura H, Yoshimura J, Arai H, Yamashita S, Kimura S, Oguni H, Morishita S, Tsuji S, Sasaki M, Hirose S.
  • Journal Title: PLoS ONE Volume: 8
  • DOI: 10.1371/journal.pone.0056120
  • Peer Reviewed
• [Journal Article] On the likelihood of SCN1A microdeletions or duplications in Dravet syndrome with missense mutation (2012)
  • Author(s): Shi X., Wang J., Kurahashi H., Ishii A., Higurashi N., Kaneko S., Hirose S.
  • Journal Title: Brain Dev Volume: 34(8) Pages: 617-619
• [Journal Article] KCNQ2 abnormality in BECTS : Benign childhood epilepsy with centrotemporal spikes following benign neonatal seizures resulting from a mutation of KCNQ2 (2012)
  • Author(s): Ishii A., Miyajima T., Kurahashi H., Wang J. W., Yasumoto S., Kaneko S., Hirose S.
  • Journal Title: Epilepsy Res Volume: 102(1-2) Pages: 122-125
• [Journal Article] Prevalence of SCN1A mutations in children with suspected Dravet syndrome and intractable childhood epilepsy (2012)
  • Author(s): Wang J. W., Shi X. Y., Kurahashi H., Hwang S. K., Ishii A., Higurashi N., Kaneko S., Hirose S., Epilepsy Genetic Study Group Japan
  • Journal Title: Epilepsy Res Volume: 102(3) Pages: 195-200
• [Journal Article] 【てんかん治療の最前線】てんかんの分子病態 (2012)
  • Author(s): 井原由紀子,石井敦士,日暮憲道,内田琢,中村友紀,友納優子,廣瀬伸一
  • Journal Title: Medical Science Digest Volume: 38(7) Pages: 292-295
• [Journal Article] 【知っておきたいてんかん診療】てんかんと社会てんかんと遺伝子 (2012)
  • Author(s): 廣瀬伸一,日暮憲道,中村友紀,黄壽卿,石井敦士
  • Journal Title: Modern Physician Volume: 32(3) Pages: 282-288
• [Journal Article] 【抑制性シナプスの基礎と臨床】疾患とその治療における抑制性シナプスの意義てんかんにおけるGABA受容体とK+チャネルの異常 (2012)
  • Author(s): 石井敦士,内田琢,中村友紀,廣瀬伸一
  • Journal Title: Clinical Neuroscience Volume: 30(12) Pages: 1397-1400
• [Journal Article] KCNQ2 abnormality in BECTS: benign childhood epilepsy with centrotemporal spikes following benign neonatal seizures resulting from a mutation of KCNQ2. (2012)
  • Author(s): Ishii A, Miyajima T, Kurahashi H, Wang JW, Yasumoto S, Kaneko S, Hirose S.
  • Journal Title: Epilepsy reserch Volume: 102 Pages: 122-5
  • DOI: 10.1016/j.eplepsyres.2012.07.011
  • Peer Reviewed
• [Journal Article] On the likelihood of SCN1A microdeletions or duplications in Dravet syndrome with missense mutation (2012)
  • Author(s): Shi X, Wang J, Kurahashi H, Ishii A, Higurashi N, Kaneko S, Hirose S
  • Journal Title: Brain Dev Volume: 34 Pages: 617-9
  • DOI: 10.1016/j.braindev.2011.11.005
  • Peer Reviewed
• [Journal Article] Epilepsy Genetic Study Group J. Prevalence of SCN1A mutations in children with suspected Dravet syndrome and intractable childhood epilepsy. (2012)
  • Author(s): Wang JW, Shi XY, Kurahashi H, Hwang SK, Ishii A, Higurashi N, Kaneko S, Hirose S,Epilepsy Genetic Study Group J.
  • Journal Title: Brain and Development Volume: 102(3) Pages: 195-200
  • DOI: 10.1016/j.eplepsyres.2012.06.006
  • Peer Reviewed
• [Journal Article] てんかんと遺伝子 (2012)
  • Author(s): 廣瀬伸一、日暮憲道、中村友紀、黄壽卿、石井敦士
  • Journal Title: Modern Physician Volume: 32巻 Pages: 282-288
  • Peer Reviewed
• [Journal Article] 【臨床に役立つてんかんの最新情報】てんかん遺伝子診断は臨床に役立つか? (2011)
  • Author(s): 廣瀬伸一,日暮憲道,中村友紀,黄壽卿,石井敦士
  • Journal Title: 神経内科 Volume: 74(5) Pages: 460-466
• [Journal Article] 【臨床に役立つてんかんの最新情報】 てんかん遺伝子診断は臨床に役立つか? (2011)
  • Author(s): 廣瀬伸一、日暮憲道、中村友紀、黄壽卿、石井敦士
  • Journal Title: 神経内科 Volume: 74巻 Pages: 460-466
  • Peer Reviewed
• [Presentation] 小児神経疾患のゲノム解析の現況と将来～てんかんとゲノム～ (2014)
  • Author(s): 石井敦士
  • Organizer: 第56回日本小児神経学会近畿地方会学会
  • Place of Presentation: 大阪市立総合医療センター
  • Invited
• [Presentation] 1. Identification of ATP1A3 mutations by exome sequencing as the cause of alternating hemiplegia of childhood in Japan (2013)
  • Author(s): Atsushi Ishii, Yoshiaki Saito, Jun Mitsui, Hiroyuki Ishiura , Jun Yoshimura, Hidee Arai, Sumimasa Yamashita, Sadami Kimura, Hirokazu Oguni, Shinichi Morishita, Shoji Tsuji, Masayuki Sasaki, Shinichi Hirose
  • Organizer: 30th International Epilepsy Congress
  • Place of Presentation: Montreal
• [Presentation] 2. 小児交互性片麻痺の病因遺伝子であるATP1A3の同定と現状について (2013)
  • Author(s): 石井敦士、佐々木征行、廣瀬伸一
  • Organizer: 第55回日本小児神経学会総会
  • Place of Presentation: 大分市
• [Presentation] ミダゾラムが片麻痺発作抑制に有効であった小児交互性片麻痺の1 例 (2013)
  • Author(s): 荒木敦、田邉裕子、石井敦士、廣瀬伸一
  • Organizer: 第55回日本小児神経学会総会
  • Place of Presentation: 大分市
• [Presentation] 家族性片麻痺性片頭痛2 型の母子例 (2013)
  • Author(s): 龍神布紀子、吉岡誠一郎、粟嶋勇也、西倉紀子、高野知行、竹内義博、石井敦士、廣瀬伸一
  • Organizer: 第55回日本小児神経学会総会
  • Place of Presentation: 大分市
• [Presentation] 小児交互性片麻痺の責任遺伝子であるATP1A3の同定 (2013)
  • Author(s): 石井敦士、廣瀬伸一、佐々木征行
  • Organizer: 第476回福岡小児科学会地方会
  • Place of Presentation: 福岡市
• [Presentation] 乳児痙攣、ICCA症候群、軽症胃腸炎に伴う痙攣でのＰＲＲＴ２遺伝子の解析 (2013)
  • Author(s): 石井敦士
  • Organizer: 第116回日本小児科学会学術集会
  • Place of Presentation: 広島市
• [Presentation] Identification of ATP1A3 mutations by exome sequencing as the cause of alternating hemiplegia of childhood in Japan (2013)
  • Author(s): Ishii A., Saito Y., Mitsui J., Ishiura H., Yoshimura J., Arai H., Yamashita S., Kimura S., Oguni H., Morishita S., Tsuji S., Sasaki M., Hirose S
  • Organizer: 30th International Epilepsy Congress
  • Place of Presentation: (国際学会・シンポジウム)
  • Year and Date: 2013-06-26
• [Presentation] 小児交互性片麻痺の病因遺伝子であるATP1A3の同定と現状について (2013)
  • Author(s): 石井敦士、佐々木征行、斎藤義朗、廣瀬伸一
  • Organizer: 第55回小児神経学会総会
  • Place of Presentation: 大分(国内学会・シンポジウム)
  • Year and Date: 2013-05-31
• [Presentation] 小児交互性片麻痺の責任遺伝子であるATP1A3の同定 (2013)
  • Author(s): 石井敦士、佐々木征行、廣瀬伸一
  • Organizer: 第474回日本小児科学会福岡地方会
  • Place of Presentation: (国内学会・シンポジウム)
  • Year and Date: 2013-04-13
