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Vitamin B-6 vitamers in human plasma and cerebrospinal fluid

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Vitamin B-6 comprises a group of 6 interrelated vitamers and is essential for numerous physiologic processes, including brain functioning. Genetic disorders disrupting vitamin B-6 metabolism have severe clinical consequences.OBJECTIVE: To adequately
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  Vitamin B-6 vitamers in human plasma and cerebrospinal fluid 1–4  Monique Albersen, Marjolein Bosma, Jurjen J Luykx, Judith JM Jans, Steven C Bakker, Eric Strengman, Paul J Borgdorff,Peter JM Keijzers, Eric PA van Dongen, Peter Bruins, Monique GM de Sain-van der Velden, Gepke Visser, Nine VVAM Knoers, Roel A Ophoff, and Nanda M Verhoeven-Duif  ABSTRACTBackground:  Vitamin B-6 comprises a group of 6 interrelated vi-tamers and is essential for numerous physiologic processes, includ-ing brain functioning. Genetic disorders disrupting vitamin B-6metabolism have severe clinical consequences. Objective:  To adequately diagnose known and novel disorders invitamin B-6 metabolism, a reference set is required containing in-formation on all vitamin B-6 vitamers in plasma and cerebrospinalfluid (CSF). Design:  Concentrations of B-6 vitamers in the plasma and CSF of 533 adult subjects were measured by ultra high-performance liquidchromatography–tandem mass spectrometry. Results:  The relative B-6 vitamer composition of plasma [pyridoxalphosphate (PLP) . pyridoxic acid (PA) . pyridoxal] differed fromthat of CSF (pyridoxal  .  PLP  .  PA  .  pyridoxamine). Sex influ-enced B-6 vitamer concentrations in plasma and CSF and shouldtherefore be taken into account when interpreting B-6 vitamer con-centrations. The strict ratios and strong correlations between B-6vitamers point to a tight regulation of B-6 vitamer concentrations inblood and CSF. Given the unique design of this study, with simul-taneously withdrawn blood and CSF from a large number of sub- jects, reliable CSF:plasma ratios and correlations of B-6 vitamerscould be established. Conclusions:  We provide an extensive reference set of B-6 vitamerconcentrations in plasma and CSF. In addition to providing insighton the regulation of individual vitamers and their intercompartmentaldistribution, we anticipate that these data will prove to be a valu-able reference set for the diagnosis and treatment of conditionsassociated with altered vitamin B-6 metabolism.  Am J Clin Nutr  doi: 10.3945/ajcn.113.082008. INTRODUCTION Pyridoxal phosphate (PLP) 5 , the predominantly active form of vitamin B-6, is well known for its cofactor function in numerousenzymatic reactions in the central nervous system, where itmainly catalyzes amino acid and neurotransmitter metabolism.In addition, PLP is required for the actions of, among  . 160other enzymes (1), glycogen phosphorylase (glucose bio-synthesis), cystathionine  b -synthase (homocysteine metabolism),and aminolevulinate synthase (heme biosynthesis). PLP-dependent enzymes also play an important role in the synthesis of neuroprotective compounds in the brain, such as kynurenic acid—an intermediate in the degradation pathway of tryptophan (2).Inverse relations of vitamin B-6 with oxidative stress (3–5),inflammation (6–10), cardiovascular disease (11), diabetes (12),and cancer (13–22) have been reported. A higher intake of vitamin B-6 is associated with a lower risk of colorectal cancer(13, 19, 22) and breast cancer (14, 21), whereas higher con-centrations of serum PLP are associated with a lower risk of lung cancer (18). Lower concentrations of plasma PLP havebeen associated with poorer cognition (23, 24).The recent elucidation of these multiple roles for vitamin B-6,and the discovery of inborn errors of metabolism resulting infunctional vitamin B-6 deficiency, have raised scientific interestin vitamin B-6. We hypothesize that, with direct analysis of vitamin B-6 in body fluids, functional vitamin B-6 deficiency canbe reliably diagnosed, and the biochemical effects of treatmentwith vitamin B-6 can be monitored. This will not only increaseour insight on B-6 vitamer concentrations in health and disease,but will also deepen our understanding of human vitamin B-6metabolism and transport. It is essential to study concentrationsof all B-6 vitamers in plasma and cerebrospinal fluid (CSF) (25,26) and, for optimal comparison between plasma and CSF, bothbody fluids should be obtained simultaneously from the sameindividual. 