Deep psychophysiological phenotyping of adolescents and adults with 22q11.2 deletion syndrome: a multilevel approach to defining core disease processes.

BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal interstitial-deletion disorder, occurring in approximately 1 in 2000 to 6000 live births. Affected individuals exhibit variable clinical phenotypes that can include velopharyngeal anomalies, heart defects, T-cell-related immune deficits, dysmorphic facial features, neurodevelopmental disorders, including autism, early cognitive decline, schizophrenia, and other psychiatric disorders. Developing comprehensive treatments for 22q11.2DS requires an understanding of both the psychophysiological and neural mechanisms driving clinical outcomes. Our project probes the core psychophysiological abnormalities of 22q11.2DS in parallel with molecular studies of stem cell-derived neurons to unravel the basic mechanisms and pathophysiology of 22q11.2-related psychiatric disorders, with a primary focus on psychotic disorders. Our study is guided by the central hypothesis that abnormal neural processing associates with psychophysiological processing and underlies clinical diagnosis and symptomatology. Here, we present the scientific background and justification for our study, sharing details of our study design and human data collection protocol. METHODS: Our study is recruiting individuals with 22q11.2DS and healthy comparison subjects between the ages of 16 and 60 years. We are employing an extensive psychophysiological assessment battery (e.g., EEG, evoked potential measures, and acoustic startle) to assess fundamental sensory detection, attention, and reactivity. To complement these unbiased measures of cognitive processing, we will develop stem-cell derived neurons and examine neuronal phenotypes relevant to neurotransmission. Clinical characterization of our 22q11.2DS and control participants relies on diagnostic and research domain criteria assessments, including standard Axis-I diagnostic and neurocognitive measures, following from the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and the North American Prodrome Longitudinal Study (NAPLS) batteries. We are also collecting measures of autism spectrum (ASD) and attention deficit/hyperactivity disorder (ADHD)-related symptoms. DISCUSSION: Studying 22q11.2DS in adolescence and adulthood via deep phenotyping across multiple clinical and biological domains may significantly increase our knowledge of its core disease processes. Our manuscript describes our ongoing study's protocol in detail. These paradigms could be adapted by clinical researchers studying 22q11.2DS, other CNV/single gene disorders, or idiopathic psychiatric syndromes, as well as by basic researchers who plan to incorporate biobehavioral outcome measures into their studies of 22q11.2DS.

Development of an interactive tool of early social responsiveness to track autism risk in infants and toddlers.

AIM: To evaluate the psychometric properties of a 4-minute assessment designed to identify early autism spectrum disorder (ASD) status through evaluation of early social responsiveness (ESR). METHOD: This retrospective, preliminary study included children between 13 and 24 months (78 males, 79 females mean age 19.4mo, SD 3.1) from two independent data sets (an experimental/training sample [n=120] and a validation/test sample [n=37]). The ESR assessment examined social behaviors (e.g. eye contact, smiling, ease-of-social-engagement) across five common play activities (e.g. rolling a ball, looking at a book). Data analyses examined reliability and accuracy of the assessment in identifying ESR abilities and in discriminating children with and without ASD. RESULTS: Results indicated adequate internal consistency and test-retest reliability of the ESR assessment. Receiver operator curve analysis identified a cutoff score that discriminated infants with ASD-risk from peers in the training sample. This score yielded moderate sensitivity and high specificity for best-estimate ASD diagnosis in the validation sample. INTERPRETATION: Preliminary findings indicated that brief, systematic observation of ESR may assist in discriminating infants with and without ASD, providing concrete evidence to validate or supplement parents', pediatricians', or clinicians' concerns. Future studies could examine the utility of ESR 'growth curves'.

School-age social behavior and pragmatic language ability in children with prenatal serotonin reuptake inhibitor exposure.

