Source-based morphometry reveals structural brain pattern abnormalities in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism.

Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects.

The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10-5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression.

Altered white matter microstructure in 22q11.2 deletion syndrome: a multisite diffusion tensor imaging study.

22q11.2 deletion syndrome (22q11DS)-a neurodevelopmental condition caused by a hemizygous deletion on chromosome 22-is associated with an elevated risk of psychosis and other developmental brain disorders. Prior single-site diffusion magnetic resonance imaging (dMRI) studies have reported altered white matter (WM) microstructure in 22q11DS, but small samples and variable methods have led to contradictory results. Here we present the largest study ever conducted of dMRI-derived measures of WM microstructure in 22q11DS (334 22q11.2 deletion carriers and 260 healthy age- and sex-matched controls; age range 6-52 years). Using harmonization protocols developed by the ENIGMA-DTI working group, we identified widespread reductions in mean, axial and radial diffusivities in 22q11DS, most pronounced in regions with major cortico-cortical and cortico-thalamic fibers: the corona radiata, corpus callosum, superior longitudinal fasciculus, posterior thalamic radiations, and sagittal stratum (Cohen's d's ranging from -0.9 to -1.3). Only the posterior limb of the internal capsule (IC), comprised primarily of corticofugal fibers, showed higher axial diffusivity in 22q11DS. 22q11DS patients showed higher mean fractional anisotropy (FA) in callosal and projection fibers (IC and corona radiata) relative to controls, but lower FA than controls in regions with predominantly association fibers. Psychotic illness in 22q11DS was associated with more substantial diffusivity reductions in multiple regions. Overall, these findings indicate large effects of the 22q11.2 deletion on WM microstructure, especially in major cortico-cortical connections. Taken together with findings from animal models, this pattern of abnormalities may reflect disrupted neurogenesis of projection neurons in outer cortical layers.

Large-scale mapping of cortical alterations in 22q11.2 deletion syndrome: Convergence with idiopathic psychosis and effects of deletion size.

The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. The imaging data were collected from 10 centers worldwide, including 474 subjects with 22q11DS (age = 18.2 ± 8.6; 46.9% female) and 315 typically developing, matched controls (age = 18.0 ± 9.2; 45.9% female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen's d = 0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d = -1.01/-1.02). 22q11DS cases vs. controls were classified with 93.8% accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3 Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia.

Simple Schizophrenia: A Forgotten Diagnosis in Psychiatry.

Clustering of symptoms to characterize simple schizophrenia is still debated, and support is needed for the characterization of simple schizophrenia as a syndrome. We conducted a systematic review to identify all cases of simple schizophrenia published until December 2017. We identified 42 cases of simple schizophrenia, 57% of which met all three diagnostic criteria (ICD-10, DSM-4 research criteria, and Black and Boffeli's criteria for simple schizophrenia). The mean age at first contact with clinical services was 30.1 (SD = 11.6) years, with a mean delay of 7.4 (SD = 6.8) years from symptom onset to first presentation. An insidious onset and negative symptoms were characteristic features in all cases. Social withdrawal, alogia, blunted affect, lack of initiative/interest, and functional impairment were found in more than 85% of cases. Our findings contribute to greater awareness and understanding of simple schizophrenia, and have the potential to reawaken interest in this clinically distinct subgroup.

Hepatitis, Interstitial Nephritis, and Pancreatitis in Association With Clozapine Treatment: A Systematic Review of Case Series and Reports.

