Pediatric Acute-Onset Neuropsychiatric Syndrome: A Data Mining Approach to a Very Specific Constellation of Clinical Variables

Gagliano, Antonella; Galati, Cecilia; Ingrassia, Massimo; Ciuffo, Massimo; Alquino, Maria Ausilia; Tanca, Marcello G; Carucci, Sara; Zuddas, Alessandro; Grossi, Enzo

doi:10.1089/cap.2019.0165

Cited by 19 publications

(37 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, an increase in serum glycine levels measured by 1 H-NMR spectra has been shown to differentiate schizophrenia (with higher glycine levels) from bipolar patients (with glycine plasma levels similar to controls), suggesting an important role for glycine in regulating cognition (Tasic et al, 2019) and affective regulation, an observation parallelled in animal models of neuropsychiatric disorders (Humer et al, 2020). Irritability, emotional lability, behavioral regression has been shown to be a crucial component of the PANS clinical presentation (Gagliano et al, 2020), rendering the involvement of glycine metabolism in PANS biologically plausible. Remarkably, antibodies directed against extracellular receptors on the synaptic surface, such as the NMDA receptor, are known to lead to NMDA receptor hypofunction in patients, resulting in behavioral and psychotic manifestations in specific forms of autoimmune encephalitis (Endres et al, 2019).…”

Section: Discussionmentioning

confidence: 98%

“…Despite this accumulating evidence, PANS is still regarded as a controversial clinical entity, consisting of a complex combination of psychiatric symptoms and adventitious changes and the expression of various serological variables of an autoimmune/inflammatory disease (Gagliano et al, 2020). In this scenario, research for new specific biomarkers is strongly desirable.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2021

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Severe psychotic symptoms can sometimes emerge in the clinical setting of PANS/PANDAS (8). Furthermore, emotional lability/depression could be highly related to autoimmune diseases in pregnancy, while anxiety symptoms could be related to recurrent infectious diseases in PANS patients (9). A recent study also found a possible involvement of serum levels of NOX2, as well as 8-isoprostaglandin F2α (8-iso-PGF2α) and lipopolysaccharide (LPS) in neuroinflammatory processes in PANDAS PANDAS patients (10).…”

Section: Introduction the Pans And Pandas Syndromesmentioning

confidence: 99%

The Impact of the COVID-19 Epidemic During the Lockdown on Children With the Pediatric Acute-Onset Neuropsychiatric Syndrome (PANDAS/PANS): The Importance of Environmental Factors on Clinical Conditions

et al. 2021

Self Cite

View full text Add to dashboard Cite

Introduction: In March 2020, SARS-CoV-2 declared a pandemic by the World Health Organization. Restrictive isolation measures have also brought psychological distress to the pediatric population. Building on the syndrome's characteristics, the present study explored the impact of lockdown on the clinical course of young people with PANDAS/PANS. The initial hypothesis considered both the reduced exposure to viral agents and the strategies of the parents and other containment actions as protective factors against the worsening of symptoms.Methods: One hundred and eight children, adolescents, and young adults were recruited according to the multicenter PANDAS/PANS research program. Parents participated in a web-based survey. Results: contrary to our hypothesis, the study results show an increase in symptoms during the block in 71% of the sample. Psychometric analyzes allowed us to exclude a relationship between the main symptoms of PANDAS and the increase in symptoms or the presence of symptoms before the block and their increase over time. The increase in symptoms is best explained by the presence of sleep disturbances and emotional lability. The exacerbation also appears to be linked to the onset of new symptoms in children and adolescents with depressed moods and eating problems. Furthermore, irritability and oppositionality are significant predictors of acute exacerbation. Equally statistically significant is the factor linked to the effects of pandemic stress, such as the fear of contracting the virus. No significant associations for symptom reduction have been identified between parental strategies or other parent-initiated actions, but the study demonstrates that caregiver perceived efficacy on the strategies used can reduce the risk of exacerbation.Conclusion: This preliminary study highlights the importance of studying the causes of increased symptoms in children with PANDAS/PANS. Life events can exacerbate the clinical condition or generate new symptoms in young patients. In particular, environmental, family, and social changes in the course of clinical symptoms in PANDAS/PANS patients should be investigated. It highlights the importance of emotional and behavioral management, which can be improved by enhancing coping strategies in young people with PANDAS/PANS and their caregivers through a combination treatment in which CBT and PMT are included, in line with guidelines.Limits: An experimental proxy-report questionnaire not yet standardized and validated on the PANS/PANDAS pediatric clinical sample was used for the exploratory study. There is also a small sample size (N = 108) and the absence of a control group (pre-lockdown or children without PANDAS/PANS). It would be interesting to evaluate the exact long-term dimensions to see the course of symptoms after covid and conduct a new study focusing on the impact of stressful events on the clinical course of the syndrome.

