Maternal lifetime stress and psychological functioning in pregnancy is associated with preschoolers' temperament: Exploring effect modification by race and ethnicity.

BACKGROUND: Psychosocial stress and psychopathology frequently co-occur, with patterns differing by race and ethnicity. We used statistical mixtures methodology to examine associations between prenatal stress and child temperament in N = 382 racially and ethnically diverse maternal-child dyads to disentangle associations among maternal stressful life events, maternal psychological functioning in pregnancy, childhood neurobehavior, and maternal race and ethnicity. METHODS: This study utilized data from a longitudinal pregnancy cohort, PRogramming of Intergenerational Stress Mechanisms (PRISM). Mothers completed the Lifetime Stressor Checklist-Revised, Edinburgh Postnatal Depression Scale, and Spielberger State-Trait Anxiety Scale during pregnancy. When their children were 3-5 years of age, they completed the Children's Behavior Questionnaire, which yields three temperament dimensions: Negative Affectivity (NA), Effortful Control (EC), and Surgency (S). We used weighted quantile sum regression to derive a weighted maternal stress index encompassing lifetime stress and depression and anxiety symptoms and examined associations between the resulting stress index and child temperament. Differential contributions of individual stress domains by race and ethnicity also were examined. RESULTS: Mothers self-identified as Black/Black Hispanic (46.1 %), non-Black Hispanic (31.9 %), or non-Hispanic White (22 %). A higher maternal stress index was significantly associated with increased child NA (ß = 0.72 95 % CI = 0.35, 1.10). Lifetime stress was the strongest contributor among Hispanic (36.7 %) and White (17.8 %) mothers, whereas depressive symptoms in pregnancy was the strongest contributor among Black (16.7 %) mothers. CONCLUSION: Prenatal stress was most strongly associated with negative affectivity in early childhood. Consideration of multiple stress measures as a mixture accounted for differential contributions of individual stress domains by maternal race and ethnicity. These findings may help elucidate the etiology of racial/ethnic disparities in childhood neurobehavior.

Prospective phenotyping of CHAMP1 disorder indicates that coding mutations may not act through haploinsufficiency.

CHAMP1 disorder is a genetic neurodevelopmental condition caused by mutations in the CHAMP1 gene that result in premature termination codons. The disorder is associated with intellectual disability, medical comorbidities, and dysmorphic features. Deletions of the CHAMP1 gene, as part of 13q34 deletion syndrome, have been briefly described with the suggestion of a milder clinical phenotype. To date, no studies have directly assessed differences between individuals with mutations in CHAMP1 to those with deletions of the gene. We completed prospective clinical evaluations of 16 individuals with mutations and eight with deletions in CHAMP1. Analyses revealed significantly lower adaptive functioning across all domains assessed (i.e., communication, daily living skills, socialization, and motor skills) in the mutation group. Developmental milestones and medical features further showed difference between groups. The phenotypes associated with mutations, as compared to deletions, indicate likely difference in pathogenesis between groups, where deletions are acting through CHAMP1 haploinsufficiency and mutations are acting through dominant negative or gain of function mechanisms, leading to a more severe clinical phenotype. Understanding this pathogenesis is important to the future of novel therapies for CHAMP1 disorder and illustrates that mechanistic understanding of mutations must be carefully considered prior to treatment development.

DDX3X Syndrome: Summary of Findings and Recommendations for Evaluation and Care.

DDX3X syndrome is a surprisingly common newly discovered genetic neurodevelopmental disorder associated with intellectual disability, autism spectrum disorder, language delays, attention-deficit/hyperactivity disorder, and medical comorbidities. Two hundred individuals with DDX3X syndrome have been described in the literature to date, with varied levels of detail. Individuals with DDX3X syndrome often have complex presentations including symptoms in the neurological, psychiatric/psychological, ophthalmologic, and gastrointestinal domains. Owing to this complex presentation, an overview of symptom prevalence, medical recommendations, and suggested medical surveillance is vital for the care and health of individuals with DDX3X syndrome. In this article, we summarize the present clinical knowledge of DDX3X syndrome and provide recommendations for clinical assessments and care based on a comprehensive review of the existing literature and of new, not yet published DDX3X syndrome cohorts. As more is learned about DDX3X syndrome, we anticipate that these recommendations will evolve.

An open-label study evaluating the safety, behavioral, and electrophysiological outcomes of low-dose ketamine in children with ADNP syndrome.

Activity-dependent neuroprotective protein (ADNP) syndrome is a rare genetic condition associated with intellectual disability and autism spectrum disorder. Preclinical evidence suggests that low-dose ketamine may induce expression of ADNP and that neuroprotective effects of ketamine may be mediated by ADNP. The goal of the proposed research was to evaluate the safety, tolerability, and behavioral outcomes of low-dose ketamine in children with ADNP syndrome. We also sought to explore the feasibility of using electrophysiological markers of auditory steady-state response and computerized eye tracking to assess biomarker sensitivity to treatment. This study utilized a single-dose (0.5 mg/kg), open-label design, with ketamine infused intravenously over 40 min. Ten children with ADNP syndrome ages 6 to 12 years were enrolled. Ketamine was generally well tolerated, and there were no serious adverse events. The most common adverse events were elation/silliness (50%), fatigue (40%), and increased aggression (40%). Using parent-report instruments to assess treatment effects, ketamine was associated with nominally significant improvement in a wide array of domains, including social behavior, attention deficit and hyperactivity, restricted and repetitive behaviors, and sensory sensitivities, a week after administration. Results derived from clinician-rated assessments aligned with findings from the parent reports. Overall, nominal improvement was evident based on the Clinical Global Impressions - Improvement scale, in addition to clinician-based scales reflecting key domains of social communication, attention deficit and hyperactivity, restricted and repetitive behaviors, speech, thinking, and learning, activities of daily living, and sensory sensitivities. Results also highlight the potential utility of electrophysiological measurement of auditory steady-state response and eye-tracking to index change with ketamine treatment. Findings are intended to be hypothesis generating and provide preliminary support for the safety and efficacy of ketamine in ADNP syndrome in addition to identifying useful endpoints for a ketamine clinical development program. However, results must be interpreted with caution given limitations of this study, most importantly the small sample size and absence of a placebo-control group.

