Sleep problems and associations with psychopathology and cognition in young people with 22q11.2 deletion syndrome (22q11.2DS).

BACKGROUND: Young people with 22q11.2 deletion syndrome (22q11.2DS) are at high risk for neurodevelopmental disorders. Sleep problems may play a role in this risk but their prevalence, nature and links to psychopathology and cognitive function remain undescribed in this population. METHOD: Sleep problems, psychopathology, developmental coordination and cognitive function were assessed in 140 young people with 22q11.2DS (mean age = 10.1, s.d. = 2.46) and 65 unaffected sibling controls (mean age = 10.8, s.d.SD = 2.26). Primary carers completed questionnaires screening for the children's developmental coordination and autism spectrum disorder. RESULTS: Sleep problems were identified in 60% of young people with 22q11.2DS compared to 23% of sibling controls (OR 5.00, p < 0.001). Two patterns best-described sleep problems in 22q11.2DS: restless sleep and insomnia. Restless sleep was linked to increased ADHD symptoms (OR 1.16, p < 0.001) and impaired executive function (OR 0.975, p = 0.013). Both patterns were associated with elevated symptoms of anxiety disorder (restless sleep: OR 1.10, p = 0.006 and insomnia: OR 1.07, p = 0.045) and developmental coordination disorder (OR 0.968, p = 0.0023, and OR 0.955, p = 0.009). The insomnia pattern was also linked to elevated conduct disorder symptoms (OR 1.53, p = 0.020). CONCLUSIONS: Clinicians and carers should be aware that sleep problems are common in 22q11.2DS and index psychiatric risk, cognitive deficits and motor coordination problems. Future studies should explore the physiology of sleep and the links with the neurodevelopment in these young people.

Bullying and psychosis: The impact of chronic traumatic stress on psychosis risk in 22q11.2 deletion syndrome - a uniquely vulnerable population.

Bullying is an adverse childhood experience that is more common among youth with special needs and is associated with increased psychopathology throughout the lifespan. Individuals with chromosome 22q11.2 deletion syndrome (22q) represent one group of special needs youth who are at increased risk for bullying due to co-occurring genetically-mediated developmental, physical, and learning difficulties. Furthermore, individuals with 22q are at increased risk for developing psychotic disorders such as schizophrenia. However, there is a paucity of research exploring the impact of bullying on individuals with 22q and the possible impact this has on risk for psychosis in this population. To explore this relationship using existing research the goals of the review are: (i) to explore the nature of bullying among youth with special needs, and (ii) to discuss its potential role as a specific risk factor in the development of adverse outcomes, including psychosis symptoms. We reviewed the relationship between bullying and its short and long-term effects on the cognitive, social, and developmental functioning of typically developing individuals and those with special needs. We propose an interactive relationship between trauma, stress, and increased psychosis risk among youth with 22q with a history of bullying. The early childhood experience of trauma in the form of bullying promotes an altered developmental trajectory that may elevate the risk for maladaptive functioning and subsequent psychotic disorders, particularly in youth with genetic vulnerabilities. Therefore, we conclude the experience of bullying among individuals with 22q should be more closely examined.

Abnormalities in gray matter microstructure in young adults with 22q11.2 deletion syndrome.

BACKGROUND: 22q11.2 Deletion Syndrome (22q11DS) is a genetic, neurodevelopmental disorder characterized by a chromosomal deletion and a distinct cognitive profile. Although abnormalities in the macrostructure of the cortex have been identified in individuals with 22q11DS, it is not known if there are additional microstructural changes in gray matter regions in this syndrome, and/or if such microstructural changes are associated with cognitive functioning. METHODS: This study employed a novel diffusion MRI measure, the Heterogeneity of Fractional Anisotropy (HFA), to examine variability in the microstructural organization of the cortex in healthy young adults (N = 30) and those with 22q11DS (N = 56). Diffusion MRI, structural MRI, clinical and cognitive data were acquired. RESULTS: Compared to controls, individuals with 22q11DS evinced increased HFA in cortical association (p = .003, d = 0.86) and paralimbic (p < .0001, d = 1.2) brain areas, whereas no significant differences were found between the two groups in primary cortical brain areas. Additionally, increased HFA of the right paralimbic area was associated with poorer performance on tests of response inhibition, i.e., the Stroop Test (rho = -0.37 p = .005) and the Gordon Diagnostic System Vigilance Commission (rho = -0.41 p = .002) in the 22q11DS group. No significant correlations were found between HFA and cognitive abilities in the healthy control group. CONCLUSIONS: These findings suggest that cortical microstructural disorganization may be a neural correlate of response inhibition in individuals with 22q11DS. Given that the migration pattern of neural crest cells is disrupted at the time of early brain development in 22q11DS, we hypothesize that these neural alterations may be neurodevelopmental in origin, and reflect cortical dysfunction associated with cognitive deficits.

