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Development of screening and diagnostic assay for mucopolysaccharidosis type II

Research Project

Project/Area Number 16K08958
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Laboratory medicine
Research InstitutionNational Center for Child Health and Development

Principal Investigator

Mashima Ryuichi  国立研究開発法人国立成育医療研究センター, 臨床検査部, 専門職 (00401365)

Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2016: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Keywordsムコ多糖症II型 / 酵素活性 / バイオマーカー / LC-MS/MS / ムコ多糖症 / 新生児スクリーニング / ID2S / LC-MS / グリコサミノグリカン / 臨床検査
Outline of Final Research Achievements

Mucopolysaccharidosis type II (MPS-II, OMIM 309900) is an X-linked disorder characterized by visceral disorder, bone deformation, CNS involvement, as well as an accumulation of glycosaminoglycan in the body. MPS-II is caused by a deficiency of iduronate-2-sulfatase enzyme activity. In this study, thus, we aimed to establish an assay procedure for enzyme activity and biomarkers for MPS-II using LC-MS/MS. First, to quantify the enzyme activity, a 3 mm punch of DBS was incubated with substrate and internal standard. After 20 h of enzyme reaction at 37°C, the enzyme reaction products were extracted and quantified using LC-MS/MS. For the quantification of dermatan sulfate and heparan sulfate, dried urine was reacted in methanolic 3M HCl at 65°C for 75 min. The reaction products were quantified using LC-MS/MS. In both assays, the population of MPS-II-affected individuals was separated from that of controls, demonstrating that diagnosis of MPS-II may be performed with one of these methods.

Academic Significance and Societal Importance of the Research Achievements

本研究開始当時において、ムコ多糖症II型患者の酵素活性は少なくとも日本国内においてほとんど蛍光法で測定されていた。従ってLC-MSで測定する有用性を示した本研究の成果は臨床検査学および分析化学的に学術的特色がある。本研究の結果、LC-MS法を採用することで、遺伝的に酵素活性値が低いが罹患しないことが知られている被検者を適切に正常と判定することや、複数疾患を同時に測定可能となった。本研究成果により正確な診断と早期発見が可能になったことから、患者おける治療上の大きなメリットがあり、医療経済的効果がある。また新生児スクリーニングに応用された場合、公衆衛生的意義も高いと考えられる。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (51 results)

All 2019 2018 2017 2016 Other

All Int'l Joint Research (2 results) Journal Article (15 results) (of which Peer Reviewed: 15 results,  Open Access: 11 results,  Acknowledgement Compliant: 8 results) Presentation (34 results) (of which Int'l Joint Research: 11 results)

  • [Int'l Joint Research] ワシントン大学(米国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] University of Washington(米国)

    • Related Report
      2016 Research-status Report
  • [Journal Article] The second report on spondyloepimetaphyseal dysplasia, aggrecan type: a milder phenotype than originally reported.2019

    • Author(s)
      Fukuhara Y, Cho SY, Miyazaki O, Hattori A, Seo JH, Mashima R, Kosuga M, Fukami M, Jin DK, Okuyama T, Nishimura G.
    • Journal Title

      Clin Dysmorphol.

      Volume: 28(1) Issue: 1 Pages: 26-29

    • DOI

      10.1097/mcd.0000000000000241

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Elevation of plasma lysosphingomyelin-509 and urinary bile acid metabolite in Niemann-Pick disease type C-affected individuals.2018

    • Author(s)
      Mashima R, Maekawa M, Narita A, Okuyama T, Mano N.
    • Journal Title

      Mol Genet Metab Rep

      Volume: 15 Pages: 90-95

    • DOI

      10.1016/j.ymgmr.2018.08.005

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Lipid biomarkers for the peroxisomal and lysosomal disorders: their formation, metabolism and measurement.2018

    • Author(s)
      Mashima R, Maekawa M.
    • Journal Title

      Biomark Med.

