Our prospective phenotyping expands the clinical spectrum of NGLY1-CDDG, offers prognostic information, and provides baseline data for evaluating therapeutic interventions.Genet Med 19 2, 160-168.

Objective Although combination pharmacotherapy is common in child/adolescent psychiatry, there has been little research evaluating it. We tested the value of adding risperidone to concurrent psychostimulant and parent training (PT) in behavior management for children with severe aggression Method We randomized 168 children age 6–12 years (mean 8.89 ±2.01) with severe physical aggression to a 9-week trial of PT, stimulant, and placebo (Basic treatment; n=84) or PT, stimulant, and risperidone (Augmented treatment; n=84). All had diagnoses of attention-deficit/ hyperactivity disorder (ADHD) and either oppositional defiant (n= 124) or conduct disorder (n= 44). Children received psychostimulant (usually OROS methylphenidate) for 3 weeks, titrated for optimal effect, while parents received PT. If there was room for improvement at the end of Week 3, either placebo or risperidone was added. Assessments included parent ratings on the Nisonger Child Behavior Rating Form (NCBRF; Disruptive-Total subscale = Primary outcome) and Antisocial Behavior Scale (ABS); blinded clinicians rated change on the Clinical Global Impressions (CGI) scale. Results Compared to Basic treatment (PT + stimulant[STIM][44.8±14.6 mg/day] + placebo [1.88±0.72]), Augmented treatment (PT + STIM[46.1±16.8 mg/day] + risperidone[1.65±0.75]) showed statistically significant improvement on the NCBRF Disruptive–Total subscale (treatment-by-time interaction p= 0.0016), the NCBRF Social Competence subscale (p= 0.0049), and ABS Reactive Aggression (p= 0.01). CGI scores were substantially improved for both groups but did not discriminate between treatments (CGI-I ≤ 2, 70% for Basic treatment vs. 79% for Augmented treatment). Prolactin elevations and gastrointestinal upset occurred more with Augmented; other adverse events differed modestly from Basic treatment; weight gain within the Augmented treatment group was minor. Conclusions Risperidone provided moderate but variable improvement in aggressive and other seriously disruptive child behavior when added to PT and optimized stimulant treatment. Clinical trial registration information—Treatment of Severe Childhood Aggression (The TOSCA Study); http://clinicaltrials.gov/; NCT00796302.

BackgroundThe causes of autism likely involve genetic and environmental factors that influence neurobiological changes and the neurological and behavioral features of the disorder. Immune factors and inflammation are hypothesized pathogenic influences, but have not been examined longitudinally.MethodsIn a cohort of 104 participants with autism, we performed an assessment of immune mediators such as cytokines, chemokines, or growth factors in serum and cerebrospinal fluid (n = 67) to determine potential influences of such mediators in autism.ResultsAs compared with 54 typically developing controls, we found no evidence of differences in the blood profile of immune mediators supportive of active systemic inflammation mechanisms in participants with autism. Some modulators of immune function (e.g., EGF and soluble CD40 ligand) were increased in the autism group; however, no evidence of group differences in traditional markers of active inflammation (e.g., IL-6, TNFα, IL-1β) were observed in the serum. Further, within-subject stability (measured by estimated intraclass correlations) of most analytes was low, indicating that a single measurement is not a reliable prospective indicator of concentration for most analytes. Additionally, in participants with autism, there was little correspondence between the blood and CSF profiles of cytokines, chemokines, and growth factors, suggesting that peripheral markers may not optimally reflect the immune status of the central nervous system. Although the relatively high fraction of intrathecal production of selected chemokines involved in monocyte/microglia function may suggest a possible relationship with the homeostatic role of microglia, control data are needed for further interpretation of its relevance in autism.ConclusionsThese longitudinal observations fail to provide support for the hypothesized role of disturbances in the expression of circulating cytokines and chemokines as an indicator of systemic inflammation in autism. ClinicalTrials.gov, NCT00298246.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-016-0115-7) contains supplementary material, which is available to authorized users.

The topic of this special issue on secondary versus idiopathic autism allows for discussion of how different groups may come to manifest autism spectrum disorder (ASD) or ASD-like symptoms despite important etiological differences. A related issue is that, because many of the social communication deficits that define ASD represent a failure to acquire developmentally expected skills, these same deficits would be expected to occur to some extent in all individuals with intellectual disability (ID). Thus, regardless of etiology, ASD symptoms may appear across groups of individuals with vastly different profiles of underlying deficits and strengths. In this focused review, we consider the impact of ID on the diagnosis of ASD. We discuss behavioral distinctions between ID and ASD, in light of the diagnostic criterion mandating that ASD should not be diagnosed if symptoms are accounted for by ID or general developmental delay. We review the evolution of the autism diagnosis and ASD diagnostic tools to understand how this distinction has been conceptualized previously. We then consider ways that operationalized criteria may be beneficial for making the clinical distinction between ID with and without ASD. Finally, we consider the impact of the blurred diagnostic boundaries between ID and ASD on the study of secondary versus idiopathic ASD. Especially pertinent to this discussion are findings that a diagnosis of ID in the context of an ASD diagnosis may be one of the strongest indicators that an associated condition or specific etiological factor is present (i.e., secondary autism).

