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Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

Editor-in-Chief: Plebani, Mario

Ed. by Gillery, Philippe / Greaves, Ronda / Lackner, Karl J. / Lippi, Giuseppe / Melichar, Bohuslav / Payne, Deborah A. / Schlattmann, Peter

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Volume 53, Issue 12


Total folate and 5-methyltetrahydrofolate in the cerebrospinal fluid of children: correlation and reference values

Tomoyuki Akiyama / Hiroko Tada
  • Division of Instrumental Analysis, Department of Instrumental Analysis and Cryogenics, Advanced Science Research Center, Okayama University, Okayama, Japan
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Tsugumi Shiokawa
  • Division of Instrumental Analysis, Department of Instrumental Analysis and Cryogenics, Advanced Science Research Center, Okayama University, Okayama, Japan
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Katsuhiro Kobayashi / Harumi Yoshinaga
  • Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2015-05-05 | DOI: https://doi.org/10.1515/cclm-2015-0208


Background: Cerebral folate deficiency (CFD) may be underdiagnosed, as it manifests with various non-specific neurological symptoms. The diagnosis of CFD requires a determination of 5-methyltetrahydrofolate (5MTHF) in the cerebrospinal fluid (CSF), which is available in a limited number of specialized laboratories. In clinical biochemistry laboratories, total folate (TF) determination in serum or plasma is routinely performed by automated analyzers. The aim of this study is to determine whether the automated assay of CSF TF is a helpful screening tool for CFD.

Methods: We analyzed CSF samples collected from 73 pediatric patients. We measured CSF TF, serum TF, and CSF 5MTHF in 73, 70, and 48 patients, respectively. The assay of 5MTHF was conducted by a newly developed system utilizing liquid chromatography-tandem mass spectrometry (LC-MS/MS). We investigated the correlation between TF and 5MTHF in the CSF.

Results: There was a strong positive correlation between CSF TF and 5MTHF (ρ=0.930, p<0.0001, n=48). Age was negatively correlated with CSF TF (ρ=−0.557, p<0.0001, n=51), serum TF (ρ=−0.457, p=0.0008, n=51), and CSF 5MTHF (ρ=−0.387, p=0.0263, n=33), but not with the CSF/serum TF ratio.

Conclusions: The automated assay of CSF TF is helpful to estimate CSF 5MTHF. The CSF TF assay may have a significant impact on the early diagnosis of CFD, because clinicians have better access to it than the 5MTHF assay.

Keywords: folate transport; liquid chromatography- tandem mass spectrometry; 5-methyltetrahydrofolate; reference value; total folate


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About the article

Corresponding author: Tomoyuki Akiyama, MD, PhD, Department of Child Neurology, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan, Phone: +81 86 2357372, Fax: +81 86 2357377, E-mail:

Received: 2015-02-28

Accepted: 2015-03-31

Published Online: 2015-05-05

Published in Print: 2015-11-01

Citation Information: Clinical Chemistry and Laboratory Medicine (CCLM), Volume 53, Issue 12, Pages 2009–2014, ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: https://doi.org/10.1515/cclm-2015-0208.

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