Studies examining associations between fetal serotonin reuptake inhibitor (SRI) exposure and child autism spectrum disorder (ASD) diagnoses or delayed language remain mixed and rarely prospectively follow children or employ gold-standard assessments. We prospectively followed a cohort of mother-child dyads from pregnancy through early elementary school (N = 178), and obtained maternal and alternate-caregiver ratings of behaviors related to ASD (N = 137), as well as direct, gold-standard assessments of child ASD symptoms and pragmatic language among dyads who experienced prenatal depression and either took SRIs or were medication free during pregnancy (N = 44). Prenatal SRI exposure was related to maternal ratings of ASD-related behaviors (ß = 0.24 95% confidence interval; CI [0.07, 0.48]), and, among boys, alternative caregiver ratings (males-only ß = 0.28 95% CI [0.02, 0.55], females-only ß = -0.21 95% CI [-0.63, 0.08]). However, results of our direct assessments suggest an association between SRI exposure and reduced pragmatic language scores (ß = -0.27, 95% CI [-0.53, -0.01], but not ASD (Autism Diagnostic Observation Schedule ß = 0.14 95% CI [-0.15, 0.41]; Social Responsiveness Scale ß = 0.08 95% CI [-0.25, 0.40]). These discrepancies point to issues regarding how ASD is assessed, and the possibility that SRIs may be more strongly associated with language or other broader behaviors that coincide with ASD. Larger prospective studies that incorporate thorough, gold-standard assessments of ASD, language, and other ASD-related behaviors are needed.

The effect of hypocalcemia in early childhood on autism-related social and communication skills in patients with 22q11 deletion syndrome.

22q11 deletion syndrome (22qDS), also known as DiGeorge syndrome, is a copy number variant disorder that has a diverse clinical presentation including hypocalcaemia, learning disabilities, and psychiatric disorders. Many patients with 22q11DS present with signs that overlap with autism spectrum disorder (ASD) yet the possible physiological mechanisms that link 22q11DS with ASD are unknown. We hypothesized that early childhood hypocalcemia influences the neurobehavioral phenotype of 22q11DS. Drawing on a longitudinal cohort of 22q11DS patients, we abstracted albumin-adjusted serum calcium levels from 151 participants ranging in age from newborn to 19.5 years (mean 2.5 years). We then examined a subset of 20 infants and toddlers from this group for the association between the lowest calcium level on record and scores on the Communication and Symbolic Behavior Scales-Developmental Profile Infant-Toddler Checklist (CSBS-DP ITC). The mean (SD) age at calcium testing was 6.2 (8.5) months, whereas the mean (SD) age at the CSBS-DP ITC assessment was 14.7 (3.8) months. Lower calcium was associated with significantly greater impairment in the CSBS-DP ITC Social (p < 0.05), Speech (p < 0.01), and Symbolic domains (p < 0.05), in regression models adjusted for sex, age at blood draw, and age at the psychological assessment. Nevertheless, these findings are limited by the small sample size of children with combined data on calcium and CSBS-DP ITC, and hence will require replication in a larger cohort with longitudinal assessments. Considering the role of calcium regulation in neurodevelopment and neuroplasticity, low calcium during early brain development could be a risk factor for adverse neurobehavioral outcomes.

Validation of an Enhanced Telehealth Platform for Toddlers at Increased Likelihood for a Diagnosis of Autism Spectrum Disorder (ASD).