      Volume: 12(1) Issue: 1 Pages: 83-95

    • DOI

      10.2217/bmm-2017-0225

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Elevation of plasma lysosphingomyelin-509 and urinary bile acid metabolite in Niemann-Pick disease type C-affected individuals2018

    • Author(s)
      Mashima R, Maekawa M, Narita A, Okuyama T, Mano N.
    • Journal Title

      Mol Genet Metab Rep

      Volume: 15 Pages: 90-95

    • DOI

      10.1016/j.ymgmr.2018.03.005

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Quantification of the enzyme activities of iduronate-2-sulfatase, N-acetylgalactosamine-6-sulfatase and N-acetylgalactosamine-4-sulfatase using liquid chromatography-tandem mass spectrometry.2017

    • Author(s)
      Mashima R, Ohira M, Okuyama T, Tatsumi A
    • Journal Title

      Mol Genet Metab Rep

      Volume: 14 Pages: 36-40

    • DOI

      10.1016/j.ymgmr.2017.12.001

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A molecular analysis of the GAA gene and clinical spectrum in 38 patients with Pompe disease in Japan.2017

    • Author(s)
      Fukuhara Y, Fuji N, Yamazaki N, Hirakiyama A, Kamioka T, Seo JH, Mashima R, Kosuga M, Okuyama T.
    • Journal Title

      Mol Genet Metab Rep

      Volume: 14 Pages: 3-9

    • DOI

      10.1016/j.ymgmr.2017.10.009

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Enzyme activities of α-glucosidase in Japanese neonates with pseudodeficiency alleles.2017

    • Author(s)
      Mashima R, Okuyama T.
    • Journal Title

      Mol Genet Metab Rep

      Volume: 12 Pages: 110-114

    • DOI

      10.1016/j.ymgmr.2017.06.007

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Aspartylglucosaminuria caused by a novel homozygous mutation in the AGA gene was identified by an exome-first approach in a patient from Japan.2017

    • Author(s)
      Yamamoto T, Shimojima K, Matsufuji M, Mashima R, Sakai E, Okuyama T.
    • Journal Title

      Brain Dev.

      Volume: 39(5) Issue: 5 Pages: 422-425

    • DOI

      10.1016/j.braindev.2016.12.004

    • Related Report
      2017 Research-status Report 2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] 複数疾患同時測定系によるライソゾーム酵素活性測定法の検討2017

    • Author(s)
      真嶋隆一、坂井英里、小須賀基通、奥山虎之
    • Journal Title

      日本マス・スクリーニング学会誌

      Volume: 印刷中

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Levels of enzyme activities in six lysosomal storage diseases in Japanese neonates determined by liquid chromatography-tandem mass spectrometry.2016

    • Author(s)
      Mashima R, Sakai E, Tanaka M, Kosuga M, Okuyama T.
    • Journal Title

      Mol Genet Metab Rep.

      Volume: 9 Pages: 6-11

    • DOI

      10.1016/j.ymgmr.2016.08.007

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] The levels of urinary glycosaminoglycans of patients with attenuated and severe type of mucopolysaccharidosis II determined by liquid chromatography-tandem mass spectrometry.2016

    • Author(s)
      Mashima R, Sakai E, Tanaka M, Kosuga M, Okuyama T.
    • Journal Title

      Mol Genet Metab Rep.

      Volume: 7 Pages: 87-91

    • DOI

      10.1016/j.ymgmr.2016.03.009

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] A selective detection of lysophosphatidylcholine in dried blood spots for diagnosis of adrenoleukodystrophy by LC-MS/MS.2016

    • Author(s)
      Mashima R, Tanaka M, Sakai E, Nakajima H, Kumagai T, Kosuga M, Okuyama T.
    • Journal Title

      Mol Genet Metab Rep.