[Child psychiatry interventions in patients with 22q11 deletion syndrome: From treatment to prevention]. / 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.

Face processing in 22q11.2 deletion syndrome: atypical development and visual scanning alterations.

BACKGROUND: Previous research links social difficulties to atypical face exploration in 22q11.2 deletion syndrome (22q11.2DS). Two types of face processing are distinguished: configural (CFP) and featural (FFP). CFP develops later in life and plays an important role in face and emotion recognition abilities. Recent studies reported atypical development of CFP in several neurodevelopmental disorders. Taking previous reports of atypical face exploration one step further, our study aims at characterizing face processing in children and adolescents with 22q11.2DS. First, we sought to identify biases in the first two fixation positions on faces and to detect differences between CFP and FFP in 22q11.2DS using eye-tracking technology. Second, we investigated the developmental trajectories of CFP and FFP using accuracy data from follow-up evaluation. METHODS: Seventy-five individuals with 22q11.2DS and 84 typically developed (TD) individuals (aged 6-21 years) completed a discrimination task ("Jane task") inducing CFP and FFP in an eye-tracking setting. Thirty-six individuals with 22q11DS and 30 TD from our sample completed a longitudinal follow-up evaluation. RESULTS: Findings revealed that individuals with 22q11.2DS demonstrate an early bias toward the mouth region during the initial fixations on the faces and reduced flexibility exploration of the faces, with a reduced number of transitions between faces and longer fixations compared to the TD group. Further, scanpaths did not differ between CFP and FFP in the 22q11.2DS group. Longitudinal analysis of accuracy data provided evidence for atypical development of CFP in 22q11.2DS. CONCLUSIONS: The current study brings new evidence of altered face exploration in 22q11.2DS and identifies developmental mechanisms that may contribute to difficulties impacting social interactions in the syndrome.

Young Adult Outcomes for Children With 22q11 Deletion Syndrome and Comorbid ADHD.

Background: 22q11.2 deletion syndrome (22q11DS) is a common microdeletion syndrome associated with a variety of negative health, cognitive, emotional, and behavioral outcomes. 22q11DS is comorbid with many psychiatric disorders including attention-deficit/hyperactivity disorder (ADHD). The current study aimed to investigate the cognitive, behavioral, and functional outcomes that a childhood ADHD diagnosis predicts to in adulthood. Methods: This longitudinal study followed 52 individuals with 22q11DS over 9 years. Childhood ADHD was operationalized both categorically (Diagnostic and statistical manual - 4th edition (DSM-IV) ADHD diagnoses) and dimensionally (inattentive and hyperactive-impulsive symptoms) and was tested as predictors of young adult outcomes. Results: As young adults, children with 22q11DS + baseline ADHD had more parent-reported executive dysfunction and lower levels of clinician-rated overall functioning than those with 22q11DS yet without ADHD. Dimensional symptoms of ADHD in childhood did not predict young adult outcomes. No self-report differences emerged between those with and without baseline ADHD. The majority (82.4%) of individuals with 22q11DS + baseline ADHD were never treated with an ADHD medication. Conclusions: A categorical diagnosis of ADHD in childhood predicted a greater variety of worse outcomes than dimensional levels of ADHD symptoms. Despite the significant impact of comorbid ADHD in 22q11DS, evidence-based treatment rates were low.

Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia.

