Identification of ultra‑rare genetic variants in pediatric acute onset neuropsychiatric syndrome (PANS) by exome and whole genome sequencing

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. – Open Access

  • The pathological mechanisms are likely heterogeneous, but we hypothesize convergence on one or more biological pathways.
  • Conducted whole exome sequencing (WES) on a U.S. cohort of 386 cases, and whole genome sequencing (WGS) on ten cases from the European Union who were selected because of severe PANS.
  • Focused on identifying potentially deleterious genetic variants that were de novo or ultra‑rare (MAF) < 0.001. Candidate mutations were found in 11 genes (PPM1D, SGCE, PLCG2, NLRC4, CACNA1B, SHANK3, CHK2, GRIN2A, RAG1, GABRG2, and SYNGAP1) in 21 cases, which included two or more unrelated subjects with ultra‑rare variants in four genes.
  • These genes converge into two broad functional categories.
    • One regulates peripheral immune responses and microglia (PPM1D, CHK2, NLRC4, RAG1, PLCG2).
    • The other is expressed primarily at neuronal synapses (SHANK3, SYNGAP1, GRIN2A, GABRG2, CACNA1B, SGCE). Mutations in these neuronal genes are also described in autism spectrum disorder and myoclonus‑dystonia.
  • 12/21 cases developed PANS superimposed on a preexisting neurodevelopmental disorder. Genes in both categories are also highly expressed in the enteric nervous system and the choroid plexus.
  • Thus, genetic variation in PANS candidate genes may function by disrupting peripheral and central immune functions, neurotransmission, and/or the blood‑CSF/brain barriers following stressors such as infection

 

Adverse Childhood Events, Post-Traumatic Stress Disorder, Infectious Encephalopathies and Immune-Mediated Disease

Citation: Bransfield, R.C. Adverse Childhood Events, Post-Traumatic Stress Disorder, Infectious Encephalopathies and Immune-Mediated Disease. Healthcare 2022, 10, 1127. https://doi.org/10.3390/healthcare10061127

In summary, insight into the underlying pathophysiology of Adverse Childhood Events, Post-Traumatic Stress Disorder, and infectious encephalopathies offers expanded treatment opportunities that include psychotherapeutic treatments that help to differentiate safety vs. danger, therapies to improve empowerment, and psychotropic medications to reduce intrusive symptoms and other symptoms, anti-infective treatments, immune-modulating treatments and education for patients and caregivers.

Untimely care: How the modern logics of coverage and medicine compromise children’s health and development

M LaRusso, DF Gallego-Pérez, CE Abadía-Barrero. Untimely care: How the modern logics of coverage and medicine compromise children’s health and development, Social Science & Medicine, 2022, 114962, DOI: 10.1016/j.socscimed.2022.114962.

  • Coverage problems for controversial conditions exist across health care systems.
  • Modern medicine fails to support new and controversial conditions like PANS/PANDAS.
  • Despite being insured, many children face barriers to diagnosis and treatment.
  • The modern logics of medicine and coverage fail to provide care in PANS/PANDAS.
  • Failures to care result in developmental disruptions in children with PANS/PANDAS.
Children With PANS May Manifest POTS

Chan A, Gao J, Houston M, Willett T, Farhadian B, Silverman M, Tran P, Jaradeh S, Thienemann M, Frankovich J. Children With PANS May Manifest POTS. Frontiers in Neurology. Vol 13, 2022 DOI: 10.3389/fneur.2022.819636

  • 204 patients: mean age of PANS onset was 8.6 years, male sex (60%), non-Hispanic White (78%).
  • Evidence of POTS was observed in 19/204 patients (9%). 5/19 have persistent POTS
  • Those with PANS & POTS were more likely to have
    • comorbid joint hypermobility (63 vs 37%, p = 0.04)
    • chronic fatigue (42 vs 18%, p = 0.03)
    • family history of chronic fatigue, POTS, palpitations and syncope
  • Showed a PANS flare was significantly associated with an exacerbation of POTS symptoms (OR 3.3, 95% CI 1.4–7.6, p < 0.01)
Unexplained post-acute infection syndromes

Choutka, J., Jansari, V., Hornig, M. et al. Unexplained post-acute infection syndromes. Nat Med 28, 911–923 (2022). https://doi.org/10.1038/s41591-022-01810-6

“SARS-CoV-2 is not unique in its ability to cause post-acute sequelae; certain acute infections have long been associated with an unexplained chronic disability in a minority of patients. These post-acute infection syndromes (PAISs) represent a substantial healthcare burden, but there is a lack of understanding of the underlying mechanisms, representing a significant blind spot in the field of medicine. The relatively similar symptom profiles of individual PAISs, irrespective of the infectious agent, as well as the overlap of clinical features with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), suggest the potential involvement of a common etiopathogenesis. In this Review, we summarize what is known about unexplained PAISs, provide context for post-acute sequelae of SARS-CoV-2 infection (PASC), and delineate the need for basic biomedical research into the underlying mechanisms behind this group of enigmatic chronic illnesses.”

