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Hybrid single-stage repair of Kommerell's diverticulum in a right aortic arch. Aortic arch anomalies, isolated or associated with congenital heart defects, are cardiovascular manifestations frequently associated with 22q11.2 deletion syndrome. Kommerell's diverticulum in the context of a right aortic arch is an exceedingly rare congenital anomaly, consisting in aneurysmal degeneration of the origin of an aberrant left subclavian artery. Open surgical repair has been the treatment paradigm, but in recent years, hybrid and endovascular procedures have also been proposed. In this report we present the case of a patient affected by 22q11.2 deletion syndrome successfully treated for Kommerell's diverticulum associated with a right-sided aortic arch through a single-stage hybrid procedure, consisting of bilateral carotid-subclavian bypass, exclusion of the diverticulum by an endovascular thoracic stent graft, and aberrant left subclavian artery plug occlusion. This type of hybrid technique can be an excellent alternative to extensive open surgical repairs or when total endovascular repair is deemed unachievable, also in the context of a complex genetic syndrome. [ABSTRACT FROM AUTHOR]

Aim: Individuals with schizophrenia demonstrate higher rates of metabolic syndrome (MetS) than the general population. Hair cortisol concentrations (HCC) reflect longer‐term cortisol secretion and can provide additional insights into the role of the hypothalamic pituitary adrenal (HPA) axis in schizophrenia and co‐occurring MetS. Methods: In a case–control study of 16 patients with schizophrenia (11 first episode psychosis [FEP] and 5 chronic) and 21 controls hair samples, representing a 3‐month retrospective window of cortisol, were collected and analysed utilizing liquid chromatography tandem mass spectrometry. We investigated whether schizophrenia and MetS co‐occurrence were associated with HCC utilizing multivariate regression models. We also explored the longitudinal trajectory of HCC in FEP patients by conducting a mixed models analysis. Results: At baseline HCC were significantly lower (Cohen's d = 0.88) in patients with schizophrenia than in controls (p =.014). HCC increased from baseline to month‐12 in FEP patients compared to controls, demonstrating a trend towards significance (p =.097). MetS was not associated with HCC at baseline, but HCC increased significantly from baseline to month‐12 in relation to MetS (p =.037). Conclusions: In a subgroup of schizophrenia patients, psychosis may be associated with a blunted HPA axis with lower long‐term cortisol output. MetS was associated with an increase in HCC and elevated cortisol levels observed in schizophrenia may be related to increased rates of MetS in schizophrenia patients. [ABSTRACT FROM AUTHOR]

Structural brain differences have been described in first-episode schizophrenia spectrum disorders (FES), and often overlap with those evident in the metabolic syndrome (MetS). We examined the associations between body mass index (BMI) and brain structures involved in food intake regulation in minimally treated FES patients (n = 117) compared to healthy controls (n = 117). The effects of FES diagnosis, BMI and their interactions on our selected prefrontal cortical thickness and subcortical gray matter volume regions of interest (ROIs) were investigated with hierarchical multivariate regressions, followed by post-hoc regressions for the individual ROIs. In a secondary analysis, we examined the relationships of other MetS risk factors and psychopathology with the brain ROIs. Both illness and BMI significantly predicted the grouped prefrontal cortical thickness ROIs, whereas only BMI predicted the grouped subcortical volume ROIs. For the individual ROIs, schizophrenia diagnosis predicted thinner left and right frontal pole and right lateral OFC thickness, and increased BMI predicted thinner left and right caudal ACC thickness. There were no significant main or interaction effects for diagnosis and BMI on any of the individual subcortical volume ROIs. Secondary analyses suggest associations between several brain ROIs and individual MetS risk factors, but not with psychopathology. Our findings indicate differential, independent effects for FES diagnosis and BMI on brain structures. Limited evidence suggests that the BMI effects are more prominent in FES. Exploratory analyses suggest associations between other MetS risk factors and some brain ROIs. • FES diagnosis and higher BMI predicted thinner prefrontal cortical thickness. • FES diagnosis predicted thinner frontal pole cortex and orbitofrontal cortex. • Higher BMI predicted thinner ACC independent of FES diagnosis. • We found illness-specific associations of BMI with subcortical brain volumes. [ABSTRACT FROM AUTHOR]

Introduction: The referral of inpatients to psychiatry team is more in India due to the increase in the morbidity rates of people. The referrals to Psychiatric Department with a specific psychiatric diagnosis are considerably very low. Most often, the diagnosis made by the clinicians doesn’t match with that of the psychiatrist. Physical illness is shown to have a strong association with psychiatric co-morbidity. Such association complicates the course and outcome of both the conditions. Aim: To evaluate the pattern of inpatient referral to the Psychiatric Department and to estimate the diagnostic concordance between the referral and psychiatric team. Materials and Methods: This retrospective study, with prior permission from the Department of psychiatry, included all the inpatient referrals (n=310) to Psychiatry Department by other departments from January 2019 to December 2019. Data collection was done from March 2020 to August 2020 and data analysis from September 2020 to November 2020, in Saveetha Medical College and Hospital, Chennai, Tamil Nadu, India. Data was obtained from a psychiatry referral register and was statistically analysed using Microsoft Excel (MS Office 2013) for percentage, mean and Standard Deviation (SD) for descriptive variables. Diagnostic concordance to assess the reason for referral and diagnostic accuracy in terms of reason of referral and psychiatric diagnosis was analysed using kappa statistics. Results: The most common psychiatric disorder for referral was alcohol dependence syndrome (n=102, 32.9%) followed by depression (n=38, 12.3%) and adjustment disorders (n=34, 10.9 %). Concordance was good for intellectual disorder (κ=1.00), depression (κ=0.969) and alcohol dependence syndrome (κ=0.963). Very low concordance was observed in diagnosing acute confusional state (κ=0.195) and panic disorder (κ =0). Conclusion: Alcohol withdrawal syndrome, adjustment disorder and depression were the most common reasons in referring inpatients to psychiatry. Lower concordance for psychiatric disorders like Acute confusional state and Panic disorder could be explained by inadequate psychiatry exposure and hence be improved by better undergraduate psychiatry training. [ABSTRACT FROM AUTHOR]

Aim: The genetic relationship between schizophrenia (SCZ) and other nonpsychiatric disorders remains largely unknown. We examined the shared genetic components between these disorders based on multipopulation data sets. Methods: We used two data sets for East Asian (EAS) and European (EUR) samples. SCZ data was based on the Psychiatric Genomics Consortium Asia with our own genome‐wide association study for EAS and Psychiatric Genomics Consortium for EUR. Nonpsychiatric data (20 binary traits [mainly nonpsychiatric complex disorders] and 34 quantitative traits [mainly laboratory examinations and physical characteristics]) were obtained from Biobank Japan and UK Biobank for EAS and EUR samples, respectively. To evaluate genetic correlation, linkage disequilibrium score regression analysis was utilized with further meta‐analysis for each result from EAS and EUR samples to obtain robust evidence. Subsequent mendelian randomization analysis was also included to examine the causal effect. Results: A significant genetic correlation between SCZ and several metabolic syndrome (MetS) traits was detected in the combined samples (meta‐analysis between EAS and EUR data) (body mass index [rg = −0.10, q‐value = 1.0 × 10−9], high‐density‐lipoprotein cholesterol [rg = 0.072, q‐value = 2.9 × 10−3], blood sugar [rg = −0.068, q‐value = 1.4 × 10−2], triglycerides [rg = −0.052, q‐value = 2.4 × 10−2], systolic blood pressure [rg = −0.054, q‐value = 3.5 × 10−2], and C‐reactive protein [rg = −0.076, q‐value = 7.8 × 10−5]. However, no causal relationship on SCZ susceptibility was detected for these traits based on the mendelian randomization analysis. Conclusion: Our results indicate shared genetic components between SCZ and MetS traits and C‐reactive protein. Specifically, we found it interesting that the correlation between MetS traits and SCZ was the opposite of that expected from clinical studies: this genetic study suggests that SCZ susceptibility was associated with reduced MetS. This implied that MetS in patients with SCZ was not associated with genetic components but with environmental factors, including antipsychotics, lifestyle changes, poor diet, lack of exercise, and living conditions. [ABSTRACT FROM AUTHOR]