1 Fromthe Department of Medical Genetics, University Medical CenterUtrecht, Utrecht, Netherlands (MA, MB, JJMJ, ES, MGMdS-vdV, NVVAMK,and NMV-D); the Neurogenetics Unit (JJL) and the Department of Psychiatry(SCB and RAO), Brain Center Rudolf Magnus, University Medical CenterUtrecht, Utrecht, Netherlands; the Department of Anesthesiology, IntensiveCare and Pain Management, Diakonessenhuis Hospital, Utrecht, Netherlands(PJB); the Department of Anesthesiology, Central Military Hospital, Utrecht,Netherlands (PJMK); the Department of Anesthesiology, Intensive Care andPain Management, St Antonius Hospital, Nieuwegein, Netherlands (EPAvDand PB); the Department of Pediatric Metabolic Diseases, Wilhelmina Children’sHospital, University Medical Center Utrecht, Utrecht, Netherlands (GV); and theCenter for Neurobehavioral Genetics, Semel Institute for Neuroscience andHuman Behavior, University of California Los Angeles, Los Angeles, CA (RAO). 2 Therewas no funding source for the research described in this article. 3 Currentaddress of JJL: Department of Psychiatry, ZNA Hospitals, Antwerp,Belgium. 4 Addresscorrespondence to NM Verhoeven-Duif, Department of MedicalGenetics, University Medical Center Utrecht, Huispost KC02.069.1, Lundlaan6, 3584 EA Utrecht, Netherlands. E-mail: n.verhoeven@umcutrecht.nl. 5 Abbreviationsused: CSF, cerebrospinal fluid; LOQ, limit of quantifica-tion; OMIM, Online Mendelian Inheritance in Man; PA, pyridoxic acid; PLP,pyridoxal phosphate; PMP, pyridoxamine phosphate; PNPO, pyridox(am)ine-5 # -phosphate oxidase; QC, quality control.ReceivedDecember 16, 2013. Accepted for publication April 18, 2014.doi:10.3945/ajcn.113.082008.  Am J Clin Nutr   doi: 10.3945/ajcn.113.082008. Printed in USA.    2014 American Society for Nutrition  1 of 6   AJCN. First published ahead of print May 7, 2014 as doi: 10.3945/ajcn.113.082008. Copyright (C) 2014 by the American Society for Nutrition  In the literature, concentrations of the B-6 vitamers pyridoxine,pyridoxamine, pyridoxamine phosphate (PMP), pyridoxal, PLP,and the degradation product of vitamin B-6, pyridoxic acid (PA)have been reported for plasma. In most publications (26–35), PLP,PA, and pyridoxal were reported to be the B-6 vitamers mostabundantly present in plasma ( see  Supplementary Table 1 under“Supplemental data” in the online issue). In the CSF of newborninfants (36) and children (37), pyridoxal was reported to be themost abundant B-6 vitamer, followed by PLP ( see  SupplementaryTable 2 under “Supplemental data” in the online issue).In the current study, we measured concentrations of pyri-doxine, pyridoxamine, PMP, pyridoxal, PLP, and PA in plasmaand the CSF of a large number of adult subjects. We studied therelation between B-6 vitamers in plasma and the CSFand betweenplasma and CSF and we investigated the possible influence of sex. SUBJECTS AND METHODS Subjects and sample collection Of 533 healthy adult subjects (18–63 y of age), fasting plasmaand CSF were collected. The first participant was recruited beforeJuly 2008, and plasma and CSF were collected preceding theadministration of spinal anesthesia for minor elective surgery atdifferent hospitals in and near Utrecht, Netherlands, between July2008 and November 2011. Subject characteristics and detailsof sample collection were described previously (38–40). Insummary, subjects were included if they were of North-WesternEuropean descent (ie, all grandparents born