Abstract
IntroductionPANS 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.DesignThis 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.MethodsThirty-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.ResultsSeparation 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.ConclusionWe 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.
Highlights
Pediatric acute-onset neuropsychiatric syndrome (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
A weak correlation was found between age and the metabolic profile (R2 was equal to 0.52) while a strong correlation was found between the phenotypic severity parameters express as Pediatric Acute Neuropsychiatric Symptom Scale (PANSS) scale evaluation and the metabolic profile (R2 was equal to 0.7)
The results of the present study suggest unique plasma metabolite profiles in PANS patients, significantly differing from healthy children, showing abnormal levels of metabolites associated with neurotransmission and generalized energy deficiency, oxidative stress, neuroinflammation
Summary
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. The major clinical features of PANS consist of an acute-onset obsessive-compulsive disorder and/or severe eating restrictions, with at least two concomitant cognitive, behavioral, or affective symptoms such as anxiety, irritability, or depression (Swedo et al, 2012; Frankovich et al, 2015). These children experience neuropsychiatric symptoms in temporal association with GAS infection, and with exposure to a wide variety of other infections and environmental or metabolic changes; thusly, the PANDAS diagnosis fell under the newly established umbrella category PANS (Swedo et al, 2012). As is the case with PANDAS, PANS is thought to be sustained by immune-mediated mechanisms (Swedo et al, 2015; Spinello et al, 2016), those of so-called molecular mimicry occurring when pathogenic microorganisms express an antigenic structure indistinguishable (in terms of the amino acid sequence or three-dimensional structure) from self-antigens
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