Biomarkers for Diagnosis and Treatment Response in Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS)

NCT07718958 | Recruiting

• 1 other identifier: BIOMA-PANS
• Study Type: observational
• Target: 80
• Locations: 1 country
• Sites: 5

Brief Summary

Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is a complex neuropsychiatric disorder characterized by the abrupt onset of symptoms and currently diagnosed mainly on clinical criteria, as reliable diagnostic biomarkers are still lacking. The primary objective of this project is to identify and validate a panel of neurophysiological, molecular, genetic, and metabolomic biomarkers associated with disease onset, clinical trajectory, and response to antimicrobial, anti-inflammatory, and immunomodulatory treatments. Identifying objective biomarkers will improve diagnostic accuracy, facilitate earlier diagnosis, clarify disease mechanisms, and support the development of more targeted therapeutic strategies. PANS is currently considered a multifactorial immune-mediated inflammatory brain disorder resulting from the interaction of genetic susceptibility, immune dysregulation, infections, and environmental factors such as stress or trauma. Current evidence suggests that both innate and adaptive immune responses contribute to disease pathophysiology through interactions between the peripheral immune system and the central nervous system. The pathogenic process may begin during fetal life through Maternal Immune Activation (MIA), whereby maternal infections or immune dysregulation induce inflammatory responses that increase susceptibility to neurodevelopmental disorders. During the postnatal period, infectious agents, including viruses, Mycoplasma pneumoniae, and Haemophilus influenzae, may trigger immune activation, leading to blood-brain barrier disruption, glial activation, and abnormalities within cortico-basal ganglia circuits thought to underlie PANS symptoms. To achieve these objectives, the project will adopt a multidisciplinary translational approach that combines the enrolment and characterization of pediatric patients with PANS with complementary studies in animal models. Particular emphasis will be placed on clinical and sleep features, together with molecular and metabolomic profiling, to identify biomarkers with diagnostic and prognostic value and to investigate the biological pathways underlying disease onset and progression. Given the high clinical, social, and economic burden of PANS, which frequently follows a chronic or relapsing-remitting course requiring long-term healthcare support, earlier diagnosis and a better understanding of disease mechanisms could significantly improve patient management. More broadly, the project will contribute to understanding the immune-mediated pathogenic pathways underlying PANS and related neurodevelopmental disorders, supporting the transition from symptom-based classification toward mechanism-based diagnosis and treatment.

Conditions

PANS; Pediatric Acute-Onset Neuropsychiatric Syndrome

Keywords

Biomarkers; PANS; Pediatric Acute-Onset Neuropsychiatric Syndrome; Neuroinflammation; sleep Disorders; Maternal Immune Activation (MIA); Microglia activation; Whole-exome sequencing (WES); microRNA (miRNA) profiling; Metabolomics (¹H-NMR spectroscopy); nflammatory biomarkers; Translational research

Outcome Measures

Primary Outcomes (1)

• Concentrations of predefined inflammatory biomarkers

  Inflammatory biomarker concentrations will be measured in biological samples using predefined laboratory assays. Associations between biomarker concentrations and psychiatric, neuropsychological, and polysomnographic measures will be evaluated using predefined statistical analyses.

  From the enrollment through study completion, an average of 36 months

Secondary Outcomes (5)

• Expression levels of selected microRNAs

  From the biological samples collection to the end of analysis, an average of 2 years

• Metabolomic profile

  From the biological samples collection to the end of analysis, an average of 2 years

• Frequency of pathogenic and likely pathogenic genetic variants

  From the biological samples collection to the end of analysis, an average of 2 years

• Molecular signatures in the maternal immune activation model

  From the biological samples collection to the end of analysis, an average of 2 years

• Diagnostic performance of candidate biomarkers

  From enrollment through study completion (approximately 36 months)

Study Arms (2)

PANS group

Children and adolescents diagnosed with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) undergoing clinical, neurophysiological, genetic, metabolomic, miRNA and sleep assessments.

Diagnostic Test: Psycodiagnostic evaluation; Diagnostic Test: Polysomnography; Diagnostic Test: 1H-NMR analysis; Diagnostic Test: miRNA sequencing

Healthy Controls

Age- and sex-matched neurotypical children without autoimmune, neurodevelopmental or psychiatric disorders undergoing the same assessment protocol for comparison.