Background: Few investigations have been carried out on metabolic syndrome in antipsychotic- naïve patients with schizophrenia.Methods: Our primary objective was to compare the prevalence of Metabolic Syndrome (MetS), as defined by the National Cholesterol Education Program, Adult Treatment Panel III in 2001 (NCEP-ATP III), between a Spanish cohort of 303 drug-naïve patients with a first episode of psychosis (FEP) without any previous cardiovascular condition, and 153 healthy individuals.Results: Participants included 303 patients with FEP (M:F 53:46) and 153 control subjects (M:F 56:43). The mean and standard deviation ages were 31(9.38) and 29 (7.57) years in the study and control groups respectively (F = 4.09; p = 0.93). We found that the prevalence of MetS in drug-naïve patients with FEP (5.6 %) was similar to the prevalence of MetS in age-sex matched controls (5.12 %). However, 60.7 % of patients with FEP met at least one of the five MetS components, while among the control subjects only 36.5 % met at least one component. Additionally, we found that other factors not included among the operational definition of MetS, but still important in cardiovascular risk, were also altered.Conclusion: FEP patients have a greater risk of presenting at least one altered MetS component than healthy controls which could indicate the need of development of screening methods detecting cardiovascular risk. Likewise, gender differences in metabolic components such as waist circumference, which is a predictor of cardiovascular events have been found. Similarly, research should focus on metabolic risk predictors that include not only MetS, but also specific parameters for the early psychosis population. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) has taken the prime position as an endocrine disease in women of reproductive age and is estimated to affect 2.2–22.5% worldwide and in Indian women it ranges from 9% to 12%. The primary defects that cause PCOS still remains unknown. A lot of genetic factors not excluding polymorphisms and mutations of multiple genes have been linked with PCOS, exact mechanisms which might be the cause of PCOS are yet unknown. Angiotensin converting enzyme (ACE) and its yields are related with angiogenesis of ovarian epithelium, restoration of meiosis, steroidogenesis, and follicular growth. Aims and Objectives: The present study was aimed to establish the association of ACE insertion/deletion (I/D) polymorphism in PCOS patients and to assess the influence of this polymorphism on the metabolic components of PCOS. Materials and Methods: Genomic DNA was extracted from blood obtained from 100 patients with PCOS and 100 healthy controls following ethical guidelines. DNA was amplified by polymerase chain reaction (PCR) using I/D distinct allele primers. PCR products were assessed after being exposed to gel electrophoresis. Results were analyzed in respect to biochemical parameters. Results: The allelic frequency and genotypic distribution of the ACE gene polymorphism is associated with PCOS in women. The concentrations of testosterones as well as luteinizing hormone/ follicle stimulating hormone ratio among the distinct genotypes were significantly different. The presence of “D” allele in a population more likely to be associated with formation of polycystic ovary and hyperandrogenism was observed. Conclusion: The data suggest that ACE I/D polymorphism and PCOS pathology are unassociated. However, aggravation of clinical symptoms of PCOS can be linked to the steroidogenesis which, in turn, is associated with the polymorphism. [ABSTRACT FROM AUTHOR]

22q11.2 deletion syndrome (DS 22q11.2) is a rare disease of genetic origin, caused by the loss of the q11.2 region of chromosome 22. It affects one in 4000 live newborns, and among the clinical manifestations that can occur in this syndrome are abnormalities in the parathyroid glands (producing calcium deficits), the palate, the heart and the thymus. It is also known as DiGeorge syndrome or velocardiofacial syndrome, among other names, depending on the clinical presentation of each individual. The main objective of the review was to update information on DS 22q11.2 from publications in the scientific literature. The daily activities of these patients are seriously impaired, due to the impact of the clinical manifestations. Interventions can be performed to improve their social, cognitive and emotional skills, thus increasing their ability to perform different daily activities. [ABSTRACT FROM AUTHOR]

Objective: Many studies so far have shown that antipsychotic therapy may have an effect on the development of metabolic syndrome in patients diagnosed with schizophrenia. Our goal was to determine whether our respondents are at risk for developing metabolic syndrome and who is more predisposed to it. Methods: In a stable phase, 60 patients diagnosed with schizophrenia were equally divided into three groups according to the drug (risperidone, clozapine, and aripiprazole monotherapy). Control group had 20 healthy examinees. Patients were evaluated first using The Positive and Negative Syndrome Scale (PANSS). Prolactin, lipid status, glycemia, insulin, cytokine values (IL-33, TGF-β, and TNF-α) and C-reactive protein (CRP) were measured. Also, Body mass index (BMI), Homeostatic Model Assesment for Insulin Resistance (HOMA index), waist and hip circumference (WHR) and blood pressure (TA) measurement were performed in the study. Results: Patients treated with risperidone compared to healthy control subjects and aripiprazol group of patients had statistically significant difference in prolactin levels. In clozapine group compared to healthy control group values of HDL cholesterol and glucose level were statistically significant different. In aripiprazole group compared to healthy control group value of BMI was statistically significant different. Statistically significant correlations were found in TNF-α with glucose and HOMA index in risperidone treated patients and with BMI in clozapine group of patients; IL-33 with glucose in risperidone and with BMI in clozapine group of patients and TGF-β with glucose in risperidone group, with insulin and HOMA index in clozapine group and statistically significant negative correlation with LDL cholesterol in aripiprazole group of patients. Conclusion: Patients on risperidone and clozapine therapy may be at greater risk of developing metabolic syndrome than patients treated with aripiprazole. Statistically significant difference in concentration of TNF-α and TGF-β was in the group of patients treated with risperidone compared to healthy control group. [ABSTRACT FROM AUTHOR]

Malan Syndrome (MS) is an ultra-rare overgrowth genetic syndrome due to heterozygous variants or deletions in the Nuclear Factor I X (NFIX) gene. It is characterized by an unusual facial phenotype, generalized overgrowth, intellectual disability (ID) and behavioral problems. Even though limitations in cognitive and adaptive functioning have been previously described, systematic studies on MS cohorts are still lacking. Here, we aim to define the cognitive and adaptive behavior profile of MS children and adolescents, providing quantitative data from standardized evaluations. Subjects included in this study were evaluated from October 2020 to January 2022 and the study is based on a retrospective data archive: fifteen MS individuals were recruited and underwent evaluation with Wechsler Intelligence Scales, Leiter International Performance Scales and Griffith Mental Development Scales for cognitive profiles and with Vineland Adaptive Behavior Scales-II Edition (VABS-II) for adaptive functioning. Language skills and visuomotor integration abilities were assessed too. Comparisons and correlations between scales and subtests were performed. All the assessed MS individuals showed both low cognitive and adaptive functioning. One subject presented with mild ID, five had moderate ID and eight showed severe ID. One female toddler received a diagnosis of psychomotor delay. Linguistic skills were impaired in all individuals, with language comprehension relatively more preserved. Results revealed significant differences between VABS-II subdomains and a strong relationship between cognitive and adaptive functioning. All subjects exhibited mild to moderate ID and adaptive behavior lower than normal, with communication skills being the most affected. Regarding the daily living skills domain, personal and community subscale scores were dramatically lower than for the domestic subdomain, highlighting the importance of considering behavior within developmental and environmental contexts. Our cognitive and adaptive MS characterization provides a more accurate quantitative MS profiling, which is expected to help clinicians to better understand the complexity of this rare disorder. [ABSTRACT FROM AUTHOR]