Use of telehealth assessments for toddlers at increased likelihood of autism spectrum disorder (ASD) began prior to the global COVID-19 pandemic; however, the value of telehealth assessments as an alternative to in-person assessment (IPA) became clearer during the pandemic. The Naturalistic Observation Diagnosis Assessment (NODA™), previously demonstrated as a valid and reliable tool to evaluate asynchronous behaviors for early diagnosis, was enhanced to add synchronous collection of behaviors to assist clinicians in making a differential diagnosis of ASD. This study was conducted to validate the information gathered through NODA-Enhanced (NODA-E™) as compared to a gold standard IPA. Forty-nine toddlers aged 16.0-32.1 months of age, recruited through community pediatric offices and a tertiary ASD clinic, participated in both NODA-E and IPA assessments. There was high agreement between the two assessment protocols for overall diagnosis (46 of 49 cases; 93.6%; κ = .878), specific diagnostic criteria for social communication and social interaction (SCI; range 95.9-98%; κ = .918-.959), and for two of four criteria specified for restricted and repetitive behaviors (RRB; range 87.8-98%; κ = .755 and .959). There was lower agreement for two subcategories of RRBs (range 65.3-67.3%; κ = .306 and .347). NODA-E is a tool that can assist clinicians in making reliable and valid early ASD diagnoses using both asynchronous and synchronous information gathered via telehealth and offers an additional tool within a clinician's assessment toolbox.

Web-based training in early autism screening: results from a pilot study.

BACKGROUND: Lack of familiarity with early signs of autism by community service providers has resulted in significant delays in children receiving early intervention services necessary to improve long-term outcomes. The Screening Tool for Autism in Toddlers and Young Children (STAT) was specifically developed to identify early behavioral features of autism. Although STAT training has been available for years, access is limited because of few STAT trainers and geographic concerns. This study evaluated the efficacy and acceptability of Web-based training of the STAT as a means of increasing accessibility to this training. MATERIALS AND METHODS: Thirty professionals from three geographic areas participated. Roughly 1 of 3 had little or no training on autism assessment. The tutorial contains a general overview, administration and scoring conventions, and item-specific content and concepts. Participants completed a pretest and then completed the STAT tutorial at their own pace, followed by a post-test and a user satisfaction questionnaire. RESULTS: Mean scores on STAT concepts significantly improved after taking the tutorial (p<0.001). At pretest, only 1 person (3%) obtained correct scores on at least 80% of the items (a priori cutoff for a "pass"), compared with 22 (73%) at post-test (p<0.001). The majority of trainees enjoyed taking the tutorial, thought it was well organized, relevant, interesting, and useful, and felt it was easy to understand and operate. DISCUSSION: Results support Web-based training as a promising method for promoting early identification of autism and may help overcome problems associated with the critical shortage of autism-screening professionals.

Social-adaptive and psychological functioning of patients affected by Fabry disease.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by the deficiency of alpha-galactosidase A. In addition to the debilitating physical symptoms of FD, there are also under-recognized and poorly characterized psychiatric features. As a first step toward characterizing psychiatric features of FD, we administered the Achenbach adult self report questionnaire to 30 FD patients and the Achenbach adult behavior checklist questionnaire to 28 partners/parents/friends of FD patients. Data from at least one of the questionnaires were available on 33 subjects. Analysis focused on social-adaptive functioning in various aspects of daily life and on criteria related to the Diagnostic and statistical manual of mental disorders IV (DSM-IV). Adaptive functioning scale values, which primarily measure social and relationship functioning and occupational success, showed that eight FD patients (six female and two male) had mean adaptive functioning deficits as compared to population norms. Greater rates of depression (P < 0.01), anxiety (P = 0.05), depression and anxiety (P = 0.03), antisocial personality (P < 0.001), attention-deficit/hyperactivity (AD/H; P < 0.01), hyperactivity-impulsivity (P < 0.01), and aggressive behavior (P = 0.03) were associated with poorer adaptive functioning. Decreased social-adaptive functioning in this study was not statistically significantly associated to disease severity, pain, or level of vitality. This study shows for the first time that FD patients, particularly women, are affected by decreased social-adaptive functioning. Comprehensive treatment plans for FD should consider assessments and interventions to evaluate and improve social, occupational, and psychological functioning. Attention to the behavioral aspects of FD could lead to improved treatment outcome and improved quality of life. Individuals affected by Fabry disease exhibited social-adaptive functioning deficits that were significantly correlated with anxiety, depression, antisocial behavior, and AD/H problems in a sampling of our male and female patients aged between 18 years and 59 years.