in the Netherlands,Belgium, France, Germany, Denmark, or the United Kingdom).Subjects with a history of self-reported psychotic or major neu-rological disorders (stroke, brain tumors, and neurodegenerativedisease) were excluded. Sample storage Afterwithdrawal,plasmaandCSFsampleswerestoredat 2 80 8 Cand protected from light until further analysis. To study theinfluence of temperature on B-6 vitamer concentrations in CSF,aliquots stored at  2 20 8 C were compared with aliquots storedat  2 80 8 C ( n  = 62), because it was previously shown that B-6vitamers are stable when samples are stored at 2 80 8 C (28, 34). Quantification of B-6 vitamers Concentrations of pyridoxine, pyridoxamine, PMP, pyridoxal,PLP, and PAwere measured in plasma and CSF by ultra HPLC–tandem mass spectrometry according to the method of van derHam et al (37). This method, developed for the analysis of CSF,was adapted for application in plasma.For the measurement of B-6 vitamer concentrations in plasma,100  m L plasma and internal standards was used. Samples werecentrifuged twice after protein precipitation with trichloroaceticacid (5 min, 13,000 rpm). Calibration curve end concentrationsof pyridoxal, PLP, and PA were adjusted for quantification of these B-6 vitamers in plasma (160, 200, and 185 nmol/L, re-spectively). For the quality-control (QC) samples, the plasma of random subjects was pooled, and B-6 vitamers were spiked toachieve 3 different concentrations (QC1–3). QC1–3 were usedto study interassay variations ( n  = 10) for the different B-6 vitamers.Limits of detection and quantification were determined by usingQC1 [ n  = 10; signal-to-noise ratios of 3 and 10, respectively] ( see Supplementary Table 3 under “Supplemental data” in the onlineissue). PMP in plasma was not detectable because of instability. Statistical analysis SPSS 20.0 (IBM Corporation) was used for the statisticalanalysis. Because none of the B-6 vitamers in plasma and CSF,nor their unstandardized residuals, showed a normal distribution,nonparametric (Mann-Whitney  U  ) tests were applied to studydifferences in B-6 vitamer concentrations, and 95% CIs werecalculated for median B-6 vitamer concentrations and their 2.5thand 97.5th percentiles by using bootstrap analysis. Spearman’s r   was used to describe correlations. RESULTS In plasma and CSF, pyridoxal, PLP, and PA were present atlevels above the limit of quantification (LOQ) of the analysismethod used. Pyridoxamine was present in quantifiable amountsin CSF only; in plasma it was below the LOQ. PMP was , LOQin CSF (37), and in plasma it was highly instable; therefore, noreliable results could be obtained. Pyridoxine was  , LOQ inboth CSF (37) and plasma ( , 0.03 and  , 0.28 nmol/L, re-spectively;  see  Supplementary Table 3 under “Supplementaldata” in the online issue).Ten of 533 subjects with one or more extremely low or highB-6vitamerconcentrationsinplasmaorCSFwereexcludedfromthe reference set. In5 of the10 excluded subjects, pyridoxinewaspresent in the CSF (0.5–125 nmol/L) and/or plasma (0.7–2.1nmol/L), which points to vitamin B-6 supplementation (26, 37).In the other 5 subjects, concentrations of one or more B-6vitamers were  . 1.5 times lower or higher than the lower orupper reference limit. As a result, B-6 vitamers of 523 subjects(plasma,  n  = 502; CSF,  n  = 424 and both  n  = 404) were furtheranalyzed, and concentrations of pyridoxamine (in CSF), pyridoxal,PLP, and PA (in plasma and CSF) were studied in more detail. B-6 vitamer concentrations in plasma and CSF The median concentrations of the different B-6 vitamers inplasma and CSF (nmol/L), and their respective ranges and 2.5th–97.5th percentile ranges, are shown in  Table 1 . The mostabundant B-6 vitamer in plasma was PLP [median concentration55.9 (2.5th–97.5th percentile range, 19.8–200) nmol/L], whereasin CSF the concentration of pyridoxal [median concentration30.0 (2.5th–97.5th percentile range, 17.4–54.5) nmol/L] was thehighest. B-6 vitamer concentrations in plasma and CSF did notcorrelate with age (data not shown).  