      Volume: 7 Pages: 16-19

    • DOI

      10.1016/j.ymgmr.2016.02.007

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Mini review on "Molecular diagnosis of 65 families with mucopolysaccharidosis type II (Hunter syndrome) characterized by 16 novel mutations in the IDS gene: Genetic, pathological, and structural studies on iduronate-2-sulfatase"2016

    • Author(s)
      Mashima R, Okuyama T.
    • Journal Title

      J Rare Dis Res Treat

      Volume: 2 Pages: 43-46

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Molecular diagnosis of 65 families with mucopolysaccharidosis type II (Hunter syndrome) characterized by 16 novel mutations in the IDS gene: Genetic, pathological, and structural studies on iduronate-2-sulfatase.2016

    • Author(s)
      Kosuga M, Mashima R, Hirakiyama A, Fuji N, Kumagai T, Seo JH, Nikaido M, Saito S, Ohno K, Sakuraba H, Okuyama T.
    • Journal Title

      Mol Genet Metab.

      Volume: 118 Issue: 3 Pages: 190-197

    • DOI

      10.1016/j.ymgme.2016.05.003

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] 極長鎖脂肪酸含有リン脂質を指標とした高速液体クロマトグラフィー/三連四重極質量分析法(LC/MS/MS)による副腎白質ジストロフィー(ALD)診断法の開発2016

    • Author(s)
      田中美砂、真嶋隆一、坂井英里、中島英規、熊谷淳之、小須賀基通、奥山虎之
    • Journal Title

      日本マス・スクリーニング学会誌

      Volume: 26 Pages: 79-84

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] Quantification of 11-plex LSD enzyme activity using liquid chromatography-tandem mass spectrometry2019

    • Author(s)
      Mashima R, Ohira, M, Okuyama T
    • Organizer
      15th WORLDSymposium
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Quantification of the enzyme activities of ID2S, GALN and ARSB using LC-MS/MS2018

    • Author(s)
      Mashima R, Ohira M, Okuyama T
    • Organizer
      66th Conference on Mass Spectrometry and Allied Topics
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Determination of the enzyme activities of ID2S, GALN and ARSB using LC-MS/MS2018

    • Author(s)
      Mashima R, Ohira, M, Okuyama T
    • Organizer
      SSIEM 2018 Annual symposium
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 成育医療における質量分析法の貢献2018

    • Author(s)
      真嶋隆一、坂井英里、大平麻里、田中美砂、奥山虎之
    • Organizer
      第66回日本質量分析総合討論会
    • Related Report
      2018 Annual Research Report
  • [Presentation] LC-MS/MSによるライソゾーム病酵素活性の同時測定:ID2S, GALN,およびARSB酵素活性測定によるMPS II, IVA, VIのスクリーニングへの応用2018

    • Author(s)
      真嶋隆一、大平麻里、奥山虎之
    • Organizer
      第45回日本マススクリーニング学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 質量分析法を使ったライソゾーム酵素活性測定系の検討2018

    • Author(s)
      真嶋隆一
    • Organizer
      第58回日本臨床化学会年次学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ニーマンピック病C型患者血清中のLyso-SM-509とスフィンゴシルホスホリルコリンの同時分析2018

    • Author(s)
      神納 勇、前川正充、真嶋隆一、成田 綾、山口浩明、眞野成康
    • Organizer
      第31回バイオメディカル分析科学シンポジウム
    • Related Report
      2018 Annual Research Report
  • [Presentation] LC-MS/MSによるライソゾーム病酵素活性の同時測定:ID2S, GALN,およびARSB酵素活性測定によるMPS II, IVA, VIのスクリーニングへの応用2018

    • Author(s)
      真嶋隆一、大平麻里、奥山虎之
    • Organizer
      日本人類遺伝学会第63回大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ニーマンピック病C型のバイオマーカーについて2018

    • Author(s)
      真嶋隆一、前川正充、成田 綾、奥山虎之、眞野成康、
    • Organizer
      第60回日本先天代謝異常学会総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] LC-MS/MSによるライソゾーム病酵素活性の同時測定2018

    • Author(s)
      大平麻里、真嶋隆一、奥山虎之
    • Organizer
      第60回日本先天代謝異常学会総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 質量分析法を利用したファブリー病バイオマーカーの検討2018

    • Author(s)
      大平麻里、真嶋隆一、奥山虎之
    • Organizer
      第60回日本先天代謝異常学会総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Levels of enzyme activities in six lysosomal storage disorders in random Japanese neonates using LC-MS/MS2017

