Schizophrenia-like neurophysiological abnormalities in 22q11.2 deletion syndrome and their association to COMT and PRODH genotypes

22q11.2 deletion syndrome (22q11.2DS) is a common genetic risk factor for the development of schizophrenia. We investigated two neurophysiological endophenotypes of schizophrenia – P50 sensory gating and mismatch negativity in 22q11.2DS subject and evaluated their association with catechol O-methyltransferase (COMT) and proline dehydrogenase (PRODH) genetic variants. We also assessed the association of neurophysiological measures with schizophrenia-like symptomatology in 22q11.2DS. Fifty-nine subjects, 41 with 22q11.2DS and 18 typically developing controls, participated in the study. The participants with 22q11.2DS were genotyped for the COMT Val¹⁵⁸Met (rs4680) and PRODH Gln¹⁹Pro (rs2008720) and Arg¹⁸⁵Trp (rs4819756) polymorphisms. Following psychiatric evaluation, all the participants underwent neurophysiological recordings and executive function assessment. The 22q11.2DS group showed poorer sensory gating of the P50 response than the controls. Within the 22q11.2DS group, the COMT Met allele was associated with poorer sensory gating, while both the COMT Met allele and the PRODH Pro-Arg haplotype were associated with smaller mismatch negativity amplitudes. Smaller mismatch negativity amplitudes predicted greater impairment of executive functions and greater severity of schizophrenia-like negative symptoms in 22q11.2DS. The current study demonstrates that sensory gating impairments that are typical of schizophrenia are found in 22q11.2DS subjects. Our results further suggest that COMT and PRODH genetic variations contribute to sensory gating and mismatch negativity schizophrenia-like impairments in 22q11.2DS, possibly via dopaminergic/glutamatergic networks. The associations of mismatch negativity impairments with increased severity of schizophrenia-like negative symptoms and poorer executive functions performance in our 22q11.2DS sample suggest that mismatch negativity is a potential endophenotype for schizophrenia in 22q11.2DS.     

Abnormal Auditory Processing and Underlying Structural Changes in 22q11.2 Deletion Syndrome

The 22q11.2 deletion syndrome (22q11.2 DS), one of the highest genetic risk for the development of schizophrenia, offers a unique opportunity to understand neurobiological and functional changes preceding the onset of the psychotic illness. Reduced auditory mismatch negativity response (MMN) has been proposed as a promising index of abnormal sensory processing and brain pathology in schizophrenia. However, the link between the MMN response and its underlying cerebral mechanisms in 22q11.2 DS remains unexamined. We measured auditory-evoked potentials to frequency deviant stimuli with high-density electroencephalogram and volumetric estimates of cortical and thalamic auditory areas with structural T1-weighted magnetic resonance imaging in a sample of 130 individuals, 70 with 22q11.2 DS and 60 age-matched typically developing (TD) individuals. Compared to TD group, the 22q11.2 deletion carriers reveal reduced MMN response and significant changes in topographical maps and decreased gray matter volumes of cortical and subcortical auditory areas, however, without any correlations between MMN alteration and structural changes. Furthermore, exploratory research on the presence of hallucinations (H⁺\H⁻) reveals no change in MMN response in 22q11.2DS (H⁺ and H⁻) as compared to TD individuals. Nonetheless, we observe bilateral volume reduction of the superior temporal gyrus and left medial geniculate in 22q11.2DSH⁺ as compared to 22q11.2DSH⁻ and TD participants. These results suggest that the mismatch response might be a promising neurophysiological marker of functional changes within the auditory pathways that might underlie elevated risk for the development of psychotic symptoms.     