Schizophrenia is a neurodevelopmental disorder that affects up to 1% of the general population. Various genes show associations with schizophrenia and a very weak nominal association with the tight junction protein, claudin-5, has previously been identified. Claudin-5 is expressed in endothelial cells forming part of the blood-brain barrier (BBB). Furthermore, schizophrenia occurs in 30% of individuals with 22q11 deletion syndrome (22q11DS), a population who are haploinsufficient for the claudin-5 gene. Here, we show that a variant in the claudin-5 gene is weakly associated with schizophrenia in 22q11DS, leading to 75% less claudin-5 being expressed in endothelial cells. We also show that targeted adeno-associated virus-mediated suppression of claudin-5 in the mouse brain results in localized BBB disruption and behavioural changes. Using an inducible 'knockdown' mouse model, we further link claudin-5 suppression with psychosis through a distinct behavioural phenotype showing impairments in learning and memory, anxiety-like behaviour and sensorimotor gating. In addition, these animals develop seizures and die after 3-4 weeks of claudin-5 suppression, reinforcing the crucial role of claudin-5 in normal neurological function. Finally, we show that anti-psychotic medications dose-dependently increase claudin-5 expression in vitro and in vivo while aberrant, discontinuous expression of claudin-5 in the brains of schizophrenic patients post mortem was observed compared to age-matched controls. Together, these data suggest that BBB disruption may be a modifying factor in the development of schizophrenia and that drugs directly targeting the BBB may offer new therapeutic opportunities for treating this disorder.

Developmental changes in the cognitive and educational profiles of children and adolescents with 22q11.2 deletion syndrome.

BACKGROUND: 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans. The presence of learning difficulty is reported in the majority of individuals with 22q11DS, but there is considerable heterogeneity in cognitive and educational profiles and in the age-related changes. METHOD: Verbal, non-verbal and spatial abilities, and educational attainment of 18 children and adolescents with 22q11DS were assessed at two time points 5 years apart. RESULTS: There was a decline in full-scale IQ, with a sharper decline in verbal than non-verbal skills, whereas spatial abilities remained stable over time. Individual profile analysis revealed discrepancies between full-scale IQ and reading skills, suggestive of "hyperlexia," for more than two-thirds of participants. CONCLUSIONS: The relative strength in verbal ability observed in 22q11DS is more apparent when children are younger, and a more even cognitive profile is observed in older children and adolescents. Educational attainments keep pace with development, and literacy skills are globally higher than might be expected from full-scale IQ.

Síndrome de Deleción 22q11.2 y su asociación con Trastornos Psiquiátricos. A propósito de un caso / 22q11.2 Deletion Syndrome and Psychiatric Disorders

El Síndrome de Deleción 22q11.2 o Síndrome de DiGeorge es una entidad genética caracterizada por la triada clínica de anomalías cardiacas conotruncales, hipoplasia tímica e hipocalcemia. No obstante, el fenotipo 22q11.2 es bastante variable, incluyendo anomalías físicas, metabólicas, endocrinológicas y a nivel conductual y del desarrollo. Incluye asociación piscopatológica con distintos síndromes psiquiátricos. Describimos el caso de un varón de 16 años con criterios diagnósticos de Trastorno del Espectro Autista enmarcado en un Síndrome de Deleción 22q11.2

22q11.2 Deletion Syndrome or DiGeorge Syndrome is a genetic disorder characterized by the clinical triad conotruncal cardiac anomalies, thymic hypoplasia and hypocalcemia. However, the 22q11.2 phenotype is quite variable, including physical, metabolic, endocrinological and behavioral and developmental abnormalities. It includes a psychopathological association with different psychiatric syndromes. We describe the case of a 16-year old male with diagnostic criteria for Autism Spectrum Disorder framed in a 22q11.2 Deletion Syndrome

22q11 deletion syndrome: Parents' and children's experiences of educational and healthcare provision in the United Kingdom.