    • Author(s)
      Mashima R, Sakai E, Kosuga M, and Okuyama T
    • Organizer
      13th WORLD Symposium
    • Place of Presentation
      San Diego, USA
    • Year and Date
      2017-02-13
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] 質量分析法を用いたライソゾーム病複数疾患同時測定系の検討2017

    • Author(s)
      真嶋隆一、奥山虎之
    • Organizer
      第65回質量分析総合討論会
    • Related Report
      2017 Research-status Report
  • [Presentation] 複数のライソゾーム病原因酵素活性の同時測定系の検討2017

    • Author(s)
      真嶋隆一、奥山虎之
    • Organizer
      第59回日本脂質生化学会
    • Related Report
      2017 Research-status Report
  • [Presentation] 質量分析法を用いたライソゾーム病酵素活性測定系の検討2017

    • Author(s)
      真嶋隆一、奥山虎之
    • Organizer
      第44回日本マススクリーニング学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] LC-MS/MSによるライソゾーム病酵素活性の同時測定2017

    • Author(s)
      真嶋隆一、奥山虎之
    • Organizer
      第30回バイオメディカル分析科学シンポジウム
    • Related Report
      2017 Research-status Report
  • [Presentation] 質量分析法を利用したライソゾーム病酵素活性測定法について2017

    • Author(s)
      真嶋隆一、大平麻里、辰巳暁哉、奥山虎之
    • Organizer
      第59回日本先天代謝異常学会
    • Related Report
      2017 Research-status Report
  • [Presentation] Enzyme activities in six lysosomal storage diseases in Japanese neonates determined by LC-MS/MS2017

    • Author(s)
      Mashima R, Kosuga M, and Okuyama T
    • Organizer
      65th Conference on Mass Spectrometry and Allied Topics
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Enzyme activities in six lysosomal storage diseases in Japanese neonates determined by LC-MS/MS2017

    • Author(s)
      Mashima R, Okuyama T
    • Organizer
      ICIEM 2017 Rio de Janeiro
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Enzyme activities of LSDs in a Japanese neonatal population2017

    • Author(s)
      Mashima R
    • Organizer
      APHL Newborn Screening and Genetic Testing Symposium
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Quantification of enzyme activities of lysosomal storage disorders in a neonatal population using mass spectrometry2017

    • Author(s)
      Mashima R, Okuyama T
    • Organizer
      14th WORLDSymposium
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] LC-MS/MSによるライソゾーム酵素活性測定法の検討2016

    • Author(s)
      真嶋隆一、坂井英里、田中美砂、小須賀基通、奥山虎之
    • Organizer
      第58回日本先天代謝異常学会総会
    • Place of Presentation
      東京
    • Year and Date
      2016-10-27
    • Related Report
      2016 Research-status Report
  • [Presentation] LC-MS/MSを用いたムコ多糖症患者の尿中グリコサミノグリカンの測定2016

    • Author(s)
      坂井英里、真嶋隆一、田中美砂、小須賀基通、奥山虎之
    • Organizer
      第58回日本先天代謝異常学会総会
    • Place of Presentation
      東京
    • Year and Date
      2016-10-27
    • Related Report
      2016 Research-status Report
  • [Presentation] エクソーム解析で明らかになったアスパルチルグルコサミン尿症2016

    • Author(s)
      山本俊至、下島圭子、松藤まゆみ、真嶋隆一、坂井英里、奥山虎之
    • Organizer
      第58回日本先天代謝異常学会総会
    • Place of Presentation
      東京
    • Year and Date
      2016-10-27
    • Related Report
      2016 Research-status Report
  • [Presentation] Levels of enzyme activities in six lysosomal storage disorders in random Japanese neonates using LC-MS/MS2016

    • Author(s)
      Mashima R
    • Organizer
      5th Asian Congress for LSD Screening
    • Place of Presentation
      Tokyo, Japan
    • Year and Date
      2016-10-25
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] ムコ多糖症II型の原因遺伝子であるIDS遺伝子の日本人家系における解析例:16の新規変異を含む65例の解析結果2016