Developmental trajectories of brain structure in adolescents with 22q11.2 deletion syndrome: a longitudinal study

The 22q11.2 deletion syndrome (22q11.2DS) is associated with very high rates of schizophrenia-like psychosis and cognitive deficits. Here we report the results of the first longitudinal study assessing brain development in individuals with 22q11.2DS. Twenty-nine children with 22q11.2DS and 29 age and gender matched controls were first assessed during childhood or early adolescence; Nineteen subjects with 22q11.2DS and 18 controls underwent follow-up during late adolescence-early adulthood. The 22q11.2DS subjects showed greater longitudinal increase in cranial and cerebellar white matter, superior temporal gyrus, and caudate nucleus volumes. They also had a more robust decrease in amygdala volume. Verbal IQ (VIQ) scores of the 22q11.2DS group that developed psychotic disorders declined significantly between assessments. Decline in VIQ in 22q11.2DS was associated with more robust reduction of left cortical grey matter volume. No volumetric differences were detected between psychotic and nonpsychotic subjects with 22q11.2DS. Brain maturation associated with verbal cognitive development in 22q11.2DS varies from that observed in healthy controls. Further longitudinal studies are likely to elucidate brain developmental trajectories in 22q11.2DS and their association to psychotic disorders and cognitive deficits in this population.     

Association of COMT and PRODH gene variants with intelligence quotient (IQ) and executive functions in 22q11.2DS subjects

The 22q11.2 deletion syndrome (22q11.2DS) carries the highest genetic risk factor for the development of schizophrenia. We investigated the association of genetic variants in two schizophrenia candidate genes with executive function (EF) and IQ in 22q11.2DS individuals.Ninety two individuals with 22q11.2 deletion were studied for the genetic association between COMT and PRODH variants and EF and IQ. Subjects were divided into children (under 12 years old), adolescents (between 12 and 18 years old) and adults (older than 18 years), and genotyped for the COMT Val158Met (rs4680) and PRODH Arg185Trp (rs4819756) polymorphisms. The participants underwent psychiatric evaluation and EF assessment. Our main finding is a significant influence of the COMT Val158Met polymorphism on both IQ and EF performance. Specifically, 22q11.2DS subjects with Met allele displayed higher IQ scores in all age groups compared to Val carriers, reaching significance in both adolescents and adults. The Met allele carriers performed better than Val carriers in EF tasks, being statistically significant in the adult group. PRODH Arg185Trp variant did not affect IQ or EF in our 22q11.2DS cohort. In conclusion, functional COMT variant, but not PRODH, affects IQ and EF in 22q11.2DS subjects during neurodevelopment with a maximal effect at adulthood. Future studies should monitor the cognitive performance of the same individuals from childhood to old age.     

The feasibility and safety of S-adenosyl-l-methionine (SAMe) for the treatment of neuropsychiatric symptoms in 22q11.2 deletion syndrome: a double-blind placebo-controlled trial

The goal of this trial was to assess the feasibility and safety of using S-adenosyl-l-methionine (SAMe) to treat depressive disorder, attention deficit/hyperactivity disorder (ADHD) and cognitive deficits in individuals with the 22q11.2 deletion syndrome (22q11.2DS). SAMe supposedly enhances the activity of the COMT enzyme. Because individuals with 22q11.2DS have only one copy of the gene responsible for the enzyme, COMT haploinsufficiency may be associated with their psychiatric morbidity and cognitive deficits. We assessed twelve 22q11.2DS individuals with depressive disorder or ADHD in a randomized double-blind cross-over placebo-controlled trial, using SAMe 800?mg bid. Individuals were evaluated for treatment safety and effectiveness during the trial and upon completion at sixth week. Compared to placebo, there were no significant differences in the rate of reported side effects between SAMe and placebo. Despite a general concern that SAMe might induce mania in vulnerable individuals, no manic or psychotic symptoms were exhibited during the SAMe treatment. Individuals with 22q11.2DS with comorbid depressive disorder with or without psychotic symptoms (n?=?5) had a larger numerical improvement on relevant clinical scales compared to placebo. No treatment effect was found on ADHD symptoms in subjects who suffered from 22q11.2DS with comorbid ADHD (n?=?7). Cognitive performance did not improve or deteriorate following treatment with SAMe compared to placebo. In conclusion SAMe treatment up to 1,600?mg/day for 6?weeks in 22q11.2DS individuals appears to be safe, well tolerated and with no serious side effects. No significant benefit in depressive or ADHD symptoms was detected.     

