The frequencies of very long-chain acyl-CoA dehydrogenase deficiency genetic variants in Japan have changed since the implementation of expanded newborn screening

Yoshimitsu Osawa; Hironori Kobayashi; Go Tajima; Keiichi Hara; Kenji Yamada; Seiji Fukuda; Yuki Hasegawa; Junko Aisaki; Miori Yuasa; Ikue Hata; Satoshi Okada; Yosuke Shigematsu; Hideo Sasai; Toshiyuki Fukao; Takumi Takizawa; Seiji Yamaguchi; Takeshi Taketani

doi:10.1016/j.ymgme.2022.03.009

The frequencies of very long-chain acyl-CoA dehydrogenase deficiency genetic variants in Japan have changed since the implementation of expanded newborn screening

Mol Genet Metab. 2022 May;136(1):74-79. doi: 10.1016/j.ymgme.2022.03.009. Epub 2022 Mar 25.

Authors

Yoshimitsu Osawa¹, Hironori Kobayashi², Go Tajima³, Keiichi Hara⁴, Kenji Yamada⁵, Seiji Fukuda⁶, Yuki Hasegawa⁷, Junko Aisaki⁸, Miori Yuasa⁹, Ikue Hata¹⁰, Satoshi Okada¹¹, Yosuke Shigematsu¹², Hideo Sasai¹³, Toshiyuki Fukao¹⁴, Takumi Takizawa¹⁵, Seiji Yamaguchi¹⁶, Takeshi Taketani¹⁷

Affiliations

¹ Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan; Department of Pediatrics, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan. Electronic address: y-osawa@gunma-u.ac.jp.
² Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan; Division of Laboratory, Shimane University Hospital, Izumo, Shimane, Japan. Electronic address: bakki@med.shimane-u.ac.jp.
³ Division of Neonatal Screening, National Center for Child Health and Development, Setagaya, Tokyo, Japan. Electronic address: tajima-g@ncchd.go.jp.
⁴ Department of Pediatrics, The NHO Kure Medical Center, Kure, Hiroshima, Japan. Electronic address: hara.keiichi.dv@mail.hosp.go.jp.
⁵ Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan. Electronic address: k-yamada@med.shimane-u.ac.jp.
⁶ Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan. Electronic address: sfukuda@med.shimane-u.ac.jp.
⁷ Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan. Electronic address: yukirin@med.shimane-u.ac.jp.
⁸ Division of Neonatal Screening, National Center for Child Health and Development, Setagaya, Tokyo, Japan. Electronic address: aisaki-j@ncchd.go.jp.
⁹ Department of Pediatrics, University of Fukui, Eiheiji-cho, Fukui, Japan. Electronic address: miori@u-fukui.ac.jp.
¹⁰ Department of Pediatrics, University of Fukui, Eiheiji-cho, Fukui, Japan. Electronic address: ikueh@u-fukui.ac.jp.
¹¹ Department of Pediatrics, Hiroshima University Graduate School of Biochemical and Health Sciences, Hiroshima, Japan. Electronic address: sokada@hiroshima-u.ac.jp.
¹² Department of Pediatrics, Uji-Tokushukai Medical Center, Uji, Kyoto, Japan.
¹³ Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan. Electronic address: sasai@gifu-u.ac.jp.
¹⁴ Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan.
¹⁵ Department of Pediatrics, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan. Electronic address: takizawt@gunma-u.ac.jp.
¹⁶ Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan. Electronic address: seijiyam@med.shimane-u.ac.jp.
¹⁷ Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan. Electronic address: ttaketani@med.shimane-u.ac.jp.

PMID: 35400565
DOI: 10.1016/j.ymgme.2022.03.009

Abstract

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency has been a target of expanded newborn screening (ENBS) using tandem mass spectrometry in Japan. Since the implementation of ENBS, a number of novel ACADVL variants responsible for VLCAD deficiency have been identified. In this study, genotypic differences in Japanese patients with VLCAD deficiency were investigated before and after ENBS. The ACADVL variants in 61 subjects identified through ENBS (ENBS group) and in 40 patients who subsequently developed clinical symptoms without undergoing ENBS (pre-ENBS group) were compared. Subjects in the ENBS group underwent genetic testing and/or VLCAD enzyme activity measurements. Patients in the pre-ENBS group were stratified into three clinical phenotypes and underwent genetic testing. This study revealed that the variants p.K264E, p.K382Q and c.996dupT were found in both groups, but their frequencies were lower in the ENBS group (5.2%, 3.1% and 4.2%, respectively) than in the pre-ENBS group (16.5%, 12.7% and 10.1%, respectively). In addition, p.C607S, p.T409M, p.M478I, p.G289R, p.C237R, p.T260M, and p.R229* were exclusively identified in the ENBS group. Among these variants, p.C607S exhibited the highest frequency (18.8%). The patients who were heterozygous for p.C607S demonstrated 7-42% of control enzyme activity. p.C607S is suspected to be unique to Japanese individuals. According to a comparison of enzyme activity, patients with the p.C607S variant may exhibit higher enzyme activity than those with the p.A416T, p.A180T, p.R450H, and p.K264E variants, which are responsible for the myopathic form of the disease. The VLCAD deficiency genotypes have changed since the initiation of ENBS in Japan.

Keywords: Common variant; Enzyme activity; Genotype-phenotype correlation; Newborn screening; Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency; p.C607S.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acyl-CoA Dehydrogenase / genetics
Acyl-CoA Dehydrogenase, Long-Chain / genetics
Congenital Bone Marrow Failure Syndromes* / epidemiology
Humans
Infant, Newborn
Japan / epidemiology
Lipid Metabolism, Inborn Errors* / epidemiology
Mitochondrial Diseases* / epidemiology
Muscular Diseases* / epidemiology
Neonatal Screening / methods

Substances

Acyl-CoA Dehydrogenase
Acyl-CoA Dehydrogenase, Long-Chain

Supplementary concepts

VLCAD deficiency