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.     

Multimodal investigation of triple network connectivity in patients with 22q11DS and association with executive functions

Large‐scale brain networks play a prominent role in cognitive abilities and their activity is impaired in psychiatric disorders, such as schizophrenia. Patients with 22q11.2 deletion syndrome (22q11DS) are at high risk of developing schizophrenia and present similar cognitive impairments, including executive functions deficits. Thus, 22q11DS represents a model for the study of neural biomarkers associated with schizophrenia. In this study, we investigated structural and functional connectivity within and between the Default Mode (DMN), the Central Executive (CEN), and the Saliency network (SN) in 22q11DS using resting‐state fMRI and DTI. Furthermore, we investigated if triple network impairments were related to executive dysfunctions or the presence of psychotic symptoms. Sixty‐three patients with 22q11DS and sixty‐eighty controls (age 6–33 years) were included in the study. Structural connectivity between main nodes of DMN, CEN, and SN was computed using probabilistic tractography. Functional connectivity was computed as the partial correlation between the time courses extracted from each node. Structural and functional connectivity measures were then correlated to executive functions and psychotic symptom scores. Our results showed mainly reduced structural connectivity within the CEN, DMN, and SN, in patients with 22q11DS compared with controls as well as reduced between‐network connectivity. Functional connectivity appeared to be more preserved, with impairments being evident only within the DMN. Structural connectivity impairments were also related to executive dysfunctions. These findings show an association between triple network structural alterations and executive deficits in patients with the microdeletion, suggesting that 22q11DS and schizophrenia share common psychopathological mechanisms. Hum Brain Mapp 38:2177–2189, 2017. © 2017 Wiley Periodicals, Inc.     

Spectrum of neuropsychiatric features associated with velocardiofacial syndrome (Deletion 22q11.2)

Microdeletion 22q11.2 (22q11DS) is the most frequent chromosomal deletion known in man. Velocardiofacial syndrome is one of numerous clinical syndromes that can be attributed to this micro deletion. There is an increasing recognition of associations with neuropsychiatric disorders. Particularly, schizophrenic psychosis, attention-deficit/hyperactivity disorder (ADHD), intellectual impairment and learning disabilities, seizures and motoric abnormalities have been identified in patients with 22q11DS. Recent studies supported the association of schizophrenia and 22q11DS, but the pathogenetic implications for idiopathic schizophrenia are still controversial. We report on two clinical cases in which psychotic symptoms led to the molecularcytogenetic diagnosis of microdeletion 22q11.2. Additionally, this article gives a systematic review of literature regarding psychiatric disorders, neurologic symptoms and partly corresponding morphological brain abnormalities in 22q11 deletion syndromes.     

Developmental changes in multivariate neuroanatomical patterns that predict risk for psychosis in 22q11.2 deletion syndrome

The primary objective of the current prospective study was to examine developmental patterns of voxel-by-voxel gray and white matter volumes (GMV, WMV, respectively) that would predict psychosis in adolescents with 22q11.2 deletion syndrome (22q11.2DS), the most common known genetic risk factor for schizophrenia. We performed a longitudinal voxel-based morphometry analysis using structural T1 MRI scans from 19 individuals with 22q11.2DS and 18 typically developing individuals. In 22q11.2DS, univariate analysis showed that greater reduction in left dorsal prefrontal cortical (dPFC) GMV over time predicted greater psychotic symptoms at Time2. This dPFC region also showed significantly reduced volumes in 22q11.2DS compared to typically developing individuals at Time1 and 2, greater reduction over time in 22q11.2DS COMT^Met compared to COMT^Val, and greater reduction in those with greater decline in verbal IQ over time. Leave-one-out Multivariate pattern analysis results (MVPA) on the other hand, showed that patterns of GM and WM morphometric changes over time in regions including but not limited to the dPFC predicted risk for psychotic symptoms (94.7-100% accuracy) significantly better than using univariate analysis (63.1%). Additional predictive brain regions included medial PFC and dorsal cingulum. This longitudinal prospective study shows novel evidence of morphometric spatial patterns predicting the development of psychotic symptoms in 22q11.2DS, and further elucidates the abnormal maturational processes in 22q11.2DS. The use of neuroimaging using MVPA may hold promise to predict outcome in a variety of neuropsychiatric disorders.     

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.     