Psychiatric disorders in people with 22q11.2 Deletion Syndrome: A population‐based prevalence study in Ireland

Background : 22q11.2 Deletion Syndrome (22q11.2 DS) is a common micro‐deletion syndrome associated with intellectual disability, brain abnormalities and a complex spectrum of psychiatric disorders in both adults and children. Many previous studies have shown that adults with 22q11.2 DS have approximately thirty times greater risk for the developing schizophrenia compared to the general population. Furthermore, studies of children and adolescents with 22q11.2 DS have found high rates of psychotic symptoms, ADHD and anxiety disorders. In this study we initially aim to characterize the psychiatric and neuropsychological phenotype of all individuals in Ireland with 22q11.2 DS and then correlate our findings with genetic association studies and brain imaging. We then intend to undertake a longitudinal study to assess for risk factors of future psychotic illness. Methods : Forty‐four individuals with 22q11.2 DS (Mean age = 14 years, SD = 9) were compared to 25 non‐affected sibling controls (Mean age = 12 years, SD = 4). Psychiatric phenotype assessment was performed using a range of standardized clinical assessments including, the Diagnostic Interview Schedule for Children (DISC), Psychotic Supplement of K‐SADS, Comprehensive Assessment of At Risk Mental State (CAARMS), the Schedule for Clinical Assessment in Neuropsychiatry (SCAN), Child Behaviour Checklist (CBCL) and the Social Communication Questionnaire (SCQ). Results : Preliminary data indicates that individuals in the 22q11.2 DS group have a higher prevalence of psychiatric disorders including; ADHD (41%), psychotic symptoms (19%), schizophrenia (2.7%), specific phobias (38%), depressive episodes (11%), and anxiety disorders (32%). Conclusion : This is the first stage in a longitudinal follow‐up study of individuals with 22q11.2DS in Ireland. Our preliminary results are consistent with previous findings of high rates of psychiatric disorders in people with 22q11.2DS. The challenge remains to identify precursor symptoms in childhood that predicts the later development of psychiatric disorders, particularly schizophrenia in this vulnerable group.     

Atypical development of the executive attention network in children with chromosome 22q11.2 deletion syndrome

Impairment in the executive control of attention has been found in youth with chromosome 22q11.2 deletion syndrome (22q11.2DS). However, how this impairment is modified by other factors, particularly age, is unknown. Forty-six typically developing and 53 children with 22q11.2DS were tested with the attention networks task (ANT) in this cross-sectional study. We used logarithmic transform and linear modeling to assess age effects on the executive index of the ANT. Mixed modeling accounted for between subject variability, age, handedness, catecholamine-O-transferase (COMT; codon 158) genotype, and gender on performance for all experimental conditions (cue × flanker) and their two-level interactions. Children with 22q11.2DS showed a relative, age-dependent executive index impairment but not orienting or alerting network index impairments. In factorial analysis, age was a major predictor of overall performance. There was a significant effect of the 22q11.2DS on overall performance. Of note, children with 22q11.2DS are specifically vulnerable to incongruent flanker interference, especially at younger ages. We did not find an overall effect of COMT genotype or handedness. Children with 22q11.2DS demonstrated age-related impairment in the executive control of attention. Future investigation will likely reveal that there are different developmental trajectories of executive attentional function likely related to the development of schizophrenia in 22q11.2DS.     

Cingulate gyral reductions are related to low executive functioning and psychotic symptoms in 22q 11.2 deletion syndrome

A similar pattern of deficits in executive function and neuroanatomical abnormalities is shared between 22q 11.2 deletion syndrome (22q 11DS) and schizophrenia, suggesting that common cerebral alterations may lead to cognitive dysfunction and promote the appearance of psychotic symptoms in 22q 11DS individuals. Specifically, there is increasing evidence for involvement of the cingulate gyrus (CG) in executive dysfunction and the expression of positive symptoms in schizophrenia. The aim of our study is to examine CG morphology in a 22q 11DS population and its potential role as a cerebral marker of executive dysfunction and the manifestation of psychotic symptoms. Using region of interest (ROI)-based analysis, we compared CG volumes from 58 children and adults affected by 22q 11DS with 64 healthy age- and gender-matched controls. After covarying for total cranium grey matter and age, a bilateral reduced CG grey matter volume, driven by a decrease in anterior CG cortex, was observed among 22q 11DS patients. Further post hoc analyses suggest correlations between right CG cortical reductions, low-executive functioning and the occurrence of psychotic symptoms. The CG structural abnormalities observed in 22q 11DS are consistent with previous reports in schizophrenic patients and are associated with pre-morbid cognitive impairments. The mechanisms by which these changes may modulate executive functioning and the expression of psychosis are discussed.     