PURPOSE/BACKGROUND: Clozapine is the criterion standard in treatment-resistant schizophrenia. We sought to review data on several inflammatory effects associated with clozapine, specifically interstitial nephritis, hepatitis, and pancreatitis. METHODS/PROCEDURES: We conducted a systematic review to identify studies, published up until December 2017, describing clozapine-induced hepatitis, nephritis, and pancreatitis. The primary objective was to characterize the clinical characteristics associated with each of the specific inflammatory reactions to clozapine. FINDINGS/RESULTS: We identified 42 cases of inflammatory reactions associated with clozapine treatment- 20 :cases of clozapine-induced hepatitis, 11 cases of nephritis, and 11 of pancreatitis. The mean (SD) age was 38.8 (11.9) years. The mean (SD) dose of clozapine used was 252.4 (133.7) mg. Time to onset of pancreatitis (17.9 [11.2] days; range 4-35 days) was shorter than that for hepatitis (34.2 [20.1] days; range, 12-90 days) and nephritis (27.9 [27.0]; range, 8-90 days) but was not statistically significant (F = 2.267, P = 0.117). The mean (SD) time to recovery was shorter for cases of pancreatitis (15.7 [18.4] days) compared with cases of hepatitis (25.9 [16.5] days) and nephritis (24.5 [18.9] days). Three cases with hepatitis died. Seven of the cases had a clozapine rechallenge (hepatitis [n = 3], nephritis [n = 1], pancreatitis [n = 3]), with 5 having a recurrence at a mean (SD) onset of 3.5 (2.5) days (range, 1-7 days); 2 hepatitis cases were successfully rechallenged. IMPLICATIONS/CONCLUSIONS: Clozapine-induced hepatitis, nephritis, and pancreatitis are uncommon adverse events, reflected in the paucity of case studies in the literature. Early recognition of the signs and symptoms of clozapine-associated hepatitis, nephritis, and pancreatitis is important, as when identified, clozapine should be urgently discontinued. Clozapine is associated with evidence of benign inflammatory processes; the extent to which hepatitis, and other inflammatory reactions, may be on a continuum with these more benign and self-limiting reactions is unclear, and this can only be resolved by prospectively following cohorts of clozapine-treated patients.

Variance of IQ is partially dependent on deletion type among 1,427 22q11.2 deletion syndrome subjects.

The 22q11.2 deletion syndrome is caused by non-allelic homologous recombination events during meiosis between low copy repeats (LCR22) termed A, B, C, and D. Most patients have a typical LCR22A-D (AD) deletion of 3 million base pairs (Mb). In this report, we evaluated IQ scores in 1,478 subjects with 22q11.2DS. The mean of full scale IQ, verbal IQ, and performance IQ scores in our cohort were 72.41 (standard deviation-SD of 13.72), 75.91(SD of 14.46), and 73.01(SD of 13.71), respectively. To investigate whether IQ scores are associated with deletion size, we examined individuals with the 3 Mb, AD (n = 1,353) and nested 1.5 Mb, AB (n = 74) deletions, since they comprised the largest subgroups. We found that full scale IQ was decreased by 6.25 points (p = .002), verbal IQ was decreased by 8.17 points (p = .0002) and performance IQ was decreased by 4.03 points (p = .028) in subjects with the AD versus AB deletion. Thus, individuals with the smaller, 1.5 Mb AB deletion have modestly higher IQ scores than those with the larger, 3 Mb AD deletion. Overall, the deletion of genes in the AB region largely explains the observed low IQ in the 22q11.2DS population. However, our results also indicate that haploinsufficiency of genes in the LCR22B-D region (BD) exert an additional negative impact on IQ. Furthermore, we did not find evidence of a confounding effect of severe congenital heart disease on IQ scores in our cohort.

Remission and recovery from first-episode psychosis in adults: systematic review and meta-analysis of long-term outcome studies.

BackgroundRemission and recovery rates for people with first-episode psychosis (FEP) remain uncertain.AimsTo assess pooled prevalence rates of remission and recovery in FEP and to investigate potential moderators.MethodWe conducted a systematic review and meta-analysis to assess pooled prevalence rates of remission and recovery in FEP in longitudinal studies with more than 1 year of follow-up data, and conducted meta-regression analyses to investigate potential moderators.ResultsSeventy-nine studies were included representing 19072 patients with FEP. The pooled rate of remission among 12301 individuals with FEP was 58% (60 studies, mean follow-up 5.5 years). Higher remission rates were moderated by studies from more recent years. The pooled prevalence of recovery among 9642 individuals with FEP was 38% (35 studies, mean follow-up 7.2 years). Recovery rates were higher in North America than in other regions.ConclusionsRemission and recovery rates in FEP may be more favourable than previously thought. We observed stability of recovery rates after the first 2 years, suggesting that a progressive deteriorating course of illness is not typical. Although remission rates have improved over time recovery rates have not, raising questions about the effectiveness of services in achieving improved recovery.

An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis.

Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100 kb), rare copy-number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1564 cases and 1748 controls all from Ireland, and further extended the analysis to include an additional 5196 UK controls. We found association with duplications at chr20p12.2 (P = 0.007) and evidence of replication in large independent European schizophrenia (P = 0.052) and UK bipolar disorder case-control cohorts (P = 0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11 707 cases and 10 carriers in 21 204 controls [meta-analysis Cochran-Mantel-Haenszel P-value = 2 × 10(-4); odds ratio (OR) = 11.3, 95% CI = 3.7, ∞]. Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68 Mb with similar breakpoints across samples. By haplotype analysis and sequencing, we identified a tandem ~149 kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P = 2.5 × 10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.

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.

Craniofacial dysmorphology in 22q11.2 deletion syndrome by 3D laser surface imaging and geometric morphometrics: illuminating the developmental relationship to risk for psychosis.

Persons with 22q11.2 deletion syndrome (22q11.2DS) are characterized inter alia by facial dysmorphology and greatly increased risk for psychotic illness. Recent studies indicate facial dysmorphology in adults with schizophrenia. This study evaluates the extent to which the facial dysmorphology of 22q11.2DS is similar to or different from that evident in schizophrenia. Twenty-one 22q11.2DS-sibling control pairs were assessed using 3D laser surface imaging. Geometric morphometrics was applied to 30 anatomical landmarks, 480 geometrically homologous semi-landmarks on curves and 1720 semi-landmarks interpolated on each 3D facial surface. Principal component (PC) analysis of overall shape space indicated PC2 to strongly distinguish 22q11.2DS from controls. Visualization of PC2 indicated 22q11.2DS and schizophrenia to be similar in terms of overall widening of the upper face, lateral displacement of the eyes/orbits, prominence of the cheeks, narrowing of the lower face, narrowing of nasal prominences and posterior displacement of the chin; they differed in terms of facial length (increased in 22q11.2DS, decreased in schizophrenia), mid-face and nasal prominences (displaced upwards and outwards in 22q11.2DS, less prominent in schizophrenia); lips (more prominent in 22q11.2DS; less prominent in schizophrenia) and mouth (open mouth posture in 22q11.2DS; closed mouth posture in schizophrenia). These findings directly implicate dysmorphogenesis in a cerebral-craniofacial domain that is common to 22q11.2DS and schizophrenia and which may repay further clinical and genetic interrogation in relation to the developmental origins of psychotic illness.

Psychiatric and neuropsychological profiles of people with psychogenic nonepileptic seizures.

OBJECTIVE: This study examined the psychiatric and neuropsychological profiles of people with psychogenic nonepileptic seizures (PNES). METHODS: Twenty-people who had been diagnosed with psychogenic nonepileptic seizures (PNES), but not epilepsy, were recruited into this study. A healthy control group was also recruited and was matched for age and gender. All participants underwent structured psychiatric assessment and psychometric assessment. Neuropsychological assessment was carried out using the Cambridge Neuropsychological Test Battery (CANTAB) after participants passed the Medical Symptom Validity Test (MSVT) of effort. RESULTS: One patient failed the MSVT and was excluded from the analysis. Therefore, data from 19 people with PNES and their matched healthy controls were analyzed. Compared with controls, people with PNES had significantly higher levels of depressive symptoms, anxiety symptoms, dissociative experiences, and alexithymic traits. In addition, people with PNES had impairments in spatial working memory and attention when compared with healthy controls. CONCLUSION: To our knowledge, this is the first study to report that, compared with controls, people with PNES have abnormal cognitive functioning after controlling for effects of effort and FSIQ. People with PNES also have high levels of anxiety, depressive, and dissociative symptoms. In addition, they appear to particularly focus on health problems and show evidence of chronic emotional dysregulation. Further studies are required to replicate our results and to help clarify the pathogenic mechanisms underlying PNES.

The impact of badmouthing of medical specialties to medical students.

