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Evaluation of C4 gene copy number in Pediatric Acute Neuropsychiatric Syndrome

Kalinowski A, Tian L, Pattni R, Ollila H, Khan M, Manko C, Silverman M, Ma M, Columbo L, Farhadian B, Swedo S, Murphy T, Johnson M, Fernell E, Gillberg C, Thienemann M, Mellins ED, Levinson DF, Urban AE, Frankovich J. Evaluation of C4 gene copy number in Pediatric Acute Neuropsychiatric Syndrome. Dev Neurosci. 2023 Jun 28. doi: 10.1159/000531707. Epub ahead of print. PMID: 37379808.

Pediatric acute-onset neuropsychiatric syndrome (PANS) is an abrupt-onset neuropsychiatric disorder. PANS patients have an increased prevalence of comorbid autoimmune illness, most commonly arthritis. In addition, an estimated one-third of PANS patients present with low serum C4 protein, suggesting decreased production or increased consumption of C4 protein. To test the possibility that copy number (CN) variation contributes to risk of PANS illness, we compared mean total C4A and total C4B CN in ethnically matched subjects from PANS DNA samples and controls (192 cases and 182 controls). Longitudinal data from the Stanford PANS cohort (n = 121) were used to assess whether the time to juvenile idiopathic arthritis (JIA) or autoimmune disease (AI) onset was a function of total C4A or C4B CN. Lastly, we performed several hypothesis-generating analyses to explore the correlation between individual C4 gene variants, sex, specific genotypes, and age of PANS onset. Although the mean total C4A or C4B CN did not differ in PANS compared to controls, PANS patients with low C4B CN were at increased risk for subsequent JIA diagnosis (hazard ratio = 2.7, p value = 0.004). We also observed a possible increase in risk for AI in PANS patients and a possible correlation between lower C4B and PANS age of onset. An association between rheumatoid arthritis and low C4B CN has been reported previously. However, patients with PANS develop different types of JIA: enthesitis-related arthritis, spondyloarthritis, and psoriatic arthritis. This suggests that C4B plays a role that spans these arthritis types.

Exploring the Complex Associations Between Prenatal and Early-Life Infections and Obsessive-Compulsive and Tic-Related Disorders
Hirschtritt ME, Mathews CA. Exploring the Complex Associations Between Prenatal and Early-Life Infections and Obsessive-Compulsive and Tic-Related Disorders. Biol Psychiatry. 2023 Jun 1;93(11):959-961. doi: 10.1016/j.biopsych.2023.03.003. PMID: 37197834.
“techniques led to an understanding that autoimmunity induced by streptococcal
throat infection caused damage to multiple organ systems in … posited a diagnostic
entity named pediatric autoimmune neuropsychiatric disorders associated with …”
Arthritis in Children with Psychiatric Deteriorations: A Case Series
Ma M, Sandberg J, Farhadian B, Silverman M, Xie Y, Thienemann M, Frankovich J. Arthritis in Children with Psychiatric Deteriorations: A Case Series. Dev Neurosci. 2023;45(6):325-334. doi: 10.1159/000530854. Epub 2023 May 12. PMID: 37231875.
We found that 55/193 (28%) of consecutive patients meeting PANS criteria developed chronic arthritis and 25/121 (21%) of those with related psychiatric deteriorations developed chronic arthritis. Here we describe 7 of these patients in detail and one sibling.
  • Many of our patients often have “dry” arthritis (no effusions found on physical exam) but subtle effusions detected by imaging and features of spondyloarthritis, enthesitis, and synovitis. Joint capsule thickening, not previously reported in children, is a common finding in the presented cases and in psoriatic arthritis in adults.
  • Due to the severity of psychiatric symptoms in some cases, which often overshadow joint symptoms, and concomitant sensory dysregulation (making the physical exam unreliable in the absence of effusions), we rely on imaging to improve sensitivity and specificity of the arthritis classification.
  • We also report the immunomodulatory treatments of these 7 patients (initially nonsteroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs with escalation to biologic medications) and note any coincidental changes to their arthritis and psychiatric symptoms while on immunomodulation.
  • Patients with overlapping psychiatric syndromes and arthritis may have a unifying cause and pose unique challenges; a multi-disciplinary team can utilize imaging to tailor and coordinate treatment for this patient population.
Pathogenesis of autoimmune disease

Pisetsky, D.S. Pathogenesis of autoimmune disease. Nat Rev Nephrol 19, 509–524 (2023). https://doi.org/10.1038/s41581-023-00720-1