    • Author(s)
      真嶋隆一、小須賀基通、櫻庭均、奥山虎之
    • Organizer
      第21回ライソゾーム病研究会
    • Place of Presentation
      東京
    • Year and Date
      2016-09-30
    • Related Report
      2016 Research-status Report
  • [Presentation] 極長鎖脂肪酸をバイオマーカーとしたX-連鎖型副腎白質ジストロフィーの臨床検査法の開発2016

    • Author(s)
      真嶋隆一、田中美砂、坂井英里、小須賀基通、奥山虎之
    • Organizer
      第89回日本生化学会大会
    • Place of Presentation
      仙台
    • Year and Date
      2016-09-25
    • Related Report
      2016 Research-status Report
  • [Presentation] 極長鎖脂肪酸をバイオマーカーとした副腎白質ジストロフィーの臨床検査法の開発2016

    • Author(s)
      真嶋隆一、田中美砂、坂井英里、中島英規、熊谷淳之、小須賀基通、奥山虎之
    • Organizer
      第41回日本医用マススペクトル学会年会
    • Place of Presentation
      名古屋
    • Year and Date
      2016-09-15
    • Related Report
      2016 Research-status Report
  • [Presentation] Blood lysophosphatidylcholine demonstrates as a diagnostic marker for X-linked adrenoleukodystrophy2016

    • Author(s)
      Mashima R, Tanaka M, Sakai E, Kumagai T, Kosuga M, Okuyama T
    • Organizer
      SSIEM Rome 2016
    • Place of Presentation
      Rome, Italy
    • Year and Date
      2016-09-06
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] X-連鎖型副腎白質ジストロフィーの臨床検査法の開発:極長鎖脂肪酸をバイオマーカーとして2016

    • Author(s)
      真嶋隆一、田中美砂、坂井英里、熊谷淳之、小須賀基通、奥山虎之
    • Organizer
      第29回バイオメディカル分析科学シンポジウム
    • Place of Presentation
      京都
    • Year and Date
      2016-09-02
    • Related Report
      2016 Research-status Report
  • [Presentation] 多疾患同時測定系によるライソゾーム酵素活性測定法の検討2016

    • Author(s)
      真嶋隆一、坂井英里、小須賀基通、奥山虎之
    • Organizer
      第43回日本マス・スクリーニング学会学術集会
    • Place of Presentation
      札幌
    • Year and Date
      2016-08-26
    • Related Report
      2016 Research-status Report
  • [Presentation] 臨床検査学的に有用である極長鎖脂肪酸をバイオマーカーとした副腎白質ジストロフィー診断法の開発2016

    • Author(s)
      真嶋隆一、田中美砂、坂井英里、熊谷淳之、小須賀基通、奥山虎之
    • Organizer
      第58回日本脂質生化学会
    • Place of Presentation
      秋田
    • Year and Date
      2016-06-09
    • Related Report
      2016 Research-status Report
  • [Presentation] 臨床検査学的に応用可能な極長鎖脂肪酸をバイオマーカーとした副腎白質ジストロフィーの診断法の開発2016

    • Author(s)
      真嶋隆一、田中美砂、坂井英里、中島英規、熊谷淳之、小須賀基通、奥山虎之、
    • Organizer
      第64回質量分析総合討論会
    • Place of Presentation
      大阪
    • Year and Date
      2016-05-18
    • Related Report
      2016 Research-status Report
  • [Presentation] A selective detection of lysophosphatidylcholine in dried blood spot for diagnosis of adrenoleukodystrophy by LC-MS/MS2016

    • Author(s)
      Mashima R, Tanaka M, Sakai E, Kumagai T, Kosuga M, Okuyama T
    • Organizer
      The 13th International Congress of Human Genetics 2016
    • Place of Presentation
      Kyoto, Japan
    • Year and Date
      2016-04-03
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research

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Published: 2016-04-21   Modified: 2022-02-16  

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