Abstract
Carnitine palmitoyltransferase (CPT) II deficiency is one of the most common forms of mitochondrial fatty acid oxidation disorder. Its clinical phenotypes are classified into the muscle, severe infantile, and lethal neonatal forms. Among Caucasians, the muscle form predominates, and the c.338C > T (p.S113L) variant is detected in most cases, whereas among the Japanese, c.1148T > A (p.F383Y) is the variant allele occurring with the highest frequency and can apparently cause symptoms of the severe infantile form. Newborn screening (NBS) for this potentially fatal disease has not been established. We encountered an infantile case of CPT II deficiency not detected in NBS using C16 and C18:1 concentrations as indices, and therefore we adopted the (C16 + C18:1)/C2 ratio as an alternative primary index. As a result, the disease was diagnosed in nine of 31 NBS-positive subjects. The values for (C16 + C18:1)/C2 in the affected newborns partly overlapped with those in unaffected ones. Among several other indices proposed previously, C14/C3 has emerged as a more promising index. Based on these findings, nationwide NBS for CPT II deficiency using both (C16 + C18:1)/C2 and C14/C3 as indices was officially approved and started in April 2018. We diagnosed the disease in four young children presenting with symptoms of the muscle form, whose values for the new indices were not elevated. Although it is still difficult to detect all cases of the muscle form of CPT II deficiency in NBS, our system is expected to save many affected children in Japan with the severe infantile form predominating.
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Acknowledgements
The authors thank Dr. Miyuki Tsumura, Dr. Reiko Kagawa, and Dr. Satoshi Okada (Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences) for helping with the genetic analysis, Dr. Nobuo Sakura (Nursing House for Severe Motor and Intellectual Severities, Suzugamine) for assistance with the enzymatic assay, Dr. Ikue Hata and Dr. Yosuke Shigematsu (Department of Pediatrics, School of Medical Sciences, University of Fukui) for assistance with the acylcarnitine analysis and the measurement of fatty acid oxidation capability, and Dr. Seiji Yamaguchi (Department of Pediatrics, Faculty of Medicine, Shimane University) for managing the pilot study on tandem mass spectrometry-based newborn screening in Japan. The authors also thank Ms. Chiyoko Yoshii, Ms. Chiyomi Morioka, and Ms. Saki Fujihara (Hiroshima City Medical Association Clinical Laboratory) for analyzing the dried blood specimens of newborns in Hiroshima prefecture. This study was supported in part by the Health and Labour Sciences Research Grants for (1) Health Research on Children, Youth and Families (Chief Investigator: Go Tajima) and (2) the Research on Rare and Intractable Diseases (Chief Investigator: Kimitoshi Nakamura), by the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development, AMED, Grant Number JP18ek0109276 (Chief Investigator: Toshiyuki Fukao), by a Grant-in-Aid for Young Scientists, No. 18K15663, from the Japan Society for the Promotion of Science (Chief Investigator: Miori Yuasa), and by a grant from The Morinaga Hoshi-Kai Foundation. This study was carried out in part at the Analysis Center of Life Science, Hiroshima University, the Institute for Clinical Research at the National Hospital Organization Kure Medical Center and Chugoku Cancer Center.
Funding
Go Tajima received Health and Labour Sciences Research Grants (Health Research on Children, Youth and Families; Chief Investigator: Go Tajima, and Research on Rare and Intractable Diseases; Chief Investigator: Kimitoshi Nakamura) from the Ministry of Health, Labour and Welfare of Japan, and a Practical Research Project for Rare/Intractable Diseases Grant from the Japan Agency for Medical Research and Development, AMED (Grant number JP18ek0109276; Chief Investigator: Toshiyuki Fukao), and a grant from The Morinaga Hoshi-Kai Foundation. Miori Yuasa received a Grant-in-Aid for Young Scientists, No. 18K15663 from the Japan Society for the Promotion of Science. Keiichi Hara did not receive any funding for this study.
Author contributions
Go Tajima developed the assay of CPT II activity, carried out the enzymatic assays for all cases in this study, managed the entire project, and wrote this paper. Keiichi Hara performed the analysis of the CPT2 and CACT genes. Miori Yuasa analyzed the acylcarnitine profiles and measured fatty acid oxidation capability using tandem mass spectrometry.
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Approval for the biochemical, enzymatic, and genetic studies was obtained from the ethics committees of the National Center for Child Health and Development, Hiroshima University, University of Fukui, National Hospital Organization Kure Medical Center and Chugoku Cancer Center. All procedures were carried out in accordance with the ethical standards of the relevant committees on human experimentation (institutional and national) and the Helsinki Declaration of 1975 as revised in 2000.
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Tajima, G., Hara, K. & Yuasa, M. Carnitine palmitoyltransferase II deficiency with a focus on newborn screening. J Hum Genet 64, 87–98 (2019). https://doi.org/10.1038/s10038-018-0530-z
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DOI: https://doi.org/10.1038/s10038-018-0530-z
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