Background: There is limited information about sexual knowledge and behaviours in adults with complex care needs, including those with 22q11.2 deletion syndrome (22q) which represents a group predisposed to intellectual disabilities. Methods: We conducted sexual health assessments with 67 adults with 22q, examining whether those with knowledge deficits and a history of engaging in sexual activities with others would be more likely to engage in high‐risk behaviours. Results: The majority (65.7%) of adults with 22q were sexually active with others; most (70.1%) had sexual knowledge deficits. Those with intellectual disabilities were more likely (p =.0012) to have deficits in certain topics. In the sexually active subgroup, most (81.8%) engaged in high‐risk sexual behaviours, regardless of intellectual disability or knowledge deficits. Conclusion: The results suggest a need for increased dialogue, repeated education, genetic counselling and preventive healthcare measures related to sexuality in 22q and potentially in other complex care conditions. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by core deficits in social communication and restricted and repetitive behaviors and interests. Recent advances in clinical genetics have improved our understanding of genetic syndromes associated with ASD, which has helped clarify distinct etiologies of ASD and document syndrome-specific profiles of neurocognitive strengths and weaknesses. Pediatric neuropsychologists have the potential to be impactful members of the care team for children with genetic syndromes and their families. We provide a critical review of the current literature related to the neuropsychological profiles of children with four genetic syndromes associated with ASD, including Tuberous Sclerosis Complex (TSC), fragile X syndrome (FXS), 22q11.2 deletion syndrome, and Angelman syndrome. Recommendations for assessment, intervention, and future directions are provided. There is vast heterogeneity in terms of the cognitive, language, and developmental abilities of these populations. The within- and across-syndrome variability characteristic of genetic syndromes should be carefully considered during clinical evaluations, including possible measurement limitations, presence of intellectual disability, and important qualitative differences in the ASD-phenotypes across groups. Individuals with genetic disorders pose challenging diagnostic and assessment questions. Pediatric neuropsychologists with expertise in neurodevelopmental processes are well suited to address these questions and identify profiles of neurocognitive strengths and weaknesses, tailor individualized recommendations, and provide diagnostic clarification. [ABSTRACT FROM AUTHOR]

These patients share several features with our patient, including DD (5 patients), scoliosis (4 patients), strabismus, and hypotonia (2 patients). [19] In patient 14 the deletion was more distal and corresponded only partially to the interval described in the 1q21.1 microdeletion syndrome, consequently, it was not clear if the deletion could explain the phenotype and was classified as LP. Keywords: chromosome 1; copy number variant; array comparative genomic hybridization; neurodevelopmental disorders; 1q21.1 syndrome EN chromosome 1 copy number variant array comparative genomic hybridization neurodevelopmental disorders 1q21.1 syndrome 265 273 9 09/07/22 20220701 NES 220701 Conflict of Interest None declared. [21] The DECIPHER database describes several patients with deletions that partially overlap with our patient CNV and sharing several features with our patient, including ID, language impairment, muscular hypotonia, and macrocephaly. [Extracted from the article]

Keywords: chromosome 16p11.2 deletion; PRRT2; familial hemiplegic migraine EN chromosome 16p11.2 deletion PRRT2 familial hemiplegic migraine 279 282 4 09/07/22 20220701 NES 220701 Conflict of Interest None declared. Introduction Chromosome 16p11.2 deletion syndrome is one of the most common genetic causes of developmental delay (DD) and autism spectrum disorder (ASD). We present the first case of FHM in a patient with this microdeletion syndrome which seems to be related to the heterozygous deletion of I PRRT2 i . [Extracted from the article]

2020, 157 (01): 23 6 Justice E. D., Barnum S. J., Kidd T. The WAGR syndrome gene PRRG4 is a functional homologue of the commissureless axon guidance gene. [5] We describe here a patient harboring the largest germline heterozygous deletion reported so far, including, among others, PSS and WAGR syndrome loci (MIM #601224 and MIM #194072). Keywords: Potocki-Schaffer syndrome; WAGR syndrome; contiguous gene deletion; array-CGH; oligohydramnios EN Potocki-Schaffer syndrome WAGR syndrome contiguous gene deletion array-CGH oligohydramnios 274 278 5 09/07/22 20220701 NES 220701 Conflict of Interest None declared. WAGR syndrome, array-CGH, Potocki-Schaffer syndrome, contiguous gene deletion, oligohydramnios. [Extracted from the article]

Polymicrogyria (PMG) is a relatively common complex malformation with cortical development, characterized by an exorbitant number of abnormally tiny gyri separated by shallow sulci. It is a neuronal migration disorder. Familial cases of PMG and the manifestation of PMG in patients with chromosomal aberrations and mutations indicate their important role of genetics in this disorder. The highly stereotyped and well-conserved nature of the cortical folding pattern in humans is suggestive of the genetic regulation of the process. The chromosomal abnormalities observed in PMG include deletions, duplications, chromosomal rearrangements, and aneuploidies. Two of the most common deletions in PMG are 22q11.2 deletion and 1p36 deletion. Further, mutations in several genes such as GPR56, TUBB2B, SRPX2, PAX6, EOMES, WDR62, TUBA8, KIAA1279, and COL18A1 are known to be associated with PMG. Intriguingly, these genes are responsible only for a small number of cases of PMG. The protein products of these genes are implicated in diverse molecular and cellular functions. Taken together, PMG could be the result of the disruption of several biological pathways. Different modes of Mendelian inheritance and non-Mendelian inheritance are seen in PMG. We have suggested a gene panel that can be used for the detection of malformations of cortical development. [ABSTRACT FROM AUTHOR]

Treatment of refractory autoimmune cytopenias (AICs) and Evans syndrome (ES) represent a great challenge in pediatric setting, where an underlying primary immunodeficiency is recurrent. Frequently, second or third line treatments are employed, with an increased risk of toxicity and infections. The advent of novel drugs is the object of research in order to modify the management of these patients. We report a case of successful use of bortezomib in a child with 22q11.2 deletion syndrome and CVID-like phenotype with a multi-refractory severe ES. Last flares were prolonged and dominated by severe and symptomatic ITP, refractory to different courses of high dose steroid and IVIG, mofetil mycophenolate, thrombopoietin receptor agonists, sirolimus, and rituximab. Persistence of AICs in subjects with depletion of CD20 + B-cells and IgG strengthens the hypothesis about the production of autoantibodies by terminally differentiated plasma-cells, not targetable from immunosuppressants and rituximab. In the attempt to enhance plasma-cells inhibition, the child was addressed to bortezomib, with a good response at 6 month follow-up without side effects. Nowadays, the use of bortezomib in ES/AICs is based only on small retrospective studies and case reports. Despite the lack of long term follow-up, our work highlights the potential role of bortezomib in the management of pediatric patients with multi-resistant AICs secondary to immune-system impairment. [ABSTRACT FROM AUTHOR]

Aims: Schizophrenia (SZ) is characterized by psychotic symptoms and cognitive impairment, and is hypothesized to be a 'dysconnection' syndrome due to abnormal neural network formation. Although numerous studies have helped elucidate the pathophysiology of SZ, many aspects of the mechanism underlying psychotic symptoms remain unknown. This study used graph theory analysis to evaluate the characteristics of the resting‐state network (RSN) in terms of microscale and macroscale indices, and to identify candidates as potential biomarkers of SZ. Specifically, we discriminated topological characteristics in the frequency domain and investigated them in the context of psychotic symptoms in patients with SZ. Methods: We performed graph theory analysis of electrophysiological RSN data using magnetoencephalography to compare topological characteristics represented by microscale (degree centrality and clustering coefficient) and macroscale (global efficiency, local efficiency, and small‐worldness) indices in 29 patients with SZ and 38 healthy controls. In addition, we investigated the aberrant topological characteristics of the RSN in patients with SZ and their relationship with SZ symptoms. Results: SZ was associated with a decreased clustering coefficient, local efficiency, and small‐worldness, especially in the high beta band. In addition, macroscale changes in the low beta band are closely associated with negative symptoms. Conclusions: The local networks of patients with SZ may disintegrate at both the microscale and macroscale levels, mainly in the beta band. Adopting an electrophysiological perspective of SZ as a failure to form local networks in the beta band will provide deeper insights into the pathophysiology of SZ as a 'dysconnection' syndrome. [ABSTRACT FROM AUTHOR]