Influence of storage temperature PLP, pyridoxamine, and pyridoxal in CSF were not stableduring storage at  2 20 8 C. Concentrations of PLP and pyridoxaldecreased with time and became undetectable after 10 and 20mo, respectively. On the contrary, concentrations of pyridox-amine increased up to 500% in 15 mo.  Influence of sex In plasma and CSF, concentrations of both pyridoxal and PLPwereinfluencedbysex.The medianconcentrationofpyridoxalin 2 of 6  ALBERSEN ET AL  CSF was lower in men [29.5 (2.5th–97.5th percentile range,16.8–56.3) compared with 32.1 (2.5th–97.5th percentile range,17.3–55.1) nmol/L;  P  = 0.022], whereas the median concen-tration of pyridoxal in plasma was higher in men [11.0 (2.5th–97.5th percentile range, 4.2–25.5) compared with 9.2 (2.5th–97.5th percentile range, 3.9–24.4) nmol/L;  P  ,  0.001] ( see Supplementary Table 4 under “Supplemental data” in the onlineissue). Median concentrations of PLP in both plasma and CSFwere higher in men than in women [60.2 (2.5th–97.5th per-centile range, 23.5–208) compared with 44.0 (2.5th–97.5thpercentile range, 16.0–167) nmol/L for plasma;  P  ,  0.001;17.0 (2.5th–97.5th percentile range, 7.4–35.2) compared with14.0 (2.5th–97.5th percentile range, 6.4–34.4) nmol/L for CSF; P , 0.001]. Concentrations of the other B-6 vitamers in plasmaand CSF did not differ between men and women (data notshown). B-6 vitamer ratios and correlations in and between plasmaand CSF The ratios and correlations between pyridoxamine, PL, PLP,and PA in plasma and CSF are shown in  Table 2 . In plasma, thestrongest correlation was observed between PLP and pyridoxal ( r   =0.564,  P ,  0.001;  Figure 1 A). In CSF, concentrations of PA andpyridoxal were correlated ( r   = 0.536,  P ,  0.001).In  Table 3 , ratios and correlations are shown for pyridoxal,PLP, and PA between CSF and plasma. Strong correlationsbetween concentrations in CSF and plasma were observed for all TABLE 1 Concentrations of PM, PL, PLP, and PA in the plasma and CSF of adult subjects (18–63 y;  n  = 523) 1 B-6 vitamer concentrationand body fluidMedian(95% CI) Range2.5th percentile(95% CI)97.5th percentile(95% CI) nmol/L nmol/L nmol/L nmol/L  PMCSF 0.36 (0.34, 0.38)  , 0.04 2 to 1.2 0.06 (0.04 2 , 0.09) 0.9 (0.8, 1.0)PL 3 Plasma 10.5 (10.2, 10.9) 3.0–56.2 4.2 (3.7, 4.5) 24.5 (20.8, 33.0)CSF 30.0 (29.1, 31.0) 13.5–78.5 17.4 (15.5, 18.4) 54.5 (49.3, 61.9)PLP 3 Plasma 55.9 (52.3, 59.1) 10.2–335 19.8 (18.0, 21.9) 200 (162, 217)CSF 16.1 (15.2, 16.8) 5.3–49.2 6.9 (6.4, 7.7) 34.0 (29.3, 37.1)PAPlasma 23.6 (22.2, 25.0) 2.7–243 6.1 (5.1, 6.8) 107 (85.3, 134)CSF 1.15 (1.04, 1.25)  , 0.09 2 to 8.7  , 0.09 2 3.8 (3.1, 5.4) 1 CSF, cerebrospinal fluid; LOQ, limit of quantification; PA, pyridoxic acid; PL, pyridoxal; PLP, pyridoxal phosphate;PM, pyridoxamine. 2 LOQ of this B-6 vitamer (37). 3 Sex-related differences in concentrations of PL and PLP in plasma and CSF are provided elsewhere ( see  Supple-mentary Table 4 under “Supplemental data” in the online issue). TABLE 2 Ratios between PM, PL, PLP, and PA in the plasma ( n  = 502) and CSF ( n  = 424) 1 B-6 vitamer ratioand body fluid 2 Median(95% CI) Range2.5th percentile(95% CI)97.5th percentile(95% CI) Correlation ( r  ) 3 PL:PMCSF 87.1 (78.3, 96.1) 16.6–774 29.1 (24.6, 35.6) 446 (347, 594) 0.154PLP:PLPlasma 5.4 (5.2, 5.7) 1.1–36.8 2.3 (1.9, 2.6) 13.7 (12.6, 16.1) 0.564**CSF 0.5 (0.5, 0.6) 0.2–1.8 0.2 (0.2, 0.3) 1.1 (1.0, 1.2) 0.265*PLP:PMCSF 50.0 (46.7, 54.8) 7.8–553 11.7 (9.9, 14.5) 274 (204, 316) 0.033PA:PLPlasma 2.4 (2.2, 2.5) 0.3–15.2 0.7 (0.5, 0.8) 7.8 (7.2, 8.7) 0.395*CSF 0.04 (0.04, 0.04) 0.00–0.13 0.00 (0.00, 0.00) 0.10 (0.09, 0.10) 0.536**PA:PLPPlasma 0.44 (0.41, 0.46) 0.03–2.5 0.12 (0.10, 0.14) 1.4 (1.2, 1.5) 0.414*CSF 0.07 (0.06, 0.08) 0.00–0.38 0.01 (0.00, 0.01) 0.24 (0.20, 0.27) 0.198*PA:PMCSF 3.2 (2.8, 3.8) 0.1–44.0 0.2 (0.2, 0.5) 16.8 (15.4, 21.8) 0.172* 1 * Significant at  P  ,  0.001. **Significant at  P  ,  0.001 and  r   .  