OBJECTIVES: This study aimed to evaluate the proportion of Irish medical students exposed to 'badmouthing' of different specialities and to ascertain: the degree of criticism of specialities based on the seniority of clinical or academic members of staff; if 'badmouthing' influenced student career choice in psychiatry; and attitudes of medical students towards psychiatry as a speciality and career choice. METHODS: Medical students in three Irish universities were invited to complete an online survey to determine the frequency and effect of non-constructive criticism on choice of medical specialty. The online questionnaire was distributed to Royal College of Surgeons in Ireland (RCSI), University of Galway (UoG) and University College Dublin (UCD) in the academic year 2020-2021. RESULTS: General practice (69%), surgery (65%) and psychiatry (50%) were the most criticised specialties. Criticism was most likely to be heard from medical students. 46% of students reported reconsidering a career in psychiatry due to criticism from junior doctors. There was a positive perception of psychiatry with 27% of respondents considering psychiatry as a first-choice specialty. CONCLUSIONS: Criticism of psychiatry by doctors, academics and student peers negatively influences students' career choice, which could be contributing to recruitment difficulties in psychiatry.

Schizophrenia two-hit hypothesis in velo-cardio facial syndrome.

Deletion of chr22q11 gives rise to velo-cardio facial syndrome (VCFS) and increases schizophrenia risk. The source of this elevated risk although unknown could result from stochastic, environmental, or genetic factors, the latter encompassing a range of complexity from polygenic mechanisms to "second-hit" mutations. For this study we tested the two-hit hypothesis where additional risk is conferred through a second CNV. We identified large (>100 kb) CNVs in 48 VCFS cases (23 with psychosis--25 without) and show in the psychotic VCFS group there is a significant (P = 0.02) increase in the average size of CNVs (354-227 kb). To identify second-hit loci we focused on individuals possessing gene-centric CNVs and through literature mining identified 4 (31%) psychotic VCFS individuals (n = 13) that overlapped loci previously implicated in neuropsychiatric disorders compared to 1 (10%) from the non-psychotic VCFS individuals (n = 10). For replication 17 VCFS patients with schizophrenia from the molecular genetics of schizophrenia dataset were used to identify further CNVs. Thirteen individuals possessing gene-centric CNVs were identified including 3 (23%) individuals possessing a potential second-hit, taking the overall total in the psychotic VCFS group (n = 26) to 7 (27%) potential second-hit loci. Notably a deletion in a psychotic VCFS patient at 2q23.1 hit the gene MBD5 which when deleted gives rise to intellectual disability, epilepsy, and autistic features. Through this study we potentially extend this phenotypic spectrum to include schizophrenia. Our results suggest the two-hit hypothesis may be relevant to a proportion of VCFS patients with psychosis but sample sizes are small and further studies warranted.

One year of psychiatric presentations to a hospital emergency department during COVID-19.

OBJECTIVES: To examine the impact of the first full year of the COVID-19 pandemic and its associated restrictions on the volume and nature of psychiatric presentations to an emergency department (ED) in a large academic hospital. METHODS: Anonymised clinical data on psychiatric presentations to the ED were collected for the 52-week period from the start of the COVID-19 pandemic and compared with corresponding 1 year periods in 2019 and 2018. RESULTS: There was a significant increase in psychiatric presentations overall to the ED during the first year of the COVID-19 pandemic compared to previous years, in contrast to a reduction in total presentations for all other specialties. There was a marked increase in psychiatric presentations of those below 18 years, and in the 30-39 years and 40-49 years age groups, but a decrease in the 18-29 years group. There was a significant increase in anxiety disorder presentations but a decrease in alcohol related presentations. There was no significant change observed in the rates of presentations for self-harm or suicidal ideation. CONCLUSIONS: Psychiatric presentations to the ED have increased during the first year of the COVID-19 pandemic in contrast to a decrease in presentations for other medical specialties, with this increase being driven by out-of-hours presentations. The fourfold increase in presentations of young people below the age of 18 years to the ED with mental health difficulties is an important finding and suggests a disproportionate burden of psychological strain placed on this group during the pandemic.

Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS.

Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the TBX1 gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2DS cases. Many of these genes were identified as risk factors for sporadic CHD in the general population. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. The genes KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models. Our findings indicate that disturbance of chromatin regulatory genes impact the TBX1 gene network serving as genetic modifiers of 22q11.2DS and sporadic CHD, suggesting that there are some shared mechanisms involving the TBX1 gene network in the etiology of CHD.

In vivo brain anatomy of adult males with Fragile X syndrome: an MRI study.

