Establishment of diagnostic methods for adult-onset fatty acid metabolism disorders and elucidation of their clinical features

• Project/Area Number: 16K09969
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Shimane University
• Principal Investigator: Hironori Kobayashi 島根大学, 学術研究院医学・看護学系, 助教 (70397868)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: アシルカルニチン分析 / LC-MS/MS / タンデムマス / 脂肪酸代謝異常症 / 成人 / 臨床検査 / 肝硬変 / VLCAD欠損症 / 血清 / グルタル酸血症2型 / 妊娠 / 心筋症 / 有機酸代謝異常症 / 先天代謝異常症 / アシルカルニチン / 質量分析 / カルニチン / 成人発症 / ミトコンドリアβ酸化

Outline of Final Research Achievements

Fatty acid oxidation disorder (FAOD) is an inborn error of metabolism in which fatty acid beta-oxidation is impaired. The cardiac muscle, skeletal muscle, and the liver, which are highly dependent on β-oxidation for energy supply, are often affected. Although there have been few reports of adult cases of FAODs, it is thought that there are many undiagnosed cases. Acylcarnitine analysis using LC-MS/MS is useful for the diagnosis of FAODs, but conventional analytical methods had challanges with precision and reproducibility. We established a new acylcarnitine analysis method that can be used as a clinical test and validated it. We applied the new method to the screening and follow-up of adult cases of FAODs, and the clinical features of one case of VLCAD deficiency and two cases of glutaric acidemia type 2 were investigated.

Academic Significance and Societal Importance of the Research Achievements

本研究においては、効率よく脂肪酸代謝異常症をスクリーニングできる血清アシルカルニチン分析法（新AC法）を確立し、実際に脂肪酸代謝異常症の診断および臨床経過のフォローアップに使用できる事を示した。今後、小児例のみならず成人期における脂肪酸代謝異常症の成人診断例の増加が期待できる。
また、新AC法を用いて脂肪酸代謝異常症患者のスクリーニングを行った。VLCAD欠損症、グルタル酸血症2型などの成人例について経時的な経過を追うことが出来た。脂肪酸代謝異常症母体の周産期におけるアシルカルニチン値の推移などの治験が得られ、今後の診療への情報を蓄積できた。