CHAMP1 disorder is associated with a complex neurobehavioral phenotype including autism, ADHD, repetitive behaviors and sensory symptoms.

CHAMP1-related neurodevelopmental disorder, or CHAMP1 disorder, is a recently described genetic syndrome associated with developmental delay, intellectual disability, behavioral symptoms, medical comorbidities, and dysmorphic features. To date, literature has focused on medical review and dysmorphology but has yet to prospectively assess neurobehavioral core domains such as autism, or behavioral, language, cognitive, and sensory features. Here, we present deep phenotyping results for 11 individuals with CHAMP1 disorder, based on approximately 12 hours of remote clinician-administered assessments and standardized caregiver questionnaires. Diagnoses of autism spectrum disorder were given to 33% of participants; repetitive behaviors and sensory-seeking symptoms were prominent in this cohort. In addition, 60% of participants met the criteria for attention-deficit/hyperactivity disorder (ADHD). High rates of ADHD and relatively low rates of treatment suggest potential areas for intervention. This study represents the first prospective phenotyping analysis of individuals with CHAMP1 disorder. The utility of specific measures as clinical endpoints, as well as benefits and limitations of remote phenotyping, are described.

Individuals with FOXP1 syndrome present with a complex neurobehavioral profile with high rates of ADHD, anxiety, repetitive behaviors, and sensory symptoms.

BACKGROUND: FOXP1 syndrome is an autosomal dominant neurodevelopmental disorder characterized by intellectual disability, developmental delay, speech and language delays, and externalizing behaviors. We previously evaluated nine children and adolescents with FOXP1 syndrome to better characterize its phenotype. We identified specific areas of interest to be further explored, namely autism spectrum disorder (ASD) and internalizing and externalizing behaviors. METHODS: Here, we assess a prospective cohort of additional 17 individuals to expand our initial analyses and focus on these areas of interest. An interdisciplinary group of clinicians evaluated neurodevelopmental, behavioral, and medical features in participants. We report results from this cohort both alone, and in combination with the previous cohort, where possible. RESULTS: Previous observations of intellectual disability, motor delays, and language deficits were confirmed. In addition, 24% of the cohort met criteria for ASD. Seventy-five percent of individuals met DSM-5 criteria for attention-deficit/hyperactivity disorder and 38% for an anxiety disorder. Repetitive behaviors were almost universally present (95%) even without a diagnosis of ASD. Sensory symptoms, in particular sensory seeking, were common. LIMITATIONS: As FOXP1 syndrome is a rare disorder, sample size is limited. CONCLUSIONS: These findings have important implications for the treatment and care of individuals with FOXP1 syndrome. Notably, standardized testing for ASD showed high sensitivity, but low specificity, when compared to expert consensus diagnosis. Furthermore, many individuals in our cohort who received diagnoses of attention-deficit/hyperactivity disorder or anxiety disorder were not being treated for these symptoms; therefore, our findings suggest that there may be immediate areas for improvements in treatment for some individuals.

Prospective and detailed behavioral phenotyping in DDX3X syndrome.

BACKGROUND: DDX3X syndrome is a recently identified genetic disorder that accounts for 1-3% of cases of unexplained developmental delay and/or intellectual disability (ID) in females, and is associated with motor and language delays, and autism spectrum disorder (ASD). To date, the published phenotypic characterization of this syndrome has primarily relied on medical record review; in addition, the behavioral dimensions of the syndrome have not been fully explored. METHODS: We carried out multi-day, prospective, detailed phenotyping of DDX3X syndrome in 14 females and 1 male, focusing on behavioral, psychological, and neurological measures. Three participants in this cohort were previously reported with limited phenotype information and were re-evaluated for this study. We compared results against population norms and contrasted phenotypes between individuals harboring either (1) protein-truncating variants or (2) missense variants or in-frame deletions. RESULTS: Eighty percent (80%) of individuals met criteria for ID, 60% for ASD and 53% for attention-deficit/hyperactivity disorder (ADHD). Motor and language delays were common as were sensory processing abnormalities. The cohort included 5 missense, 3 intronic/splice-site, 2 nonsense, 2 frameshift, 2 in-frame deletions, and one initiation codon variant. Genotype-phenotype correlations indicated that, on average, missense variants/in-frame deletions were associated with more severe language, motor, and adaptive deficits in comparison to protein-truncating variants. LIMITATIONS: Sample size is modest, however, DDX3X syndrome is a rare and underdiagnosed disorder. CONCLUSION: This study, representing a first, prospective, detailed characterization of DDX3X syndrome, extends our understanding of the neurobehavioral phenotype. Gold-standard diagnostic approaches demonstrated high rates of ID, ASD, and ADHD. In addition, sensory deficits were observed to be a key part of the syndrome. Even with a modest sample, we observe evidence for genotype-phenotype correlations with missense variants/in-frame deletions generally associated with more severe phenotypes.