Fragile X Syndrome (FraX) is caused by the expansion of a single trinucleotide gene sequence (CGG) on the X chromosome, and is a leading cause of learning disability (mental retardation) worldwide. Relatively few studies, however, have examined the neuroanatomical abnormalities associated with FraX. Of those that are available many included mixed gender populations, combined FraX children and adults into one sample, and employed manual tracing techniques which measures bulk volume of particular regions. Hence, there is relatively little information on differences in grey and white matter content across whole brain. We employed magnetic resonance imaging to investigate brain anatomy in 17 adult males with FraX and 18 healthy controls that did not differ significantly in age. Data were analysed using stereology and VBM to compare (respectively) regional brain bulk volume, and localised grey/white matter content. Using stereology we found that FraX males had a significant increase in bulk volume bilaterally of the caudate nucleus and parietal lobes and of the right brainstem, but a significant decrease in volume of the left frontal lobe. Our complimentary VBM analysis revealed an increased volume of grey matter in fronto-striatal regions (including bilaterally in the caudate nucleus), and increased white matter in regions extending from the brainstem to the parahippocampal gyrus, and from the left cingulate cortex extending into the corpus callosum. People with FraX have regionally specific differences in brain anatomy from healthy controls with enlargement of the caudate nuclei that persists into adulthood.

Down syndrome with and without dementia: an in vivo proton Magnetic Resonance Spectroscopy study with implications for Alzheimer's disease.

It is poorly understood why people with Down syndrome (DS) are at extremely high-risk of developing Alzheimer's disease (AD) compared to the general population. One explanation may be related to their extra copy of risk factors modulated by chromosome 21. Myo-inositol (mI), whose transporter gene is located on chromosome 21, has been associated with dementia in the non-DS population; however, nobody has contrasted brain mI in DS with (DS+) and without (DS-) dementia to other non-DS groups. Our primary aim was to compare the hippocampal concentration of mI ([mI]) and other brain metabolites such as N-acetylaspartate (NAA; a proxy measure of neuronal density and mitochondrial function) in DS+, DS-, and age-matched healthy controls using proton Magnetic Resonance Spectroscopy (((1))H-MRS). We compared hippocampal [mI] and other metabolites in 35 individuals with genetically-confirmed DS [DS+ (n=17, age=53±6) and DS- (n=18, age=47±8)] to age-matched healthy controls (n=13, age=51±10) adjusting for proportion of the MRS voxel occupied by cerebrospinal spinal fluid, and gray/white matter. DS+ had a significantly higher [mI] than both DS- and healthy controls. In contrast neither DS+ nor DS- differed significantly from controls in [NAA] (although NAA in DS+ was significantly lower than DS-). Our secondary aim of comparing brain metabolites in DS+ and DS- to Alzheimer's disease (AD; n=39; age=77±5) revealed that the DS+ group had significantly elevated [mI] compared to AD or DS-. [mI] may modify risk for dementia in this vulnerable population.

Anti-NMDA receptor encephalitis: an important differential diagnosis in psychosis.

We present four cases of confirmed anti-NMDA receptor encephalitis; three presented initially with serious psychiatric symptoms and the other developed significant psychiatric symptoms during the initial phase of illness. Brain biopsy findings of one patient are also described. Psychiatrists should consider anti-NMDA receptor encephalitis in patients presenting with psychosis and additional features of dyskinesias, seizures and catatonia, particularly where there is no previous history of psychiatric disorder.

COMT Val(158) met genotype and striatal D(2/3) receptor binding in adults with 22q11 deletion syndrome.

Although catechol-O-methyltransferase (COMT) activity evidently affects dopamine function in prefrontal cortex, the contribution is assumed less significant in striatum. We studied whether a functional polymorphism in the COMT gene (Val(158) Met) influences striatal D(2/3) R binding ratios (D(2/3) R BP(ND) ) in 15 adults with 22q11 deletion syndrome and hemizygous for this gene, using single photon emission computed tomography and the selective D(2/3) radioligand [(123) I]IBZM. Met hemizygotes had significantly lower mean D(2/3) R BPND than Val hemizygotes. These preliminary data suggest that low COMT activity may affect dopamine levels in striatum in humans and this may have implications for understanding the contribution of COMT activity to psychiatric disorders.