Risk factors for the emergence of psychotic disorders in adolescents with 22q11.2 deletion syndrome

OBJECTIVE: The 22q11.2 deletion syndrome is the most common known genetic risk factor for the development of schizophrenia. The authors conducted a longitudinal evaluation of adolescents with 22q11.2 deletion syndrome to identify early risk factors for the development of psychotic disorders. METHOD: Sixty children, 31 with 22q11.2 deletion syndrome and 29 comparison subjects with idiopathic developmental disability matched for age and IQ, underwent a baseline evaluation between 1998 and 2000; of these, 51 children (28 and 23 in the two groups, respectively) underwent follow-up evaluation between 2003 and 2005. A standardized comprehensive psychiatric, psychological, and adaptive functioning evaluation was conducted in both waves. Participants with 22q11.2 deletion syndrome were also genotyped for the catechol O-methyltransferase (COMT) Met/Val polymorphism and underwent magnetic resonance imaging scans. RESULTS: The two groups had similar baseline neuropsychiatric profiles. At follow-up, 32.1% of subjects with 22q11.2 deletion syndrome had developed psychotic disorders as compared with 4.3% of comparison subjects. In the 22q11.2 deletion syndrome group, baseline subthreshold psychotic symptoms interacted both with the COMT genotype and with baseline symptoms of anxiety or depression to predict 61% of the variance in severity of psychosis at follow-up evaluation. Lower baseline verbal IQ was also associated with more severe psychotic symptoms at follow-up evaluation. CONCLUSIONS: Genetic, cognitive, and psychiatric risk factors for the evolution of psychotic disorders in 22q11.2 deletion syndrome during adolescence were identified. Early intervention in the subgroup of children with subthreshold signs of psychosis and internalizing symptoms (especially anxiety symptoms) may reduce the risk of developing psychotic disorders during adolescence.     

Psychotic symptoms in children and adolescents with 22q11.2 deletion syndrome: Neuropsychological and behavioral implications

Individuals with 22q11.2 deletion syndrome (22q11DS) are at increased risk for developing schizophrenia: half of affected adolescents report transient psychotic experiences and up to 30% of adults are diagnosed with schizophrenia. Prospective studies have shown that psychotic symptoms in childhood are predictive of later schizophreniform disorders. The current study aimed to define the prevalence and correlates of psychotic symptoms (PS) in young children and adolescents with 22q11DS. Forty-three children and adolescents with 22q11DS (mean age = 10.62+/-11.19) participated in this study. The occurrence of PS and their neuropsychological and behavioral correlates were investigated through semi-structured interviews and standardized measures. Psychotic symptoms were reported in 28% of the total sample and 17% of pre-adolescent children, and associated with decreased verbal IQ scores [F(1) = 4.41, p = 0.042]. Compared to young patients without PS, young patients with PS were perceived by their parents as more anxious-depressed [F(1) = 4.76, p = 0.035] and withdrawn [F(1) = 7.63, p = 0.009], with reduced adaptive socialization skills [F(1) = 6.88, p = 0.012]. Results suggest that psychotic manifestations are present earlier than typically reported in youngsters with 22q11DS and are accompanied by reduced verbal IQ performance and decreased adaptative social skills. The symptomatic, neuropsychological and behavioral characteristics observed in the current study may constitute central markers of increased risk for psychosis in 22q11DS.     

Cognitive phenotype and psychiatric disorder in 22q11.2 deletion syndrome: A review

The behavioural phenotype of 22q11.2 deletion syndrome syndrome (22q11DS), one of the most common human multiple anomaly syndromes, frequently includes intellectual disability (ID) together with high risk of diagnosis of psychotic disorders including schizophrenia. Candidate cognitive endophenotypes include problems with retrieval of contextual information from memory and in executive control and focussing of attention. 22q11DS may offer a model of the relationship between ID and risk of psychiatric disorder. This paper reviews research on the relationship between the cognitive phenotype and the development of psychiatric disorders in 22q11DS.Aspects of cognitive function including verbal I.Q., visual memory, and executive function, are associated with mental health outcome in people with 22q11DS. This relationship may result from a common neurobiological basis for the cognitive difficulties and psychiatric disorders. Some of the cognitive difficulties experienced by people with 22q11DS, especially in attention, memory retrieval, and face processing, may, however, in themselves constitute risk factors for development of hallucinations and paranoid delusions.Future research into factors leading to psychiatric disorder in people with 22q11DS should include assessment of social and psychological factors including life events, symptoms associated with trauma, attachment, and self-esteem, which together with cognitive risk factors may mediate mental health outcome.     

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.     

High rates of schizophrenia in adults with velo-cardio-facial syndrome.

