Fragile X-associated tremor/ataxia syndrome (FXTAS) is a recently recognized neurodegenerative disorder in fragile X premutation carriers with FMR1 alleles containing 55-200 CGG repeats. Previously, we developed a Drosophila model of FXTAS and demonstrated that transcribed premutation repeats alone are sufficient to cause neurodegeneration, suggesting that rCGG-repeat-binding proteins (RBPs) may be sequestered from their normal function by rCGG binding. Here, we identify Pur alpha and hnRNP A2/B1 as RBPs. We show that Pur alpha and rCGG repeats interact in a sequence-specific fashion that is conserved between mammals and Drosophila. Overexpression of Pur alpha in Drosophila could suppress rCGG-mediated neurodegeneration in a dose-dependent manner. Furthermore, Pur alpha is also present in the inclusions of FXTAS patient brains. These findings support the disease mechanism of FXTAS of rCGG repeat sequestration of specific RBPs, leading to neuronal cell death, and implicate that Pur alpha plays an important role in the pathogenesis of FXTAS.

A multisite study investigated the test-retest reliability and practice effects of a battery of assessments to measure neurocognitive function in individuals with Down syndrome (DS). The study aimed to establish the appropriateness of these measures as potential endpoints for clinical trials. Neurocognitive tasks and parent report measures comprising the Arizona Cognitive Test Battery (ACTB) were administered to 54 young participants with DS (7–20 years of age) with mild to moderate levels of intellectual disability in an initial baseline evaluation and a follow-up assessment 3 months later. Although revisions to ACTB measures are indicated, results demonstrate adequate levels of reliability and resistance to practice effects for some measures. The ACTB offers viable options for repeated testing of memory, motor planning, behavioral regulation, and attention. Alternative measures of executive functioning are required.

The cause of the high degree of variability in cognition and behavior among individuals with Down syndrome (DS) is unknown. We hypothesized that birth defects requiring surgery in the first years of life (congenital heart defects and gastrointestinal defects) might affect an individual's level of function. We used data from the first 234 individuals, age 6-25 years, enrolled in the Down Syndrome Cognition Project (DSCP) to test this hypothesis. Data were drawn from medical records, parent interviews, and a cognitive and behavior assessment battery. Results did not support our hypothesis. That is, we found no evidence that either birth defect was associated with poorer outcomes, adjusting for gender, race/ethnicity, and socioeconomic status. Implications for study design and measurement are discussed.

PurposeThe goal of this study was to identify the contribution of large copy number variants (CNV) to Down syndrome (DS) associated atrioventricular septal defects (AVSD), whose risk in the trisomic population is 2000-fold more compared to general disomic population.MethodsGenome-wide CNV analysis was performed on 452 individuals with DS (210 cases with complete AVSD; 242 controls with structurally normal hearts) using Affymetrix SNP 6.0 arrays, making this the largest heart study conducted to date on a trisomic background.ResultsLarge common CNVs with substantial effect sizes (OR>2.0) do not account for the increased risk observed in DS-associated AVSD. In contrast, cases had a greater burden of large rare deletions (p<0.01) and intersected more genes (p<0.007) when compared to controls. We also observed a suggestive enrichment of deletions intersecting ciliome genes in cases compared to controls.ConclusionOur data provide strong evidence that large rare deletions increase the risk of DS-associated AVSD, while large common CNVs do not appear to increase the risk of DS-associated AVSD. The genetic architecture of AVSD is complex and multifactorial in nature.