Essential oils can cause false-positive results of medium-chain acyl-CoA dehydrogenase deficiency

Yasuko Mikami-Saito, Masamitsu Maekawa, Yoichi Wada, Tomoe Kanno, Ai Kurihara, Yuko Sato, Toshio Yamamoto, Natsuko Arai-Ichinoi, Shigeo Kure, Yasuko Mikami-Saito, Masamitsu Maekawa, Yoichi Wada, Tomoe Kanno, Ai Kurihara, Yuko Sato, Toshio Yamamoto, Natsuko Arai-Ichinoi, Shigeo Kure

Abstract

Newborn screening is a public health care program worldwide to prevent patients from critical illness or conditions. Tandem mass spectrometry allows multiplex, inexpensive, and rapid newborn screening. However, mass spectrometry used for newborn screening to date is not able to separate peaks of compounds with similar m/z, which could lead to false-positive results without additional second-tier tests, such as fragmentation. We experienced three neonatal cases with high levels of markers, octanoylcarnitine and octanoylcarnitine/decanoylcarnitine ratio used to pick up possible cases of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. The babies were born consecutively in a maternity hospital. Their second acylcarnitine profiles were normal, and the genetic tests for ACADM were negative. Analysis of samples extracted from their first Guthrie cards where blood was not stained also showed peaks equivalent to octanoylcarnitine and decanoylcarnitine, indicating contamination. Environmental surveillance in the maternity ward suggested that essential oils used there might contain the contaminated compound. LC-HRMS/MS and in silico analysis revealed that false-positive results might be due to contamination with the essential oils in Guthrie cards, and causal agents were sphinganine (d17:0) and 2-[2-hydroxyethyl(pentadecyl)amino]ethanol. Thus, health care providers should be cautioned about use of essential oils when collecting blood samples on Guthrie cards. False-positive results can waste costly social resources and cause a physical and psychological burden for children and parents.

Keywords: C10, decanoylcarnitine,; C8, octanoylcarnitine,; Decanoylcarnitine; Essential oils; FAOD, fatty acid oxidation disorder,; False-positive; LC-HRMS/MS, liquid chromatography-high resolution-tandem mass spectrometry; LC-MS/MS, liquid chromatography-tandem mass spectrometry,; MCAD deficiency; MCAD, medium-chain acyl-CoA dehydrogenase,; NBS, newborn screening; Newborn screening; Octanoylcarnitine.

Conflict of interest statement

The authors have no conflicts of interest to disclose.

© 2020 The Authors.

Figures

Fig. 1
Fig. 1
LC-MS/MS spectra of blood-stained and non-blood-stained portions of the first Guthrie card. (a, c, and e) Blood-stained portions of the first Guthrie card in Cases 1, 2, and 3, respectively. (b, d, and f) Non-blood-stained portions of the first Guthrie card in Cases 1, 2, and 3. respectively (g) Sample taken from a new Guthrie card. The open and closed arrows indicate the peaks of C8 (m/z of 288) and C10 (m/z of 316), respectively. Abbreviation: LC-MS/MS, liquid chromatography-tandem mass spectrometry.
Fig. 2
Fig. 2
LC-HRMS/MS spectra of a non-blood-stained portion of the first Guthrie cards compared with Guthrie cards stained with the essential oils from Lavandula angustifolia ssp. angustifolia (lavender), Melaleuca alternifolia (tea tree), and Cupressus sempervirens (cypress). (a, i) Non-blood-stained portion of the first Guthrie cards. Guthrie cards were stained with essential oils as follows: (b, j) lavender, (c, k) tea tree, (d, l) cypress, (e, m) lavender and tea tree, (f, n) lavender and cypress, (g, o) tea tree and cypress, and (h, p) lavender, tea tree, and cypress. The columns from left to right are MS spectra around m/z 288.2893, MS/MS spectra of m/z 288.2893, MS spectra around m/z 316.3206, and MS/MS spectra of m/z 316.3206. The open and closed arrows indicate the peaks of m/z 288 and 316, consistent with C8 and C10, respectively. Abbreviations: LC-HRMS/MS, liquid chromatography-high resolution tandem mass spectrometry; MS, mass spectrometry; MS/MS, tandem mass spectrometry.
Fig. 3
Fig. 3
LC-HRMS/MS analysis of standard reference materials. Upper, middle, and lower panels of each figure show MS, retention time, and MS/MS analysis. Samples are as follows: (a, d) non-blood-stained portion of the first Guthrie cards, (b) sphinganine (d17:0), (e) 2-[2-hydroxyethyl(pentadecyl)amino]ethanol, and (c, f) mixture of sphinganine (d17:0) and 2-[2-hydroxyethyl(pentadecyl)amino]ethanol. (a, b, c) and (d, e, f) were focused on m/z 288.2893 and 316.3206, respectively. The open and closed arrows indicate the peaks of m/z 288 and 316, which were consistent with C8 and C10, respectively. Retention times of respective peaks matched exactly. Abbreviations: LC-HRMS/MS, liquid chromatography-high resolution tandem mass spectrometry; MS, mass spectrometry; MS/MS, tandem mass spectrometry.
Fig. 4
Fig. 4
LC-MS/MS spectra in Guthrie cards stained with vaporized essential oils. (a) Lavender, (b) tea tree, and (c) cypress. MS spectra, MS/MS spectra of m/z 288.2893, and MS/MS spectra of m/z 316.3206 are shown in order from the top to bottom rows. The open arrow in (c) indicates the peak of m/z 288.2893. Abbreviations: MS, mass spectrometry; MS/MS, tandem mass spectrometry.