BACKGROUND: Velo-cardio-facial syndrome (VCFS), a syndrome characterized by an increased frequency of schizophrenia and bipolar disorder, is associated with small interstitial deletions of chromosome 22q11. METHODS: We evaluated 50 adults with VCFS using a structured clinical interview (Schedules for Clinical Assessment in Neuropsychiatry or Psychiatric Assessment Schedule for Adults With Developmental Disability if IQ <50) to establish a DSM-IV diagnosis. The schizophrenia phenotype in individuals with VCFS and schizophrenia was compared with a matched series of individuals with schizophrenia and without VCFS (n = 12). The King's Schizotypy Questionnaire was administered to individuals with VCFS (n = 41), their first-degree relatives (n = 68), and a series of unrelated normal controls (n = 316). All individuals with VCFS deleted for the N25 probe (n = 48) were genotyped for a genetic polymorphism in the COMT gene that results in variations in enzymatic activity. RESULTS: Fifteen individuals with VCFS (30%) had a psychotic disorder, with 24% (n = 12) fulfilling DSM-IV criteria for schizophrenia. In addition, 6 (12%) had major depression without psychotic features. The individuals with schizophrenia had fewer negative symptoms and a relatively later age of onset compared with those with schizophrenia and without VCFS. We found no evidence that possession of the low-activity COMT allele was associated with schizophrenia in our sample of individuals with VCFS. CONCLUSIONS: The high prevalence of schizophrenia in this group suggests that chromosome 22q11 might harbor a gene or genes relevant to the etiology of schizophrenia in the wider population.     

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.     

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.     

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.     

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.     

Epilepsy,neuropsychiatric phenotypes,neuroimaging findings,and genotype-neurophenotype correlation in 22q11.2 deletion syndrome

Objectives:To describe the epilepsy, neuropsychiatric manifestations, and neuroimaging findings in a group of patients with 22q11.2 DS, and to correlate the size of the deleted genetic material with the severity of the phenotype.Methods:We retrospectively analyzed the medical records of 28 patients (21 pediatric patients and 7 adults) with a genetically confirmed diagnosis of 22q11.2 DS. Clinical data (epilepsy, neurological exam, neuropsychological and developmental assessment, and psychiatric disorders), neuroimaging, and cytogenetic tests were analyzed.Results:Of the 28 patients with 22q11.2 DS, 6 (21.4%) had epileptic seizures, 2 had symptomatic hypocalcemic seizures, 4 (14.2%) had a psychiatric disorder, which comprised of attention deficit hyperactivity disorder, autism spectrum disorder, psychosis, and mood disorder, and 17 (60.7%) had developmental delay. All patients with epilepsy had a developmental delay. Twelve patients underwent a neuropsychology assessment. Intellectual levels ranged from moderate intellectual disability (7/12, 58%) to average (5/12, 41.6%). Of the 16 patients, 6 (37.5%) had a normal brain, while 10 (62.5%) had abnormal neuroimaging findings. No significant correlation was found between the size of the deleted genetic material and the severity of the phenotype.Conclusion:22q11.2DS patients are at high risk to develop epilepsy, neuropsychiatric manifestations, and structural brain abnormalities. This indicates that this defined genetic locus is crucial for the development of the nervous system, and patients with 22q11.2 DS have genetic susceptibility to develop epilepsy.

22q11.2 deletion syndrome (22q11.2DS) has to many names such as velocardiofacial syndrome and DiGeorge syndrome, which is the most common microdeletion syndrome.1 It is due to hemizygous microdeletions on chromosome 22q11.2, it occurs 1 in 4000 live births, and 90% occur de novo. Most individuals with 22q11.2 DS lost about 3 Megabases (Mb) of DNA on chromosome 22 at position 22q11.2 in each cell.2 Some affected individuals have smaller deleted genetic material in this region. The clinical picture has a markedly different expression and incomplete penetrance. Therefore, 22q11.2DS has symptoms affecting several systems in the body, including congenital heart anomalies, palatal anomalies, hypocalcemia due to hypoplasia of parathyroid glands, immunodeficiency due to hypoplastic thymus, facial dysmorphism, disorders of cognition and behavior, and psychiatric disorders.3 However, few studies have been conducted on the epilepsy, neurological, neuroimaging, and neuropsychiatric features of 22q11.2 DS.This study aimed to examine the epilepsy, neurological, neuropsychiatric phenotypes, and neuroimaging findings in a series of individuals with 22q11.2 DS and to correlate the genotype with the neurophenotype.     