0.500. CSF, cerebrospinal fluid; LOQ, limit of quantification; PA, pyridoxic acid; PL, pyridoxal; PLP, pyridoxal phosphate; PM, pyridoxamine. 2 For ratio calculations, B-6 vitamer concentrations , LOQ were replaced by the determined LOQ of the respectiveB-6 vitamer ( n  = 6 for PM and  n  = 21 for PA). 3 Spearman’s  r  . VITAMIN B-6 IN PLASMA AND CSF  3 of 6  B-6 vitamers. The strongest correlation was found for PLP ( r   =0.629,  P  , 0.001; Figure 1B). DISCUSSION To date, we do not know the physiologic importance of eachB-6 vitamer. On the basis of PLP analyses only, vitamin B-6 wasreported to be inversely associated with oxidative stress, in-flammation, cardiovascular disease, diabetes, and cancer (3–22).Whether concentrations of the other B-6 vitamers are also rel-evant remains to be elucidated.This study provides an extensive reference set containingconcentrations of all B-6 vitamers in plasma and CSF, whichcontributes to an adequate diagnosis of known and novel dis-orders associated with vitamin B-6 metabolism. Because of theunique nature of the study design, with simultaneously with-drawn blood and CSF, B-6 vitamer concentrations could becompared between both body fluids, which provides furtherinsight on normal human B-6 vitamers and their interrelations. Itmust be warranted, however, that CSF and plasma are storedat  2 80 8 C to retain B-6 vitamer stability. In addition, concen-trations of certain B-6 vitamers in plasma and CSF are influ-enced by sex. B-6 vitamers in human plasma and CSF Humans depend on dietary sources of vitamin B-6, becauseweare unable to synthesize vitamin B-6. In our diet, various B-6vitamers are present, which are converted into PLP. The B-6vitamer composition of plasma (PLP . PA . pyridoxal) differsfrom that of CSF (pyridoxal . PLP . PA . pyridoxamine). Inrecent in vitro studies, we showed that the intestine plays animportant role in the conversion of precursor B-6 vitamers(pyridoxine and pyridoxamine) into PLP and pyridoxal (41).Both uptake of vitamin B-6 from the diet and subsequent in-testinal and hepatic metabolism result in PLP being the domi-nant B-6 vitamer in plasma. This is in contrast with CSF, wherepyridoxal is most abundant. Pyridoxamine is not detectable inplasma, as was also previously reported (34, 35). Likewise,pyridoxine is not present in plasma or in CSF, unless subjects aresupplemented with vitamin B-6 (26, 37).In addition to the previously mentioned processes associatedwith vitamin B-6 status, altered B-6 vitamer concentrations canalso beusedin thediagnosisoffunctionalvitaminB-6deficiency,which can result from antiquitin deficiency [Online MendelianInheritance in Man (OMIM) 266100] (42), pyridox(am)ine-5 # -phosphate oxidase (PNPO) deficiency (OMIM 610090) (25),hypophosphatasia (alkaline phosphatase deficiency; OMIM241500) (43, 44) and hyperprolinemia type II (pyrroline-5-carboxylate dehydrogenase deficiency; OMIM 239510) (45). Inaddition, yet unknown causes of functional vitamin B-6 de-ficiency have been reported (25, 46–48). Patients present withconvulsions and, frequently, developmental delay (49). Al-though treatment with vitamin B-6 (pyridoxine or PLP) is oftensuccessful in reducing convulsions, developmental delay stilloccurs (49, 50).Indeed, decreased concentrations of PLP (25, 51, 52) andpyridoxal (25) havebeen found in the CSFof patients with PNPOdeficiency and antiquitin deficiency [decreased PLP only (53)].Concentrations of the other B-6 vitamers were not reported,whereas these might be abnormal as well and may have an effecton diagnosis and treatment. In plasma, B-6 vitamer concentrationshave been published only for PNPO- and antiquitin-deficient FIGURE 1.  