Objective: Anorectal malformations (ARM) are classified as a multifactorial disease. The etiology of ARM is still not clear due to the complexity of the pathological anomalies. Materials and Methods: The microarray-based comparative genomic hybridization (array CGH) results of 10 patients with ARM not associated with a specific syndrome were analyzed using the 8x60K ISCA Agilent microarray platform (Human Genome CGH Microarray; Agilent Technologies, Inc., Santa Clara, CA, USA). Pathogenic copy number variants were further confirmed using fluorescence in situ hybridization or quantitative real-time polymerase chain reaction testing. Results: Chromosome 22q11.2 deletion was detected in 2 patients. One of these patients had anal stenosis, minor cardiac abnormalities, and a small 0.89-Mb deletion. The second patient had anal atresia, immune deficiency, inguinal hernia, and a 2.7-Mb cryptic deletion. The overlapping genes in the deletion regions of the 2 patients were the DGCR5, DGCR6, and PRODH genes. Conclusion: DGCR6 alters the expression of important genes such as TBX1 and affects neural crest migration. Given that ARM are caused by abnormalities in neural crest cell migration, it may be that these genes play a role in the etiology. To our knowledge, this is one of the smallest interstitial deletions in the chromosome 22q11.2 region to be published to date. Further research on the DGCR6 gene, which may be a candidate gene responsible for anal atresia, will clarify this point. [ABSTRACT FROM AUTHOR]

COVID-19 manifestations range from asymptomatic to life-threatening infections. The outcome in different inborn errors of immunity (IEI) is still a matter of debate. In this retrospective study, we describe the experience of the of the Italian Primary Immunodeficiencies Network (IPINet). Sixteen reference centers for adult or pediatric IEI were involved. One hundred fourteen patients were enrolled including 35 pediatric and 79 adult patients. Median age was 32 years, and male-to-female ratio was 1.5:1. The most common IEI were 22q11.2 deletion syndrome in children (26%) and common variable immunodeficiency (CVID) in adults (65%). Ninety-one patients did not require hospital admission, and among these, 33 were asymptomatic. Hospitalization rate was 20.17%. Older age (p 0.004) and chronic lung disease (p 0.0008) represented risk factors for hospitalization. Hospitalized patients mainly included adults suffering from humoral immunodeficiencies requiring immunoglobulin replacement therapy and as expected had lower B cell counts compared to non-hospitalized patients. Infection fatality rate in the whole cohort was 3.5%. Seroconversion was observed is 86.6% of the patients evaluated and in 83.3% of CVID patients. 16.85% of the patients reported long-lasting COVID symptoms. All but one patient with prolonged symptoms were under IgRT. The fatality rate observed in IEI was slightly similar to the general population. The age of the patients who did not survive was lower compared to the general population, and the age stratified mortality in the 50–60 age range considerable exceeded the mortality from 50 to 60 age group of the Italian population (14.3 vs 0.6%; p < 0.0001). We hypothesize that this is due to the fact that comorbidities in IEI patients are very common and usually appear early in life. [ABSTRACT FROM AUTHOR]

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The patient with DiGeorge's anomaly (deletion 22q11.2) was diagnosed at a later age, with the initial presentation immediately after birth with infection. Since early childhood, the patient often suffers from various respiratory and viral infections that require medical assistance. The clinical picture of DiGeorge's anomaly is incomplete and includes: thymic hypoplasia affecting cellular immunity (changes in T cells), facial dysmorphism, hypertelorism, high palate, and foot deformities. The deletion -- 22q11.2 was confirmed by genetic testing. Follow-up of the patient's mental state reveals that the patient's expressive and receptive speech disorders are leading, with subsequent disorders in the development of student skills (arithmetic skills and reading) and difficulties in adaptation. The results of the mental status follow-up reveal a transition from verbal to dominant non-verbal impairments. The patient is directed to the specialized help, including a speech therapist, a psychologist and a special educational needs teacher, starting from kindergarten and continuing in the initial stages of education. The mental status of the patient needs to be monitored by a child psychiatrist and then by a psychiatrist, in view of the significant frequency of mental disorders associated with this deletion. Tracking the dynamics in mental status reveals that this patient is at high risk for the development of emotional and behavioral disorders. [ABSTRACT FROM AUTHOR]

Objective: Congenital defects/diseases Background: Long arm (q) deletion syndrome of chromosome 18 is a congenital chromosomal disorder. The specialist dental management of patients with 18q deletion is a challenge, as these individuals fall into the category of patients with special needs. The aim of this work was to describe the surgical and dental management in hospital of a patient with long arm deletion syndrome of chromosome 18 (18q). Case Report: An 8-year-old patient with deletion syndrome of chromosome 18 (18q) was referred to the Department of Dentistry and Oral Surgery. The patient presented dental pain and difficult feeding. The examination of the oral cavity revealed a destructive carious lesion of the lower right second deciduous molar and the need to perform a frenectomy due to the short lingual frenulum, which limited the movements of the tongue. Given the complex management of the patient, it was necessary to carry out surgical procedures in the operating room. Frenectomies of the lower labial and lingual frenulum were carried out with the aid of an electric scalpel with an ultra-sharp microdissection needle. At 2-month follow-up, the patient presented with good extraction site healing and satisfactory lingual mobility, along with improvements of speech and feeding. Conclusions: Dental involvement in patients with deletion syndrome of the long arm of chromosome 18 is poorly documented in the literature. The hospital regimen appears to be the criterion standard for the management of the patient with long arm deletion syndrome of chromosome 18. [ABSTRACT FROM AUTHOR]

Deficit syndrome schizophrenia is a characteristic subtype defined by persistent negative symptoms and poor functional outcomes; however, the biological mechanisms underlying this specific subtype have not yet been elucidated in detail. The present magnetic resonance imaging study examined the prevalence of duplicated Heschl's gyrus (HG), a potential neurodevelopmental marker, in schizophrenia patients with (N = 38) and without (N = 37) the deficit syndrome. The prevalence of the HG duplication pattern bilaterally was higher in the whole schizophrenia group than in 59 matched healthy controls. Furthermore, the prevalence of right HG duplication was significantly higher in the deficit schizophrenia group than in the non-deficit schizophrenia group. The HG pattern in schizophrenia was not associated with clinical variables, including illness duration, medication, and symptom severity, while right HG duplication correlated with higher scores for Proxy for the Deficit Syndrome. The present results suggest that the prominent neurodevelopmental pathology associated with gyral formation of HG may contribute to enduring negative symptomatology in schizophrenia. [ABSTRACT FROM AUTHOR]

Stroke in infancy is a rare phenomenon but can lead to significant long-term disability. We present the story of a 6-month-old Old Order Amish infant with underlying Williams syndrome, a rare neurodevelopmental disorder caused by a microdeletion, encompassing the elastin gene that produces abnormalities in elastic fibers of the lungs and vessels. This infant presented with lethargy, irritability, and a new-onset generalized tonic-clonic seizure. Brain magnetic resonance imaging (MRI) was consistent with ischemic stroke in the supratentorial regions. MR angiogram demonstrated bilateral narrowing of the internal carotid arteries with "ivy sign," suggestive of Moyamoya. Moyamoya disease/syndrome is a cerebrovascular condition that is associated with progressive stenosis of the intracranial vessels and can cause ischemic stroke in young children. Targeted mutation analysis revealed a homozygous c.1411–2A > G splice site variant in the SAMHD1 gene, consistent with a diagnosis of Aicardi–Goutières syndrome type 5 (AGS5), an autosomal recessive condition with multisystem involvement. In our unique case of infantile stroke with Moyamoya syndrome and dual diagnosis of Williams syndrome and AGS5, both diagnoses likely contributed to the cerebrovascular pathology. This case report highlights the importance of suspecting and testing for multiple genetic abnormalities in children presenting with Moyamoya-related stroke. [ABSTRACT FROM AUTHOR]

