Study of diversity in organic and fatty acid disorders in Asia

• Project/Area Number: 19K08347
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Shimane University
• Principal Investigator: Yamaguchi Seiji 島根大学, 学術研究院医学・看護学系, 客員教授 (60144044)
• Co-Investigator(Kenkyū-buntansha): 竹谷 健 島根大学, 学術研究院医学・看護学系, 教授 (30359880)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 新生児マススクリーニング / タンデムマス / 有機酸代謝異常症 / 脂肪酸代謝異常症 / 障害予防 / 疫学調査 / アジア / 国際協力 / 国際比較 / 対象疾患 / アジア諸国 / 疾患頻度 / 疾患発見頻度 / 遺伝疫学 / ハイリスクスクリーニング / アミノ酸血症 / 有機酸血症 / タンデムマス法 / 疾患多様性

Outline of Research at the Start

有機酸・脂肪酸代謝異常症は、ふだんは無症状で感染などを契機に急性発症して後遺症を残したり、乳幼児突然死する症例が少なくない。最近タンデムマス法などの質量分析技術によって簡単に診断できるようになり、アジア諸国でもこの領域の疾患への関心が高まっている。
一方、この領域の疾患の頻度は稀少疾患であり、病態解明、治療法向上のためには国際協力が不可欠である。将来のアジア諸国との共同研究を目的として、国ごとの疾患種類、頻度、重症度、遺伝背景の多様性を明らかにする。そして必要に応じて、質量分析による生化学診断、遺伝子解析等を提供しながら、各国の情報を収集して、国際協力体制の構築に貢献する。

Outline of Final Research Achievements

Newborn screening (NBS) has been recently becoming popular in Asian countries. A questionnaire survey was conducted to obtain information on inherited metabolic diseases of organic acid and fatty acid, detected by the tandem mass screening (TMS). In Japan, Korea, China, Taiwan, Philippines, Vietnam, Singapore and Thai, countries for which information was available, the country-specific high-frequency disorders included propionic acidemia (Japan), methylmalonic acidemia (China), MSUD (Philippines), MCAD deficiency (Philippines, Singapore and Japan) and 3-ketothiolase deficiency (Vietnam), each with ethnic-specific high frequency genetic variants.
Future widespread of TMS screening would reveal accurate disease incidence in each country and genetic epidemiological information, which would be useful for the international cooperation.

Academic Significance and Societal Importance of the Research Achievements

タンデムマス法（TMS）による新生児スクリーニングで発見される有機酸・脂肪酸代謝異常症の頻度は、欧米とアジア諸国では異なるといわれてきた。今回のアジア諸国の調査を通じて、東アジア諸国の中だけでも疾患頻度は異なり遺伝的多様性のあることが示された。
日本ではプロピオン酸血症の頻度が高く軽症型が多く、日本人固有の高頻度遺伝子変異がある。同様に中国のメチルマロン酸血症、フィリピンのMSUD、ベトナムの３-ケトチオラーゼ欠損症なども民族固有の高頻度遺伝子変異があり、他の国に比べて突出して高頻度である。TMSの普及に伴い各国での正確な頻度、遺伝疫学的多様性が明らかになり、病因病態研究、国際協力に貢献する。