Research Products

• [Journal Article] Blood carnitine profiling on tandem mass spectrometry in liver cirrhotic patients (2020)
  • Author(s): Miyaaki Hisamitsu、Kobayashi Hironori、Miuma Satoshi、Fukusima Masanori、Sasaki Ryu、Haraguchi Masafumi、Nakao Kazuhiko
  • Journal Title: BMC Gastroenterology Volume: 20 Issue: 1 Pages: 41-41
  • DOI: 10.1186/s12876-020-01190-6
  • NAID: 120006988288
  • Peer Reviewed / Open Access
• [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] Primary carnitine deficiency with severe acute hepatitis following rotavirus gastroenteritis (2019)
  • Author(s): Ishige Mika、Fuchigami Tatsuo、Furukawa Maki、Kobayashi Hironori、Fujiki Ryoji、Ogawa Erika、Ishige Nobuyuki、Sasai Hideo、Fukao Toshiyuki、Hashimoto Koji、Inamo Yasuji、Morioka Ichiro
  • Journal Title: Journal of Infection and Chemotherapy Volume: 25 Issue: 11 Pages: 913-916
  • DOI: 10.1016/j.jiac.2019.04.020
  • Peer Reviewed / Open Access
• [Journal Article] Serum C14:1/C12:1 ratio is a useful marker for differentiating affected patients with very long-chain acyl-CoA dehydrogenase deficiency from heterozygous carriers (2019)
  • Author(s): Yamada Kenji、Osawa Yoshimitsu、Kobayashi Hironori、Hasegawa Yuki、Fukuda Seiji、Yamaguchi Seiji、Taketani Takeshi
  • Journal Title: Molecular Genetics and Metabolism Reports Volume: 21 Pages: 100535-100535
  • DOI: 10.1016/j.ymgmr.2019.100535
  • 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] Flavin adenine dinucleotide synthase deficiency due to FLAD1 mutation presenting as multiple acyl-CoA dehydrogenation deficiency-like disease: A case report (2019)
  • Author(s): Yamada Kenji、Ito Michinori、Kobayashi Hironori、Hasegawa Yuki、Fukuda Seiji、Yamaguchi Seiji、Taketani Takeshi
  • Journal Title: Brain and Development Volume: 41 Issue: 7 Pages: 638-642
  • DOI: 10.1016/j.braindev.2019.04.002
  • Peer Reviewed
• [Journal Article] Diversity in the incidence and spectrum of organic acidemias, fatty acid oxidation disorders, and amino acid disorders in Asian countries: Selective screening vs. expanded newborn screening. (2018)
  • Author(s): Shibata N, Hasegawa Y, Yamada K, Kobayashi H, Purevsuren J, Yang Y, Dung VC, Khanh NN, Verma IC, Bijarnia-Mahay S, Lee DH, Niu DM, Hoffmann GF, Shigematsu Y, Fukao T, Fukuda S, Taketani T, Yamaguchi S
  • Journal Title: Molecular genetics and metabolism reports Volume: 16 Pages: 5-10
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of bezafibrate on fibroblasts of glutaric acidemia type II patients evaluated using an in vitro probe acylcarnitine assay (2017)
  • Author(s): Yamada K, Kobayashi H, Bo R, Purevsuren J, Mushimoto Y, Takahashi T, Hasegawa Y, Taketani T, Fukuda S, Yamaguchi S
  • Journal Title: Brain & Development Volume: 39 Pages: 45-49
  • Peer Reviewed
• [Journal Article] A newborn case with carnitine palmitoyltransferase II deficiency initially judged as unaffected by acylcarnitine analysis soon after birth. (2017)
  • Author(s): Yamada K, Bo R, Kobayashi H, Hasegawa Y, Ago M, Fukuda S, Yamaguchi S, Taketani T
  • Journal Title: Mol Genet Metab Reports Volume: 11 Pages: 59-61
  • NAID: 120006373818
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and molecular investigation of 14 Japanesepatients with complete TFP deficiency: a comparisonwith Caucasian cases (2017)
  • Author(s): Bo R, Yamada K, Kobayashi H, Jamiyan P, Hasegawa Y, Taketani T, Fukuda S, Hata I, Niida Y, Shigematsu Y, Iijima K, Yamagushi S
  • Journal Title: Journal of Human Genetics Volume: 62 Pages: 809-814
  • Peer Reviewed
• [Journal Article] Clinical and molecular investigation of 14 Japanese patients with complete TFP deficiency: a comparison with Caucasian cases. (2017)
  • Author(s): Bo R, Yamada K, Kobayashi H, Jamiyan P, Hasegawa Y, Taketani T, Fukuda S, Hata I, Niida Y, Shigematsu Y, Iijima K, Yamaguchi S