Diagnostic Test: Psycodiagnostic evaluation; Diagnostic Test: Polysomnography; Diagnostic Test: 1H-NMR analysis; Diagnostic Test: miRNA sequencing

Interventions

Psycodiagnostic evaluation DIAGNOSTIC_TEST

Psycodiagnostic scales and tests to identify and quantify symptoms: Pediatric Acute Neuropsychiatric Symptom Scale (PANSS); Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS); punteggio Yale Global Tic Severity Scale (YGTSS); Pediatric Anxiety Rating Scale (PARS); Children's Global Assessment Scale (C-GAS). Il quoziente intellettivo (QI) sarà misurato mediante la WPPSI-III (Wechsler Preschool and Primary Scale of Intelligence- III) o la WISC-IV (Wechsler Intelligence Scale for Children - IV), according to children's age

Healthy Controls; PANS group

1H-NMR analysis DIAGNOSTIC_TEST

the samples will be analyzed with a Varian UNITY INOVA 500 spectrometer, which will operate at 499 MHz and equip with a 5 mm triple resonance probe with z-axis pulsed field gradients and an auto-sampler with 50 locations. One dimensional 1H-NMR spectra will be collected at 300 K with a pre-sat pulse sequence to suppress the residual water's signal. The spectra will be recorded with a spectral width of 6,000 Hz; a frequency of 2 Hz; an acquisition time of 1.5 s; a relaxation delay of 2 ms; and a 90 pulse of 9.5 ms. The number of scans will be at least of 250. Using MestReNova software, each 1H-NMR spectrum will be divided into consecutive "bins" of 0.04 ppm. A spectral area will be selected for the investigation, excluding the other regions in order to remove variations in the pre-saturation of the residual water resonance and spectral regions of noise. The study aims to isolate genomic DNA from PANS patients' peripheral blood leukocytes. Whole-exome sequencing (WES) analysis will be c

Healthy Controls; PANS group

miRNA sequencing DIAGNOSTIC_TEST

miRNA sequencing will be performed at the Center for Omics Sciences facility at IRCCS Ospedale San Raffaele. Bioinformatic analysis will be performed on the raw data obtained from sequencing. To detect differentially expressed miRNAs, a negative binomial regression considering several biological covariates will be used, and miRNAs with log2(FC)\>\|1 a p-value\<0.05 will be selected. Multiple testing correction will be applied to control the false-discovery rate using the Benjamini-Hochberg (BH) procedure. Blood level expression of selected miRNAs will be evaluated by qPCR. Plasma/Serum levels of selected markers will be evaluated by qPCR, western blot or ELISA analyses.

Healthy Controls; PANS group

Polysomnography DIAGNOSTIC_TEST

will be performed by means of a video complete polysomnography (PSG), following the AASM standard criteria. The following parameters will be included in the PSG study: EEG, electrooculogram, electromyogram (EMG) of submental muscle, EMG of bilateral tibialis anterior muscle and one single-lead ECG. The sleep respiratory pattern will be assessed by means of nasal airflow, thoracic and abdominal respiratory effort, and oxygen saturation, during the study night. Sleep signals will be stored on hard disk in European data format for further analysis. The polysomnographic parameters to be evaluated are: Total Sleep Time (TST), Sleep Efficiency (SE), Sleep Latency (SL), REM Latency, N1% TST, N2% TST, N3% TST, REM% TST, Wake After Sleep Onset % (WASO%), Awakenings, Periodic Limb Movement Index (PLMI), RSWA (REM Sleep Without Atonia), RAI (REM atonia index), and the presence of frequent change position. Standard EEG will be performed following International 10-20 system

Healthy Controls; PANS group

Eligibility Criteria

• Age: 3 Years - 18 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

The study population consists of children and adolescents with a diagnosis of Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) recruited at the referral center, together with age- and sex-matched neurotypical healthy controls recruited from the same geographical area.

You may qualify if:

• (I) PANS diagnosis made according to 2010 NIH criteria

You may not qualify if:

• (I) onset of specific rheumatologic or immunologic diseases;
• (II) presence of a diagnosed cancer or other severe medical illnesses;
• (III) active treatment with steroidal or non-steroidal anti-inflammatory drugs
• The control group must include children without autoimmune diseases, neurodevelopmental or psychiatric disorders, and with adequate academic performance and functional level.

