A multilevel analysis of cognitive dysfunction and psychopathology associated with chromosome 22q11.2 deletion syndrome in children

The Children's Hospital of Philadelphia, Filadelfia, Pennsylvania, United States
Development and Psychopathology (Impact Factor: 4.89). 02/2005; 17(3):753-84. DOI: 10.1017/S0954579405050364
Source: PubMed


We present a multilevel approach to developing potential explanations of cognitive impairments and psychopathologies common to individuals with chromosome 22q11.2 deletion syndrome. Results presented support our hypothesis of posterior parietal dysfunction as a central determinant of characteristic visuospatial and numerical cognitive impairments. Converging data suggest that brain development anomalies, primarily tissue reductions in the posterior brain and changes to the corpus callosum, may affect parietal connectivity. Further findings indicate that dysfunction in "frontal" attention systems may explain some executive cognition impairments observed in affected children, and that there may be links between these domains of cognitive function and some of the serious psychiatric conditions, such as attention-deficit/hyperactivity disorder, autism, and schizophrenia, that have elevated incidence rates in the syndrome. Linking the neural structure and the cognitive processing levels in this way enabled us to develop an elaborate structure/function mapping hypothesis for the impairments that are observed. We show also, that in the case of the catechol-O-methyltransferase gene, a fairly direct relationship between gene expression, cognitive function, and psychopathology exists in the affected population. Beyond that, we introduce the idea that variation in other genes may further explain the phenotypic variation in cognitive function and possibly the anomalies in brain development.

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Available from: Tony J Simon
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    • "results from a 1.5- to 3-megabase microdeletion on the long (q) arm of chromosome 22 (Carlson et al., 1997) and occurs in approximately one in 2000–4000 live births (Oskarsdóttir et al., 2004; Shprintzen, 2008). Children with this disorder have mild to moderate intellectual impairments (median full scale IQ 70 ± 15) (Scambler, 2000) and a cognitive profile with difficulties on a range of functions including attention and quantitative processing (Simon et al., 2005; Simon, 2008; Simon and Luck, 2011), as well as cognitive control (Bish et al., 2005; Sobin et al., 2005). Importantly, children with 22q11.2DS "
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    ABSTRACT: Chromosome 22q11.2 Deletion Syndrome (22q11.2DS) is caused by the most common human microdeletion, and it is associated with cognitive impairments across many domains. While impairments in cognitive control have been described in children with 22q11.2DS, the nature and development of these impairments are not clear. Children with 22q11.2DS and typically developing children (TD) were tested on four well-validated tasks aimed at measuring specific foundational components of cognitive control: response inhibition, cognitive flexibility, and working memory. Molecular assays were also conducted in order to examine genotype of catechol-O-methyltransferase (COMT), a gene located within the deleted region in 22q11.2DS and hypothesized to play a role in cognitive control. Mixed model regression analyses were used to examine group differences, as well as age-related effects on cognitive control component processes in a cross-sectional analysis. Regression models with COMT genotype were also conducted in order to examine potential effects of the different variants of the gene. Response inhibition, cognitive flexibility, and working memory were impaired in children with 22q11.2DS relative to TD children, even after accounting for global intellectual functioning (as measured by full-scale IQ). When compared with TD individuals, children with 22q11.2DS demonstrated atypical age-related patterns of response inhibition and cognitive flexibility. Both groups demonstrated typical age-related associations with working memory. The results of this cross-sectional analysis suggest a specific aberration in the development of systems mediating response inhibition in a sub-set of children with 22q11.2DS. It will be important to follow up with longitudinal analyses to directly examine these developmental trajectories, and correlate neurocognitive variables with clinical and adaptive outcome measures.
    Full-text · Article · Jun 2014 · Frontiers in Psychology
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    • " location . The model also suggests that decreased working memory capacity may be due to limitations of attention ( e . g . , selection bottlenecks ) . Limited attention capacity has been reported across a variety of paradigms in individuals with 22q11 . 2DS ( Bish , Ferrante , McDonald - McGinn , Zackai , & Simon , 2005 ; Cabaral et al . , 2012 ; Simon et al . , 2005 ) , Future studies collecting eye position data are needed to test how this model can enhance our understanding of individuals with 22q11 . 2DS . Finally , working memory capacity limitations may be due to time limitations ( McAfoose & Baune , 2009 ) . For example , individuals with reduced capacity may maintain items in active memory f"
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    ABSTRACT: Abstract Individuals with chromosome 22q11.2 deletion syndrome (22q11.2DS) have been shown to have impairments in processing spatiotemporal information. The authors examined whether children with 22q11.2DS exhibit impairments in spatial working memory performance due to these weaknesses, even when controlling for maintenance of attention. Children with 22q11.2DS (n = 47) and typically developing controls (n = 49) ages 6-15 years saw images within a grid and after a delay, then indicated the positions of the images in the correct temporal order. Children with 22q11.2DS made more spatial and temporal errors than controls. Females with 22q11.2DS made more spatial and temporal errors than males. These results extend findings of impaired spatiotemporal processing into the memory domain in 22q11.2DS by documenting their influence on working memory performance.
    Full-text · Article · Mar 2014 · American Journal on Intellectual and Developmental Disabilities
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    • "Using this adjustment, the RT remains unchanged with 100% accuracy and is increased in proportion to the number of errors. This measure accounts for speed/accuracy trade-offs and has been used to examine spatial cueing in children in previous studies [8,19,27]. Paired t-tests and two-sample t-tests were used to compare adjusted median RTs between conditions within a group or between groups. "
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    ABSTRACT: Chromosome 22q11.2 deletion syndrome (22q11.2DS) results from a 1.5- to 3-megabase deletion on the long arm of chromosome 22 and occurs in approximately 1 in 4000 live births. Previous studies indicate that children with 22q11.2DS are impaired on tasks involving spatial attention. However, the degree to which these impairments are due to volitionally generated (endogenous) or reflexive (exogenous) orienting of attention is unclear. Additionally, the efficacy of these component attention processes throughout child development in 22q11.2DS has yet to be examined. Here we compared the performance of a wide age range (7 to 14 years) of children with 22q11.2DS to typically developing (TD) children on a comprehensive visual cueing paradigm to dissociate the contributions of endogenous and exogenous attentional impairments. Paired and two-sample t-tests were used to compare outcome measures within a group or between groups. Additionally, repeated measures regression models were fit to the data in order to examine effects of age on performance. We found that children with 22q11.2DS were impaired on a cueing task with an endogenous cue, but not on the same task with an exogenous cue. Additionally, it was younger children exclusively who were impaired on endogenous cueing when compared to age-matched TD children. Older children with 22q11.2DS performed comparably to age-matched TD peers on the endogenous cueing task. These results suggest that endogenous but not exogenous orienting of attention is selectively impaired in children with 22q11.2DS. Additionally, the age effect on cueing in children with 22q11.2DS suggests a possible altered developmental trajectory of endogenous cueing.
    Full-text · Article · Feb 2012 · Journal of Neurodevelopmental Disorders
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