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

Abstract

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-Omethyltransferase 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.In recent years, a great deal has been learned about a disorder that is one of the most common genetic causes of developmental disability, mental retardation, and psychopathology. Resulting from a 1.5-to 3-Mb microdeletion on the long (q) arm of chromosome 22 , this disorder is most accurately characterized as the "chromosome 22q11.2 deletion syndrome" (DS22q11.2). Thus defined, the disorder encompasses previously described phenotypes including DiGeorge (1965), velocardiofacial (Shprintzen, Goldberg, Lewin, Sidoti, Berkman, Argamaso, & Young, 1978, and conotruncal anomaly face (Burn, Takao, Wilson, Cross, Momma, Wadey, Scambler, & Goodship, 1993) syndromes, and some cases of Cayler cardiofacial syndrome (Giannotti, Digilio, Marino, Mingarelli, & Dallapiccola, 1994) and Opitz G/BBB syndrome (McDonald-McGinn, Driscoll, Bason, Christensen, Lynch, Sullivan, Canning, Zavod, Quinn, & Rome, 1995). A molecular fluorescence in situ hybridization probe for the deletion set the prevalence at 1 in 4,000 live (Burn & Goodship, 1996), an estimate currently thought to be quite conservative (e.g., Shashi, Muddasani, Santos, Berry, Kwapil, Lewandowski, & Keshavan, 2004). Furthermore, several factors point to a significant growth in the identified population of individuals with DS22q11.2 in the near future. One is that the major cause for mortality in the syndrome, congenital heart defects, is now routinely resolved surgically. Another is that, because this is a contiguous gene deletion syndrome with no effect on reproductive fitness, adults with...

Domain specific attentional impairments in children with chromosome 22q11.2 deletion syndrome

“…First, the difficulties in spatially mediated attentional shifts, demonstrated here as an increased cost of the I-B condition relative to the valid condition, have been shown to be a hallmark cognitive impairment in this group (Simon et al, 2005b). Surprisingly, these same children clearly showed significant facilitation in performance when using of object-based attention.…”

“…In this paper we extend our previous analyses into two closely related spatiotemporal aspects of visual attention, that we have previously claimed to be a key foundational cognitive competence for children with DS22q11.2 (Simon et al, 2005a). Specifically we demon-strated that children with DS22q11.2 are impaired in the ability to effectively disengage attention from an invalidly cued location and re-engage attentional processing in a new target location (Simon et al, 2005b). This impairment in visuospatial processing seems to extend into the ability to move between and enumerate greater than four objects (Simon et al, 2005b).…”

“…Specifically we demon-strated that children with DS22q11.2 are impaired in the ability to effectively disengage attention from an invalidly cued location and re-engage attentional processing in a new target location (Simon et al, 2005b). This impairment in visuospatial processing seems to extend into the ability to move between and enumerate greater than four objects (Simon et al, 2005b). Similar in nature to space-based attention, object-based attention involves the ability to use cues within an object to enhance the processing of target information elsewhere within the confines of the same object.…”

A new account of the neurocognitive foundations of impairments in space, time, and number processing in children with chromosome 22q11.2 deletion syndrome

“…I contend also that this dysfunction creates a suboptimal foundation for the subsequent development of numerical and mathematical competence, thereby "cascading" impairments into those more academic domains. This view is essentially a refinement of my earlier claim that visuospatial dysfunction is the basis for most of the nonverbal cognitive impairments manifested by children with DS22q11.2 (Simon et al 2005a;Simon et al 2005b). Recent findings lead me to suggest that many of the structures involved in these circuits, especially the subcortical ones, suffer atypical early development, possibly driven to some extent by the genetics of the disorder.…”

The hippocampi of children with chromosome 22q11.2 deletion syndrome have localized anterior alterations that predict severity of anxiety

“…4,6,7 These include shared genetic (e.g., COMT genotypes 8 ), neural (e.g., enlarged cavum septum pellucidum and lateral ventricles 9,10 ) and cognitive (e.g., impaired executive [11][12][13][14] and attentional functions [15][16][17][18] ) traits. Major neuranatomical features of 22q11.2DS and schizophrenia centrally involve the hippocampus.…”