Sponsors & Collaborators

• University of Cagliari: lead
• University of Palermo: collaborator
• Azienda Ospedaliera Universitaria Policlinico "G. Martino": collaborator
• Oasi Research Institute-IRCCS: collaborator
• Universita Telematica E-Campus: collaborator
• Azienda Ospedaliero Universitaria di Cagliari: collaborator

Study Sites (5)

Centro di Medicina del Sonno, SC Neurologia, AOU Cagliari

Cagliari, Cagliari, 09042, Italy

ACTIVE NOT RECRUITING

Università degli Studi eCampus

Novedrate, CO, 22060, Italy

ACTIVE NOT RECRUITING

UOC Neuropsichiatria

Troina, Enna, 94018, Italy

ACTIVE NOT RECRUITING

Azienda Ospedaliera Universitaria Gaetano Martino

Messina, Messina, 98124, Italy

RECRUITING

Dipartimento di Scienze Psicologiche, Pedagogiche, dell¿Esercizio Fisico e della Formazione

Palermo, Palermo, 90128, Italy

ACTIVE NOT RECRUITING

Related Publications (19)

• Swedo E. from research subgroup to clinical syndrome: modifying the PANDAS criteria to describe PANS (Pediatric Acute-onset Neuropsychiatric Syndrome). Pediatr Ther. 2012;02(02). doi:10.41 72/2161-0665.1000113

  BACKGROUND

• Santoni M, Sagheddu C, Serra V, Mostallino R, Castelli MP, Pisano F, Scherma M, Fadda P, Muntoni AL, Zamberletti E, Rubino T, Melis M, Pistis M. Maternal immune activation impairs endocannabinoid signaling in the mesolimbic system of adolescent male offspring. Brain Behav Immun. 2023 Mar;109:271-284. doi: 10.1016/j.bbi.2023.02.002. Epub 2023 Feb 4.

  PMID: 36746342 BACKGROUND

• De Felice M, Melis M, Aroni S, Muntoni AL, Fanni S, Frau R, Devoto P, Pistis M. The PPARalpha agonist fenofibrate attenuates disruption of dopamine function in a maternal immune activation rat model of schizophrenia. CNS Neurosci Ther. 2019 May;25(5):549-561. doi: 10.1111/cns.13087. Epub 2018 Nov 21.

  PMID: 30461214 BACKGROUND

• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

  PMID: 25741868 BACKGROUND

• Vetri L, Cali F, Vinci M, Amato C, Roccella M, Granata T, Freri E, Solazzi R, Romano V, Elia M. A de novo heterozygous mutation in KCNC2 gene implicated in severe developmental and epileptic encephalopathy. Eur J Med Genet. 2020 Apr;63(4):103848. doi: 10.1016/j.ejmg.2020.103848. Epub 2020 Jan 20.

  PMID: 31972370 BACKGROUND

• Ieraci A, Beggiato S, Ferraro L, Barbieri SS, Popoli M. Kynurenine pathway is altered in BDNF Val66Met knock-in mice: Effect of physical exercise. Brain Behav Immun. 2020 Oct;89:440-450. doi: 10.1016/j.bbi.2020.07.031. Epub 2020 Jul 26.

  PMID: 32726686 BACKGROUND

• Carini G, Mingardi J, Bolzetta F, Cester A, Bolner A, Nordera G, La Via L, Ieraci A, Russo I, Maggi S, Calza S, Popoli M, Veronese N, Musazzi L, Barbon A. miRNome Profiling Detects miR-101-3p and miR-142-5p as Putative Blood Biomarkers of Frailty Syndrome. Genes (Basel). 2022 Jan 26;13(2):231. doi: 10.3390/genes13020231.

  PMID: 35205276 BACKGROUND

• Musazzi L, Carini G, Barbieri SS, Maggi S, Veronese N, Popoli M, Barbon A, Ieraci A. Phenotypic Frailty Assessment in SAMP8 Mice: Sex Differences and Potential Role of miRNAs as Peripheral Biomarkers. J Gerontol A Biol Sci Med Sci. 2023 Oct 28;78(11):1935-1943. doi: 10.1093/gerona/glad160.

  PMID: 37422721 BACKGROUND

• Hesselmark E, Bejerot S. Biomarkers for diagnosis of Pediatric Acute Neuropsychiatric Syndrome (PANS) - Sensitivity and specificity of the Cunningham Panel. J Neuroimmunol. 2017 Nov 15;312:31-37. doi: 10.1016/j.jneuroim.2017.09.002. Epub 2017 Sep 9.

  PMID: 28919236 BACKGROUND

• Cunningham MW. Rheumatic fever, autoimmunity, and molecular mimicry: the streptococcal connection. Int Rev Immunol. 2014 Jul-Aug;33(4):314-29. doi: 10.3109/08830185.2014.917411. Epub 2014 Jun 3.

  PMID: 24892819 BACKGROUND

• Bejerot S, Hesselmark E. The Cunningham Panel is an unreliable biological measure. Transl Psychiatry. 2019 Jan 31;9(1):49. doi: 10.1038/s41398-019-0413-x. No abstract available.