References

    1. McCandless S.E., Wright E.J. Mandatory newborn screening in the United States: history, current status, and existential challenges. Birth Defects Res. 2020;112:350–366.
    1. Tajima G. Screening of MCAD deficiency in Japan: 16 years’ experience of enzymatic and genetic evaluation. Mol. Genet. Metab. 2016;119:322–328.
    1. Kølvraa S., Gregersen N., Christensen E., Hobolth N. In vitro fibroblast studies in a patient with C6-C10-dicarboxylic aciduria: evidence for a defect in general acyl-CoA dehydrogenase. Clin. Chim. Acta. 1982;126:53–67.
    1. Matsubara Y. Molecular cloning of cDNAs encoding rat and human medium-chain acyl-CoA dehydrogenase and assignment of the gene to human chromosome 1. Proc National Acad Sci. 1986;83:6543–6547.
    1. Venditti L.N. Newborn screening by tandem mass spectrometry for medium-chain acyl-CoA dehydrogenase deficiency: a cost-effectiveness analysis. Pediatrics. 2003;112:1005–1015.
    1. Rhead W.J. Newborn screening for medium-chain acyl-CoA dehydrogenase deficiency: a global perspective. J. Inherit. Metab. Dis. 2006;29:370–377.
    1. Hove J.L.V. Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: diagnosis by acylcarnitine analysis in blood. Am. J. Hum. Genet. 1993;52:958–966.
    1. McCandless S.E., Chandrasekar R., Linard S., Kikano S., Rice L. Sequencing from dried blood spots in infants with “false positive” newborn screen for MCAD deficiency. Mol. Genet. Metab. 2013;108:51–55.
    1. Kratz L.E., Albert J.S. 2-Ethylhexanoic acid, found in common plasticizers, leads to an artificial increase in C8 acylcarnitine levels in two neonates treated with extracorporeal membrane oxygenation (ECMO) Clin. Chim. Acta. 2016;461:59–60.
    1. Hara K. Significance of ACADM mutations identified through newborn screening of MCAD deficiency in Japan. Mol. Genet. Metab. 2016;118:9–14.
    1. Yamada K., Taketani T. Management and diagnosis of mitochondrial fatty acid oxidation disorders: focus on very-long-chain acyl-CoA dehydrogenase deficiency. J. Hum. Genet. 2019;64:73–85.
    1. Lai Z. Identifying metabolites by integrating metabolome databases with mass spectrometry cheminformatics. Nat. Methods. 2018;15:53–56.
    1. Shigematsu Y., Hata I., Tajima G. Useful second-tier tests in expanded newborn screening of isovaleric acidemia and methylmalonic aciduria. J. Inherit. Metab. Dis. 2010;33:S283–S288.
    1. Gurian E.A., Kinnamon D.D., Henry J.J., Waisbren S.E. Expanded newborn screening for biochemical disorders: the effect of a false-positive result. Pediatrics. 2006;117:1915–1921.
    1. O’Connor K. Psychosocial impact on mothers receiving expanded newborn screening results. Eur. J. Hum. Genet. 2018;26:477–484.
    1. Pierce L.J. Association of perceived maternal stress during the perinatal period with electroencephalography patterns in 2-month-old infants. JAMA Pediatr. 2019;173:561.