22q11 deletion syndrome (22q11DS) is a genetic syndrome, prevalence around 1:4000-1:6000 live births, with a complex array of associated features, impacting on healthcare and educational support. This study reports the perceptions of families and individuals with 22q11DS in relation to these needs. Individuals and families of those with 22q11DS were approached though two national charities - the Max Appeal and 22Crew. An initial observational survey design was used to gather views via questions probing access to healthcare and educational experiences. Thirty-four responses were received and the data subjected to descriptive analysis. Over half of the respondents were diagnosed before the age of 1. Ninety-one percent reported ongoing difficulties with learning at school, compounded by school attendance being compromised as a result of medical interventions. Individuals reported engaging heavily with educational support and a high number of health professions (mean 9.5; mode 10). Age of diagnosis of 22q11DS ranged from birth to nine years. Families had ongoing concerns about aspects of education and healthcare services, and lack of knowledge and awareness of the difficulties faced by individuals with 22q11DS was raised. Healthcare and education providers should be aware of the range of services individuals required on a regular basis so as to provide a more holistic approach to care.

Emergent, remitted and persistent psychosis-spectrum symptoms in 22q11.2 deletion syndrome.

Individuals with 22q11.2 deletion syndrome (22q11DS) are at markedly elevated risk for schizophrenia-related disorders. Stability, emergence, remission and persistence of psychosis-spectrum symptoms were investigated longitudinally. Demographic, clinical and cognitive predictors of psychosis were assessed. Prospective follow-up over 2.8 years was undertaken in 75 individuals with 22q11DS aged 8-35 years. Mood, anxiety, attention-deficit hyperactivity disorders and psychosis-spectrum symptoms were assessed with the Kiddie-Schedule for Affective Disorders and Schizophrenia and Scale of Prodromal Symptoms (SOPS). Four domains of cognition were evaluated with the Penn Computerized Neurocognitive Battery (executive functioning, memory, complex cognition and social cognition). Psychotic disorder or clinically significant SOPS-positive ratings were consistently absent in 35%, emergent in 13%, remitted in 22% and persistent in 31% of participants. Negative symptoms and functional impairment were found to be predictive of the emergence of positive psychosis-spectrum symptoms and to reflect ongoing deficits after remission of positive symptoms. Dysphoric mood and anxiety were predictive of emergent and persistent-positive psychosis-spectrum symptoms. Lower baseline global cognition and greater global cognitive decline were predictive of psychosis-spectrum outcomes but no particular cognitive domain stood out as being significantly more discriminating than others. Our findings suggest that negative symptoms, functioning and dysphoric mood are important predictors of psychosis risk in this population.

Prevalence and treatment of psychiatric disorders other than psychosis in children and adolescents with 22q11DS: Examining associations with social and role functioning.

Individuals with chromosome 22q11 deletion syndrome (22q11DS) have high rates of psychotic disorders. Less is known about their psychopathology and how it is treated prior to the peak period of risk for psychotic disorder. There is also a lack of evidence on how functioning is impacted by psychopathology in this population. The aim of this study was to investigate the prevalence and treatment of non-psychotic psychiatric disorders, and how these factors are associated with psychosocial functioning in children and adolescents with 22q11DS. 126 individuals with 22q11DS aged 8-17 participated in the study. Participants were assessed for psychiatric diagnoses, social and role functioning, anxiety and depressive symptoms and IQ. Information on current treatments was collected. 52.4% of the sample presented with at least one psychiatric disorder. Mood and anxiety disorders were the most frequent, followed by behavioural disorder. Individuals with a psychiatric disorder had significantly lower general, role and social functioning. Only 27% of participants with a psychiatric diagnosis were receiving any mental health treatment at the time of assessment. Findings suggest the high prevalence of psychiatric disorders in youth with 22q11DS, which significantly impacts psychosocial functioning. Despite this, psychiatric disorders tend to remain untreated in this population.

No age effect in the prevalence and clinical significance of ultra-high risk symptoms and criteria for psychosis in 22q11 deletion syndrome: Confirmation of the genetically driven risk for psychosis?