BackgroundInflammation is associated with major depressive disorder (MDD). Translocator protein 18 kDa (TSPO), a putative biomarker of neuroinflammation, is quantified using positron emission tomography (PET) and 11C-PBR28, a TSPO tracer. We sought to (1) investigate TSPO binding in MDD subjects currently experiencing a major depressive episode, (2) investigate the effects of antidepressants on TSPO binding, and (3) determine the relationship of peripheral and central inflammatory markers to cerebral TSPO binding. Twenty-eight depressed MDD subjects (unmedicated (n = 12) or medicated (n = 16)) and 20 healthy controls (HC) underwent PET imaging using 11C-PBR28. Total distribution volume (VT, proportional to Bmax/Kd) was measured and corrected with the free fraction in plasma (fp). The subgenual prefrontal cortex (sgPFC) and anterior cingulate cortex (ACC) were the primary regions of interest. Peripheral blood samples and cerebrospinal fluid were analyzed to investigate the relationship between TSPO binding and peripheral and central inflammatory markers, including interleukins and neurotrophic factors previously linked to depression.ResultsTSPO binding was higher in MDD versus HC in the sgPFC (Cohen’s d = 0.64, p = .038, 95% CI 0.04–1.24) and ACC (d = 0.60, p = .049, 95% CI 0.001–1.21), though these comparisons missed the corrected threshold for statistical significance (α = .025). Exploratory analyses demonstrated that unmedicated MDD subjects had the highest level of TSPO binding, followed by medicated MDD subjects, who did not differ from HC. TSPO binding correlated with interleukin-5 in cerebrospinal fluid but with no other central inflammatory markers.ConclusionsThis study found a trend towards increased TSPO binding in the brains of MDD subjects, and post hoc analysis extended these findings by demonstrating that this abnormality is significant in unmedicated (but not medicated) MDD subjects.Electronic supplementary materialThe online version of this article (10.1186/s13550-018-0401-9) contains supplementary material, which is available to authorized users.

Objective Aside from features associated with risk of neurogenetic syndromes in general (e.g., cognitive impairment), limited progress has been made in identifying phenotype-genotype relationships in autism spectrum disorder (ASD). Method This study extends work in the Simons Simplex Collection (SSC) by comparing the phenotypic profiles of ASD probands with or without identified de novo loss of function mutations (LoF) or Copy Number Variants (CNV) in high confidence ASD-associated genes/loci (Sanders et al., 2015). Analyses pre-emptively accounted for documented differences in sex and IQ in affected individuals with de novo mutations, by matching probands with and without these genetic events on sex, IQ, and age before comparing them on multiple behavioral domains. Results Children with de novo mutations (n=112) showed greater likelihood of motor delays during early development (i.e., later age of walking), but less impairment in certain measures of ASD core symptoms (parent-rated social-communication impairment and clinician-rated diagnostic certainty) in later childhood. These children also showed relative strengths in verbal and language abilities, including a smaller discrepancy between nonverbal and verbal IQ and a greater likelihood of having achieved fluent language. Conclusions Children with ASD with de novo mutations may exhibit a “muted” symptom profile with respect to social-communication and language deficits, relative to those with ASD with no identified genetic abnormalities. Such findings suggest that examining early milestone differences and standardized testing results may be helpful in etiologic efforts, and potentially in clinical differentiation of various subtypes of ASD, but only if developmental/demographic variables are properly accounted for first.

From a psychometric perspective, researchers may elect to administer only the CADSS depersonalization subscale, given that it was most closely related to antidepressant response. From a neurobiological perspective, mechanistic similarities may exist between ketamine-induced depersonalization and antidepressant response, although off-target effects cannot be excluded.

LAY ABSTRACT Measuring the severity of autism is a challenge for researchers and clinicians. Recently, Gotham et al., (2009) addressed this issue by creating calibrated severity scores (CSS) based on raw total scores of the Autism Diagnostic Observation Schedule (ADOS), a standardized measure commonly used in autism diagnosis. We tested the utility of the CSS by comparing its scores to raw scores from the ADOS in a sample of 368 children aged 2–12 years with autism, PDD-NOS, non-spectrum delay, or typical development. As expected, we found that the CSS were more uniformly distributed within diagnostic categories and across ADOS modules than were raw scores. In particular, CSS were useful in controlling for differences in verbal development. Follow-up evaluations showed good temporal stability of the CSS over 12–24 months in children with autism. The results of this study support the use of the CSS to measure the severity of the core symptoms of autism. Further research is needed to determine if the CSS can also be used to measure changes in symptom severity and serve as a tool for clinical research. SCIENTIFIC ABSTRACT Measurement of the severity of autism at a single time point, and over time, is a widespread challenge for researchers. Recently, Gotham et al., (2009) published a severity metric (calibrated severity scores; CSS) that takes into account age and language level and is based on raw total scores of the Autism Diagnostic Observation Schedule (ADOS), a standardized measure commonly used in autism diagnosis. The present study examined psychometric characteristics of the CSS compared to raw scores in an independent sample of 368 children aged 2–12 years with autism, PDD-NOS, non-spectrum delay, or typical development. Reflecting the intended calibration, the CSS were more uniformly distributed within clinical diagnostic category and across ADOS modules than were raw scores. Cross sectional analyses examining raw and severity scores and their relationships to participant characteristics revealed that verbal developmental level was a significant predictor of raw score, but accounted for significantly less variance in the CSS. Longitudinal analyses indicated overall stability of the CSS over 12–24 months in children with autism. Findings from this study support the use of the CSS as a more valid indicator of autism severity than the ADOS raw total score, and extend the literature by examining the stability over 12–24 months of the CSS in children with ASD.