ABSTRACT
Mendelian and early-onset severe psychiatric phenotypes often involve genetic variants having a large effect, offering opportunities for genetic discoveries and early therapeutic interventions. Here, the index case is an 18-year-old boy, who at 14 years of age had a decline in cognitive functioning over the course of a year and subsequently presented with catatonia, auditory and visual hallucinations, paranoia, aggression, mood dysregulation, and disorganized thoughts. Exome sequencing revealed a stop-gain mutation in RCL1 (NM_005772.4:c.370 C > T, p.Gln124Ter), encoding an RNA 3'-terminal phosphate cyclase-like protein that is highly conserved across eukaryotic species. Subsequent investigations across two academic medical centers identified eleven additional cases of RCL1 copy number variations (CNVs) with varying neurodevelopmental or psychiatric phenotypes. These findings suggest that dosage variation of RCL1 contributes to a range of neurological and clinical phenotypes.
Subject(s)
DNA Copy Number Variations , Adolescent , DNA Copy Number Variations/genetics , Humans , Male , Mutation/genetics , Phenotype , Exome SequencingABSTRACT
AIM: To determine predictors of full-scale IQ (FSIQ) in an international pediatric opsoclonus myoclonus syndrome (OMS) cohort. METHOD: In this retrospective and prospective cohort study at three academic medical centers (2006-2013), the primary outcome measure, FSIQ, was categorized based on z-score: above average (≥+1), average (+1 to -1), mildly impaired (-1 to -2), and impaired (<-2). Univariate analysis and multivariable linear regression modeling using stepwise selection with Akaike's information criterion was performed to understand the relationship between exposures and FSIQ. RESULTS: Of 81 participants, 37 with sufficient data had mean FSIQ 84.38 (SD 20.55) and median 90 (40-114) at latest available evaluation (mean age 8y 5mo). Twenty (54%), nine (24.3%), and eight (21.6%) had normal, mildly impaired, and impaired FSIQ respectively. The final multivariable linear regression model included 34 participants with evaluable data: number of relapses occurring before neuropsychological testing (p<0.001) and OMS severity score at last follow-up (p<0.001) predicted FSIQ (adjusted R2 =0.64). There was a mean decrease of 2.4 FSIQ points per OMS relapse. INTERPRETATION: Number of relapses negatively correlates with FSIQ in pediatric OMS. Demographic and clinical measures available at OMS onset did not predict FSIQ. Strategies to reduce OMS relapses may improve intellectual outcomes.
Subject(s)
Intelligence/physiology , Opsoclonus-Myoclonus Syndrome/physiopathology , Adolescent , Child , Female , Humans , Male , Opsoclonus-Myoclonus Syndrome/therapy , Prospective Studies , Recurrence , Retrospective Studies , Severity of Illness IndexABSTRACT
Given the propensity for clinical assessment of Attention-Deficit/Hyperactivity Disorder (ADHD) to focus on core behavioral symptoms, the current study examined how well other predictors classified children who were diagnosed with ADHD by licensed practitioners. Participants were 91 children (39 ADHD-identified, 52 without ADHD), aged 8 to 13 years. In addition to significantly more ADHD symptoms, the ADHD-identified group exhibited significantly more externalizing problems and internalizing symptoms, less adaptive functioning, and greater problem pervasiveness and severity. Binary logistic regression analyses indicated that problem pervasiveness and severity significantly predicted diagnostic group membership when controlling for other predictors, and pervasiveness added unique variance beyond measures of core ADHD symptoms. Diagnostic utility analyses showed measurement of problem pervasiveness and severity to be a useful tool in the identification of ADHD. Findings provide support for the practical use of a parent-report measure of impairment in the home as part of evidence-based assessment of ADHD.
