Schizophrenia and 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22qDS) is a genetic syndrome associated with a chromosome 22q11.2 deletion and variable phenotypic expression that commonly includes schizophrenia. Approximately 1% of patients with schizophrenia have 22qDS. The schizophrenia in 22qDS appears broadly similar to that found in the general population with respect to core signs and symptoms, treatment response, neurocognitive profile, and MRI brain anomalies. However, individuals with a 22qDS form of schizophrenia typically have distinguishable physical features, have a lower IQ, and may differ in auxiliary clinical features. IQ, length of 22q11.2 deletions, and COMT functional allele do not appear to be major risk factors for schizophrenia in 22qDS. Ascertainment biases and small sample sizes are limitations of most studies. Larger studies over the lifespan and continuing education about this underrecognized condition are needed. 22qDS-schizophrenia is an important genetic subtype and a valuable model of neurodevelopmental mechanisms involved in the pathogenesis of schizophrenia.     

Abnormal patterns of cortical gyrification in velo-cardio-facial syndrome (deletion 22q11.2): an MRI study

Velo-cardio-facial syndrome (VCFS), also known as 22q11.2 deletion syndrome, is a common genetic condition associated with increased risk for developing schizophrenia. Given that cortical malformations play an integral role in the pattern of neuroanatomical alterations associated with VCFS, the aim of the present study was to quantify and localize gyral abnormalities. Magnetic resonance images were obtained on a 1.5 T scanner. The gyrification index (GI), a measure of the degree of cortical complexity, was differentially calculated for each lobe using a semi-automated protocol. The GI was calculated for 37 patients affected by VCFS as well as for 36 comparison individuals group-matched for age, handedness, and gender. The subjects affected by VCFS showed a significant decrease in the GI in the frontal and parietal lobes compared with the control group. The pattern of decreased gyrification in the frontal and parietal lobes further defines the structural changes associated with the syndrome and suggests underlying abnormalities in neural connectivity. Aberrant connectivity may be partially responsible for the cognitive and behavioral impairments in the syndrome, as well as the high incidence of schizophrenia among affected individuals.     

Neurological manifestation of 22q11.2 deletion syndrome

Neurological Sciences - 22q11.2 deletion syndrome is the most common microdeletion syndrome. This article reviews the different neurological manifestations of 22q11.2 deletion syndrome. The...     

Shyness discriminates between children with 22q11.2 deletion syndrome and Williams syndrome and predicts emergence of psychosis in 22q11.2 deletion syndrome

Background

22q11.2 deletion syndrome (22q11.2DS) is a common neurogenetic syndrome associated with high rates of psychosis. The aims of the present study were to identify the unique temperament traits that characterize children with 22q11.2DS compared to children with Williams syndrome (WS) and typically developing (TD) controls, and to examine temperamental predictors of the emergence of psychosis in 22q11.2DS.

Methods

The temperament of 55 children with 22q11.2DS, 36 with WS, and 280 TD children was assessed using the Emotionality, Activity, Sociability (EAS) Temperament Survey, Parental Ratings. The presence of a psychotic disorder was evaluated in 49 children and adolescents with 22q11.2DS at baseline and again 5.43 ± 2.23 years after baseline temperament assessment.

Results

Children with 22q11.2DS scored higher on Shyness compared to WS and TD controls. Children with 22q11.2DS and WS scored higher on Emotionality and lower on Activity compared to TD controls. Shyness was more severe in older compared to younger children with 22q11.2DS. Baseline Shyness scores significantly predicted the later emergence of a psychotic disorder at follow-up, in children with 22q11.2DS.

Conclusions

Our results suggest that shyness is an early marker associated with the later emergence of psychosis in 22q11.2DS.     