Hippocampal volume reduction in chromosome 22q11.2 deletion syndrome (22q11.2DS): A longitudinal study of morphometry and symptomatology

Recent studies observed an association between the structural integrity of the hippocampal structure and the manifestations of clinically significant psychotic symptoms in participants at high risk for psychosis. The present study sought to investigate the longitudinal trajectory of the hippocampal volume and its subregions among a sample of participants affected by 22q11.2 deletion syndrome (22q11.2DS), a neurogenetic disorder associated with elevated risk for psychosis. We specifically investigated possible correlations between hippocampal volumes, as measured by magnetic resonance imaging (MRI), and the manifestation of positive psychotic symptoms (hallucinations and delusions). Regional hippocampal volumes were measured twice with cerebral MRI obtained at 3-year intervals in 30 healthy participants and 31 gender-matched 22q11.2 microdeletion carriers aged 6 to 22. We examined potential associations between psychotic symptom manifestations and volumetric parameters at both time points. We found a hippocampal body-driven significant reduction in hippocampal volume among patients with 22q11DS compared to controls. No significant group by time interaction for the total or the subregional volumes were observed. In patients, larger hippocampal head at baseline was associated with the presence of hallucinations at follow-up. We first discuss the reduced hippocampal body finding in light of potentially abnormal mesiocortical circuits. We further discuss the association between baseline hippocampal head volume in participants with 22q11DS as a possible marker related to the later unfolding of psychotic symptoms.     

A comparative study of the neuropsychiatric and neurocognitive phenotype in two microdeletion syndromes: Velocardiofacial (22q11.2 deletion) and Williams (7q11.23 deletion) syndromes

Purpose22q11.2 deletion syndrome (22q11.2DS) and Williams syndrome (WS) are common neurogenetic microdeletion syndromes. The aim of the present study was to compare the neuropsychiatric and neurocognitive phenotypes of 22q11.2DS and WS.MethodsForty-five individuals with 22q11.2DS, 24 with WS, 22 with idiopathic developmental disability (DD) and 22 typically developing (TD) controls were compared for the rates of psychiatric disorders as well as cognitive executive and visuospatial functions.ResultsWe found that while anxiety, mood and disruptive disorders had an equally high prevalence among individuals with 22q11.2DS, WS and DDs, the 22q11.2DS group had the highest rates of psychotic disorders and the WS group had the highest rates of specific phobia. We also found that the WS group demonstrated more severe impairments in both executive and visuospatial functions than the other groups. WS and 22q11.2DS subjects had worse Performance-IQ than Verbal-IQ, a feature typical of non-verbal learning disorders.ConclusionThese findings offer a wide perspective on unique versus common phenotypes in 22q11.2DS and WS.     

Increased incidence and size of cavum septum pellucidum in children with chromosome 22q11.2 deletion syndrome

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a result of a hemizygotic microdeletion that results in a variety of impairments in children including greater risk for psychiatric ailments in adulthood. We used high-resolution magnetic resonance imaging to accurately quantify the length and, for the first time, volume, of the cavum septum pellucidum (CSP) in children aged 7 to 14 years with 22q11.2DS and typically developing (TD) controls. Significantly greater anteroposterior length and greater CSP volumes were found in children with 22q11.2DS compared with controls. Furthermore, the largest CSP were found only in the 22q11.2DS group and with a much higher incidence than previously reported in the literature. Given the significant midline anomalies in the brains of those affected by 22q11.2DS, large CSP may be a biomarker of atypical brain development. The implication of these larger CSP for cognitive and behavioral development is a topic in need of further investigation.     