  PMID: 30705260 BACKGROUND

• Frankovich J, Thienemann M, Pearlstein J, Crable A, Brown K, Chang K. Multidisciplinary clinic dedicated to treating youth with pediatric acute-onset neuropsychiatric syndrome: presenting characteristics of the first 47 consecutive patients. J Child Adolesc Psychopharmacol. 2015 Feb;25(1):38-47. doi: 10.1089/cap.2014.0081.

  PMID: 25695943 BACKGROUND

• Gagliano A, Galati C, Ingrassia M, Ciuffo M, Alquino MA, Tanca MG, Carucci S, Zuddas A, Grossi E. Pediatric Acute-Onset Neuropsychiatric Syndrome: A Data Mining Approach to a Very Specific Constellation of Clinical Variables. J Child Adolesc Psychopharmacol. 2020 Oct;30(8):495-511. doi: 10.1089/cap.2019.0165. Epub 2020 May 28.

  PMID: 32460516 BACKGROUND

• Gagliano A, Carta A, Tanca MG, Sotgiu S. Pediatric Acute-Onset Neuropsychiatric Syndrome: Current Perspectives. Neuropsychiatr Dis Treat. 2023 May 24;19:1221-1250. doi: 10.2147/NDT.S362202. eCollection 2023.

  PMID: 37251418 BACKGROUND

• Gagliano A, Murgia F, Capodiferro AM, Tanca MG, Hendren A, Falqui SG, Aresti M, Comini M, Carucci S, Cocco E, Lorefice L, Roccella M, Vetri L, Sotgiu S, Zuddas A, Atzori L. 1H-NMR-Based Metabolomics in Autism Spectrum Disorder and Pediatric Acute-Onset Neuropsychiatric Syndrome. J Clin Med. 2022 Nov 1;11(21):6493. doi: 10.3390/jcm11216493.

  PMID: 36362721 BACKGROUND

• Murgia F, Gagliano A, Tanca MG, Or-Geva N, Hendren A, Carucci S, Pintor M, Cera F, Cossu F, Sotgiu S, Atzori L, Zuddas A. Metabolomic Characterization of Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS). Front Neurosci. 2021 May 28;15:645267. doi: 10.3389/fnins.2021.645267. eCollection 2021.

  PMID: 34121984 BACKGROUND

• Zheng J, Frankovich J, McKenna ES, Rowe NC, MacEachern SJ, Ng NN, Tam LT, Moon PK, Gao J, Thienemann M, Forkert ND, Yeom KW. Association of Pediatric Acute-Onset Neuropsychiatric Syndrome With Microstructural Differences in Brain Regions Detected via Diffusion-Weighted Magnetic Resonance Imaging. JAMA Netw Open. 2020 May 1;3(5):e204063. doi: 10.1001/jamanetworkopen.2020.4063.

  PMID: 32364596 BACKGROUND

• Gagliano A, Puligheddu M, Ronzano N, Congiu P, Tanca MG, Cursio I, Carucci S, Sotgiu S, Grossi E, Zuddas A. Artificial Neural Networks Analysis of polysomnographic and clinical features in Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS): from sleep alteration to "Brain Fog". Nat Sci Sleep. 2021 Jul 23;13:1209-1224. doi: 10.2147/NSS.S300818. eCollection 2021.

  PMID: 34326674 BACKGROUND

• Trifiletti R, Lachman HM, Manusama O, Zheng D, Spalice A, Chiurazzi P, Schornagel A, Serban AM, van Wijck R, Cunningham JL, Swagemakers S, van der Spek PJ. Identification of ultra-rare genetic variants in pediatric acute onset neuropsychiatric syndrome (PANS) by exome and whole genome sequencing. Sci Rep. 2022 Jun 30;12(1):11106. doi: 10.1038/s41598-022-15279-3.

  PMID: 35773312 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

blood samples will be collected

MeSH Terms

Conditions

Pediatric acute-onset neuropsychiatric syndrome; Neuroinflammatory Diseases; Sleep Wake Disorders

Interventions

Polysomnography

Condition Hierarchy (Ancestors)

Nervous System Diseases; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neurologic Manifestations; Signs and Symptoms; Mental Disorders

Intervention Hierarchy (Ancestors)

Monitoring, Physiologic; Diagnostic Techniques and Procedures; Diagnosis

Central Study Contacts

Monica MF Puligheddu, MD, PHD

CONTACT

070 5109 6016; puligheddu@unica.it

Antonella Gagliano, MD, PhD

CONTACT

agagliano@oasi.en.it

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Target Duration: 1 Year
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof.

Study Record Dates

• First Submitted: July 3, 2026
• First Posted: July 22, 2026
• Study Start: August 8, 2024
• Primary Completion (Estimated): February 28, 2027
• Study Completion (Estimated): February 28, 2027
• Last Updated: July 31, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will not share

Locations

IT (5)