Regional cortical volumes and congenital heart disease: a MRI study in 22q11.2 deletion syndrome

Children with congenital heart disease (CHD) who survive surgery often present impaired neurodevelopment and qualitative brain anomalies. However, the impact of CHD on total or regional brain volumes only received little attention. We address this question in a sample of patients with 22q11.2 deletion syndrome (22q11DS), a neurogenetic condition frequently associated with CHD. Sixty-one children, adolescents, and young adults with confirmed 22q11.2 deletion were included, as well as 80 healthy participants matched for age and gender. Subsequent subdivision of the patients group according to CHD yielded a subgroup of 27 patients with normal cardiac status and a subgroup of 26 patients who underwent cardiac surgery during their first years of life (eight patients with unclear status were excluded). Regional cortical volumes were extracted using an automated method and the association between regional cortical volumes, and CHD was examined within a three-condition fixed factor. Robust protection against type I error used Bonferroni correction. Smaller total cerebral volumes were observed in patients with CHD compared to both patients without CHD and controls. The pattern of bilateral regional reductions associated with CHD encompassed the superior parietal region, the precuneus, the fusiform gyrus, and the anterior cingulate cortex. Within patients, a significant reduction in the left parahippocampal, the right middle temporal, and the left superior frontal gyri was associated with CHD. The present results of global and regional volumetric reductions suggest a role for disturbed hemodynamic in the pathophysiology of brain alterations in patients with neurodevelopmental disease and cardiac malformations.     

Neural correlates of socio-emotional perception in 22q11.2 deletion syndrome

Background

Social impairments are described as a common feature of the 22q11.2 deletion syndrome (22q11DS). However, the neural correlates underlying these impairments are largely unknown in this population. In this study, we investigated neural substrates of socio-emotional perception.

Methods

We used event-related functional magnetic resonance imaging (fMRI) to explore neural activity in individuals with 22q11DS and healthy controls during the visualization of stimuli varying in social (social or non-social) or emotional (positive or negative valence) content.

Results

Neural hyporesponsiveness in regions of the default mode network (inferior parietal lobule, precuneus, posterior and anterior cingulate cortex and frontal regions) in response to social versus non-social images was found in the 22q11DS population compared to controls. A similar pattern of activation for positive and negative emotional processing was observed in the two groups. No correlation between neural activation and social functioning was observed in patients with the 22q11DS. Finally, no social × valence interaction impairment was found in patients.

Conclusions

Our results indicate atypical neural correlates of social perception in 22q11DS that appear to be independent of valence processing. Abnormalities in the social perception network may lead to social impairments observed in 22q11DS individuals.

     

Basal ganglia calcification and psychosis in 22q11.2 deletion syndrome

Intracerebral calcifications are a facultative symptom of hypoparathyreoidism in 22q11.2 deletion syndrome (22qDS). We describe a patient with 22qDS, basal ganglia calcification (BGC) and psychotic symptoms and discuss the etiological connection of BGC with psychiatric symptoms. Future work needs to determine the prevalence of BGC in 22qDS and psychiatric disorders.     

Thalamic reductions in children with chromosome 22q11.2 deletion syndrome

Children with chromosome 22q11.2 deletion syndrome (22q) suffer from physical and behavioral dysfunctions, including neuroanatomical anomalies, visuo-spatial processing deficits, and increased risk for psychopathology. Reduced total brain volume, parietal lobe volume, and cerebellar volumes, enlarged ventricles, and increased basal ganglia volumes have been reported. Since previous literature has related the pulvinar nucleus of the thalamus to visuo-spatial processing, we compared the thalamic volume in children with 22q to typically developing controls. Children with 22q showed a significant reduction of the thalamus compared with normally developing children, specifically in the posterior portion of the thalamus, including the pulvinar nucleus. These results provide the first evidence for a potential relationship between posterior thalamic reductions and the characteristic visuo-spatial deficits demonstrated in this group.     