Prodromal symptoms in adolescents with 22q11.2 deletion syndrome and schizotypal personality disorder

Adolescents with 22q11.2 Deletion Syndrome (22q11.2DS) and Schizotypal Personality Disorder (SPD) are at increased risk for the development of psychosis based, respectively, on genetic or behavioral factors. Thus both groups would be expected to manifest heightened rates of the prodromal signs that typically precede psychosis. Although there are now standardized procedures for assessing prodromal symptoms, there has been little research on the manifestation of these symptoms in 22q11.2DS patients, and no studies of differences in prodromal symptom patterns between genetically and behaviorally defined at-risk groups. In this study, demographically matched groups of 23 SPD, 23 22q11.2DS, and 23 control participants were administered the Structured Interview for Prodromal Syndromes (SIPS). Both risk groups showed elevated positive, negative, disorganized, and general prodromal symptoms, as well as elevations on 10 of the same individual symptom items, relative to the control group. Approximately 60% of individuals in the 22q11.2DS group and 70% of individuals in the SPD group met symptom criteria for a prodromal psychosis syndrome. The 22q11.2DS group scored significantly higher than the SPD group on the "decreased ideational richness" item and showed a trend toward greater motor abnormalities. The results suggest that these two high-risk groups are similar in prodromal symptom presentation, possibly as a result of overlapping causal mechanisms, and that standardized measures of prodromal syndromes like the SIPS can be used to identify 22q11.2DS patients at greatest risk for conversion to psychosis.     

Evidence of gray matter reduction and dysfunction in chromosome 22q11.2 deletion syndrome

Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with cognitive deficits and morphometric brain abnormalities in childhood and a markedly elevated risk of schizophrenia in adolescence/early adulthood. Determining the relationship between neurocognition and neuroimaging findings would yield crucial information about childhood neurodevelopment and provide a basis for the study of the trajectory that occurs on the pathway to psychosis. We compared morphometric brain findings between non-psychotic children with 22q11DS (n = 22) and healthy controls (n = 16), and examined the association between neurocognitive functioning and morphometric brain findings. Volumetric regional gray matter differences between the 22q11DS and control subjects were measured, and correlations of the regional gray matter volumes and neurocognition were performed. Children with 22q11DS demonstrated reductions in gray matter in several brain regions, chiefly the frontal cortices, the cingulate gyrus and the cerebellum. The volumetric reductions in these salient areas were associated with poor performance in sustained attention, executive function and verbal memory; however, the relation of brain volume with cognitive performance did not differ between the patient and control groups. Thus, children with 22q11DS demonstrate gray matter reductions in multiple brain regions that are thought to be relevant to schizophrenia. The correlation of these volumetric reductions with poor neurocognition indicates that these brain regions may mediate higher neurocognitive functions implicated in schizophrenia.     

White matter abnormalities in 22q11.2 deletion syndrome: Preliminary associations with the Nogo-66 receptor gene and symptoms of psychosis

BackgroundThis study utilized diffusion tensor imaging (DTI) to analyze white matter tractography in the anterior limb of the internal capsule (ALIC), fornix, and uncinate fasciculus (UF) of individuals with 22q11.2 deletion syndrome and controls. Aberrations in these tracts have been previously associated with schizophrenia. With up to 25% of individuals with 22q11.2DS developing schizophrenia in adulthood, we hypothesized reduction in structural integrity of these tracts, including an association with prodromal symptoms of psychosis. We further predicted an association between allelic variation in a functional polymorphism of the Nogo-66 receptor gene and 22q11.2DS white matter integrity.MethodsTractography was conducted using fiber assignment by streamline tracking algorithm in DTI Studio. Subjects were genotyped for the rs701428 SNP of the Nogo-66 receptor gene, and assessed for presence of prodromal symptoms.ResultsWe found significant group differences between 22q11.2DS and controls in DTI metrics for all three tracts. DTI metrics of ALIC and UF were associated with prodromal symptoms in 22q11.2DS. Further, ALIC DTI metrics were associated with allelic variation of the rs701428 SNP of the Nogo-66 receptor gene in 22q11.2DS.ConclusionsAlterations in DTI metrics suggest white matter microstructural anomalies of the ALIC, fornix, and UF in 22q11.2DS. Structural differences in ALIC appear to be associated with the Nogo-66 receptor gene, which has been linked to myelin-mediated axonal growth inhibition. Moreover, the association between psychosis symptoms and ALIC and UF metrics suggests that the Nogo-66 receptor gene may represent a susceptibility gene for psychosis through its disruption of white matter microstructure and myelin-associated axonal growth.     