BACKGROUND: The 22q11.2 deletion syndrome (22q11DS) is one of the highest known risk factors for schizophrenia. Thus, the detection of 22q11DS patients at particularly high risk of psychosis is important, yet studies on the clinical significance of the widely used ultra-high risk (UHR) criteria in 22q11DS are inconclusive. Since age was reported to moderate clinical significance of UHR symptoms in community samples, we explored whether age at presentation of UHR symptoms and criteria may explain part of this heterogeneity. METHODS: 111 patients with 22q11DS (8-30 years; 15.7±4.7) were assessed for UHR symptoms/criteria. Information on diagnoses, psychosocial functioning, and IQ were collected. RESULTS: Any UHR symptom was reported by 38.7%, any UHR criterion by 27%. No significant influence of age on the prevalence of UHR symptoms or criteria was detected. Moreover, age did not significantly modulate the association between UHR symptoms and functioning. However, significant interaction terms suggested that younger age groups were more likely to meet UHR criteria in the presence of UHR symptoms compared to the adult group. DISCUSSION: Compared to the general population, prevalence of UHR symptoms and criteria was 3.8-fold and 20.8-fold in our 22q11DS sample. Contrary to the general population, age only modulated the prevalence of UHR criteria among those with UHR symptoms, but not their prevalence per se or their clinical significance. This suggests that UHR symptoms might develop as a trait factor in terms of a genetically driven schizotypal disposition in 22q11DS, thus necessitating future studies on psychosis-risk indicators in this genetic high-risk group.

Autism Spectrum and psychosis risk in the 22q11.2 deletion syndrome. Findings from a prospective longitudinal study.

BACKGROUND: Individuals with 22q11.2 deletion syndrome (22q11DS) have a 25% risk for schizophrenia and related psychotic disorders. Some have hypothesized that Autism Spectrum Disorders (ASDs) diagnosed in children with 22q11DS may actually represent the social-communicative defects often observed during the early developmental stages of schizophrenia. METHODS: We prospectively studied 89 children with 22q11DS to test this hypothesis. At baseline, the Autism Diagnostic Interview was used to assess ASD, evaluating both current and early childhood behaviors. At follow-up, the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) was used to determine development of a psychotic disorder or psychotic symptoms. RESULTS: The average age (±SD) at first and last assessments was 14.3±1.9 and 19.0±3.0years, respectively. Nineteen (21.3%) children developed a psychotic disorder. Contrary to our hypothesis, there was no significant difference in the proportion that developed a psychotic disorder, comparing those with (n=9, 17.3%) and those without ASD at baseline (n=10, 27%; OR=0.500, 95% CI=0.160-1.569, p=0.235). Similar results were obtained using autistic symptom severity as quantitative predicting variable, psychotic symptoms as the outcome, and when correcting for age, gender and full scale IQ. CONCLUSION: Results indicate that in children with 22q11DS, early childhood autistic features are not associated with an increased risk for subsequent development of psychotic disorders or symptoms, replicating previous retrospective findings in adults with 22q11DS. These results indicate that ASD and psychotic disorders can emerge independently, as pleiotropic phenotypes in the context of 22q11DS.

Negative and paranoid symptoms are associated with negative performance beliefs and social cognition in 22q11.2 deletion syndrome.

AIMS: 22q11.2 deletion syndrome (22q11.2DS) is a neurogenetic condition associated with an increased risk of developing schizophrenia. Previous studies have shown that negative symptoms represent the most specific clinical characteristic of psychosis in 22q11.2DS and are strongly associated with outcome. However, the psychological mechanisms associated with these symptoms in this population are poorly understood. In accordance with recent conceptualizations in the field of schizophrenia, the present study aims at investigating whether negative symptoms are associated with the presence of negative performance beliefs and cognitive deficits. METHODS: Thirty-five participants with 22q11.2DS and 24 typically developing individuals aged between 11 and 24 years were included in the study. Self-reported schizotypal symptoms (cognitive-perceptual, paranoid, negative and disorganization symptoms) and dysfunctional beliefs (negative performance beliefs and need for approval) were assessed. Measures of processing speed, verbal memory, working memory, executive functioning and face recognition were also extracted from a broad cognitive evaluation protocol. RESULTS: Adolescents with 22q11.2DS reported significantly higher score on the negative dimension of the Schizotypal Personality Questionnaire than controls, even when controlling for the influence of anxiety/depression and intellectual functioning. Negative and paranoid symptoms were associated with the severity of negative performance beliefs and lower face recognition abilities. Mediation analyses revealed that negative performance beliefs significantly mediated the association between face recognition and negative/paranoid symptoms. CONCLUSIONS: These findings suggest that negative performance beliefs and basic social cognitive mechanisms are associated with negative and paranoid symptoms in individuals with 22q11.2DS. Implications for intervention are discussed in this article.

