Faculty Profiles - TAKASHIMA Hiroshi

野崎章仁, 森未央子, 熊田知浩, 橋口昭大, 高嶋　博, 村山　圭, 藤井達哉 . SUCLA2関連ミトコンドリアDNA枯渇症候群の1例 . 脳と発達52 ( 5 ) 318 - 322 2020.9SUCLA2関連ミトコンドリアDNA枯渇症候群の1例

Hidaka Masaoki, Higashi Eiji, Uwatoko Takeshi, Uwatoko Kiku, Urashima Mayumi, Takashima Hiroshi, Watanabe Yoriko, Kitazono Takanari, Sugimori Hiroshi . Late-onset ornithine transcarbamylase deficiency: a rare cause of recurrent abnormal behavior in adults(和訳中) . Acute Medicine & Surgery7 ( 1 ) 1 of 4 - 4 of 4 2020.9Late-onset ornithine transcarbamylase deficiency: a rare cause of recurrent abnormal behavior in adults(和訳中)

Language：English Publisher：(一社)日本救急医学会

症例は34歳男性で、異常行動と嗜眠が突然出現し、入院となった。高アンモニア血症(108μmol/L)を認めた。臨床所見から焦点性てんかんと診断し、レベチラセタム治療を開始したところ、2日目に霧視を除いて症状は改善し、血清アンモニア濃度は正常化した。31日目に異常行動、嗜眠、高アンモニア血症(122μmol/L)が再び出現したため、再入院となった。鶏肉に対する不耐症と早世の家族歴から尿素サイクル異常症を疑い、33日目よりタンパク質制限食およびアルギニン治療を開始した。その結果、翌日に霧視を含めて症状は消失し、血清アンモニア濃度は正常化した。34日目よりフェニル酪酸ナトリウム治療を追加した。血清アミノ酸プロファイルから遅発型のオルニチントランスカルバミラーゼ(OTC)欠損症が示唆された。44日目に退院に至り、その後は再発を認めていない。OTC遺伝子にR40H(c.119G>A)変異が同定された。

Daisuke Kodama, Masakazu Tanaka, Toshio Matsuzaki, Kimiko Izumo, Nobuaki Nakano, Eiji Matsuura, Mineki Saito, Masahiro Nagai, Masahisa Horiuchi, Atae Utsunomiya, Hiroshi Takashima, Ryuji Kubota, Shuji Izumo . Inhibition of abl1 tyrosine kinase reduces htlv-1 proviral loads in peripheral blood mononuclear cells from patients with htlv-1-associated myelopathy/tropical spastic paraparesis . PLoS Neglected Tropical Diseases14 ( 7 ) 1 - 21 2020.7Inhibition of abl1 tyrosine kinase reduces htlv-1 proviral loads in peripheral blood mononuclear cells from patients with htlv-1-associated myelopathy/tropical spastic paraparesis

Publishing type：Research paper (scientific journal)

Publishing type：Research paper (scientific journal)