Frontal dysconnectivity in 22q11.2 deletion syndrome: an atlas-based functional connectivity analysis

Background

22q11.2 deletion syndrome (22q11DS) is a neurodevelopmental syndrome associated with deficits in cognitive and emotional processing. This syndrome represents one of the highest risk factors for the development of schizophrenia. Previous studies of functional connectivity (FC) in 22q11DS report aberrant connectivity patterns in large-scale networks that are associated with the development of psychotic symptoms.

Methods

In this study, we performed a functional connectivity analysis using the CONN toolbox to test for differential connectivity patterns between 54 individuals with 22q11DS and 30 healthy controls, between the ages of 17–25 years old. We mapped resting-state fMRI data onto 68 atlas-based regions of interest (ROIs) generated by the Desikan-Killany atlas in FreeSurfer, resulting in 2278 ROI-to-ROI connections for which we determined total linear temporal associations between each. Within the group with 22q11DS only, we further tested the association between prodromal symptoms of psychosis and FC.

Results

We observed that relative to controls, individuals with 22q11DS displayed increased FC in lobar networks involving the frontal–frontal, frontal–parietal, and frontal–occipital ROIs. In contrast, FC between ROIs in the parietal–temporal and occipital lobes was reduced in the 22q11DS group relative to healthy controls. Moreover, positive psychotic symptoms were positively associated with increased functional connections between the left precuneus and right superior frontal gyrus, as well as reduced functional connectivity between the bilateral pericalcarine. Positive symptoms were negatively associated with increased functional connectivity between the right pericalcarine and right postcentral gyrus.

Conclusions

Our results suggest that functional organization may be altered in 22q11DS, leading to disruption in connectivity between frontal and other lobar substructures, and potentially increasing risk for prodromal psychosis.

     

A longitudinal examination of the psychoeducational,neurocognitive, and psychiatric functioning in children with 22q11.2 deletion syndrome

The present study sought to examine the longitudinal psychoeducational, neurocognitive, and psychiatric outcomes of children and adolescents with chromosome 22q11.2 deletion syndrome (22q11DS), a population with a high incidence of major psychiatric illnesses appearing in late adolescence/early adulthood. Little is known of the developmental changes that occur in the early teen years, prior to the age of highest psychosis risk. Data were collected from 71 participants (42 subjects with 22q11DS and 29 control subjects) at Time 1 (T1) and Time 2 (T2), approximately 3.5 years later. The 22q11DS group was significantly lower functioning than controls on IQ, neurocognition, and academic achievement at both T1 and T2. Children with 22q11DS also showed significantly greater social-behavioral difficulties and psychiatric symptoms, and were more likely to meet criteria for psychiatric disorders at both time points. In evaluating change over time from T1 to T2, the 22q11DS group did not show significant changes in psychoeducational or psychiatric outcomes relative to the controls, however, lack of expected age-related gains in attention regulation were noted. Within the 22q11DS group, an increase in the Attenuated Prodrome for Schizophrenia (number of psychiatric symptoms) was noted from T1 to T2 and four children with 22q11DS met criteria for Psychosis for the first time. Predictors at T1 that uncovered psychopathology symptoms at T2 included full-scale IQ, externalizing symptoms, and problem social behaviors. Overall, younger adolescent and preadolescent children with 22q11DS in this study exhibited slowed growth in attention regulation, with an increase in subclinical symptoms of schizophrenia, suggestive of increasing impairments in domains that are relevant to the high risk of Schizophrenia. Early predictors of later psychopathology included both cognitive and behavioral abnormalities. These findings begin to elucidate the trajectory of changes in psychopathology in children with 22q11DS in the years leading up to the onset of major psychiatric illnesses.     

