Dynamical features in fetal and postnatal zinc-copper metabolic cycles predict the emergence of autism spectrum disorder

Paul Curtin*, Christine Austin, Austen Curtin, Chris Gennings, Manish Arora, Emergent Dynamical Systems Group, Kristiina Tammimies, Charlotte Willfors, Steve Berggren, Paige Siper, Dheeraj Rai, Kristin Meyering, Alexander Kolevzon, Josephine Mollon, Anthony S. David, Glyn Lewis, Stanley Zammit, Lynne Heilbrun, Raymond F. Palmer, Robert O. WrightSven Bölte, Abraham Reichenberg

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

14 Citations (Scopus)
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Abstract

Metals are critical to neurodevelopment, and dysregulation in early life has been documented in autism spectrum disorder (ASD). However, underlying mechanisms and biochemical assays to distinguish ASD cases from controls remain elusive. In a nationwide study of twins in Sweden, we tested whether zinc-copper cycles, which regulate metal metabolism, are disrupted in ASD. Using novel tooth-matrix biomarkers that provide direct measures of fetal elemental uptake, we developed a predictive model to distinguish participants who would be diagnosed with ASD in childhood from those who did not develop the disorder. We replicated our findings in three independent studies in the United States and the UK. We show that three quantifiable characteristics of fetal and postnatal zinc-copper rhythmicity are altered in ASD: the average duration of zinc-copper cycles, regularity with which the cycles recur, and the number of complex features within a cycle. In all independent study sets and in the pooled analysis, zinc-copper rhythmicity was disrupted in ASD cases. In contrast to controls, in ASD cases, the cycle duration was shorter (F = 52.25, P < 0.001), regularity was reduced (F = 47.99, P < 0.001), and complexity diminished (F = 57.30, P < 0.001). With two distinct classification models that used metal rhythmicity data, we achieved 90% accuracy in classifying cases and controls, with sensitivity to ASD diagnosis ranging from 85 to 100% and specificity ranging from 90 to 100%. These findings suggest that altered zinc-copper rhythmicity precedes the emergence of ASD, and quantitative biochemical measures of metal rhythmicity distinguish ASD cases from controls.
Original languageEnglish
Article numbereaat1293
Number of pages9
JournalScience Advances
Volume4
Issue number5
DOIs
Publication statusPublished - 30 May 2018

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    NIHR BRC Mental Health

    Gunnell, D. J.

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    Cite this

    Curtin, P., Austin, C., Curtin, A., Gennings, C., Arora, M., Emergent Dynamical Systems Group, Tammimies, K., Willfors, C., Berggren, S., Siper, P., Rai, D., Meyering, K., Kolevzon, A., Mollon, J., David, A. S., Lewis, G., Zammit, S., Heilbrun, L., Palmer, R. F., ... Reichenberg, A. (2018). Dynamical features in fetal and postnatal zinc-copper metabolic cycles predict the emergence of autism spectrum disorder. Science Advances, 4(5), [eaat1293]. https://doi.org/10.1126/sciadv.aat1293