  • Autoimmune diseases lead to diverse patterns of inflammation and organ dysfunction.
  • Autoantibodies are valuable markers for diagnosis, classification and of disease activity.
  • Although T cells play a key part in disease, their assessment is challenging.
  • Autoimmune disease reflects the interplay of genetic and environmental factors.
  • Pre-clinical autoimmune disease provides a window of time for early or preventive treatment.
Pediatric Acute Onset Neuropsychiatric Syndrome Presenting with Atypical Eating Disorder: A Case Report
Biswas T, Sinha A, Abhijita B, Mishra S, Padhy SK. Pediatric Acute Onset Neuropsychiatric Syndrome Presenting with Atypical Eating Disorder: A Case Report. Journal of Indian Association for Child and Adolescent Mental Health. 2022;18(4):364-366. doi:10.1177/09731342231170695
“This case illustrates an atypical eating disorder presentation, resulting from PANS wherein a meticulous ruling out of organic causes andtimely institution of specific serotonin reuptake inhibitor facilitated remission. Through this case report the authors highlight the need of awareness of other medical practitioners regarding the symptomatology and presentation of PANS so as to facilitate early intervention in a collaborative approach.”
Distinct Th17 effector cytokines differentially promote microglial and blood-brain barrier inflammatory responses during post-infectious encephalitis
Wayne CR, Bremner L, Faust TE, Durán-Laforet V, Ampatey N, Ho SJ, Feinberg PA, Arvanitis P, Ciric B, Ruan C, Elyaman W, Delaney SL, Vargas WS, Swedo S, Menon V, Schafer DP, Cutforth T, Agalliu D. Distinct Th17 effector cytokines differentially promote microglial and blood-brain barrier inflammatory responses during post-infectious encephalitis. bioRxiv [Preprint]. 2023 May 9:2023.03.10.532135. doi: 10.1101/2023.03.10.532135. PMID: 37215000; PMCID: PMC10197575.

Group A Streptococcus (GAS) infections can cause neuropsychiatric sequelae in children due to post-infectious encephalitis. Multiple GAS infections induce migration of Th17 lymphocytes from the nose into the brain, which are critical for microglial activation, blood-brain barrier (BBB) and neural circuit impairment in a mouse disease model. How endothelial cells (ECs) and microglia respond to GAS infections, and which Th17-derived cytokines are essential for these responses are unknown. Using single-cell RNA sequencing and spatial transcriptomics, we found that ECs downregulate BBB genes and microglia upregulate interferon-response, chemokine and antigen-presentation genes after GAS infections. Several microglial-derived chemokines were elevated in patient sera. Administration of a neutralizing antibody against interleukin-17A (IL-17A), but not ablation of granulocyte-macrophage colony-stimulating factor (GM-CSF) in T cells, partially rescued BBB dysfunction and microglial expression of chemokine genes. Thus, IL-17A is critical for neuropsychiatric sequelae of GAS infections and may be targeted to treat these disorders.

Pharmacotherapy for Sydenham’s chorea: where are we and where do we need to be?

Roberta Bovenzi, Matteo Conti & Tommaso Schirinzi (2023) Pharmacotherapy for Sydenham’s chorea: where are we and where do we need to be?, Expert Opinion on Pharmacotherapy, 24:11, 1317-1329, DOI: 10.1080/14656566.2023.2216380

  • Sydenham’s chorea (SC) is the most common acquired chorea in children worldwide; still, its therapeutic strategies are empirical and non-evidence based.
  • Current pharmacotherapy for SC basically consists of three pillars: antibiotic, symptomatic and immunomodulant medications.
  • Antibiotic prophylaxis should be initiated as soon as SC is diagnosed, according to the WHO guidelines, to prevent beta-hemolytic streptococcal (GABHS) re-infection and reduce the risk of cardiac involvement.
  • Symptomatic treatments, which consist in anti-seizure medications (ASMs) and dopamine depleting agents, should be considered when symptoms are clinically relevant; however, no consensus exist on which should be the first choice.
  • Immunomodulant strategies are gaining increasingly attention given the autoimmune pathogenesis of SC, with promising results.
  • There are numerous gaps and unmet needs in SC management and treatment, which highlights the necessity of a deeper comprehension of its pathogenesis and sizable controlled studies to define standardized guidelines.
Young adults’ experiences of living with paediatric acute-onset neuropsychiatric syndrome. An interview study

Ulla-KarinSchön (2023) Young adults’ experiences of living with paediatric acute-onset neuropsychiatric syndrome. An interview study, International Journal of Qualitative Studies on Health and Well-being, 18:1, DOI: 10.1080/17482631.2023.2267268

This article explores experiential knowledge of living with paediatric acute-onset neuropsychiatric syndrome (PANS), and the factors that are associated with perceived good care.

  • Young adults living fairly isolated lives, dependent on care from relatives.
  • The illness was a tangible presence.
  • They perceived a lack of knowledge among healthcare staff on PANS in healthcare, and negative consequences linked to this. Their experience-based knowledge of their own illness is devalued in healthcare encounters.
  • A feeling of being pushed around in healthcare, without anyone taking responsibility for the treatment
  • Emphasized the need for increased knowledge among staff to identify PANS and be able to offer effective treatment.