A: Correlation (Spearman’s  r  ,  P  value) between PLP and PLin plasma ( r   = 0.564,  P  ,  0.001;  n  = 502). B: Correlation (Spearman’s  r  , P  value) betweenPLPinCSFandPLP inplasma ( r   =0.629, P , 0.001; n =404).CSF, cerebrospinal fluid; PL, pyridoxal; PLP, pyridoxal phosphate. TABLE 3 Ratios of PL, PLP, and PA between CSF and plasma ( n  = 404) 1 B-6 vitamerCSF:plasma 2 Median(95% CI) Range2.5th percentile(95% CI)97.5th percentile(95% CI) Correlation ( r  ) 3 PL 2.9 (2.8, 3.1) 0.9–10.6 1.6 (1.4, 1.7) 7.2 (6.3, 7.6) 0.467*PLP 0.3 (0.3, 0.3) 0.1–0.9 0.1 (0.1, 0.1) 0.7 (0.6, 0.8) 0.629**PA 0.04 (0.04, 0.05) 0.00–0.35 0.00 (0.00, 0.01) 0.17 (0.13, 0.22) 0.486* 1 *Significant at  P  ,  0.001. **Significant at  P  ,  0.001 and  r   .  0.500. CSF, cerebrospinal fluid; LOQ, limit of quantification; PA, pyridoxic acid; PL, pyridoxal; PLP, pyridoxal phosphate. 2 For ratio calculations, B-6 vitamer concentrations , LOQ were replaced by the determined LOQ of the respectiveB-6 vitamer ( n  = 21 for PA). 3 Spearman’s  r  . 4 of 6  ALBERSEN ET AL  patients receiving vitamin B-6 supplementation (26). Indirectly,altered B-6 vitamer concentrations can also reflect riboflavinstatus, because the PNPO enzyme requires flavin mononucleotideas an indispensable cofactor (54). Vitamin B-6 metabolism The strict ratios and strong correlations between PLP andpyridoxal in plasma and between PA and pyridoxal in CSFsuggest that concentrations of these B-6 vitamers are tightlyregulated. Disturbances of these B-6 vitamer ratios in plasma andCSF may therefore indicate possible deficiencies of the enzymesinvolved in vitamin B-6 metabolism: pyridoxal kinase (whichphosphorylates pyridoxal into PLP) and pyridoxal phosphatase[which hydrolyzes PLP into pyridoxal (55)] and pyridoxal oxi-dase, which is involved in the degradation of pyridoxal into PA(56).ItisthereforerelevanttodetermineconcentrationsofallB-6vitamerswheninvestigatingpossiblevitaminB-6–related disease( see  Supplementary Table 5 under “Supplemental data” in theonline issue for ratios and correlations between B-6 vitamers asreported in literature). Vitamin B-6 transport Little is known about the mechanism by which any of the B-6vitamers is transported from blood to brain. At a biochemicallevel, there is evidence for carrier-mediated transport in thechoroid plexus and blood-brain barrier (57), but a vitamin B-6transporter protein has not yet been characterized. The strongcorrelations for pyridoxal and PLP between CSF and plasma mayreflect transport at the blood-brain barrier or choroid plexus.Disturbances of B-6 vitamer ratios between CSF and plasma maytherefore point toward a problem in vitamin B-6 transport, inawaysimilar to the decreased CSF:plasmaratio of glucose thatisfound in GLUT1 (blood-brain barrier glucose transporter) de-ficiency (OMIM 606777). We therefore advocate to not onlyanalyze B-6 vitamers in plasma or CSF, but in both body fluidssimultaneously when investigating a functional vitamin B-6deficiency of unknown cause. Conclusion With this study, we provide an extensive reference set of B-6vitamer concentrations in the plasma and CSF of adult subjects.Our data suggest a tight regulation of B-6 vitamers in and be-tween blood and CSF. For adequate interpretation of B-6 vitamerconcentrations, the influence of sex should be taken into accountand samples should be stored adequately. In addition to providinginsight on the regulation of individual vitamers and their inter-compartmental distribution, we anticipate that these data willprove to be a valuable reference set for the diagnosis andtreatment of conditions associated with altered vitamin B-6metabolism. We thank Jacobine E Buizer-Voskamp for her coordinational support andare grateful to Teus H Kappen for providing the plasma and CSF samples.The authors’ responsibilities were as follows—MA, JJL, SCB, ES, PJB,PJMK, EPAvD, PB, GV, RAO, and NMV-D: designed the research; MA,MB, JJMJ, JJL, SCB, ES, PJB, PJMK, EPAvD, PB, MGMdS-vdV, GV,NVVAMK, RAO, and NMV-D: conducted the research and wrote the man-uscript; MA, MB, JJMJ, MGMdS-vdV, GV, and NMV-D: analyzed the data;and NMV-D: had primary responsibility for the final content. 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