Brief Report: Relationship Between ADOS-2, Module 4 Calibrated Severity Scores (CSS) and Social and Non-Social Standardized Assessment Measures in Adult Males with Autism Spectrum Disorder (ASD).

The ADOS-2 Modules 1-3 now include a standardized calibrated severity score (CSS) from 1 to 10 based on the overall total raw score. Subsequent research published CSS for Module 4 (Hus, Lord, Journal of Autism and Developmental Disorders 44(8):1996-2012, 2014); however more research is needed to examine the psychometric properties of this CSS. Forty males with ASD completed an assessment battery consisting of ADOS-2 Module 4 and other clinical measures assessing core ASD symptomology and comorbidity. Pearson correlation analyses found that CSS did not correlate with measures that assessed core social deficits of ASD or general psychiatric co-morbidity, but CSS did correlate negatively with intellectual quotient. These findings provide information on the limitations and relevance of CSS to be taken into account in future clinical evaluations of ASD.

Subthreshold Psychosis in 22q11.2 Deletion Syndrome: Multisite Naturalistic Study.

Nearly one-third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop a psychotic disorder during life, most of them by early adulthood. Importantly, a full-blown psychotic episode is usually preceded by subthreshold symptoms. In the current study, 760 participants (aged 6-55 years) with a confirmed hemizygous 22q11.2 microdeletion have been recruited through 10 medical sites worldwide, as part of an international research consortium. Of them, 692 were nonpsychotic and with complete measurement data. Subthreshold psychotic symptoms were assessed using the Structured Interview for Prodromal Syndromes (SIPS). Nearly one-third of participants met criteria for positive subthreshold psychotic symptoms (32.8%), less than 1% qualified for acute positive subthreshold symptoms, and almost a quarter met criteria for negative/disorganized subthreshold symptoms (21.7%). Adolescents and young adults (13-25 years) showed the highest rates of subthreshold psychotic symptoms. Additionally, higher rates of anxiety disorders and attention deficit/hyperactivity disorder (ADHD) were found among the study participants with subthreshold psychotic symptoms compared to those without. Full-scale IQ, verbal IQ, and global functioning (GAF) scores were negatively associated with participants' subthreshold psychotic symptoms. This study represents the most comprehensive analysis reported to date on subthreshold psychosis in 22q11.2DS. Novel findings include age-related changes in subthreshold psychotic symptoms and evidence that cognitive deficits are associated with subthreshold psychosis in this population. Future studies should longitudinally follow these symptoms to detect whether and how early identification and treatment of these manifestations can improve long-term outcomes in those that eventually develop a psychotic disorder.

Attention-deficit hyperactivity disorder symptoms in a clinic sample of children and adolescents with pervasive developmental disorders.

OBJECTIVES: The aims of this systematic chart review were to determine the frequency of attention-deficit/hyperactivity disorder (ADHD) in a clinic sample of children and adolescents with autism spectrum disorders (ASD), to compare ADHD symptoms in children with Autistic Disorder, Asperger's Disorder, and pervasive developmental disorders-not otherwise specified (PDD-NOS), to compare ADHD symptoms in individuals with and without ADHD-related chief complaints, and to determine the correlation between ADHD Rating Scale (ADHD RS) scores and age. METHOD: This systematic chart review examined data from children and adolescents who were consecutively referred to a university-based autism psychopharmacology program. All individuals were diagnosed by semistructured interview for ASD and ADHD, and ADHD symptoms were assessed using ADHD RS scores. RESULTS: Of 83 children, 78% fulfilled Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria for ADHD and exceeded the 93rd percentile norm for the ADHD RS. Hyperactivity-impulsivity scores were significantly greater in individuals with autism than those with other ASDs. DSM-IV ADHD diagnosis was represented equally in individuals with and without ADHD as their chief complaints. ADHD RS hyperactivity-impulsivity and total scores were negatively correlated with age. CONCLUSION: ADHD symptoms are pervasive in clinically referred children and adolescents with ASD.