    1. Tim-Aroon T., Harmon H.M., Nock M.L., Viswanathan S.K., McCandless S.E. Stopping parenteral nutrition for 3 hours reduces false positives in Newborn screening. J. Pediatr. 2015;167:312–316.
    1. Schymik I. Pitfalls of neonatal screening for very-long-chain acyl-CoA dehydrogenase deficiency using tandem mass spectrometry. J. Pediatr. 2006;149:128–130.
    1. Edmondson A.C., Salant J., Ierardi-Curto L.A., Ficicioglu C. Missed newborn screening case of carnitine Palmitoyltransferase-II Deficiency. JIMD Rep. 2016:93–97.
    1. Dowsett L., Lulis L., Ficicioglu C., Cuddapah S. Utility of genetic testing for confirmation of abnormal Newborn screening in disorders of long-chain fatty acids: a missed case of carnitine Palmitoyltransferase 1A (CPT1A) deficiency. Int J Neonatal Screen. 2017;3:10.
    1. Anderson D.R., Viau K., Botto L.D., Pasquali M., Longo N. Clinical and biochemical outcomes of patients with medium-chain acyl-CoA dehydrogenase deficiency. Mol. Genet. Metab. 2019;129:13–19.
    1. Hsu H.-W. Spectrum of medium-chain acyl-CoA dehydrogenase deficiency detected by Newborn screening. Pediatrics. 2008;121:e1108–e1114.
    1. Tsai S.-S., Wang H.-H., Chou F.-H. The effects of aromatherapy on postpartum women: a systematic review. J. Nurs. Res. 2019;1 Latest Articles.
    1. Perry R., Terry R., Watson L.K., Ernst E. Is lavender an anxiolytic drug? A systematic review of randomised clinical trials. Phytomedicine. 2012;19:825–835.
    1. Re L. Linalool modifies the nicotinic receptor–ion channel kinetics at the mouse neuromuscular junction. Pharmacol. Res. 2000;42:177–181.
    1. Carling R.S. Introduction of a simple second tier screening test for C5 isobars in dried blood spots: reducing the false positive rate for Isovaleric Acidaemia in expanded Newborn screening. JIMD Rep. 2018;38:75–80.
    1. Jager E.A. A nationwide retrospective observational study of population newborn screening for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in the Netherlands. J. Inherit. Metab. Dis. 2019;42:890–897.
    1. Touw C.M.L. Risk stratification by residual enzyme activity after newborn screening for medium-chain acyl-CoA dehydrogenase deficiency: data from a cohort study. Orphanet J. Rare Dis. 2012;7:30.
    1. Peng G. Reducing false-positive results in Newborn screening using machine learning. Int J Neonatal Screen. 2020;6:16.
    1. da Oliveira W.S., Ubeda S., Nerín C., Padula M., Godoy H.T. Identification of non-volatile migrants from baby bottles by UPLC-Q-TOF-MS. Food Res. Int. 2019;123:529–537.
    1. Hannich J.T., Mellal D., Feng S., Zumbuehl A., Riezman H. Structure and conserved function of iso-branched sphingoid bases from the nematode Caenorhabditis elegans. Chem. Sci. 2017;8:3676–3686.
    1. Dietrich C.R. Loss-of-function mutations and inducible RNAi suppression of Arabidopsis LCB2 genes reveal the critical role of sphingolipids in gametophytic and sporophytic cell viability. Plant J. 2008;54:284–298.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe