Interface of neural activity, immunity and metabolism in acute encephalopathy

• Project/Area Number: 15H04872
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: The University of Tokyo
• Principal Investigator: MIZUGUCHI Masashi 東京大学, 大学院医学系研究科(医学部), 教授 (20209753)
• Co-Investigator(Kenkyū-buntansha): 高梨 潤一 東京女子医科大学, 医学部, 教授 (00302555) ; 齋藤 真木子 東京大学, 医学部附属病院, 特任助教 (20225733)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2017: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2016: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2015: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: 急性脳症 / 急性壊死性脳症 / けいれん重積型（二相性）急性脳症 / イオンチャネル / 自然免疫 / ミトコンドリア / けいれん重積型急性脳症 / 脳梁膨大部脳症 / サイトカイン / ヒト白血球抗原 / ミトコンドリア代謝 / 血液脳関門

Outline of Final Research Achievements

To explore abnormal intracellular signal transduction in acute encephalopathy including acute necrotizing encephalopathy (ANE) and acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), we conducted gene and functional analyses of factors associated with the crosstalk between neural activity, immunity and metabolism. We identified cytokine and HLA polymorphisms as genetic predisposition in Japanese patients with sporadic ANE. We elucidated the association of RANBP2, the causative gene of familial ANE in Caucasians, with mitochondrial metabolism. We identified a polymorphism of CTLA4, a suppressor of innate immunity, as a risk factor for AESD. We also found the association of mutations of sodium channels, SCN1A and SCN2A, with multiple syndromes, and that of thermolabile variation of a mitochondrial enzyme, CPT2, with overall acute encephalopathy.

Academic Significance and Societal Importance of the Research Achievements

急性脳症の多因子疾患としての本質が解明され、免疫、神経、代謝の全てが関連する複雑な病態の理解が進んだ。遺伝的背景の解明により、急性脳症の遺伝相談の道が開かれるとともに、自然免疫、神経興奮、エネルギー代謝に関わる新しい治療の標的分子が見つかった。

Research Products

• [Journal Article] Acute necrotizing encephalopathy and a carnitine palmitoyltransferase 2 variant in an adult. (2019)
  • Author(s): Kobayashi Y, Kanazawa H, Hoshino A, Takamatsu R, Watanabe R, Hoshi K, Ishii W, Yahikozawa H, Mizuguchi M, Sato S.
  • Journal Title: Journal of clinical neuroscience Volume: 61 Pages: 264-266
  • DOI: 10.1016/j.jocn.2018.11.045
  • Peer Reviewed
• [Journal Article] MYRF is associated with encephalopathy with reversible myelin vacuolization (2018)
  • Author(s): Kurahashi Hirokazu、Azuma Yoshiteru、Masuda Akio、Okuno Tatsuya、Nakahara Eri、Imamura Takuji、Saitoh Makiko、Mizuguchi Masashi、Shimizu Toshiaki、Ohno Kinji、Okumura Akihisa
  • Journal Title: Annals of Neurology Volume: 83 Issue: 1 Pages: 98-106
  • DOI: 10.1002/ana.25125
  • Peer Reviewed / Open Access
• [Journal Article] Brain edema with clasmatodendrosis complicating ataxia telangiectasia (2017)
  • Author(s): Shimoda Konomi、Mimaki Masakazu、Fujino Shuhei、Takeuchi Masato、Hino Rumi、Uozaki Hiroshi、Hayashi Masaharu、Oka Akira、Mizuguchi Masashi
  • Journal Title: Brain and Development Volume: 39 Issue: 7 Pages: 629
  • DOI: 10.1016/j.braindev.2017.02.007
  • URL: https://pure.teikyo.jp/en/publications/0d5531f8-7cb2-424f-ab9e-b42e166de0ca
  • Peer Reviewed
• [Journal Article] けいれん重積型（二相性）急性脳症の病因・病態 (2017)
  • Author(s): 齋藤真木子, 水口雅
  • Journal Title: Neuroinfection Volume: 22 Pages: 51-56
• [Journal Article] A Single Vaccination of Nonhuman Primates with Highly Attenuated Smallpox Vaccine, LC16m8, Provides Long-term Protection against Monkeypox (2017)
  • Author(s): Nishimura N, Higuchi Y, Kimura N, Nozaki F, Kumada T, Hoshino A, Saitoh M, Mizuguchi M.
  • Journal Title: Japanese Journal of Infectious Diseases Volume: 70 Issue: 4 Pages: 408-415
  • DOI: 10.7883/yoken.JJID.2016.417
  • NAID: 130005851920
  • ISSN: 1344-6304, 1884-2836
  • Peer Reviewed
• [Journal Article] Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy. (2016)
  • Author(s): Abe Y, Sakai T, Okumura A, Akaboshi S, Fukuda M, Haginoya K, Hamano SI, Hirano K, Kikuchi K, Kubota M, Lee S, Maegaki Y, Sanefuji M, Shimozato S, Suzuki M, Suzuki Y, Takahashi M, Watanabe K, Mizuguchi M, Yamanouchi H.
  • Journal Title: Brain and Development Volume: 38 Issue: 7 Pages: 638-647
  • DOI: 10.1016/j.braindev.2016.01.007
  • Peer Reviewed
• [Journal Article] <b>Prevalence of low-penetrant germline </b><i><b>TP53</b></i><b> D49H mutation in Japanese cancer </b><b>patients </b> (2016)
  • Author(s): Yamaguchi Y, Torisu H, Kira R, Ishizaki Y, Sakai Y, Sanefuji M, Ichiyama T, Oka A, Kishi T, Kimura S, Kubota M, Takanashi J, Takahashi Y, Tamai H, Natsume J, Hamano S, Hirabayashi S, Maegaki Y, Mizuguchi M, Minagawa K, Yoshikawa H, Kira J, Kusunoki S, Hara T.
  • Journal Title: Biomedical Research Volume: 37 Issue: 4 Pages: 259-264
  • DOI: 10.2220/biomedres.37.259
  • NAID: 130005405218
  • ISSN: 0388-6107, 1880-313X
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Specific HLA genotypes confer susceptibility to acute necrotizing encephalopathy (2016)
  • Author(s): Hoshino A, Saitoh M, Miyagawa T, Kubota M, Takanashi JI, Miyamoto A, Tokunaga K, Oka A, Mizuguchi M
  • Journal Title: Genes and Immunity Volume: 17(6) Issue: 6 Pages: 367-369
  • DOI: 10.1038/gene.2016.32
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Cytokine-related and sodium channel polymorphism as candidate predisposing factors for childhood encephalopathy FIRES/AERRPS (2016)
  • Author(s): Saitoh, M., Kobayashi, K., Ohmori, I., Tanaka, Y., Tanaka, K., Inoue, T., Horino, A., Ohmura, K., Kumakura, A., Takei, Y., Hirabayashi, S., Kajimoto, M., Uchida, T., Yamazaki, S., Shiihara, T., Kumagai, T., Kasai, M., Terashima, H., Kubota, M., Mizuguchi, M.
  • Journal Title: Journal of the Neurological Sciences Volume: 368 Pages: 272-276
  • DOI: 10.1016/j.jns.2016.07.040
  • Peer Reviewed
• [Journal Article] Clinical and genetic features of acute encephalopathy in children taking theophylline. (2015)
  • Author(s): Saitoh M, Shinohara M, Ishii A, Ihara Y, Hirose S, Shiomi M, Kawawaki H, Kubota M, Yamagata T, Miyamoto A, Yamanaka G, Amemiya K, Kikuchi K, Kamei A, Akasaka M, Anzai Y, Mizuguchi M.
  • Journal Title: Brain Dev Volume: 37 Issue: 5 Pages: 463-70
  • DOI: 10.1016/j.braindev.2014.07.010
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A case of recurrent encephalopathy with SCN2A missense mutation. (2015)
  • Author(s): Fukasawa T, Kubota T, Negoro T, Saitoh M, Mizuguchi M, Ihara Y, Ishii A, Hirose S.
  • Journal Title: Brain Dev Volume: 37(6) Issue: 6 Pages: 631-4
  • DOI: 10.1016/j.braindev.2014.10.001
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Missense mutations in sodium channel SCN1A and SCN2A predispose children to encephalopathy with severe febrile seizures. (2015)
  • Author(s): Saitoh M, Ishii A, Ihara Y, Hoshino A, Terashima H, Kubota M, Kikuchi K, Yamanaka G, Amemiya K, Hirose S, Mizuguchi M.
  • Journal Title: Epilepsy Res Volume: 117. Pages: 1-6
  • DOI: 10.1016/j.eplepsyres.2015.08.001
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Disrupted glutamate-glutamine cycle in acute encephalopathy with biphasic seizures and late reduced diffusion. (2015)
  • Author(s): Takanashi JI, Mizuguchi M, Terai M, Barkovich AJ.
  • Journal Title: Neuroradiology Volume: 57 Issue: 11 Pages: 1163-1168
  • DOI: 10.1007/s00234-015-1573-x
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Predictive score for early diagnosis of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD). (2015)
  • Author(s): Tada H, Takanashi J, Okuno H, Kubota M, Yamagata T, Kawano G, Shiihara T, Hamano S, Hirose S, Hayashi T, Osaka H, Mizuguchi M.
  • Journal Title: NEUROL SCI. Volume: 358(1-2) Issue: 1-2 Pages: 62-5
  • DOI: 10.1016/j.jns.2015.08.016
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 横紋筋融解症を来したToxic shock syndrome (2015)
  • Author(s): 加藤昭生, 野田雅裕, 小林匠, 大場邦弘, 小鍛冶雅之, 黒田誠, 齋藤真木子, 水口雅, 阿部淳.
  • Journal Title: 日本小児科学会雑誌 Volume: 119 Pages: 1391-1396
  • Peer Reviewed
• [Journal Article] 病態と輸液・栄養管理―脳炎・脳症・髄膜炎 (2015)
  • Author(s): 水口雅.
  • Journal Title: 小児科診療 Volume: 78 Pages: 771-774
• [Presentation] 急性脳症overview 最新の疫学調査を踏まえて (2018)
  • Author(s): 水口雅
  • Organizer: 第60回日本小児神経学会学術集会
  • Invited
• [Presentation] けいれん重積型急性脳症におけるKCNQ2遺伝子の解析 (2018)
  • Author(s): 柴田明子, 齋藤真木子, 松本浩, 山崎佐和子, 星野愛, 石井敦士, 廣瀬伸一, 岡明, 水口雅
  • Organizer: 第60回日本小児神経学会学術集会
• [Presentation] 急性壊死性脳症における遺伝的素因―HLA及びTLR3遺伝子解析― (2017)
  • Author(s): 星野愛, 齋藤真木子, 西山里美, 久保田雅也, 高梨潤一,宮本晶恵, 岡明, 水口雅
  • Organizer: 第120回日本小児科学会学術集会
• [Presentation] Analysis of RANBP2 gene variants in acute necrotizing encephalopathy. (2017)
  • Author(s): Saitoh M, Hoshino A, Nishiyama S, Anzai Y, Kubota M, Takanshi J-I, Oka A, Mizuguchi M
  • Organizer: 14th Asian and Oceanian Congress of Child Neurology
  • Int'l Joint Research
• [Presentation] Association of COX gene polymorphism with acute necrotizing encephalopahy. (2017)
  • Author(s): Hoshino A, Saitoh M, Kubota M, Takanshi J-I, Oka A, Mizuguchi M.
  • Organizer: 14th Asian and Oceanian Congress of Child Neurology
  • Int'l Joint Research
• [Presentation] Six cases of mild acute encephalitis/encephalopathy showing paradoxical arousal responses in the electroencephalogram. (2017)
  • Author(s): Terashima H, Anzai M, Kumagai T, Takenaka S, Kasai M, Watanabe Y, Saito M, Mizuguchi M, Kubota M.
  • Organizer: 14th Asian and Oceanian Congress of Child Neurology
  • Int'l Joint Research
• [Presentation] Recent acvances in the research of acute encephalopathy. (2017)
  • Author(s): Mizuguchi M, Hishino A, Saitoh S.
  • Organizer: 14th Asian and Oceanian Congress of Child Neurology
  • Int'l Joint Research / Invited
• [Presentation] NLRP3 polymorphism and risk of acute encephalopathy with status epilepticus. (2017)
  • Author(s): Saitoh M, Hoshino A, Kikuchi K, Yamanaka G, Kubota M, Takanashi J, Goto T, Oka A, Mizuguchi M.
  • Organizer: 第59回日本小児神経学会学術集会
• [Presentation] 急性脳症の診断と治療～小児急性脳症診療ガイドラインから～ (2017)
  • Author(s): 水口雅.
  • Organizer: 第217回大阪小児科学会
  • Invited
• [Presentation] 急性壊死性脳症における遺伝的リスクファクター (2017)
  • Author(s): 星野愛, 齋藤真木子,久保田雅也 高梨潤一, 岡明, 水口雅.
  • Organizer: 第121回日本小児科学会学術集会会
• [Presentation] ロタウイルスワクチン２回接種後にロタウイルスとノロウイルスの混合感染により死亡した１例 (2017)
  • Author(s): 林優佳, 白神一博, 浦田晋, 朝海廣子, 進藤考洋, 犬塚亮, 平田洋一郎, 高梨さやか, 水口雅, 岡明
  • Organizer: 第644回日本小児科学会東京都地方会講和会
• [Presentation] Complications of influenza: Neurological complications. (2016)
  • Author(s): Mizuguchi M.
  • Organizer: Options IX for the Control of Influenza.
  • Place of Presentation: Chicago (USA)
  • Year and Date: 2016-08-24
  • Int'l Joint Research / Invited
• [Presentation] Definition, classification and epidemiology of acute encephalopathy. (2016)
  • Author(s): Mizuguchi M, Hoshino A, Saitoh M.
  • Organizer: The 18th annual meeting of Infantile Seizure Society. International symposium on acute encephalopathy in infancy and its related disorders.
  • Place of Presentation: 一橋講堂（東京都千代田区）
  • Year and Date: 2016-07-01
  • Int'l Joint Research / Invited
• [Presentation] Genetic predisposition to acute encephalopathy with status epilepsticus. (2016)
  • Author(s): Saitoh M, Hoshino A, Ishii A, Ihara Y, Hirose S, Mizuguchi M.
  • Organizer: The 18th annual meeting of Infantile Seizure Society. International symposium on acute encephalopathy in infancy and its related disorders.
  • Place of Presentation: 一橋講堂（東京都千代田区）
  • Year and Date: 2016-07-01
  • Int'l Joint Research
• [Presentation] Gene polymorphisms confer susceptibility to acute necrotizing encephalopathy. (2016)
  • Author(s): Hoshino A, Saitoh M, Kubota M, Takanashi J-i, Oka A, Mizuguchi M.
  • Organizer: The 18th annual meeting of Infantile Seizure Society. International symposium on acute encephalopathy in infancy and its related disorders.
  • Place of Presentation: 一橋講堂（東京都千代田区）
  • Year and Date: 2016-07-01
  • Int'l Joint Research
• [Presentation] Acute necrotizing encephalopathy: Clinical, pathologic and genetic studies. (2016)
  • Author(s): Mizuguchi M, Hoshino A, Saitoh M.
  • Organizer: The 18th annual meeting of Infantile Seizure Society. International symposium on acute encephalopathy in infancy and its related disorders.
  • Place of Presentation: 一橋講堂（東京都千代田区）
  • Year and Date: 2016-07-01
  • Int'l Joint Research / Invited
• [Presentation] Biochemical and genetic prognostic factors in acute encephalopathy with biphasic seizures and late reduced diffusion. (2016)
  • Author(s): Matsumoto H, Zaha K, Nakamura Y, Saitoh M, Mizuguchi M, Nonoyama S.
  • Organizer: The 18th annual meeting of Infantile Seizure Society. International symposium on acute encephalopathy in infancy and its related disorders.
  • Place of Presentation: 一橋講堂（東京都千代田区）
  • Year and Date: 2016-07-01
  • Int'l Joint Research
• [Presentation] 小児のウイルス感染症と意識障害 (2016)
  • Author(s): 水口雅
  • Organizer: 第55回日本臨床ウイルス学会
  • Place of Presentation: ロイトン札幌（北海道札幌市）
  • Year and Date: 2016-06-14
  • Invited
• [Presentation] 急性脳症―小児神経学会によるガイドラインの策定：急性脳症―疫学と診療の現状―. (2016)
  • Author(s): 水口雅
  • Organizer: 第58回日本小児神経学会学術集会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-06-03
  • Invited
• [Presentation] 覚醒障害を主徴とする軽症急性脳症６症例の検討. (2016)
  • Author(s): 寺嶋宙, 熊谷淳之, 竹中暁, 安西真衣, 葛西真梨子, 渡邉優, 齋藤真木子, 水口雅, 久保田雅也.
  • Organizer: 第58回日本小児神経学会学術集会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-06-03
• [Presentation] Polymorphism of cytokine-related and sodium channel genes in AERRPS. (2016)
  • Author(s): Saitoh M, Kobayashi K, Hoshino A, Mizuguchi M.