Research Products

• [Journal Article] ：わが国のタンデムマス・スクリーニングの現状と課題 (2023)
  • Author(s): 山口清次
  • Journal Title: 特殊ミルク情報 Volume: 58 Pages: 59-64
• [Journal Article] The frequencies of very long-chain acyl-CoA dehydrogenase deficiency genetic variants in Japan have changed since the implementation of expanded newborn screening (2022)
  • Author(s): Osawa Yoshimitsu、Kobayashi Hironori、Tajima Go、Hara Keiichi、Yamada Kenji、Fukuda Seiji、Hasegawa Yuki、Aisaki Junko、Yuasa Miori、Hata Ikue、Okada Satoshi、Shigematsu Yosuke、Sasai Hideo、Fukao Toshiyuki、Takizawa Takumi、Yamaguchi Seiji、Taketani Takeshi
  • Journal Title: Molecular Genetics and Metabolism Volume: 136 Issue: 1 Pages: 74-79
  • DOI: 10.1016/j.ymgme.2022.03.009
  • Peer Reviewed / Open Access
• [Journal Article] A Simple Flow Injection Analysis-Tandem Mass Spectrometry Method to Reduce False Positives of C5-Acylcarnitines Due to Pivaloylcarnitine Using Reference Ions (2022)
  • Author(s): Takanari Hattori, Yoshitomo Notsu, Misa Tanaka, Miki Matsui, Tetsuo Iida, Jun Watanabe, Yoshimitsu Osawa, Seiji Yamaguchi, Shozo Yano, Takeshi Taketani, Hironori Kobayashi
  • Journal Title: Children Volume: 9 Issue: 5 Pages: 694-694
  • DOI: 10.3390/children9050694
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and molecular investigation of 37 Japanese patients with multiple acyl-CoA dehydrogenase deficiency: p.Y507D in ETFDH, a common Japanese variant, causes a mortal phenotype (2022)
  • Author(s): Yamada Kenji、Osawa Yoshimitsu、Kobayashi Hironori、Bo Ryosuke、Mushimoto Yuichi、Hasegawa Yuki、Yamaguchi Seiji、Taketani Takeshi
  • Journal Title: Molecular Genetics and Metabolism Reports Volume: 33 Pages: 100940-100940
  • DOI: 10.1016/j.ymgmr.2022.100940
  • Peer Reviewed / Open Access
• [Journal Article] Long-Term Neurological Outcomes of Adult Patients with Phenylketonuria before and after Newborn Screening in Japan (2021)
  • Author(s): Yamada Kenji、Yamaguchi Seiji、Yokoyama Kazunori、Aoki Kikumaro、Taketani Takeshi
  • Journal Title: International Journal of Neonatal Screening Volume: 7 Issue: 2 Pages: 21-21
  • DOI: 10.3390/ijns7020021
  • Peer Reviewed / Open Access
• [Journal Article] Glycosaminoglycans as biomarkers for mucopolysaccha-ridoses and other disorders (2021)
  • Author(s): Paige C. Amendum PC, Khan S, Yamaguchi S, Kobayashi H, Ago Y, Suzuki Y, Celik B, Rintz E, Hossain J, Xiao W, Tomatsu S
  • Journal Title: Diagnosis Volume: 11 Issue: 9 Pages: 1-18
  • DOI: 10.3390/diagnostics11091563
  • Peer Reviewed / Open Access
• [Journal Article] Dried Blood Spot Screening System for Spinal Muscular Atrophy with Allele-Specific Polymerase Chain Reaction and Melting Peak Analysis (2021)
  • Author(s): Wijaya Yogik Onky Silvana、Nishio Hisahide、Niba Emma Tabe Eko、Shiroshita Tomoyoshi、Kato Masako、Bouike Yoshihiro、Tode Chisato、Ar Rochmah Mawaddah、Harahap Nur Imma Fatimah、Nurputra Dian Kesumapramudya、Okamoto Kentaro、Saito Toshio、Takeuchi Atsuko、Lai Poh San、Yamaguchi Seiji、Shinohara Masakazu
  • Journal Title: Genetic Testing and Molecular Biomarkers Volume: 25 Issue: 4 Pages: 293-301
  • DOI: 10.1089/gtmb.2020.0312
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Diagnosis of mucopolysaccharidoses and mucolipidosis as-saying multiplex enzymes and glycosaminoglycans (2021)
  • Author(s): Arunkumar N, Vu DC, Khan S, Kobayashi H, Ngoc Can TB, Oguni T, Watanabe J, Tanaka M, Yamaguchi S, Taketani T, Ago Y, Ohnishi H, Saikia S, Álvarez JV, Tomatsu S.