Multimodal MRI reveals structural connectivity differences in 22q11 deletion syndrome related to impaired spatial working memory.

INTRODUCTION: Impaired spatial working memory is a core cognitive deficit observed in people with 22q11 Deletion syndrome (22q11DS) and has been suggested as a candidate endophenotype for schizophrenia. However, to date, the neuroanatomical mechanisms describing its structural and functional underpinnings in 22q11DS remain unclear. We quantitatively investigate the cognitive processes and associated neuroanatomy of spatial working memory in people with 22q11DS compared to matched controls. We examine whether there are significant between-group differences in spatial working memory using task related fMRI, Voxel based morphometry and white matter fiber tractography. MATERIALS AND METHODS: Multimodal magnetic resonance imaging employing functional, diffusion and volumetric techniques were used to quantitatively assess the cognitive and neuroanatomical features of spatial working memory processes in 22q11DS. Twenty-six participants with genetically confirmed 22q11DS aged between 9 and 52 years and 26 controls aged between 8 and 46 years, matched for age, gender, and handedness were recruited. RESULTS: People with 22q11DS have significant differences in spatial working memory functioning accompanied by a gray matter volume reduction in the right precuneus. Gray matter volume was significantly correlated with task performance scores in these areas. Tractography revealed extensive differences along fibers between task-related cortical activations with pronounced differences localized to interhemispheric commissural fibers within the parietal section of the corpus callosum. CONCLUSIONS: Abnormal spatial working memory in 22q11DS is associated with aberrant functional activity in conjunction with gray and white matter structural abnormalities. These anomalies in discrete brain regions may increase susceptibility to the development of psychiatric disorders such as schizophrenia. Hum Brain Mapp 37:4689-4705, 2016. © 2016 Wiley Periodicals, Inc.

Glutamatergic markers, age, intellectual functioning and psychosis in 22q11 deletion syndrome.

RATIONALE: Patients with 22q11 deletion syndrome (22q11DS) have a high prevalence of intellectual disabilities and psychiatric disorders, including psychosis. Haplo-insufficiency of genes in the deleted region may offer a partial explanation for the increased vulnerability for psychosis and intellectual disability. One gene of particular interest is the gene coding for proline dehydrogenase (PRODH), an enzyme responsible for the conversion of proline into glutamate. OBJECTIVES: Because abnormalities in glutamatergic signaling are thought to be responsible for cognition and psychosis in the general population, we hypothesized that PRODH haplo-insufficiency may underlie some of the cognitive and psychotic features seen in 22q11DS. METHODS: In this explorative study, we investigated the relation between plasma proline, glutamate, and glutamine and age, intelligence, and psychosis in 64 adults with 22q11DS. RESULTS: Hyperprolinemia was found in 31.3% of subjects with 22q11DS. A relation between glutamine, glutamate, proline, and presence of psychosis was not observed. Regression analysis revealed a positive relation between plasma glutamate and age, a positive relation of glutamate with antipsychotic drugs, a relation of glutamine and gender, and a positive relation of glutamine and mood stabilizing drugs, and a negative relation of the ratio glutamine/glutamate and age. The group with relatively lower IQ had higher glutamate levels compared to the group with relatively higher IQ. CONCLUSIONS: Our results suggest that 22q11DS is accompanied by abnormalities in glutamatergic metabolism. Future longitudinal studies are needed to further investigate the glutamatergic system in 22q11DS and how this affects the development of cognitive problems and psychopathology.

PRODH rs450046 and proline x COMT Val¹58 Met interaction effects on intelligence and startle in adults with 22q11 deletion syndrome.