Objective: Metabolic syndrome is a health-threatening condition suffered by approximately one third of schizophrenia patients and largely attributed to antipsychotic medication. Previous evidence reports a common genetic background of psychotic and metabolic disorders. In this study, we aimed to assess the role of polygenic risk scores (PRSs) on the progression of the metabolic profile in a first-episode psychosis (FEP) cohort.Method: Of the 231 FEP individuals included in the study, 192-220 participants were included in basal analysis and 118-179 in longitudinal 6-month models. Eleven psychopathologic and metabolic PRSs were constructed. Basal and longitudinal PRSs association with metabolic measurements was assessed by statistical analyses.Results: No major association of psychopathological PRSs with the metabolic progression was found. However, high risk individuals for depression and cholesterol-related PRSs reported a higher increase of cholesterol levels during the follow-up (FDR ≤ 0.023 for all analyses). Their effect was comparable to other well-established pharmacological and environmental risk factors (explaining at least 1.2% of total variance).Conclusion: Our findings provide new evidence of the effects of metabolic genetic risk on the development of metabolic dysregulation. The future establishment of genetic profiling tools in clinical procedures could enable practitioners to better personalize antipsychotic treatment selection and dosage. [ABSTRACT FROM AUTHOR]

Purpose: The study aimed to clarify the cognitive impairments of schizophrenia with metabolic syndrome while evaluating their potential as risk factors. Patients and Methods: We recruited 153 participants and divided them into three groups according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria and the guideline standards for the prevention and treatment of dyslipidemia in Chinese adults in 2007 for metabolic syndrome, as follows: healthy control group (n = 47); nonmetabolic syndrome group (n = 58); and metabolic syndrome group (n = 48). Psychotic symptoms were evaluated using the Positive and Negative Syndrome Scale. Cognitive function and automatic thinking were estimated using the Montreal Cognitive Assessment Scale, Verbal Fluency Test, and Automatic Thoughts Questionnaire. Serum biochemical parameters were measured by automatic biochemistry analyzer. Results: One-way ANOVA analysis revealed that differential cognition impairments in schizophrenia patients compared to controls. Furthermore, results of multiple comparisons showed that more serious barriers in orientation, language fluency, and negative automatic thinking existed in the metabolic syndrome group than in the healthy and non-metabolic syndrome groups. Spearman correlation and stepwise linear regression analyses showed that psychopathological symptoms, high waist circumference, and high triglyceride were the predictive factors for negative automatic thoughts, orientation, and language fluency. Those results collectively revealed that high waist circumference, high triglyceride and negative automatic thinking had validity and effectiveness in predicting the cognitive function impairments of the metabolic syndrome group. Conclusion: The present findings strongly supported the notion that aberrant parameters of high waist circumference, high triglyceride and high negative automatic thoughts had validity and effectiveness predictive role for cognitive impairments in the schizophrenics with metabolic syndrome. The schizophrenia patients with metabolic syndrome should receive regular monitoring and adequate treatment for metabolic and psychological risk factors. [ABSTRACT FROM AUTHOR]

Congenital heart diseases represent one of the hallmarks of 22q11.2 deletion syndrome. In particular, conotruncal heart defects are the most frequent cardiac malformations and are often associated with other specific additional cardiovascular anomalies. These findings, together with extracardiac manifestations, may affect perioperative management and influence clinical and surgical outcome. Over the past decades, advances in genetic and clinical diagnosis and surgical treatment have led to increased survival of these patients and to progressive improvements in postoperative outcome. Several studies have investigated long-term follow-up and results of cardiac surgery in this syndrome. The aim of our review is to examine the current literature data regarding cardiac outcome and surgical prognosis of patients with 22q11.2 deletion syndrome. We thoroughly evaluate the most frequent conotruncal heart defects associated with this syndrome, such as tetralogy of Fallot, pulmonary atresia with major aortopulmonary collateral arteries, aortic arch interruption, and truncus arteriosus, highlighting the impact of genetic aspects, comorbidities, and anatomical features on cardiac surgical treatment. [ABSTRACT FROM AUTHOR]

ObjectiveChromosome 22q11.2 deletion syndrome (22q11.2DS) is associated with a more than 20-fold increased risk for developing schizophrenia. The aim of this study was to identify additional genetic factors (i.e., "second hits") that may contribute to schizophrenia expression.MethodThrough an international consortium, the authors obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), the authors compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: a schizophrenia group and those with no psychotic disorder at age ≥25 years. The authors assessed whether genes overlapped by rare CNVs were overrepresented in functional pathways relevant to schizophrenia.ResultsRare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a stepwise logistic regression model and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had, on average, more genes overlapped. The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci.ConclusionsThe results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.

Reciprocal chromosomal rearrangements at the 22q11.2 locus are associated with elevated risk of neurodevelopmental disorders. The 22q11.2 deletion confers the highest known genetic risk for schizophrenia, but a duplication in the same region is strongly associated with autism and is less common in schizophrenia cases than in the general population. Here we conducted the first study of 22q11.2 gene dosage effects on brain structure in a sample of 143 human subjects: 66 with 22q11.2 deletions (22q-del; 32 males), 21 with 22q11.2 duplications (22q-dup; 14 males), and 56 age- and sex-matched controls (31 males). 22q11.2 gene dosage varied positively with intracranial volume, gray and white matter volume, and cortical surface area (deletion < control < duplication). In contrast, gene dosage varied negatively with mean cortical thickness (deletion > control > duplication). Widespread differences were observed for cortical surface area with more localized effects on cortical thickness. These diametric patterns extended into subcortical regions: 22q-dup carriers had a significantly larger right hippocampus, on average, but lower right caudate and corpus callosum volume, relative to 22q-del carriers. Novel subcortical shape analysis revealed greater radial distance (thickness) of the right amygdala and left thalamus, and localized increases and decreases in subregions of the caudate, putamen, and hippocampus in 22q-dup relative to 22q-del carriers. This study provides the first evidence that 22q11.2 is a genomic region associated with gene-dose-dependent brain phenotypes. Pervasive effects on cortical surface area imply that this copy number variant affects brain structure early in the course of development.SIGNIFICANCE STATEMENT Probing naturally occurring reciprocal copy number variation in the genome may help us understand mechanisms underlying deviations from typical brain and cognitive development. The 22q11.2 genomic region is particularly susceptible to chromosomal rearrangements and contains many genes crucial for neuronal development and migration. Not surprisingly, reciprocal genomic imbalances at this locus confer some of the highest known genetic risks for developmental neuropsychiatric disorders. Here we provide the first evidence that brain morphology differs meaningfully as a function of reciprocal genomic variation at the 22q11.2 locus. Cortical thickness and surface area were affected in opposite directions with more widespread effects of gene dosage on cortical surface area.