Cognitive decline preceding the onset of psychosis in patients with 22q11.2 deletion syndrome.

IMPORTANCE: Patients with 22q11.2 deletion syndrome (22q11DS) have an elevated (25%) risk of developing schizophrenia. Recent reports have suggested that a subgroup of children with 22q11DS display a substantial decline in cognitive abilities starting at a young age. OBJECTIVE: To determine whether early cognitive decline is associated with risk of psychotic disorder in 22q11DS. DESIGN, SETTING, AND PARTICIPANTS: Prospective longitudinal cohort study. As part of an international research consortium initiative, we used the largest data set of intelligence (IQ) measurements in patients with 22q11DS reported to date to investigate longitudinal IQ trajectories and the risk of subsequent psychotic illness. A total of 829 patients with a confirmed hemizygous 22q11.2 deletion, recruited through 12 international clinical research sites, were included. Both psychiatric assessments and longitudinal IQ measurements were available for a subset of 411 patients (388 with ≥1 assessment at age 8-24 years). MAIN OUTCOMES AND MEASURES: Diagnosis of a psychotic disorder, initial IQ, longitudinal IQ trajectory, and timing of the last psychiatric assessment with respect to the last IQ test. RESULTS: Among 411 patients with 22q11DS, 55 (13.4%) were diagnosed as having a psychotic disorder. The mean (SD) age at the most recent psychiatric assessment was 16.1 (6.2) years. The mean (SD) full-scale IQ at first cognitive assessment was lower in patients who developed a psychotic disorder (65.5 [12.0]) compared with those without a psychotic disorder (74.0 [14.0]). On average, children with 22q11DS showed a mild decline in IQ (full-scale IQ, 7.04 points) with increasing age, particularly in the domain of verbal IQ (9.02 points). In those who developed psychotic illness, this decline was significantly steeper (P < .001). Those with a negative deviation from the average cognitive trajectory observed in 22q11DS were at significantly increased risk for the development of a psychotic disorder (odds ratio = 2.49; 95% CI, 1.24-5.00; P = .01). The divergence of verbal IQ trajectories between those who subsequently developed a psychotic disorder and those who did not was distinguishable from age 11 years onward. CONCLUSIONS AND RELEVANCE: In 22q11DS, early cognitive decline is a robust indicator of the risk of developing a psychotic illness. These findings mirror those observed in idiopathic schizophrenia. The results provide further support for investigations of 22q11DS as a genetic model for elucidating neurobiological mechanisms underlying the development of psychosis.

Prodromal and autistic symptoms in schizotypal personality disorder and 22q11.2 deletion syndrome.

Despite clear diagnostic distinctions, schizophrenia and autism share symptoms on several dimensions. Recent research has suggested the two disorders overlap in etiology, particularly with respect to inherited and noninherited genetic factors. Studying the relationship between psychotic-like and autistic-like symptoms in risk groups such as 22q11 deletion syndrome (22q11DS) and schizotypal personality disorder (SPD) has the potential to shed light on such etiologic factors; thus, the current study examined prodromal symptoms and autistic features in samples of 22q11DS and SPD subjects using standardized diagnostic measures, including the Structured Interview for Prodromal Symptoms (SIPS) and the Autism Diagnostic Inventory-Revised (ADI-R). Results showed that SPD subjects manifested significantly more severe childhood and current social as well as stereotypic autistic features, as well as more severe positive prodromal symptoms. The two groups did not differ on negative, disorganized, or general prodromal symptoms, but were distinguishable based on correlations between prodromal and autistic features; the relationships between childhood autistic features and current prodromal symptoms were stronger for the SPD group. The results suggest that childhood autistic features are less continuous with subsequent prodromal signs in 22q11DS patients relative to those with SPD, and the findings highlight the importance of studying the overlap in diagnostic phenomenology in groups at risk for developing psychosis and/or autism.