RATIONALE: 22q11 deletion syndrome (22q11DS) is associated with an increased risk for psychotic disorders, suggesting a relationship between genotypes and the pathophysiology of psychotic disorders. Two genes in the deleted region, catechol-O-methyl-transferase (COMT) and proline dehydrogenase (oxidase) 1 (PRODH), contain polymorphisms associated with neuropsychiatric phenotypes. OBJECTIVES: Here, we explored the association between polymorphisms and full-scale intelligence (FSIQ), startle reactivity (SR) and prepulse inhibition (PPI) in adults with 22q11DS. METHODS: Forty-five adults with 22q11DS were genotyped for PRODH rs450046, rs372055 and COMT Val(158)Met. Plasma proline levels, FSIQ, SR and PPI were measured. RESULTS: Thirty-five percent of the subjects were hyperprolinemic with a median proline value of 456 µmol/L. C allele carriers of PRODH rs450046 had a lower FSIQ compared to T allele carriers, indicating the C allele to be a risk allele (C allele: mean FSIQ 60.2 (sd 8.7); T allele: mean FSIQ 73.7 (sd 11.5); F 1,43 = 7.59; p = 0.009; partial η (2) = 0.15). A significant interaction effect of proline levels and COMT Val(158)Met genotype was found for SR (F 1,16 = 7.9; p = 0.01; partial η (2) = 0.33), but not for PPI and FSIQ. In subjects with hyperprolinemia, the COMT Val(158)Met genotype effect on SR was stronger than in subjects with normal proline levels. CONCLUSIONS: Overall, these data provide further evidence for the risk effect of elevated proline levels combined with the COMT Met allele and support the possibilities of using 22q11DS as a model to investigate genotype effects on psychiatric disorders.

Cognitive ability is associated with altered medial frontal cortical circuits in the LgDel mouse model of 22q11.2DS.

We established a relationship between cognitive deficits and cortical circuits in the LgDel model of 22q11 Deletion Syndrome (22q11DS)-a genetic syndrome with one of the most significant risks for schizophrenia and autism. In the LgDel mouse, optimal acquisition, execution, and reversal of a visually guided discrimination task, comparable to executive function tasks in primates including humans, are compromised; however, there is significant individual variation in degree of impairment. The task relies critically on the integrity of circuits in medial anterior frontal cortical regions. Accordingly, we analyzed neuronal changes that reflect previously defined 22q11DS-related alterations of cortical development in the medial anterior frontal cortex of the behaviorally characterized LgDel mice. Interneuron placement, synapse distribution, and projection neuron frequency are altered in this region. The magnitude of one of these changes, layer 2/3 projection neuron frequency, is a robust predictor of behavioral performance: it is substantially and selectively lower in animals with the most significant behavioral deficits. These results parallel correlations of volume reduction and altered connectivity in comparable cortical regions with diminished executive function in 22q11DS patients. Apparently, 22q11 deletion alters behaviorally relevant circuits in a distinct cortical region that are essential for cognitive function.

What binds biosociality? The collective effervescence of the parent-led conference.

Questions of community are central to many research settings in the social sciences. Rabinow argued that, in the wake of the Human Genome Project, an increasingly important form of collectivity would be biosociality. Biosociality recognises a central role for biomedical knowledge in constructing genetic identities and producing and reproducing social relationships. Accordingly, it is often imagined as a new form of social solidarity. We draw on observations of parent-led conferences to explore the way in which biosociality is expressed at events organised around a particular genetic syndrome - 22q11 deletion syndrome. The parent-led conferences took place within the United Kingdom between 2007 and 2010 and were observed as part of a multi-sited ethnographic study. By bringing together a geographically dispersed group of people together within the same physical location, conferences offer an ideal platform to empirically examine sociality. Durkheim used the term collective effervescence to describe the collective expression of heightened emotion. We suggest that in the case of the 22q11 deletion syndrome activities discussed in this paper, collective effervescence is a mechanism through which individuals become a collective. We argue that parent-led conferences gather individuals in one location on the basis of common biological factors, but it is the shared emotional experience of being together that consolidates and renews the connection between members.