Daisuke Kodama, Masakazu Tanaka, Toshio Matsuzaki, Kimiko Izumo, Nobuaki Nakano, Eiji Matsuura, Mineki Saito, Masahiro Nagai, Masahisa Horiuchi, Atae Utsunomiya, Hiroshi Takashima, Ryuji Kubota, Shuji Izumo . Inhibition of ABL1 tyrosine kinase reduces HTLV-1 proviral loads in peripheral blood mononuclear cells from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis . PLOS NEGLECTED TROPICAL DISEASES14 ( 7 ) 2020.7Inhibition of ABL1 tyrosine kinase reduces HTLV-1 proviral loads in peripheral blood mononuclear cells from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Human T-cell leukemia virus type 1 (HTLV-1) causes incurable adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Patients with HAM/TSP have increased levels of HTLV-1-infected cells compared with asymptomatic HTLV-1 carriers. However, the roles of cellular genes in HTLV-1-infected CD4+ T cells await discovery. We performed microarray analysis of CD4+ T cells from HAM/TSP patients and found that theABL1is an important gene in HAM/TSP.ABL1is a known survival factor for T- and B-lymphocytes and is part of the fused gene (BCR-ABL) known to be responsible for chronic myelogenous leukemia (CML). ABL1 tyrosine kinase inhibitors (TKIs), including imatinib, nilotinib, and dasatinib, are used clinically for treating CML. To evaluate whetherABL1is indeed important for HAM/TSP, we investigated the effect of TKIs on HTLV-1-infected cells. We developed a propidium monoazide-HTLV-1 viability quantitative PCR assay, which distinguishes DNA from live cells and dead cells. Using this method, we were able to measure the HTLV-1 proviral load (PVL) in live cells alone when peripheral blood mononuclear cells (PBMCs) from HAM/TSP cases were treated with TKIs. Treating the PBMCs with nilotinib or dasatinib induced significant reductions in PVL (21.0% and 17.5%, respectively) in live cells. Furthermore,ABL1siRNA transfection reduced cell viability in HTLV-1-infected cell lines, but not in uninfected cell lines. A retrospective survey based on our clinical records found a rare case of HAM/TSP who also suffered from CML. The patient showed an 84.2% PVL reduction after CML treatment with imatinib. We conclude that inhibiting the ABL1 tyrosine kinase specifically reduced the PVL in PBMCs from patients with HAM/TSP, suggesting thatABL1is an important gene for the survival of HTLV-1-infected cells and that TKIs may be potential therapeutic agents for HAM/TSP.Author summary Human T-cell leukemia virus type 1 (HTLV-1) is integrated as a provirus in the genomic DNA mainly of CD4+ T cell population in the infected people. HTLV-1-infected CD4+ T cells are transmitted via breast milk, semen, and blood transfusions. HTLV-1 is endemic in Japan, the Middle East, Africa, Caribbean islands, and Central and South America. A small proportion of infected people develop adult T-cell leukemia, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and other diseases. HAM/TSP, a chronic neuroinflammatory disorder, is characterized by spastic paraparesis and urinary disturbance. HTLV-1-infected CD4+ T cells infiltrate the spinal cord and cause inflammation, which results in such neurological symptoms. We have identified the tyrosine kinase geneABL1as a gene frequently found in the signal transduction pathways in HTLV-1-infected CD4+ T cells. Therefore,ABL1appears to be important in the pathogenesis of HAM/TSP. Inhibiting ABL1 with tyrosine kinase inhibitors (TKIs), which is used for chronic myelogenous leukemia (CML), reduced the proviral load (PVL)in vitro. We found a rare case of a patient with HAM/TSP and CML by our clinical records, who showed a decrease in PVL after TKI treatment for CML. Hence, TKIs are potential therapeutic agents for HAM/TSP.

Web of Science

Daisuke Kodama, Masakazu Tanaka, Toshio Matsuzaki, Kimiko Izumo, Nobuaki Nakano, Eiji Matsuura, Mineki Saito, Masahiro Nagai, Masahisa Horiuchi, Atae Utsunomiya, Hiroshi Takashima, Ryuji Kubota, Shuji Izumo . Inhibition of ABL1 tyrosine kinase reduces HTLV-1 proviral loads in peripheral blood mononuclear cells from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis. . PLoS neglected tropical diseases14 ( 7 ) e0008361 2020.7Inhibition of ABL1 tyrosine kinase reduces HTLV-1 proviral loads in peripheral blood mononuclear cells from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis.International journal

Language：English Publishing type：Research paper (scientific journal)

Kodama D, Tanaka M, Matsuzaki T, Izumo K, Nakano N, Matsuura E, Saito M, Nagai M, Horiuchi M, Utsunomiya A, Takashima H, Kubota R, Izumo S . Inhibition of ABL1 tyrosine kinase reduces HTLV-1 proviral loads in peripheral blood mononuclear cells from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis. . PLoS neglected tropical diseases14 ( 7 ) e0008361 2020.7Inhibition of ABL1 tyrosine kinase reduces HTLV-1 proviral loads in peripheral blood mononuclear cells from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis.