  • Organizer: 第58回日本小児神経学会学術集会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-06-03
• [Presentation] けいれん重積型急性脳症と熱性けいれんのCTL4遺伝子多型の比較. (2016)
  • Author(s): 齋藤真木子, 星野愛, 石井敦士, 井原由紀子, 廣瀬伸一, 水口雅
  • Organizer: 第119回日本小児科学会学術集会会
  • Place of Presentation: ロイトン札幌（北海道札幌市）
  • Year and Date: 2016-05-13
• [Presentation] 結節性硬化症を基礎疾患として有する急性脳症の２例. (2016)
  • Author(s): 上田有里子, 下田木の実, 葛西真梨子, 竹中暁, 太田さやか, 佐藤敦志, 水口雅, 岡明.
  • Organizer: 第65回日本小児神経学会関東地方会
  • Place of Presentation: 千葉大学医学部附属病院（千葉県千葉市）
• [Presentation] サルモネラ腸炎を契機に発症した可逆性脳梁膨大部病変を有する急性脳症(MERS)の１例 (2015)
  • Author(s): 大森紹玄, 葛西真梨子, 遠山聡, 太田さやか, 水野葉子, 下田木の実, 佐藤敦志, 梅原真帆, 清原鋼二, 高橋尚人, 水口雅, 岡明
  • Organizer: 第623回日本小児科学会東京都地方会講話会
  • Place of Presentation: 飯田橋レインボービル（東京都新宿区）
  • Year and Date: 2015-12-12
• [Presentation] Acute encephalopathy associated with viral infections of infancy and childhood. (2015)
  • Author(s): Mizuguchi, M
  • Organizer: The 15th Annual Meeting of Asian & Oceanic Society of Pediatric Radiology/ The 51st Annual Meeting of Japanese Society of Pediatric Radiology
  • Place of Presentation: グランドホール品川（東京都港区）
  • Year and Date: 2015-06-11
  • Int'l Joint Research / Invited
• [Presentation] Cytokine genes and risk of acute encephalopathy with status epilepticus. (2015)
  • Author(s): Saitoh M, Kou S, Hoshino A, Kikuchi K, Yamanaka G, Kuobta M, Takanashi J, Goto T, Mizuguchi M
  • Organizer: 第57回日本小児神経学会学術集会
  • Place of Presentation: 帝国ホテル大阪（大阪市北区）
  • Year and Date: 2015-05-28
• [Presentation] HHE症候群の遺伝的素因. (2015)
  • Author(s): 齋藤真木子, 星野愛, 菊池健二郎, 山中岳, 久保田雅也, 石井敦士, 井原由紀子, 廣瀬伸一, 水口雅
  • Organizer: 第118回日本小児科学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪市北区）
  • Year and Date: 2015-04-17
• [Presentation] 当院における急性脳症10例における遺伝子解析と神経学的予後 (2015)
  • Author(s): 松本浩, 座波清誉, 中村康子, 斉藤真木子, 水口雅, 野々山恵章
  • Organizer: 第118回日本小児科学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪市北区）
  • Year and Date: 2015-04-17
• [Presentation] 日本人急性壊死性脳症におけるRANBP2遺伝子解析. (2015)
  • Author(s): 星野愛, 齋藤真木子, 安西有紀, 久保田雅也, 高梨潤一, 岡明, 水口雅
  • Organizer: 第118回日本小児科学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪市北区）
  • Year and Date: 2015-04-17
• [Book] Acute encephalopathy and encephalitis in infancy and its related disorders. (2018)
  • Author(s): Yamanouchi H, Moshe SL, Okumura A
  • Total Pages: 244
  • Publisher: Elsevier
  • ISBN: 9780323530880
• [Book] 小児急性脳症診療ガイドライン2016 (2016)
  • Author(s): 小児急性脳症診療ガイドライン策定委員会（編）
  • Total Pages: 129
  • Publisher: 診断と治療社
• [Book] 今日の診断指針, 第７版 (2015)
  • Author(s): 水口雅
  • Total Pages: 2103
  • Publisher: 医学書院
• [Book] 臨床てんかん学 (2015)
  • Author(s): 水口雅
  • Total Pages: 671
  • Publisher: 医学書院
• [Remarks] 東京大学発達医科学HP
  • URL: http://www.development.m.u-tokyo.ac.jp
• [Remarks] 東京大学発達医科学HP
  • URL: http://www.development.m.u-tokyo.ac.jp/