Genetic and clinical features of social cognition in 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11.2 DS) is widely known as one of the most compelling genetic models of schizophrenia so far, being almost 40% of the carriers affected by psychotic symptoms. Moreover, most of these subjects also show impairment in social cognition, which is a comprehensive array of function that guides social interaction with the others, leading as well to the acquisition of new cognitive and social skills. In the last decade researchers have argued whether social cognition dysfunctions could be underlined by specific genetic alterations, and whether these are linked to specific clinical features. Some valid candidate genes are RTN4R, that encodes a protein which inhibits axonal sprouting, DGCR8, crucial in mRNA processing, or catechol‐O‐methyltransferase (COMT) and proline oxydase 1 (PRODH), involved in catecholamine metabolism in frontal cortex. This is the first article to address the topic of social cognition in 22q11.2 DS from a wide perspective, with a highlight on its genetic characteristics. We will provide a narrative review of the most recent findings and we will point out new directions on this research path, in order to achieve an effective characterization of the neurobiological system underlying social behavior.     

Prise en charge pédopsychiatrique des patients présentant un syndrome microdélétionnel 22q11.2 : du soin à la prévention

22q11.2DS is one of the more frequent genetic syndromes associated to psychiatric symptoms. It has been associated to an increased risk to develop schizophrenia in adolescence or early adulthood. However, psychiatric symptoms appear early on, and should be recognized as soon as possible by child psychiatrists in order to improve the present well-being of children and their family, and to prevent further risks of developing severe and chronic psychiatric diseases later on. In this paper, we present a review of the recent literature concerning the 22q11.2DS syndrome focused on the risk factors that may be associated to an increased risk of psychotic transition. We advocate for the development of systematic specialized child psychiatry consultations for these patients, included in networks with geneticists, adult psychiatrists, and family associations, in order to improve their psychiatric prognosis and to support the development of translational research.     

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.     

Axis I psychiatric diagnoses in adolescents and young adults with 22q11 deletion syndrome

Background22q11.2 deletion syndrome (22q11DS) associates with schizophrenia spectrum disorders (SSDs), autism spectrum disorders (ASDs), and other psychiatric disorders, but co-occurrence of diagnoses are not well described.MethodsWe evaluated the co-occurrence of SSDs, ASDs and other axis I psychiatric diagnoses in 31 adolescents and adults with 22q11DS, assessing ASDs using either stringent Collaborative Program for Excellence in Autism (ASD-CPEA) criteria, or less stringent DSM-IV criteria alone (ASD-DSM-IV).ResultsTen (32%) individuals met criteria for an SSD, five (16%) for ASD-CPEA, and five others (16%) for ASD-DSM-IV. Of those with ASD-CPEA, one (20%) met SSD criteria. Of those with ASD-DSM-IV, four (80%) met SSD criteria. Depressive disorders (8 individuals; 26%) and anxiety disorders (7; 23%) sometimes co-occurred with SSDs and ASDs. SSDs, ASDs, and anxiety occurred predominantly among males and depression predominantly among females.ConclusionsIndividuals with 22q11DS can manifest SSDs in the presence or absence of ASDs and other axis I diagnoses. The results suggest that standard clinical care should include childhood screening for ASDs, and later periodic screening for all axis I diagnoses.     

Pre-pulse inhibition and antisaccade performance indicate impaired attention modulation of cognitive inhibition in 22q11.2 deletion syndrome (22q11DS)

Background

22q11.2 deletion syndrome (22q11DS) is associated with a number of physical anomalies and neuropsychological deficits including impairments in executive and sensorimotor function. It is estimated that 25% of children with 22q11DS will develop schizophrenia and other psychotic disorders later in life. Evidence of genetic transmission of information processing deficits in schizophrenia suggests performance in 22q11DS individuals will enhance understanding of the neurobiological and genetic substrates associated with information processing. In this report, we examine information processing in 22q11DS using measures of startle eyeblink modification and antisaccade inhibition to explore similarities with schizophrenia and associations with neurocognitive performance.

Methods

Startle modification (passive and active tasks; 120- and 480-ms pre-pulse intervals) and antisaccade inhibition were measured in 25 individuals with genetically confirmed 22q11DS and 30 healthy control subjects.

Results

Individuals with 22q11DS exhibited increased antisaccade error as well as some evidence (trend-level effect) of impaired sensorimotor gating during the active condition, suggesting a dysfunction in controlled attentional processing, rather than a pre-attentive dysfunction using this paradigm.

Conclusions

The findings from the present study show similarities with previous studies in clinical populations associated with 22q11DS such as schizophrenia that may indicate shared dysfunction of inhibition pathways in these groups.