橋口昭大, 吉村明子, 安藤匡宏, 樋口雄二郎, 中村友紀, 岡本裕嗣, 松浦英治, 高嶋　博 . GARS変異による遺伝性末梢神経障害7例の臨床的特徴 . 末梢神経31 ( 1 ) 98 - 104 2020.6GARS変異による遺伝性末梢神経障害7例の臨床的特徴

菊池晃, 岡本裕嗣, 橋口裕, 吉重幸一, 谷口雄大, 出口尚寿, 高嶋博, 西尾善彦 . 認知機能低下を契機に発見されたミトコンドリア糖尿病の1例 . 糖尿病63 ( 5 ) 344 - 349 2020.5認知機能低下を契機に発見されたミトコンドリア糖尿病の1例

Ishihara S, Okamoto Y, Tanabe H, Yoshimura A, Higuchi Y, Yuan JH, Hashiguchi A, Ishiura H, Mitsui J, Suwazono S, Oya Y, Sasaki M, Nakagawa M, Tsuji S, Ohya Y, Takashima H. . Clinical Features of Inherited Neuropathy With BSCL2 Mutations in Japan . J Peripher Nerv Syst. 2020.2Clinical Features of Inherited Neuropathy With BSCL2 Mutations in Japan Reviewed

Hosokawa S, Kubo Y, Arakawa R, Takashima H, Saito K. . Analysis of Spinal Muscular Atrophy-Like Patients by Targeted Resequencing . Brain Dev. 42 ( 2 ) 148 - 156 2020.2Analysis of Spinal Muscular Atrophy-Like Patients by Targeted Resequencing Reviewed

Hosokawa Shinichi, Kubo Yuji, Arakawa Reiko, Takashima Hiroshi, Saito Kayoko . 脊髄性筋萎縮症によく似た所見を呈する患者を対象としたターゲットリシケーンシング法による解析(Analysis of spinal muscular atrophy-like patients by targeted resequencing) . Brain & Development42 ( 2 ) 148 - 156 2020.2脊髄性筋萎縮症によく似た所見を呈する患者を対象としたターゲットリシケーンシング法による解析(Analysis of spinal muscular atrophy-like patients by targeted resequencing)

Publisher：エルゼビア・ジャパン(株)

下位運動ニューロン症状がみられ、当初は脊髄性筋萎縮症が疑われたが診断がつかなかった患者を分子診断するため、次世代シーケンス解析(NGS)と従来式のシーケンス解析を適用した。2005〜2016年に当施設を受診した上記患者のうち、最終的に8家系に属する12名を対象に、NGSを利用したターゲットリシケーンシング解析を施行した。検出された遺伝子変異体を文献検索とデータベースに基づいて選別し、病原性変異体の候補となったものについてはSanger法によるシーケンス解析にて検証した。その結果、2家系に属する患者3名から新規変異体を発見した。患者1と2は共に6歳の男児で双生児であり、TTN遺伝子の2種の変異体を有する複合ヘテロ接合体(c.6621delG, p.W2207Cfs*28およびc.23718T>A, p.F7906L)であった。患者3はKIF1A遺伝子変異体の複合ヘテロ接合体(c.3871C>T, p.R1291Cおよびc.3898G>A,p.V1300M)であった。このように未診断患者3名において新規原因遺伝子の発見に成功したことから、本アプローチは有効であることが示された。

Hosokawa S. . Analysis of spinal muscular atrophy-like patients by targeted resequencing . Brain and Development42 ( 2 ) 148 - 156 2020.2Reviewed International journal

Hidaka M, Higashi E, Uwatoko T, Uwatoko K, Urashima M, Takashima H, Watanabe Y, Kitazono T, Sugimori H . Late-onset ornithine transcarbamylase deficiency: a rare cause of recurrent abnormal behavior in adults. . Acute medicine & surgery7 ( 1 ) e565 2020.1Late-onset ornithine transcarbamylase deficiency: a rare cause of recurrent abnormal behavior in adults.

