Metabolomic Characterization of Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS)

Federica Murgia; Antonella Gagliano; Marcello G Tanca; Noga Or-Geva; Aran Hendren; Sara Carucci; Manuela Pintor; Francesca Cera; Fausto Cossu; Stefano Sotgiu; Luigi Atzori; Alessandro Zuddas

doi:10.3389/fnins.2021.645267

Metabolomic Characterization of Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS)

Front Neurosci. 2021 May 28:15:645267. doi: 10.3389/fnins.2021.645267. eCollection 2021.

Authors

Federica Murgia¹, Antonella Gagliano^{2

3}, Marcello G Tanca², Noga Or-Geva⁴, Aran Hendren^{1

5}, Sara Carucci^{2

3}, Manuela Pintor³, Francesca Cera², Fausto Cossu⁶, Stefano Sotgiu⁷, Luigi Atzori¹, Alessandro Zuddas^{2

3}

Affiliations

¹ Clinical Metabolomics Unit, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
² Child and Adolescent Neuropsychiatry Unit, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
³ Child and Adolescent Neuropsychiatry Unit, "A. Cao" Peditric Hosptal, "G. Brotzu" Hospital Trust, Cagliari, Italy.
⁴ Interdepartmental Program in Immunology, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, United States.
⁵ Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.
⁶ Paediatric Clinic, "A. Cao" Hospital, Cagliari, Italy.
⁷ Child Neuropsychiatry Unit, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy.

Abstract

Introduction: PANS is a controversial clinical entity, consisting of a complex constellation of psychiatric symptoms, adventitious changes, and expression of various serological alterations, likely sustained by an autoimmune/inflammatory disease. Detection of novel biomarkers of PANS is highly desirable for both diagnostic and therapeutic management of affected patients. Analysis of metabolites has proven useful in detecting biomarkers for other neuroimmune-psychiatric diseases. Here, we utilize the metabolomics approach to determine whether it is possible to define a specific metabolic pattern in patients affected by PANS compared to healthy subjects.

Design: This observational case-control study tested consecutive patients referred for PANS between June 2019 to May 2020. A PANS diagnosis was confirmed according to the PANS working criteria (National Institute of Mental Health [NIMH], 2010). Healthy age and sex-matched subjects were recruited as controls.

Methods: Thirty-four outpatients referred for PANS (mean age 9.5 years; SD 2.9, 71% male) and 25 neurotypical subjects matched for age and gender, were subjected to metabolite analysis. Serum samples were obtained from each participant and were analyzed using Nuclear Magnetic Resonance (NMR) spectroscopy. Subsequently, multivariate and univariate statistical analyses and Receiver Operator Curves (ROC) were performed.

Results: Separation of the samples, in line with the presence of PANS diagnosis, was observed by applying a supervised model (R²X = 0.44, R²Y = 0.54, Q² = 0.44, p-value < 0.0001). The significantly altered variables were 2-Hydroxybutyrate, glycine, glutamine, histidine, tryptophan. Pathway analysis indicated that phenylalanine, tyrosine, and tryptophan metabolism, as well as glutamine and glutamate metabolism, exhibited the largest deviations from neurotypical controls.

Conclusion: We found a unique plasma metabolic profile in PANS patients, significantly differing from that of healthy children, that suggests the involvement of specific patterns of neurotransmission (tryptophan, glycine, histamine/histidine) as well as a more general state of neuroinflammation and oxidative stress (glutamine, 2-Hydroxybutyrate, and tryptophan-kynurenine pathway) in the disorder. This metabolomics study offers new insights into biological mechanisms underpinning the disorder and supports research of other potential biomarkers implicated in PANS.

Keywords: biomarkers; metabolomics; neuroinflammation; oxidative stress; pediatric acute-onset neuropsychiatric syndrome.