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

Trifiletti, Rosario Rich; Lachman, Herbert M.; Manusama, Olivia; Zheng, Deyou; Spalice, Alberto; Chiurazzi, Pietro; Schornagel, Allan; Serban, Andreea M; Wijck, Rogier van; Cunningham, Janet L.; Swagemakers, Sigrid; Spek, Peter J. van der

doi:10.1038/s41598-022-15279-3

Cited by 20 publications

(15 citation statements)

References 121 publications

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“…It can represent a trigger for developing PANS symptoms, as already suggested by other research groups ( 15 , 16 ). Regarding etiopathogenesis, a recent study ( 17 ) suggests a possible genetic role of some “PANS gene” as PPM1D, CHK2, RAG1 , and PLCG2 , highly expressed in peripheral immune responses and microglia and the enteric nervous system and the choroid plexus. 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.…”

Section: Discussionmentioning

confidence: 99%

Steroid treatment response to post SARS-CoV-2 PANS symptoms: Case series

Berloffa

Salvati²,

Pantalone³

et al. 2023

Front. Neurol.

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BackgroundPediatric acute-onset neuropsychiatric syndrome (PANS) is characterized by a wide spectrum of symptoms, including the onset of obsessive-compulsive disorder and/or severely restricted food intake, associated with emotional symptoms, behavioral symptoms, developmental regression, and somatic symptoms. Among the possible triggering agents, infectious agents have been extensively explored. More recently, sporadic case reports describe a possible association between PANS and SARS-CoV-2 infection but data on clinical presentation and treatment are still scarce.MethodsWe describe a case series (10 children) with acute onset or relapse of PANS symptoms after SARS-CoV-2 infection. Standardized measures (CBCL, CPRS, C-GAS, CGI-S, Y-BOCS, PANSS, and YGTSS) were used to describe the clinical picture. The efficacy of a pulse treatment with steroids for three consecutive months was assessed.ResultsOur data suggest that the clinical presentation of the COVID-19-triggered PANS is largely similar to that reported in typical PANS, including acute onset, with OCD and/or eating disorders, and associated symptoms. Our data suggest that treatment with corticosteroids may be beneficial for both global clinical severity and global functioning. No serious adverse effects were observed. Both OCD symptoms and tics consistently improved. Among psychiatric symptoms, affective and oppositional symptoms appeared more sensitive to the steroid treatment than the other symptoms.ConclusionOur study confirms that COVID-19 infection in children and adolescents could trigger acute-onset neuropsychiatric symptoms. Thus, in children and adolescents with COVID-19, a specific neuropsychiatric follow-up should be routinely included. Even if a small sample size and a follow-up with only two points (baseline and endpoint, after 8 weeks) limit the conclusions, it seems that steroid treatment in the acute phase may be beneficial and well tolerated.

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Section: Discussionmentioning

confidence: 99%

Steroid treatment response to post SARS-CoV-2 PANS symptoms: Case series

Berloffa

Salvati²,

Pantalone³

et al. 2023

Front. Neurol.

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“…More recently, concerns for a possible neuroinflammatory complication of this condition have emerged, with three people having unexplained developmental regression. One individual was diagnosed with Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections (PANDAS) at age 6 (Trifiletti et al, 2022), one experienced loss of language at age 16, and one had recurrent episodes of inability to walk and regression of other skills at age 6–7. A unifying etiology for these abnormalities has not been uncovered.…”

Section: Resultsmentioning

confidence: 99%

“…As ES is now recommended as a first‐line test for those with intellectual disability (Manickam et al, 2021), it is likely that additional novel variants in other exons of this gene will be identified, and the clinical features seen in our cohort differentiated from the features seen with variants in other exons. To date, the features seen in those with pathogenic variants in other exons seem generally dissimilar to those seen with variants in exons 5 and 6 and should not be confused with JdVS (Trifiletti et al, 2022). Further research into the manifestations of damaging germline variants in exons 1–4 of PPM1D is warranted.…”

