We recently identified variants in 10 genes that are members of either the p53 pathway or Fanconi Anemia Complex (FAC), regulators of the DNA repair (DNA damage response; DDR) in 17 cases with Pediatric Acute-Onset Neuropsychiatry Syndrome (PANS) or regression in autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDD). We aimed to identify additional cases with genetic vulnerabilities in DDR and related pathways. Whole exome sequencing (WES) and whole genome sequencing (WGS) data from 32 individuals were filtered and analyzed to identify ultrarare pathogenic or likely pathogenic variants. Variants affecting DDR were found in 14 cases diagnosed with PANS or regression (CUX1, USP45, PARP14, UVSSA, EP300, TREX1, SAMHD1, STK19, MYTl1, TEP1, PIDD1, ADNP, FANCD2, and RAD54L). The CUX1 variant is de novo, as are two cases who had mutations in genes that affect mitochondrial functions that are connected directly or indirectly to mitophagy (PRKN and POLG), which can trigger the same innate immune pathways when disrupted as abnormal DDR. We also found pathogenic or likely pathogenic secondary mutations in several genes that are primarily expressed in the gut that have been implicated in gut microbiome homeostasis (e.g., LGALS4, DUOX2, CCR9). These findings align with previous genetic findings and strengthen the hypothesis that abnormal DDR and mitochondrial dysfunction underly pathogenic processes in neuropsychiatric decompensation. The potential involvement of genetic variants in gut microbiome homeostasis is a novel aspect of our study. Functional characterization of the downstream impact of DDR deficits may point to novel treatment strategies.

Investigations into mechanisms of cyclic(al) vomiting syndrome (CVS) began at the bedside more than a century ago. The modern era started with the formation of the Cyclic Vomiting Syndrome Association in 1993 that helped initiate robust efforts in education, advocacy, family physician conferences, scientific symposia, dedicated clinical programs, therapeutic guidelines, and research. Even today, bedside clues continue to emerge with the recent description of cannabinoid hyperemesis syndrome (CHS) and subsequent evidence of a perturbed endocannabinoid system. The clinical picture of CVS has evolved from that of a straightforward emetic disorder related to migraine requiring short-term antiemetics or prophylactic anti-migraine therapy, to a complicated, heterogenous one with multiple comorbid associations (anxiety, dysautonomia) and endophenotypes (migraine, Sato, CHS). This expanded view has important therapeutic implications which necessitate managing the comorbidities which can in turn impact the disease itself and proffered promising evidence that behavioral management (meditation) and vagal neuromodulation appear efficacious with few untoward effects, perhaps by reestablishing autonomic (parasympathetic) balance. The pathophysiologic picture now appears to be inscribed on an autonomic polyvagal design but multiple additional pathways interact, some confirmed (NK1, CB1, HPA axis, PPM1D gene, biological calendar, estrogen), and others, possible (TRPV-1, CGRP, GDF-15, mitochondrial dysfunction, impaired cation transport). CVS and its cousin CHS continue to challenge clinicians and perplex investigators and in the current era require not only a critical mass of specific pathway expertise but also syncretic biopsychosocial thinking to integrate these disparate threads. We may have reached such a tipping point at this Symposium.

<p>Introduction: Acute onset of severe psychiatric symptoms or regression may occur in children with premorbid neurodevelopmental disorders, although typically developing children can also be affected. Infections or other stressors are likely triggers. The underlying causes are unclear, but a current hypothesis suggests the convergence of genes that influence neuronal and immunological function. We previously identified 11 genes in pediatric acute-onset neuropsychiatric syndrome (PANS), in which two classes of genes related to either synaptic function or the immune system were found. Among the latter, three affect the DNA damage response (DDR): PPM1D, CHK2, and RAG1. We now report an additional 17 cases with mutations in PPM1D and other DDR genes in patients with acute onset of psychiatric symptoms and/or regression that their clinicians classified as PANS or another inflammatory brain condition. We analyzed genetic findings obtained from parents and carried out whole-exome sequencing on a total of 17 cases, which included 3 sibling pairs and a family with 4 affected children. The DDR genes include clusters affecting p53 DNA repair (PPM1D, ATM, ATR, 53BP1, and RMRP), and the Fanconi Anemia Complex (FANCE, SLX4/FANCP, FANCA, FANCI, and FANCC). We hypothesize that defects in DNA repair genes, in the context of infection or other stressors, could contribute to decompensated states through an increase in genomic instability with a concomitant accumulation of cytosolic DNA in immune cells triggering DNA sensors, such as cGAS-STING and AIM2 inflammasomes, as well as central deficits on neuroplasticity. In addition, increased senescence and defective apoptosis affecting immunological responses could be playing a role. These compelling preliminary findings motivate further genetic and functional characterization as the downstream impact of DDR deficits may point to novel treatment strategies. </p>.

Jansen-de Vries syndrome (JDVS) is a rare autosomal dominant neurodevelopmental disorder caused by truncating variants in exons 5 and 6 of the PPM1D gene. Its diagnosis is often delayed due to symptom overlap with more common conditions such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). This case report highlights the unique presentation of JDVS in one of a pair of dichorionic diamniotic (DCDA) twin brothers, both with ASD/ADHD, underscoring the diagnostic value of genetic testing. A 6-year-old boy presented with delayed language development, learning difficulties, behavioral issues, restrictive eating, and impaired autonomy. His twin brother, although also diagnosed with ASD/ADHD, exhibited milder symptoms. Trio-whole-exome sequencing revealed a de novo frameshift mutation (c.1411_1412del) in PPM1D in the proband, classified as pathogenic. The brother had no such variant. The proband received multidisciplinary interventions including behavioral therapy and speech support. Follow-up showed improvements in language, sleep, and academic performance, though behavioral and sphincter issues persist. The twin without the mutation was discharged from mental health services, while his brother remains under annual review. This case emphasizes the expanding phenotypic spectrum of JDVS and illustrates the diagnostic value of trio-WES in neurodevelopmental disorders with overlapping features. It also highlights the potential for discordant phenotypic expression in twins and the need for individualized diagnostic assessment.

Jansen-de Vries syndrome (JdVS) is an autosomal dominant neurodevelopmental disorder with intellectual disability and gastrointestinal (GI) abnormalities, including recurrent vomiting. This study aimed to understand the frequency and severity of GI symptoms in JdVS patients and to investigate the potential association with cyclic vomiting syndrome (CVS), which has not been previously reported. An international online survey assessed the prevalence and features of CVS and GI disorders in JdVS patients using Rome IV Criteria. The anonymous survey was conducted via Google Forms in April 2021. A total of 21 patients/guardians responded to the survey. The average age at JdVS diagnosis was 8.22 years (range: 1-42). Of the respondents, 6 (28.5%) had a CVS diagnosis, 5 (23.8%) had migraine, and 2 (9.5%) had abdominal migraine. Additionally, 8 (38%) had gastroesophageal reflux disease (GERD) and 8 (38%) had functional constipation. An analysis targeted questions showed that 7 (33%) met the Rome IV Criteria for CVS but were undiagnosed, leading to a CVS prevalence of 61% in this cohort. This study highlights a high prevalence of CVS in JdVS patients and underscores the need for increased awareness and accurate diagnosis to address misdiagnosis.