  • Journal Title: Journal of Human Genetics Volume: 62 Pages: 809-814
  • Peer Reviewed
• [Journal Article] Metabolic survey of hidden inherited metabolic diseases in children with apparent life-threatening event (ALTE) or sudden unexpected death in infancy (SUDI) by analyses of organic acids and acylcarnitines using mass spectrometries (2016)
  • Author(s): Takahashi T, Hasegawa Y, Yamada K, Bo R, Kobayashi H, Taketani T, Fukuda S, Yamaguchi S
  • Journal Title: Shimane Journal of Medical Science Volume: 32 Pages: 61-68
  • NAID: 120005749747
  • Peer Reviewed
• [Journal Article] Clinical Features of Carnitine Deficiency Secondary to Pivalate-Conjugated Antibiotic Therapy (2016)
  • Author(s): Kobayashi H, Fukuda S, Yamada K, Hasegawa Y, Takahashi T, Purevsuren J, Yamaguchi S
  • Journal Title: J Pediatr. Volume: April Pages: 183-187
  • DOI: 10.1016/j.jpeds.2016.02.080
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] VLCAD欠損症患者の遺伝子型はタンデムマス・スクリーニング導入前後で変化している (2019)
  • Author(s): 小林弘典、大澤好充、原圭一、山田健治、長谷川有紀、相﨑潤子、重松陽介、但馬剛、山口清次、竹谷健
  • Organizer: 第46回日本マススクリーニング学会
• [Presentation] 先天代謝異常検査への質量分析の応用-尿中有機酸分析と血中アシルカルニチン分析- (2017)
  • Author(s): 小林弘典
  • Organizer: 日本臨床検査自動化学会第31回春季セミナー
  • Invited
• [Presentation] ガイドラインからみた脂肪酸代謝異常症 (2017)
  • Author(s): 小林弘典
  • Organizer: 第120回 日本小児科学会
• [Presentation] Diversity of organic acidemias and fatty acid oxidation defects in Asian Countries (2017)
  • Author(s): Shibata N, Hasegawa Y, Kobayashi H, Yamada K, Fukuda S, Taketani T, Yamaguchi S
  • Organizer: The 1st Taiwan Korea Japan Joint congress on Neonatolohy &27th Annual Meeting of Taiwan Society of Neonatology
• [Presentation] 患者登録コホート体制の現状と今後の課題 (2017)
  • Author(s): 小林弘典
  • Organizer: 第44回日本マススクリーニング学会
  • Invited
• [Presentation] 陰イオンモードによるオロト酸測定を加えたタンデムマスによる新生児スクリーニング対象疾患の拡大 (2017)
  • Author(s): 小林弘典
  • Organizer: 第42回日本医用マススペクトル学会年会
• [Presentation] Neurological outcome of adult PKU patients detected by NBS in JAPAN (2017)
  • Author(s): Yamada K, Aoki K, Yokoyama K, Kobayashi H, Hasegawa Y, Tajima G, Shintaku H, Taketani T, Yamaguchi S
  • Organizer: 10th ISNS-ASIA PACIFIC REGIONAL MEETING 2017
• [Presentation] 脂肪酸代謝異常症患者に対するカルニチン投与の実態に関する横断的調査 (2016)
  • Author(s): 小林弘典, 山田健治, 坊亮輔, 長谷川有紀, 山口清次, 竹谷健, 深尾敏幸
  • Organizer: 第58回日本先天代謝異常学会
  • Place of Presentation: 東京
  • Year and Date: 2016-10-27
• [Presentation] LC-MS/MS による血清中アシルカルニチンの定量分析の新規非誘導体化法の開発及び既存簡易測定法との比較検討 (2016)
  • Author(s): 小林弘典，山田 健治，坊 亮輔，長谷川有紀，山口清次，大山直子，竹内一博，城下友義，井手野 晃
  • 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
• [Presentation] The effect of riboflavin is limited in Japanese patients with multiple acyl-CoA dehydrogenase deficiency (MADD) (2016)
  • Author(s): Yamada K, Kobayashi H, Hasegawa Y, Yamaguchi S
  • Organizer: Society for the Study of Inborn Errors of Metabolism Annual Symposium 2016
  • Place of Presentation: Roma, Italy
  • Year and Date: 2016-09-06
  • Int'l Joint Research
• [Presentation] Clinical and genetic aspects of 50 Japanese cases of VLCAD deficiency (2016)
  • Author(s): Yamaguchi S, Hasegawa Y, Furui M, Yamada K, Bo R, Kobayashi H, Taketani T, Fukuda S, Fukao T, Nishino I
  • Organizer: Society for the Study of Inborn Errors of Metabolism Annual Symposium 2016
  • Place of Presentation: Roma, Italy
  • Year and Date: 2016-09-06
• [Presentation] Diversity of disease distribution and genetic background of inherited metabolic disease of organic and fatty acids in Asian countries (2016)
  • Author(s): Yamaguchi S, Hasegawa Y, Shibata N, Kobayashi H, Yamada K, Bo R, Taketani T, Chi DV, Thu NN
  • Organizer: The 13th International Congress of Human Genetics
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2016-04-03
  • Int'l Joint Research