Increasing evidence shows that risk preference is associated with schizophrenia. However, the causality and direction of this association are not clear; Therefore, we used Mendelian randomization (MR) to examine the potential bidirectional relationship between risk preference and schizophrenia. Genome-wide association studies (GWAS) summary data on risk preference of 939,908 participants from the UK Biobank and 23andMe were used to identify general risk preference. Data from 320,404 subjects (76,755 cases and 243,649 controls) from The Psychiatric Genomics Consortium were used to identify schizophrenia. The weighted median (WM), the inverse variance weighted (IVW), and the Mendelian randomization-Egger (MR-Egger) methods were used for the MR analysis to estimate the causal effect and detect the directional pleiotropy. The GWAS summary data were respectively from two combined samples, containing 939,908 and 320,404 subjects of European ancestry. Mendelian randomization evidence suggested that risk preference was associated with increased onset of schizophrenia (OR = 2.84, 95CI%: 1.77–4.56, P = 1.58*10 − 5) and that schizophrenia was also associated with raised risk preference (OR = 1.11, 95CI%: 1.07–1.15, P = 7.98*10 − 8). With the use of large-scale GWAS data, robust evidence suggests an interaction between risk preference and schizophrenia. This also indicates that early identification of and intervention for increased risk preference may improve the prognosis of schizophrenia. [ABSTRACT FROM AUTHOR]

Close Homolog of L1 (CHL1) is a member of the L1 family of cell adhesion molecules. CHL1 gene is located on human chromosome 3 and has been linked to several pathologies, including 3p deletion syndrome, schizophrenia, and tumor growth and metastasis. The goal of the present study was to determine which region of the CHL1 promoter is most competent in driving CHL1 gene expression. Methods: Five candidate DNA fragments in the promoter regions were selected by screening across six species for evolutionary conserved sequences. The activity of these five promoter regions was quantitatively evaluated using a GFP reporter gene in transfection experiments, performed in C6 glioma cells. Of the five promoter regions tested, three drove reporter GFP expression, with the conserved region 6 (CR6, Gene ID AC066595.5, 25851-26850) being the most active for transcription. The identification of the CR6 activity provides a better understanding of the regulatory mechanisms underlying CHL1 expression. It may help future discovery of therapeutic strategies that involve influencing critical promoter regions to drive transcriptional regulation of the mammalian CHL1 gene. Conserved regions of CHL1 promoter sequences were identified by in-silico analysis. Five conserved regions were tested for gene regulatory activity using a reporter assay. Conserved regions CR5, CR6 and CR7 show gene regulatory function in a reporter assay. Co-transfection of CR5 and CR6 yielded the highest reporter activity. The core region of CR6 (CR6core) was identified as a cis-acting element. In-tandem promoter CR5core-CR6core was the best in a reporter assay. [ABSTRACT FROM AUTHOR]

Aims: To define the peculiar features of patients with the deletion of the chromosome 20 long arm (del20q), data from 69 patients with myelodysplastic syndromes (MDSs) and isolated del20q, followed by the Gruppo Romano-Laziale Sindromi Mielodisplastiche (GROM-L) and Ospedale Torrette of Ancona, were collected and compared with those of 502 MDS patients with normal karyotype (NK-MDS). Results: Compared to the NK-MDS group, patients with del20q at diagnosis were older (p = 0.020) and mainly male (p = 0.006). They also had a higher rate of bone marrow blast < 5% (p = 0.004), a higher proportion of low and int-1 risk according to IPSS score (p = 0.023), and lower median platelet (PLT) count (p < 0.001). To date, in the del20q cohort, 21 patients (30.4%) received no treatment, 42 (61.0%) were treated with erythropoiesis-stimulating agents (ESA), 3 (4.3%) with hypomethylating agents, and 3 (4.3%) with other treatments. Among 34 patients evaluable for response to ESA, 21 (61.7%) achieved stable erythroid response according to IWG 2006 criteria and 13 (38.2%) were resistant. Nine patients (13.0%) progressed to acute myeloid leukaemia (AML) after a median time from diagnosis of 28 months (IR 4.1–51.7). The median overall survival (OS) of the entire cohort was 60.6 months (95% CI 54.7–66.4). the 5-year cumulative OS was 55.9% (95% CI 40.6–71.2). Conclusion: According to our results, we hypothesize that MDSs with isolated del 20q may represent a distinct biological entity, with peculiar clinical and prognostic features. The physio-pathological mechanisms underlying the deletion of the chromosome 20 long arm are still unclear and warrant future molecular analysis. [ABSTRACT FROM AUTHOR]

This review compares the main brain abnormalities in schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and 22q11.2 Deletion Syndrome (22q11DS) determined by ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) consortium investigations. We obtained ranked effect sizes for subcortical volumes, regional cortical thickness, cortical surface area, and diffusion tensor imaging abnormalities, comparing each of these disorders relative to healthy controls. In addition, the studies report on significant associations between brain imaging metrics and disorder‐related factors such as symptom severity and treatments. Visual comparison of effect size profiles shows that effect sizes are generally in the same direction and scale in severity with the disorders (in the order SZ > BD > MDD). The effect sizes for 22q11DS, a rare genetic syndrome that increases the risk for psychiatric disorders, appear to be much larger than for either of the complex psychiatric disorders. This is consistent with the idea of generally larger effects on the brain of rare compared to common genetic variants. Cortical thickness and surface area effect sizes for 22q11DS with psychosis compared to 22q11DS without psychosis are more similar to those of SZ and BD than those of MDD; a pattern not observed for subcortical brain structures and fractional anisotropy effect sizes. The observed similarities in effect size profiles for cortical measures across the psychiatric disorders mimic those observed for shared genetic variance between these disorders reported based on family and genetic studies and are consistent with shared genetic risk for SZ and BD and structural brain phenotypes. [ABSTRACT FROM AUTHOR]

Phelan-McDermid syndrome (PHMDS)/22q13.3 deletion syndrome is a rare genetic disorder associated with autism spectrum disorder (ASD), intellectual disability (ID), and bipolar disorder. While numerous cases have been reported describing successful pharmacological treatment of bipolar disorder in PHMDS, there is currently little guidance available on how to organize and execute such treatment. The aim of the current case study was to explore how pharmacological treatment of bipolar disorder in PHMDS may be organized and evaluated in an outpatient setting. Through a complex process of try and fail, including systematic evaluation of any change to the intervention and never implementing more than one change at the time, the patient gradually improved, regaining his communicative and adaptive skills. Four years passed from referral to this result was achieved. Organizing assessment and treatment as a collaborative effort involving specialized mental health professionals, professional caregivers and the patient's family proved feasible. Many of the challenges present in assessment of psychiatric disorder in individuals with ASD and ID are likely to be present also in evaluation of treatment effects, particularly in disorders where symptoms occur in phases. The approach described in the current paper may contribute to reducing the impact of these challenges. [ABSTRACT FROM AUTHOR]

Recent studies have shown higher rates of radicalization of adolescents than in the 2000s. Since 2015, radicalization prevention units have been implemented in child and adolescent psychiatry departments in France. We aimed to report on the psychopathology of adolescents who were followed up in a university department due to their "radical conduct." Based on the available clinical data (from child psychiatry consultations, long-term family and/or individual therapy, and psychological testing) for 20 adolescents with "radical conduct," we examined the nature of their radical conduct, their psychopathology, their family characteristics, and the existence or absence of traumatic experiences. Among the 20 adolescents, 4 had radical conduct associated with a delusional syndrome (schizophrenia or a psychotic episode after substance abuse). For the other 16, we found no psychotic conditions. The analysis of other data showed that the adolescents shared some characteristics, such as an important prevalence of intrafamilial violence, sexual abuse, imprisonment of family members, traumatic family histories, and significant psychological control or dependence phenomena occurring in divided families. This diversity of psychopathologies appears consistent with previous studies highlighting the relevance of diverse profiles depending on the presence of a delusional syndrome, the individual's gender and the individual's attraction to violence. Finally, we discuss some psychopathological hypotheses and make therapeutic recommendations. We believe that child and adolescent psychotherapy/psychiatry has a role to play in countering violent extremism by offering adolescents a way out of radical commitment. [ABSTRACT FROM AUTHOR]