Sawada Jun, Katayama Takayuki, Tokashiki Takashi, Kikuchi Shiori, Kano Kohei, Takahashi Kae, Saito Tsukasa, Adachi Yoshiki, Okamoto Yuji, Yoshimura Akiko, Takashima Hiroshi, Hasebe Naoyuki . 一卵性双生児における脊髄小脳失調症8型の初の症例(The First Case of Spinocerebellar Ataxia Type 8 in Monozygotic Twins) . Internal Medicine59 ( 2 ) 277 - 283 2020.1一卵性双生児における脊髄小脳失調症8型の初の症例(The First Case of Spinocerebellar Ataxia Type 8 in Monozygotic Twins)

Publisher：(一社)日本内科学会

症例1は女性で、26歳時によろめき歩行、発話および嚥下障害が出現して徐々に悪化し、32歳時に来院した。症例2は症例1の一卵性双生児の姉。25歳時によろめき歩行が出現し、31歳時に来院した。両症例ともに眼振、構語障害、四肢および体幹の運動失調を認め、脳MRIで小脳萎縮が判明した。母方の祖父と叔父、症例2の次男でも眼振が認められた。遺伝子検査では、両症例ともにアタキシン8逆鎖(ATXN8OS)CTA/CTG反復が25/97であり、脊髄小脳失調症8型と診断した。タルチレリン水和物による治療を行ったが、失調症は徐々に悪化した。本症例は、ATXN8OS遺伝子反復伸長を認めた一卵性双生児についての初の報告であった。

Nozaki Fumihito, Mori Mioko, Kumada Tomohiro, Hashiguchi Akihiro, Takashima Hiroshi, Murayama Kei, Fujii Tatsuya . A rare case of SUCLA2-related mitochondrial DNA depletion syndrome . NO TO HATTATSU52 ( 5 ) 318 - 322 2020Reviewed

Language：Japanese Publisher：The Japanese Society of Child Neurology

SUCLA2-related mitochondrial DNA depletion syndrome is known as Leigh syndrome with methylmalonic aciduria. The patient was a 12-year-old girl with non-consanguineous parents. The clinical features included psychomotor retardation, hypotonia, sensorineural hearing impairment, feeding difficulty, growth retardation, muscular atrophy, external ophthalmoplegia, blepharoptosis, gastroesophageal reflux, recurrent vomiting, sagittal craniosynostosis, peripheral axonal neuropathy, restrictive respiratory failure and kyphoscoliosis. Lactate levels in blood and cerebrospinal fluid were elevated at 8 months of age, and brain MRI showed cerebral atrophy. The MRI at 2 years of age revealed hyperintense areas in the bilateral basal ganglia on T2-weighted imaging. Therefore, the patient was diagnosed with Leigh syndrome. Although the serum acylcarnitine profile revealed slightly elevated propionylcarnitine, urine organic acid analysis was decided as normal. At 9 years of age, exome sequencing for the research of peripheral neuropathy revealed novel compound heterozygous variants, NM_003850.2 (SUCLA2) : c.1300del (p.Asp434Metfs＊8) ＋c.664-1G＞A. Her parents were heterozygous of each variant. A second analysis of urine organic acid showed mildly elevated methylmalonic acid. Muscle biopsy revealed that the activities of complexes Ⅰ and Ⅳ were at the lower limit of the normal range. Thus, the patient was diagnosed with SUCLA2-related mitochondrial DNA depletion syndrome. It is important to pay attention to elevated serum propionylcarnitine and mildly elevated urinary methylmalonic acid levels in patients with mitochondrial diseases.

DOI： 10.11251/ojjscn.52.318