Pediatric neuropsychiatric syndromes associated with infection and microbiome alterations: clinical findings, possible role of the mucosal epithelium, and strategies for the development of new animal models
Hoffman KL, Cano-Ramírez H. Pediatric neuropsychiatric syndromes associated with infection and microbiome alterations: clinical findings, possible role of the mucosal epithelium, and strategies for the development of new animal models. Expert Opin Drug Discov. 2022 May 11. doi: 10.1080/17460441.2022.2074396. Epub ahead of print. PMID: 35543072.
“Although data from existing animal models are consistent with an important role for anti-neuronal antibodies in PANS triggered by GAS infection, we lack models for identifying pathophysiological mechanisms of PANS associated with other infectious and non-infectious triggers. The authors propose a strategy for developing such models that incorporates known vulnerability and triggering factors for PANS into the modeling process. This novel strategy should expand our understanding of the pathophysiology of PANS, as well as facilitate the development of new pharmacological treatments for PANS and related syndromes.”
Bowel and Bladder Dysfunction Is Associated with Psychiatric Comorbidities and Functional Impairment in Pediatric Obsessive-Compulsive Disorder
Clara Westwell-Roper, John R. Best, Zainab Naqqash, Kourosh Afshar, Andrew E. MacNeily, and S. Evelyn Stewart.Journal of Child and Adolescent Psychopharmacology. Published Online: ahead of printhttp://doi.org/10.1089/cap.2021.0059

“Neuropsychiatric disorders are common in children with bowel and bladder dysfunction (BBD), a syndrome associated with urinary frequency, urgency, holding, incontinence, and constipation. We evaluated BBD symptom severity in children and youth attending a tertiary care obsessive-compulsive disorder (OCD) clinic….. BBD symptoms are common and associated with high OCD-related impairment and psychiatric comorbidities. Standardized assessment may facilitate identification of BBD symptoms in this population and is critical to mitigating long-term physical and mental health impacts. Further studies are required to assess the relationship between BBD and OCD treatment outcomes.”

Reader Response: Lack of Association of Group A Streptococcal Infections and Onset of Tics

Reader Response: Lack of Association of Group A Streptococcal Infections and Onset of Tics

“Schrag et al. reported that Group A streptococcal (GAS) exposure is unrelated to tics in children at risk for tic disorders.1 The critical limitations of this study are that only children with genetic risks for tics were studied and information about risk for autoimmunity, infection susceptibility, and antibiotics use are absent.1 The EMTICS home page states that many patients refused to participate when told that antibiotic use would be limited. This would introduce a negative selection bias against families who perceive themselves as high risk and patients procuring antibiotics outside the trial.2

In response to:

Schrag AE, Martino D, Wang H, Ambler G, Benaroya-Milstein N, Buttiglione M, Cardona F, Creti R, Efstratiou A, Hedderly T, Heyman I, Huyser C, Mir P, Morer A, Moll N, Müller NE, Müller-Vahl KR, Plessen KJ, Porcelli C, Rizzo R, Roessner V, Schwarz M, Tarnok Z, Walitza S, Dietrich A, Hoekstra PJ; European Multicentre Tics in Children Study (EMTICS). Lack of Association of Group A Streptococcal Infections and Onset of Tics: European Multicenter Tics in Children Study. Neurology. 2022 Mar 15;98(11):e1175-e1183. doi: 10.1212/WNL.0000000000013298. Epub 2022 Feb 2. PMID: 35110379.
Novel Drug Significantly Reduces Tics in Tourette’s ― Without Side Effects

An investigational drug that blocks the dopamine-1 (D1) receptor reduces tics and is safe and well tolerated in children with Tourette syndrome (TS), a new study shows.

Importantly, unlike current medications for the disorder, ecocipam does not lead to weight gain, anxiety, depression, or tardive dyskinesia compared to placebo ― a factor that may lead to better adherence.

A case of Obsessive-compusive and related disorders against the background of Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections (PANDAS)
Madaan A, Das A, Das SK, Das RC. A case of Obsessive-compusive and related disorders against the background of Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections (PANDAS). Indian J Psychiatry. 2022 Mar;64(Suppl 3):S659. doi: 10.4103/0019-5545.341932. Epub 2022 Mar 24. PMCID: PMC9129622.
Conclusion: In all school-age children presenting with obsessive compulsive and related disorder with other symptoms or not, a possible link to PANDAS should be evaluated and ruled out.
Case Report – Pedijatrijsko autoimuno neuropsihijatrijsko oboljenje udruženo sa streptokokom

Pedijatrijsko autoimuno neuropsihijatrijsko oboljenje udruženo sa streptokokom

Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection


Jasmina Škorić1, Bojan Pavković1.
1 Dom zdravlja Dr Simo Milošević’, Beograd, Srbija

http://prevped.preventivnapedijatrija.rs/index.php/casopis/article/download/41/24

Conclusion: The patient showed signs of improvement after the intravenous administration of immunoglobulin which confirmed the underlying immunological aspect of the disease. Additionally, serologic test results that showed elevated antistreptolysin O titer and antideoxyribonucleaseB titer indicated streptococcal etiology. Precisely, these misdirected antibodies set off an inflammatory response that led to the basal ganglia damage resulting in behavioral changes, motor, cognitive and emotional disorders.

PANDAS in an Adult?: A Case Report

PANDAS in an Adult?: A Case Report. Deshmukh RP, Mane AB, Singh S.Ind J Priv Psychiatry 2022; 16 (1):44-45. DOI: 10.5005/jp-journals-10067-0104

“We report a case in order to suggest that we should be alert while assessing OCD in young patients, as it might be secondary to streptococcal infection. This has therapeutic implications. Trials of immunomodulator therapy can be given as suggested in a few kinds of literature. Although still experimental, it may have potential for the future, especially in those not responding to conventional treatment… This report might suggest that PANDAS-like syndrome may occur in adults also. We should be cautious of this syndrome during treatment.”