The 22q11 deletion syndrome (DS) is the most common microdeletion syndrome in humans and gives a high probability of developing psychiatric disorders. Synaptic and neuronal malfunctions appear to be at the core of the symptoms presented by patients. In fact, it has long been suggested that the behavioural and cognitive impairments observed in 22q11DS are probably due to alterations in the mechanisms regulating synaptic function and plasticity. Often, synaptic changes are related to structural and functional changes observed in patients with cognitive dysfunctions, therefore suggesting that synaptic plasticity has a crucial role in the pathophysiology of the syndrome. Most interestingly, among the genes deleted in 22q11DS, six encode for mitochondrial proteins that, in mouse models, are highly expressed just after birth, when active synaptogenesis occurs, therefore indicating that mitochondrial processes are strictly related to synapse formation and maintenance of a correct synaptic signalling. Because correct synaptic functioning, not only requires correct neuronal function and metabolism, but also needs the active contribution of astrocytes, we summarize in this review recent studies showing the involvement of synaptic plasticity in the pathophysiology of 22q11DS and we discuss the relevance of mitochondria in these processes and the possible involvement of astrocytes. [ABSTRACT FROM AUTHOR]

The 22q11.2 deletion is associated with >20-fold increased risk for schizophrenia. The presence of gene DGCR8 in the 22q11.2 deletion region has suggested microRNA (miRNA) dysregulation as possibly contributing to this risk. We therefore investigated the role of miRNA target genes in the context of previously identified genome-wide risk for schizophrenia conveyed by additional copy number variation (CNV) in 22q11.2 deletion syndrome (22q11.2DS). Using a cohort of individuals with 22q11.2DS and documented additional rare CNVs overlapping protein coding genes, we compared those with schizophrenia (n = 100) to those with no psychotic illness (n = 118), assessing for rare CNVs that overlapped experimentally supported miRNA target genes. We further characterized the contributing miRNA target genes using gene set enrichment analyses and identified the miRNAs most implicated. Consistent with our hypothesis, we found a significantly higher proportion of individuals in the schizophrenia than in the non-psychotic group to have an additional rare CNV that overlapped one or more miRNA target genes (odds ratio = 2.12, p = 0.0138). Gene set analyses identified an enrichment of FMRP targets and genes involved in nervous system development and postsynaptic density amongst these miRNA target genes in the schizophrenia group. The miRNAs most implicated included miR-17-5p, miR-34a-5p and miR-124-3p. These results provide initial correlational evidence in support of a possible role for miRNA perturbation involving genes affected by rare genome-wide CNVs in the elevated risk for schizophrenia in 22q11.2DS, consistent with the multi-hit and multi-layered genetic mechanisms implicated in this and other forms of schizophrenia. [ABSTRACT FROM AUTHOR]

Sigma-1 receptor (Sig-1R) is a protein present in several organs such as brain, lung, and heart. In a cell, Sig-1R is mainly located across the membranes of the endoplasmic reticulum and more specifically at the mitochondria-associated membranes. Despite numerous studies showing that Sig-1R could be targeted to rescue several cellular mechanisms in different pathological conditions, less is known about its fundamental relevance. In this review, we report results from various studies and focus on the importance of Sig-1R in physiological conditions by comparing Sig-1R KO mice to wild-type mice in order to investigate the fundamental functions of Sig-1R. We note that the Sig-1R deletion induces cognitive, psychiatric, and motor dysfunctions, but also alters metabolism of heart. Finally, taken together, observations from different experiments demonstrate that those dysfunctions are correlated to poor regulation of ER and mitochondria metabolism altered by stress, which could occur with aging. [ABSTRACT FROM AUTHOR]

We report a female infant with complete DiGeorge syndrome who has craniofacial and skeletal abnormalities, feeding problems, cardiac defect, hypocalcemia induced seizure, thymic aplasia, and severe combined immune deficiency. Her mother also had a partial type of disease and was diagnosed at the same time with her baby. FISH analysis of both mother and the infant revealed a deletion in 22q11.2. This family's findings indicate that 22q11 deletion syndrome is a genetic condition with wide interfamilial and intrafamilial variability in clinical expression. [ABSTRACT FROM AUTHOR]

Objective: Executive functions (EF) and focal attention have been identified as a weakness in the profile of 22q11.2 deletion syndrome (22q11DS). However, due to a high variety of tasks used across previous studies, it remains unclear whether impairments may be more pronounced for specific subdomains of EF and focal attention. Furthermore, age-related changes have only been examined in a few studies, so far only yielding a partial view of the overall developmental profile. Method: In a broad age range (8–35 years) composed of longitudinal data, 183 participants (103 diagnosed with 22q11DS) completed an extensive assessment of EF and attention. To get a more comprehensive overview of specific versus global impairments, several tasks were assessed within multiple domains. Results: Results suggest differential impairments and trajectories in specific EF subdomains. Specifically, our findings suggest that individuals with 22q11DS not only showed lower overall inhibition skills, but also that initiation skills developed at a slower pace compared to healthy controls. Results are less clear regarding cognitive flexibility, updating and focal attention, for which performance strongly depended on the tasks that was selected to assess the domain. Conclusions: Findings confirm and extend knowledge on differential developmental patterns of EF and attention domains in 22q11DS. They further stress the necessity to administer extensive, multifaceted evaluations to gain a more reliable overview of patients' cognitive profile. [ABSTRACT FROM AUTHOR]

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a primary immunodeficiency characterized by a broad and heterogeneous clinical presentation associated with various degrees of T-cell deficiency. We report the clinical, immunologic, and genetic findings of a cohort of eight patients presenting with a clinical phenotype that is highly suggestive of this syndrome but without the 22q11.2 deletion. The cardinal features of 22q11.2DS, such as congenital heart defects, hypoparathyroidism, and facial dysmorphisms, were observed in the majority of the patient cohort. The unusual features are described in detail. The immunologic assessment showed various degrees of immunodeficiency of the T-cell compartment, notably a reduction in the thymic output. Half of the patient cohort exhibited a reduction in total dendritic cells. Array comparative genomic hybridization (CGH) revealed six patients harboring copy number variations (CNVs) never reported in normal subjects. The gene content of these CNVs was carefully analyzed to understand the mechanisms leading to 22q11.2DS phenocopies. According to these results, we suggested that array-CGH should be used as a first-tier tool for patients resembling 22q11.2DS. [ABSTRACT FROM AUTHOR]

22q11.2-deletion syndrome is a genetic disorder caused by a small deletion of chromosome 22. This deletion often results in developmental delays, learning disabilities, medical conditions, and comorbid psychiatric conditions. Patients with 22q11.2DS may present with a variety of behavioral phenotypes including obsessiveness and rigidity, poor social skills, and anxiety. In some cases, the phenotype can consist of destructive and inappropriate behavior including harming self and others. Behavioral difficulties are reported as one of the most challenging aspects of 22q11.2-deletion syndrome for families of patients, however, few studies have examined behavioral interventions as a possible therapeutic treatment for this population. Using principles derived from operant-behavioral psychology, we conducted functional assessments to determine the environmental correlates of destructive and inappropriate behaviors in two adult men with 22q11.2-deletion syndrome. Subsequently, behavioral interventions based on differential reinforcement were incorporated into each participant's natural environment to eliminate these behaviors. Significant reductions in destructive and inappropriate behavior were observed with both participants and therapeutic gains were maintained at follow-up. We discuss the role of behavioral interventions in combination with appropriate psychotropic medication when addressing challenging behaviors in this population. [ABSTRACT FROM AUTHOR]