  • Journal Title: Diagnostics (Basel) Volume: 11 Issue: 8 Pages: 1347-62
  • DOI: 10.3390/diagnostics11081347
  • Peer Reviewed / Open Access
• [Journal Article] 新生児マススクリーニングの歴史と変遷 (2021)
  • Author(s): 山口清次
  • Journal Title: 周産期医学 Volume: 50 Pages: 155-159
• [Journal Article] 自治体の枠を超えた新生児スクリーニングの標準化・効率化 (2021)
  • Author(s): 山口清次、但馬剛
  • Journal Title: 公衆衛生情報 Volume: 51 Pages: 10-12
• [Journal Article] Efficacy of bezafibrate for preventing myopathic attacks in patients with very long-chain acyl-CoA dehydrogenase deficiency (2021)
  • Author(s): Shiraishi H、Yamada K、Egawa K、Ishige M、Ochi F、Watanabe A、Kawakami S、Kuzume K、Watanabe K、Sameshima K、Nakamagoe K、Tamaoka A、Asahina N、Yokoshiki S、Kobayashi K、Miyakoshi T、Oba K、Isoe T、Hayashi H、Yamaguchi S、Sato N
  • Journal Title: Brain and Development Volume: 43 Issue: 2 Pages: 214-219
  • DOI: 10.1016/j.braindev.2020.07.019
  • Peer Reviewed
• [Journal Article] Long-Term Outcomes of Adult Patients with Homocystinuria before and after Newborn Screening (2020)
  • Author(s): Yamada Kenji、Yokoyama Kazunori、Aoki Kikumaro、Taketani Takeshi、Yamaguchi Seiji
  • Journal Title: International Journal of Neonatal Screening Volume: 6 Issue: 3 Pages: 60-60
  • DOI: 10.3390/ijns6030060
  • Peer Reviewed / Open Access
• [Journal Article] Assessment of Spinal Muscular Atrophy Carrier Status by Determining SMN1 Copy Number Using Dried Blood Spots (2020)
  • Author(s): Wijaya YOS, Purevsuren J, Harahap NIF, Niba ETE, Bouike Y, Nurputra DK, Rochmah MA, Thursina C, Hapsara S, Yamaguchi S, Nishio H, Shinohara M.
  • Journal Title: Int J Neonatal Screen. Volume: 29 Issue: 2 Pages: 43-55
  • DOI: 10.3390/ijns6020043
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Need for strict clinical management of patients with carnitine palmitoyltransferase II deficiency: Experience with two cases detected by expanded newborn screening (2020)
  • Author(s): Bo Ryosuke、Musha Ikuma、Yamada Kenji、Kobayashi Hironori、Hasegawa Yuki、Awano Hiroyuki、Arao Masato、Kikuchi Toru、Taketani Takeshi、Ohtake Akira、Yamaguchi Seiji、Iijima Kazumoto
  • Journal Title: Molecular Genetics and Metabolism Reports Volume: 24 Pages: 100611-100611
  • DOI: 10.1016/j.ymgmr.2020.100611
  • NAID: 120006882474
  • Peer Reviewed / Open Access
• [Journal Article] Association between birth weight-for-gestational age and HIF3A DNA methylation in archived dried blood spots of used neonatal screening cards (2019)
  • Author(s): Tay Zar Kyaw, Seiji Yamaguchi S, Imai C, Uematsu M, Sato N
  • Journal Title: J.Hum Genet Volume: 64 Issue: 8 Pages: 795-801
  • DOI: 10.1038/s10038-019-0621-5
  • Peer Reviewed / Open Access
• [Journal Article] Clinical course in a patient with myopathic VLCAD deficiency during pregnancy with an affected baby (2019)
  • Author(s): Yamada Kenji、Matsubara Keiichi、Matsubara Yuko、Watanabe Asami、Kawakami Sanae、Ochi Fumihiro、Kuwabara Kozue、Mushimoto Yuichi、Kobayashi Hironori、Hasegawa Yuki、Fukuda Seiji、Yamaguchi Seiji、Taketani Takeshi
  • Journal Title: JIMD Reports Volume: 49 Issue: 1 Pages: 17-20
  • DOI: 10.1002/jmd2.12061
  • Peer Reviewed / Open Access
• [Journal Article] Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl‐CoA thiolase (T2) deficiency. (2019)
  • Author(s): Elsayed Abdelkreem, Rajesh K. Harijan, Seiji Yamaguchi, Rikkert K. Wierenga, Toshiyuki Fukao