Section: Discussionmentioning

confidence: 99%

Jansen‐de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families

Wojcik

Srivastava

Agrawal

et al. 2023

American J of Med Genetics Pt A

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Jansen-de Vries syndrome (JdVS) is a neurodevelopmental condition attributed to pathogenic variants in Exons 5 and 6 of PPM1D. As the full phenotypic spectrum and natural history remain to be defined, we describe a large cohort of children and adults with JdVS. This is a retrospective cohort study of 37 individuals from 34 families with disease-causing variants in PPM1D leading to JdVS. Clinical data were provided by treating physicians and/or families. Of the 37 individuals, 27 were male and 10 female, with median age 8.75 years (range 8 months to 62 years). Four families document autosomal dominant transmission, and 32/34 probands were diagnosed via exome sequencing. The facial gestalt, including a broad forehead and broad mouth with a thin and tented upper lip, was most recognizable between 18 and 48 months of age. Common manifestations included global developmental delay (35/36, 97%), hypotonia (25/34, 74%), short stature (14/33, 42%), constipation (22/31, 71%), and cyclic vomiting (6/35, 17%). Distinctive personality traits include a hypersocial affect (21/31, 68%) and moderate-to-severe anxiety (18/28, 64%). In conclusion, JdVS is a clinically recognizable neurodevelopmental syndrome with a characteristic personality and distinctive facial features. The association of pathogenic variants in PPM1D with cyclic vomiting bears not only medical attention but also further pathogenic and mechanistic evaluation.

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“…Identifying genes that underlie PANDAS/PANS and studying their effect on the immune system and neuronal function in cell lines, animal models, and peripheral blood mononuclear cells could potentially identify novel genetic and molecular biomarkers. While the field is still in its infancy, there is one published genetic analysis that used whole genome and whole exome sequencing to identify ultra-rare genetic variants in PANS [75]. This study identified a heterogeneous mix of genetic variants affecting immune and glutamatergic neuronal function.…”

Section: Autoantibodies and Proinflammatory Monocytesmentioning

confidence: 99%

Postinfectious Inflammation, Autoimmunity, and Obsessive-Compulsive Disorder: Sydenham Chorea, Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection, and Pediatric Acute-Onset Neuropsychiatric Disorder

Vreeland,

Calaprice,

Or-Geva

et al. 2023

Dev Neurosci

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Post-infectious neuroinflammation has been implicated in multiple models of acute onset obsessive-compulsive disorder (OCD) including Sydenham’s chorea (SC), pediatric acute-onset neuropsychiatric syndrome (PANS), and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). These conditions are associated with a range of autoantibodies which are thought to be triggered by an infections, most notably group A streptococci (GAS). Based on animal models using huma sera, these autoantibodies are thought to cross-react with neural antigens in the basal ganglia and modulate neuronal activity and behavior. As is true for many childhood neuroinflammatory diseases and rheumatological diseases, SC, PANS, and PANDAS lack clinically available, rigorous diagnostic biomarkers and randomized clinical trials. In this review article, we outline the accumulating evidence supporting the role neuroinflammation plays in these disorders. We describe work with animal models including patient-derived anti-neuronal autoantibodies, and we outline imaging studies that show alterations in the basal ganglia. In addition, we present research on metabolites, which are helpful in deciphering functional phenotypes, and on the implication of sleep in these disorders. Finally, we encourage future researchers to collaborate across medical specialties (e.g., pediatrics, psychiatry, rheumatology, immunology, and infectious disease) in order to further research on clinical syndromes presenting with neuropsychiatric manifestations.

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

Cited by 20 publications

References 121 publications

Steroid treatment response to post SARS-CoV-2 PANS symptoms: Case series

Steroid treatment response to post SARS-CoV-2 PANS symptoms: Case series

Jansen‐de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families

Postinfectious Inflammation, Autoimmunity, and Obsessive-Compulsive Disorder: Sydenham Chorea, Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection, and Pediatric Acute-Onset Neuropsychiatric Disorder

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