Background: The world has suffered immeasurably during the COVID‐19 pandemic. Increased distress and mental and medical health concerns are collateral consequences to the disease itself. The Genes to Mental Health (G2MH) Network consortium sought to understand how individuals affected by the rare copy number variations of 22q11.2 deletion and duplication syndrome, associated with neurodevelopmental/neuropsychiatric conditions, were coping. The article focuses on worry and disruptions in medical care caused by the pandemic. Methods: The University of Pennsylvania COVID‐19 Stressor List and care disruption questions were circulated by 22 advocacy groups in English and 11 other languages. Results: A total of 512 people from 23 countries completed the survey; most were caregivers of affected individuals. Worry about family members acquiring COVID‐19 had the highest average endorsed worry, whilst currently having COVID‐19 had the lowest rated worry. Total COVID‐19 worries were higher in individuals completing the survey towards the end of the study (later pandemic wave); 36% (n = 186) of the sample reported a significant effect on health due to care interruption during the pandemic; 44% of individuals (n = 111) receiving care for their genetic syndrome in a hospital setting reported delaying appointments due to COVID‐19 fears; 12% (n = 59) of the sample reported disruptions to treatments; and of those reporting no current disruptions, 59% (n = 269) worried about future disruptions if the pandemic continued. Higher levels of care disruptions were related to higher COVID‐19 worries (Ps < 0.005). Minimal differences by respondent type or copy number variation type emerged. Conclusions: Widespread medical care disruptions and pandemic‐related worries were reported by individuals with 22q11.2 syndrome and their family members. Reported worries were broadly consistent with research results from prior reports in the general population. The long‐term effects of COVID‐19 worries, interruptions to care and hospital avoidance require further study. [ABSTRACT FROM AUTHOR]

Schizophrenia (SCZ) is known as a complicated mental disease with an unknown etiology. The microdeletion of 22q11.2 is the most potent genetic risk factor. Researchers are still trying to find which genes in the deletion region are linked to SCZ. MIR185, encoding microRNA (miR)-185, is present in the minimal 1.5 megabase deletion. Nonetheless, the miR-185 expression profile and its corresponding target genes in animal models and patients with 22q11.2 deletion syndrome (22q11.2DS) imply that more study is required about miR-185 and its corresponding downstream pathways within idiopathic SCZ. The expression of hsa-miR-185-5p and its corresponding target gene, shisa family member 7 (SHISA7), sometimes called CKAMP59, were evaluated in the peripheral blood (PB) samples of Iranian Azeri patients with idiopathic SCZ and healthy subjects, matched by gender and age as control groups by quantitative polymerase chain reaction (qPCR). Fifty SCZ patients (male/female: 22/28, age (mean ± standard deviation (SD)): 35.9 ± 5.6) and 50 matched healthy controls (male/female: 23/27, age (mean ± SD): 34.7 ± 5.4) were enrolled. The expression of hsa-miR-185-5p in the PB samples from subjects with idiopathic SCZ was substantially lower than in that of control groups (posterior beta = -0.985, adjusted P-value < 0.0001). There was also a difference within the expression profile between female and male subgroups (posterior beta = -0.86, adjusted P-value = 0.046 and posterior beta = -1.015, adjusted P-value = 0.004, in turn). Nevertheless, no significant difference was present in the expression level of CKAMP59 between PB samples from patients and control groups (adjusted P-value > 0.999). The analysis of the receiver operating characteristic (ROC) curve suggested that hsa-miR-185-5p may correctly distinguish subjects with idiopathic SCZ from healthy people (the area under curve (AUC) value: 0.722). Furthermore, there was a strong positive correlation between the expression pattern of the abovementioned genes in patients with SCZ and healthy subjects (r = 0.870, P < 0.001 and r = 0.812, P < 0.001, respectively), indicating that this miR works as an enhancer. More research is needed to determine if the hsa-miR-185-5p has an enhancer activity. In summary, this is the first research to highlight the expression of the miR-185 and CKAMP59 genes in the PB from subjects with idiopathic SCZ. Our findings suggest that gene expression alterations mediated by miR-185 may play a role in the pathogenesis of idiopathic and 22q11.2DS SCZ. It is worth noting that, despite a substantial and clear relationship between CKAMP59 and hsa-miR-185-5p, indicating an interactive network, their involvement in the development of SCZ should be reconsidered based on the whole blood sample since the changed expression level of CKAMP59 was not significant. Further research with greater sample sizes and particular leukocyte subsets can greatly make these results stronger. [ABSTRACT FROM AUTHOR]

At present, the diagnosis of schizophrenia is based entirely on phenotype with no established biologically based examinations for either overall diagnosis or pathophysiologically based subdivision. Moreover, the borders between schizophrenia and other illnesses such as affective psychosis are ill-defined and may not correspond to underlying biological mechanisms. At present, neurochemical models provide the strongest basis for etiologically based subdivision. Dopaminergic models, which date back to the discovery of chlorpromazine in the 1950's, are particularly relevant for forms of psychotic illness characterized by high positive symptoms, low negative symptoms and neurocognitive dysfunction, and rapid treatment response. Glutamatergic models focusing on N-methyl-d-aspartate receptor (NMDAR) dysfunction may be particularly relevant to poor outcome forms of the disorder. Event-related potential (ERP) biomarkers such as mismatch negativity (MMN) may distinguish between subgroups and facilitate development of effective glutamatergic agents. Advances in glutamate-based biomarker development are discussed along with remaining barriers to effective treatment development. [ABSTRACT FROM AUTHOR]

Background: Population-based neonatal screening using T-cell receptor excision circles (TRECs) identifies infants with profound T lymphopenia, as seen in cases of severe combined immunodeficiency, and in a subgroup of infants with 22q11 deletion syndrome (22q11DS). Purpose: To investigate the long-term prognostic value of low levels of TRECs in newborns with 22q11DS. Methods: Subjects with 22q11DS and low TRECs at birth (22q11Low, N=10), matched subjects with 22q11DS and normal TRECs (22q11Normal, N=10), and matched healthy controls (HC, N=10) were identified. At follow-up (median age 16 years), clinical and immunological characterizations, covering lymphocyte subsets, immunoglobulins, TRECs, T-cell receptor repertoires, and relative telomere length (RTL) measurements were performed. Results: At follow-up, the 22q11Low group had lower numbers of naïve T-helper cells, naïve T-regulatory cells, naïve cytotoxic T cells, and persistently lower TRECs compared to healthy controls. Receptor repertoires showed skewed V-gene usage for naïve T-helper cells, whereas for naïve cytotoxic T cells, shorter RTL and a trend towards higher clonality were found. Multivariate discriminant analysis revealed a clear distinction between the three groups and a skewing towards Th17 differentiation of T-helper cells, particularly in the 22q11Low individuals. Perturbations of B-cell subsets were found in both the 22q11Low and 22q11Normal group compared to the HC group, with larger proportions of naïve B cells and lower levels of memory B cells, including switched memory B cells. Conclusions: This long-term follow-up study shows that 22q11Low individuals have persistent immunologic aberrations and increased risk for immune dysregulation, indicating the necessity of lifelong monitoring. Clinical Implications: This study elucidates the natural history of childhood immune function in newborns with 22q11DS and low TRECs, which may facilitate the development of programs for long-term monitoring and therapeutic choices. [ABSTRACT FROM AUTHOR]

Childhood T-cell acute lymphoblastic leukemia (T-ALL) still remains a therapeutic challenge due to relapses which are resistant to further treatment. l-asparaginase (ASNase) is a key therapy component in pediatric T-ALL and lower sensitivity of leukemia cells to this drug negatively influences overall treatment efficacy and outcome. PTEN protein deletion and/or activation of the PI3K/Akt signaling pathway leading to altered cell growth and metabolism are emerging as a common feature in T-ALL. We herein investigated the relationship amongst PTEN deletion, ASNase sensitivity and glucose metabolism in T-ALL cells. First, we found significant differences in the sensitivity to ASNase amongst T-ALL cell lines. While cell lines more sensitive to ASNase were PTEN wild type (WT) and had no detectable level of phosphorylated Akt (P-Akt), cell lines less sensitive to ASNase were PTEN-null with high P-Akt levels. Pharmacological inhibition of Akt in the PTEN-null cells rendered them more sensitive to ASNase and lowered their glycolytic function which then resembled PTEN WT cells. In primary T-ALL cells, although P-Akt level was not dependent exclusively on PTEN expression, their sensitivity to ASNase could also be increased by pharmacological inhibition of Akt. In summary, we highlight a promising therapeutic option for T-ALL patients with aberrant PTEN/PI3K/Akt signaling. [ABSTRACT FROM AUTHOR]