show abstract

“…In the European cohort, two affected siblings (cases 1 and 2) were found with an ultra-rare missense mutation in PPM1D (c.131C>G; p.S44W). They inherited the variant from an asymptomatic parent who has a family history autoimmune disorders, a common scenario in PANS families 20, 21 . S44W is a known single nucleotide variant (SNV), rs373862041, with a minor allele frequency (MAF) of 0.000255, based on the TOPMed database of more than 125,000 samples 22 .…”

Section: Resultsmentioning

confidence: 99%

Identification of ultra-rare genetic variants in Pediatric Acute Onset Neuropsychiatric Syndrome (PANS) by exome and whole genome sequencing

Trifiletti¹,

Manusama

et al. 2021

Preprint

View full text Add to dashboard Cite

Pediatric acute onset neuropsychiatric syndrome (PANS) is viewed as an autoimmune/autoinflammatory condition characterized by the abrupt onset of severe neurological and psychiatric symptoms, in particular obsessive-compulsive disorder (OCD), tics, anxiety, mood swings, irritability, and restricted eating, often triggered by infections. However, direct evidence of autoimmunity, infections, or a proinflammatory state is often lacking, and there is no unifying pathogenic pathway. This could be due to underlying genetic heterogeneity, which could lead to the development of PANS through different cellular and molecular pathways. Unfortunately, little is known about the genetic basis of PANS. Consequently, we carried out whole exome sequencing (WES) on a U.S. cohort of 386 cases who met diagnostic criteria for PANS, including 133 family triads, and whole genome sequencing (WGS) on ten cases from the European Union, who were selected for WGS because of severe PANS symptoms. We focused on identifying potentially deleterious genetic variants that were either de novo or ultra-rare with a minor allele frequency (MAF) < 0.001. Candidate mutations were found in 11 genes: PPM1D, SGCE, PLCG2, NLRC4, CACNA1B, SHANK3, CHK2, GRIN2A, RAG1, GABRG2, and SYNGAP1 in a total of 20 cases, which included two sets of siblings, and two or more unrelated subjects with ultra-rare variants in SGCE, NLRC4, RAG1, and SHANK3. The PANS candidate genes we identified separate into two broad functional categories. One group regulates peripheral innate and adaptive immune responses (e.g., PPM1D, CHK2, NLRC4, RAG1, PLCG2), some of which also influence microglia function. Another is expressed primarily at neuronal synapses or directly modulates synaptic function (SHANK3, SYNGAP1, GRIN2A, GABRG2, CACNA1B, SGCE). These neuronal PANS candidate genes are often mutated in autism spectrum disorder, developmental disorders, and myoclonus-dystonia. In fact, eight out of 20 cases in this study developed PANS superimposed on a preexisting neurodevelopmental disorder. There is, however, clinical overlap between these two groups and some crossover expression (e.g., some neuronal genes are expressed in immune cells and vice versa) that diminishes the neuronal/immune dichotomy. Genes in both categories are also highly expressed in the enteric nervous system, and in the choroid plexus and brain vasculature, suggesting they might contribute to a breach in the blood-CSF barrier and blood-brain barrier (BBB) that would permit the entry of autoantibodies, inflammatory cytokines, chemokines, prostaglandins, and autoantibodies into the brain. Thus, PANS is a genetically heterogeneous condition that can occur as a stand-alone neuropsychiatric condition or co-morbid with neurodevelopmental disorders, with candidate genes functioning at several levels of the neuroinflammatory axis.

show abstract

Pediatric Acute-Onset Neuropsychiatric Syndrome: A Data Mining Approach to a Very Specific Constellation of Clinical Variables

Cited by 19 publications

References 78 publications

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

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

The Impact of the COVID-19 Epidemic During the Lockdown on Children With the Pediatric Acute-Onset Neuropsychiatric Syndrome (PANDAS/PANS): The Importance of Environmental Factors on Clinical Conditions

Identification of ultra-rare genetic variants in Pediatric Acute Onset Neuropsychiatric Syndrome (PANS) by exome and whole genome sequencing

Contact Info

Product

Resources

About