  • Journal Title: Hum Mut Volume: 2019 Issue: 10 Pages: 1-23
  • DOI: 10.1002/humu.23831
  • Peer Reviewed / Open Access
• [Journal Article] Medical mass spectrometrist (MMS) training and certification: A key step to expanding routine clinical mass spectrometry usage in Japan (2019)
  • Author(s): 7) Fumio Nomura, Toyofumi Nakanishi, Kazuo Igarashi, Seiji Yamaguchi, Mitsutoshi Setou, Toshimitsu Niwa
  • Journal Title: Clinical Mass Spectrometry 15: 13-15, 2019 (Nov) https Volume: 15 Pages: 13-15
  • DOI: 10.1016/j.clinms.2019.11.001
  • Peer Reviewed / Open Access
• [Journal Article] 自治体事業として行われている「新生児マススクリーニング」の全国ネットワーク化 (2019)
  • Author(s): 山口清次、但馬剛、森岡久尚、鶴田憲一
  • Journal Title: 公衆衛生情報 49 (6): 10-12, 2019 Volume: 49 Pages: 10-12
• [Presentation] Difference in the prevalernce of inborn metabolic diseases detected by TMS screening in Asian countries (2023)
  • Author(s): Yamaguchi Seij
  • Organizer: 6th Asian Congress on Inherited Metabolic Diseases
  • Int'l Joint Research / Invited
• [Presentation] Current status of newborn mass screening in Asian countries (2023)
  • Author(s): Yamaguchi Seiji, Lee Dong-Hwan, Niu Dau-Ming, Gu Xue-Fang, Padilla Carmencita, Vu Chi Dung, Thong Meoyv-Keong, Tan Ee Shien, Lim James, Alijanpour Mortaza, Purevsuren Jamiyan, Sunita Bijarnia-Mahay, Liammongkolkul Somporn, Vatanavicharn Nithhvat
  • Organizer: 6th Asian Congress on Inherited Metabolic Diseases
  • Int'l Joint Research
• [Presentation] 東アジア諸国のタンデムマスによる新生児スクリーニング結果の比較 (2022)
  • Author(s): 山口清次、山田 健治, 長谷川 有紀、小林 弘典, 但馬剛, 竹谷 健
  • Organizer: 第49回日本マススクリーニング学会
• [Presentation] アジア諸国のタンデムマスによる新生児スクリーニング結果の比較 (2020)
  • Author(s): 山口清次、山田 健治, 長谷川 有紀、小林 弘典, 但馬剛, 竹谷 健
  • Organizer: 第47回日本マススクリーニング学会
• [Presentation] 検量線を用いたアシルカルニチン分析法における血清・血漿検体のアシルカルニチンの安定性に関する検討 (2020)
  • Author(s): 大澤好充、小林 弘典, 野津 吉友, 山田 健治, 長谷川 有紀, 山口 清次, 竹谷 健
  • Organizer: 第47回日本マススクリーニング学会
• [Presentation] Newborn Screening Support System of Japan: Role of the Government and Japanese Society of Neonatal Screening (JSNS) (2019)
  • Author(s): Yamaguchi S
  • Organizer: 5th Korean Congress of Neonatal Screening
  • Int'l Joint Research / Invited
• [Presentation] Global trend of neonatal screening (NBS) for metabolic disorders (2019)
  • Author(s): Yamaguchi S
  • Organizer: 1st Mongorean Congress of Neonatal Screening
  • Int'l Joint Research / Invited
• [Presentation] Diversity in disease spectrum of organic acidemia and fatty acid oxidation defect in ASIA (2019)
  • Author(s): Yamaguchi S
  • Organizer: Pediatric Scientific Conference of National Children’s Hospital
  • Int'l Joint Research / Invited
• [Presentation] Fatty Acid Oxidation Disorder: Changes of clinical presentation with age (2019)
  • Author(s): Yamaguchi S
  • Organizer: The Life Course of Inherited Metabolic Disease
  • Int'l Joint Research / Invited
• [Presentation] Diversity of disease spectrum of the MS/MS screening targets in Asia (2019)
  • Author(s): 8) Yamaguchi S, Shibata N, Hasegawa Y, Kobayashi H, Yamada K, Ohsawa Y, Fukuda S, Taketani
  • Organizer: 第61回先天代謝異常学会アジアセッション
• [Book] よくわかる新生児マススクリーニングガイドブック (2019)
  • Author(s): 山口清次（編著）
  • Total Pages: 150
  • Publisher: 診断と治療社
  • ISBN: 9784787823892
• [Book] 医用質量分析学テキスト (2019)
  • Author(s): 丹羽利充、中西豊文（山口清次、分担執筆）
  • Total Pages: 120
  • Publisher: 診断と治療社
  • ISBN: 9784787824189