Psychosis in children with velocardiofacial syndrome (22q11.2 deletion syndrome)

Velocardiofacial syndrome, now known as 22q11.2 deletion syndrome (22qDS), is estimated to affect more than 700 children born in the United States each year. Some clinical studies have found increased rates of schizophrenia in adults with 22qDS. However, these studies have been limited by small sample size and possible ascertainment bias. The psychiatric disorders most commonly reported in children and adolescents with 22qDS have been attention-deficit/hyperactivity disorder, oppositional defiant disorder, anxiety disorders, and major depression. Psychotic symptoms have been observed in 14% to 28% of children with 22qDS, but their clinical significance remains uncertain. A 5-year follow-up study of 22qDS children who reported psychotic symptoms at baseline found they had an increased risk for a subsequent psychotic disorder. Thus, a broad differential diagnosis should be considered when 22qDS children present with psychotic symptoms. Longitudinal studies are needed to better understand the full extent of the psychopathology associated with 22qDS.     

Abnormal cortical activation during response inhibition in 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11.2DS) is a well-known genetic risk factor for schizophrenia. The catechol-O-methyltransferase (COMT) gene falls within the 22q11.2 minimal critical region of the deletion. Brain activity, as measured by functional magnetic resonance imaging (fMRI) during a Go/NoGo, response inhibition task was assessed in adolescents with 22q11.2DS (n = 13), typically developing (TD) controls (n = 14), and controls with developmental disability (DD, n = 9). Subjects with 22q11.2DS were also genotyped for the COMT Met/Val polymorphism. Groups did not differ on task performance. However, compared to both control groups, the 22q11.2DS group showed greater brain activation within left parietal regions. Comparison of brain activation between 22q11.2DS Met and Val subgroups revealed significantly increased activation (Met>Val) in the cingulate but not the dorsolateral prefrontal cortex. These preliminary findings suggest that adolescents with 22q11.2DS compensate for executive dysfunction via recruitment of parietal regions. Further, the COMT Met subgroup of 22q11.2DS may recruit additional cingulate activation for tasks requiring attention and inhibition. 22q11.2DS is a unique model for learning about the deleterious effects of decreased dosage of the COMT gene on brain function.     

Reduced NoGo-anteriorisation during continuous performance test in deletion syndrome 22q11.2

Deletion syndrome 22q11.2 (DS22q11.2) is a high-risk factor for psychiatric disorders. Alterations in brain morphology and function including the anterior cingulate cortex (ACC) are suggested to underlie the increased psychiatric disposition. We assessed response-inhibition in patients with DS22q11.2 (n = 13) and healthy controls (n = 13) matched for age, sex, and handedness by means of a Go-NoGo-Task during recording of a multi-channel electroencephalography (EEG). Analysis of event-related potentials (P300) resulted in an aberrant topographical pattern and NoGo-anteriorisation (NGA) as a parameter of medial prefrontal function was significantly reduced in patients with DS22q11.2 compared to controls. Differences in IQ between groups did not account for the findings. Source localization analysis (LORETA) revealed diminished left temporal brain activation during the Go-condition, but no altered ACC activation in DS22q11 during the NoGo-condition. Despite recent reports of structural alterations of the ACC in DS22q11.2 our findings suggest that response-inhibition mediated by the ACC is not impaired in DS22q11.2.     

Corpus callosum morphology and ventricular size in chromosome 22q11.2 deletion syndrome

In this paper, novel methods were used to map the corpus callosum morphology of children with chromosome 22q11.2 deletion syndrome in order to further investigate changes to that structure and to examine their possible effects on cognitive function. The callosal profiles were extracted from the centermost MRI midsagittal slice by supervised thresholding and the structure's boundary and midline were computed automatically. Difference analysis was based on non-rigid registration, in which a template image is warped to conform to the shape of each corpus callosum in the sample. Boundaries and midlines were registered to a template and the results used to determine the average callosal shapes for children with the deletion and for controls. Pointwise registration also enabled the detailed evaluation of callosal curvature, width, area and length. Significant differences between the two groups were found in shape, size and bending angle. Results showed group differences that were concentrated in the anterior part of the structure, more specifically in the rostrum, which was larger and longer in the group with the syndrome. Correlation analyses showed that ventricular enlargement does not fully account for callosal morphology differences in children with the deletion. However, areal measurements did reveal important relationships between changes in callosal morphology and cognitive function. These novel findings reveal intricate relationships between genetic and disease-specific factors in the callosal anatomy and the potential impact of those changes on cognitive functions.