The 22q11.2 deletion in children: high rate of autistic disorders and early onset of psychotic symptoms

OBJECTIVE: To examine psychopathology and influence of intelligence level on psychiatric symptoms in children with the 22q11.2 deletion syndrome (22q11DS). METHOD: Sixty patients, ages 9 through 18 years, were evaluated. Assessments followed standard protocols, including structured and semistructured interviews of parents, videotaped psychiatric interview, and intelligence assessment of the child. Intelligence level, psychiatric symptoms, and classification provided the main outcome. RESULTS: High rates of autism spectrum disorders (30 of 60, 50.0%) and psychotic symptoms (16 of 60, 26.7%) were found in this sample. In 7 of 60 (11.7%), the psychotic symptoms interfered with behavior and caused considerable distress. In these cases, the diagnosis of a psychotic disorder was applied. The average age of the children with psychotic symptoms at time of assessment was 14.2 years. Although it is likely that the high rate of psychopathology in this sample is to some extent associated with the lower level of cognitive function, a major effect of the degree of cognitive impairment on psychiatric morbidity was not found. CONCLUSION: Autism spectrum disorders and subthreshold autistic symptomatology are common in children with 22q11DS. Furthermore, a high rate of psychosis and psychotic symptoms is found in this childhood sample, suggesting an early onset of psychosis in 22q11DS patients. Autistic and psychotic disorders should be considered to be main elements of the behavioral phenotype of 22q11DS children.     

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.     

COMT implication in cognitive and psychiatric symptoms in chromosome 22q11 microdeletion syndrome: a selective review

22q11.2 deletion syndrome (22q11DS) is a genetic syndrome associated with a microdeletion of the chromosome 22 band q11.2 with an estimated prevalence between 1:2,500 and 1:4,000. Studies of school-age children have shown that individuals with 22q11DS have high rates of psychiatric morbidity. In particular, by late adolescence, about 30% of patients with 22q11DS develop psychotic symptoms. One of the genes located in the microdeletion region of 22q11DS is the Catechol-O-Methyl transferase (COMT) which codes for an enzyme critically involved in the catabolic clearance of dopamine. COMT is critically involved in cognitive related disturbances, and it has often been suggested as a sensitive factor in the development of psychiatric disorders. Several studies have been conducted on the impact of COMT functional polymorphism in 22q11DS and its related cognitive/psychiatric correlates. In this review, we summarize mainly current knowledge on the correlation between schizophrenia/cognitive related symptoms and COMT genetic variations in 22q11DS. A selective literature review on this topic was undertaken. COMT might play an important role in modulating cognitive functions in 22q11DS but a clear relationship between COMT polimorphism and schizophrenia in 22q11DS need further investigation. Despite controversial results, 22q11DS represent a powerful model for studying the role of COMT and other genetic variations in schizophrenia. This is due to high risk in 22qDS patients of developing this disorder and their relative genetic homogeneity. Further research is needed to evaluate all of the polymorphic markers in the COMT gene and its nearby regulatory elements for association with schizophrenia. Identification of specific COMT-dependent molecular, cellular and circuit deficits will provide targets for the development of more efficient treatments for the cognitive and psychiatric symptoms in 22q11DS.     

The social brain network in 22q11.2 deletion syndrome: a diffusion tensor imaging study

Background

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a neurogenetic disorder that is associated with a 25-fold increase in schizophrenia. Both individuals with 22q11.2DS and those with schizophrenia present with social cognitive deficits, which are putatively subserved by a network of brain regions that are involved in the processing of social cognitive information. This study used two-tensor tractography to examine the white matter tracts believed to underlie the social brain network in a group of 57 young adults with 22q11.2DS compared to 30 unaffected controls.

Results

Results indicated that relative to controls, participants with 22q11.2DS showed significant differences in several DTI metrics within the inferior fronto-occipital fasciculus, cingulum bundle, thalamo-frontal tract, and inferior longitudinal fasciculus. In addition, participants with 22q11.2DS showed significant differences in scores on measures of social cognition, including the Social Responsiveness Scale and Trait Emotional Intelligence Questionnaire. Further analyses among individuals with 22q11.2DS demonstrated an association between DTI metrics and positive and negative symptoms of psychosis, as well as differentiation between individuals with 22q11.2DS and overt psychosis, relative to those with positive prodromal symptoms or no psychosis.

Conclusions

Findings suggest that white matter disruption, specifically disrupted axonal coherence in the right inferior fronto-occipital fasciculus, may be a biomarker for social cognitive difficulties and psychosis in individuals with 22q11.2DS.