• [Presentation] 小児交互性片麻痺の原因遺伝子を見つける意義とは、新学術「ゲノム支援」 (2013)
  • Author(s): 石井敦士
  • Organizer: 公開シンポジウム「次世代ゲノム科学の最前線」
  • Place of Presentation: 京都大学(国内学会・シンポジウム)
  • Year and Date: 2013-02-19
• [Presentation] Genetic analysis of Alternating Hemiplegia of Childhood (2012)
  • Author(s): Atsushi Ishii, Yoshiaki Saito, Masayuki Sasaki, Shinichi Hirose
  • Organizer: 10th European Congress of Epileptology
  • Place of Presentation: London
• [Presentation] Genetic analysis of PRRT2 for benign infantile epilepsy, infantile convulsions with choleoathetosis syndrome, and benign convulsions with mild gastroenteritis (2012)
  • Author(s): Atsushi Ishii, Sawa Yasumoto, Yukiko Ihara, Takahito Inoue, Takako Fujita, Noriko Nakamura, Masaharu Ohfu, Wang-Tso Lee, Sunao Kaneko, and Shinichi Hirose
  • Organizer: 2012 Korea Epilepsy Congress
  • Place of Presentation: Inchon
• [Presentation] Identification of ATP1A3 mutations by exome sequencing as the cause of AHC in Japanese patients. (2012)
  • Author(s): Atsushi Ishii
  • Organizer: Symposium ATP1A3 in Disease.
  • Place of Presentation: Belgium
  • Invited
• [Presentation] 遺伝子研究からのてんかんの分子病態の解明を目指して (2012)
  • Author(s): 石井 敦士
  • Organizer: 第22回遺伝医学セミナー
  • Place of Presentation: 大阪
  • Invited
• [Presentation] Identification of ATP1A3 mutations by exome sequencing as the cause of AHC in Japanese patients (2012)
  • Author(s): Ishii A.
  • Organizer: Symposium ATP1A3 in Disease
  • Place of Presentation: Brussels, Belgium(国際学会・シンポジウム)
  • Year and Date: 2012-12-11
• [Presentation] 小児交互性片麻痺の分子病態の解明 (2012)
  • Author(s): 石井敦士
  • Organizer: 24-7「脳形成異常を主とする発達期障害の病因・態と治療に関する研究」22-6「発達障害の診断および治療法開に関する臨床研究」班合同シンポジウム
  • Place of Presentation: 国立精神・神経医療研究センター(国内学会・シンポジウム)
  • Year and Date: 2012-11-24
• [Presentation] Genetic analysis of Alternating Hemiplegia of Childhood (2012)
  • Author(s): Ishii A., Saito Y., Sasaki M., Hirose S.
  • Organizer: 10th European Congress of Epileptology
  • Place of Presentation: London(国際学会・シンポジウム)
  • Year and Date: 2012-09-30
• [Presentation] 遺伝子研究からのてんかんの分子病態の解明を目指して (2012)
  • Author(s): 石井敦士
  • Organizer: 第22回遺伝医学セミナー
  • Place of Presentation: ホテル阪急エキスポパーク(国内学会・シンポジウム)
  • Year and Date: 2012-09-08
• [Presentation] Genetic analysis of PRRT2 for benign infantile epilepsy, infantile convulsions with choleoathetosis syndrome, and benign convulsions with mild gastroenteritis (2012)
  • Author(s): Ishii A., Yasumoto S., Ihara Y., Inoue T., Fujita T., Nakamura N., Ohfu M., Lee WT., Kaneko S., Hirose S.
  • Organizer: 2012 Korea Epilepsy Congress
  • Place of Presentation: Inchon(国際学会・シンポジウム)
  • Year and Date: 2012-06-08
• [Presentation] 小児交互性片麻痺の原因遺伝子を見つける意義とは
  • Author(s): 石井 敦士
  • Organizer: 新学術「ゲノム支援」公開シンポジウム「次世代ゲノム科学の最前線」
  • Place of Presentation: 京都
  • Invited