title: Screening of MCAD deficiency in Japan: 16years' experience of enzymatic and genetic evaluation.
abstract: Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a representative disorder of fatty acid oxidation and is one of the most prevalent inborn errors of metabolism among Caucasian populations. In Japan, however, it was as late as 2000 when the first patient was found, and enzymatic and genetic evaluation of MCAD deficiency began.
  
  
  
  We measured octanoyl-CoA dehydrogenase activity in lymphocytes of symptomatic children and newborn screening (NBS)-positive subjects who showed elevated levels of C8-acylcarnitine in blood. The results were further confirmed by direct sequencing of the ACADM gene.
  
  
  
  The disease was diagnosed in 9 out of 18 symptomatic children. The affected patients showed residual activities from 0% to 3% of the normal average value, except for one patient with 10% activity. Concerning 50 NBS-positive subjects, 18 with enzymatic activities around 10% or lower and 14 with activities ranging from 13% to 30% were judged to be affected patients, and biallelic variants were detected in most of the cases tested. Newborns with higher enzymatic activities were estimated to be heterozygous carriers or healthy subjects, though biallelic variants were detected in 5 of them. Genetic analysis detected 22 kinds of variant alleles. The most prevalent was c.449_452delCTGA (p.T150Rfs), which was followed by c.50G>A (p.R17H), c.1085G>A (p.G362E), c.157C>T (p.R53C), and c.843A>T (p.R281S); these five variants accounted for approximately 60% of all the alleles examined.
  
  
  
  Our study has revealed the unique genetic backgrounds of MCAD deficiency among Japanese, based on the largest series of non-Caucasian cases. A continuous spectrum of severity was also observed in our series of NBS-positive cases, suggesting that it is essential for every nation and ethnic group to accumulate its own information on gene variants, together with their enzymatic evaluation, in order to establish an efficient NBS system for MCAD deficiency.
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan; Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan. Electronic address: isleofmaple@me.com.
authors.forename: Go
authors.initials: G
authors.lastname: Tajima
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan; Department of Pediatrics, National Hospital Organization Kure Medical Center, 3-1 Aoyama-cho, Kure 737-0023, Japan. Electronic address: keiichi1973hara@yahoo.co.jp.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Hara
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. Electronic address: m055@hiroshima-u.ac.jp.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Tsumura
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. Electronic address: ykagawa@ja2.so-net.ne.jp.
authors.forename: Reiko
authors.initials: R
authors.lastname: Kagawa
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. Electronic address: saok969@gmail.com.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okada
authors.affiliation: Nursing House for Severe Motor and Intellectual Severities, Suzugamine, 104-27 Minaga, Itsukaichi-cho, Saeki-ku, Hiroshima 731-5122, Japan. Electronic address: misasa_sakura@yahoo.co.jp.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sakura
authors.affiliation: Department of Pediatrics, School of Medical Sciences, University of Fukui, 23 Shimogogetsu, Matsuoka, Eiheiji-cho, Fukui 910-1193, Japan. Electronic address: ikueh@u-fukui.ac.jp.
authors.forename: Ikue
authors.initials: I
authors.lastname: Hata
authors.affiliation: Department of Pediatrics, School of Medical Sciences, University of Fukui, 23 Shimogogetsu, Matsuoka, Eiheiji-cho, Fukui 910-1193, Japan. Electronic address: yosuke@u-fukui.ac.jp.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Shigematsu
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. Electronic address: masak@hiroshima-u.ac.jp.
authors.forename: Masao
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D042964:Acyl-CoA Dehydrogenase / Q000097:blood / Q000172:deficiency* / Q000235:genetics*; D000483:Alleles; D002675:Child, Preschool; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007003:Hypoglycemia / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D007223:Infant; D007231:Infant, Newborn; D007564:Japan / Q000453:epidemiology; D008052:Lipid Metabolism, Inborn Errors / Q000097:blood / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D009154:Mutation; D015997:Neonatal Screening; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D042964:Acyl-CoA Dehydrogenase
keywords: Japanese; MCAD deficiency; Newborn screening; Non-Caucasian; Phenotype-genotype correlation; Tandem mass spectrometry