The relationship between oxidative stress and psychotic disorders in 22q11.2 deletion syndrome.

BACKGROUND: 22q11.2 Deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans. This condition is associated with a wide range of symptoms including immune and neuropsychiatric disorders. Notably, psychotic disorders including schizophrenia have a prevalence of âˆ¼ 30%. A growing body of evidence indicates that neuroinflammation and oxidative stress (OS) play a role in the pathophysiology of schizophrenia. In this study, we aim to assess the interaction between 22q11.2DS, OS and schizophrenia. METHODS: Blood samples were collected from 125 participants (including individuals with 22q11.2DS [n = 73] and healthy controls [n = 52]) from two sites: Sheba Medical Center in Israel, and University Hospital Gasthuisberg in Belgium. Baseline OS levels were evaluated by measuring Myeloperoxidase (MPO) activity. A sub-sample of the Israeli sample (n = 50) was further analyzed to examine survival of Peripheral Blood Mononuclear Cells (PBMCs) following induction of OS using vitamin K3. RESULTS: The levels of MPO were significantly higher in all individuals with 22q11.2DS, compared to healthy controls (0.346 ± 0.256 vs. 0.252 ± 0.238, p =.004). In addition, when comparing to healthy controls, the PBMCs of individuals with 22q11.2DS were less resilient to induced OS, specifically the group diagnosed with psychotic disorder (0.233 ± 0.206 for the 22q11.2DS individuals with psychotic disorders, 0.678 ± 1.162 for the 22q11.2DS individuals without psychotic disorders, and 1.428 ± 1.359 for the healthy controls, p =.003, η2 = 0.207). CONCLUSIONS: Our results suggest that dysregulation of OS mechanisms may play a role in the pathophysiology of the 22q11.2DS phenotype. The 22q11.2DS individuals with psychotic disorders were more sensitive to induction of OS, but did not present significantly different levels of OS at baseline. These results may be due to the effect of antipsychotic treatment administered to this sup-group. By elucidating novel molecular pathways, early identification of biochemical risk markers for 22q11.2DS and psychotic disorders can be detected. This can ultimately pave the way to the design of early and more precise interventions of individuals with 22q11.2DS.

The 22q11 low copy repeats are characterized by unprecedented size and structural variability.

Low copy repeats (LCRs) are recognized as a significant source of genomic instability, driving genome variability and evolution. The Chromosome 22 LCRs (LCR22s) mediate nonallelic homologous recombination (NAHR) leading to the 22q11 deletion syndrome (22q11DS). However, LCR22s are among the most complex regions in the genome, and their structure remains unresolved. The difficulty in generating accurate maps of LCR22s has also hindered localization of the deletion end points in 22q11DS patients. Using fiber FISH and Bionano optical mapping, we assembled LCR22 alleles in 187 cell lines. Our analysis uncovered an unprecedented level of variation in LCR22s, including LCR22A alleles ranging in size from 250 to 2000 kb. Further, the incidence of various LCR22 alleles varied within different populations. Additionally, the analysis of LCR22s in 22q11DS patients and their parents enabled further refinement of the rearrangement site within LCR22A and -D, which flank the 22q11 deletion. The NAHR site was localized to a 160-kb paralog shared between the LCR22A and -D in seven 22q11DS patients. Thus, we present the most comprehensive map of LCR22 variation to date. This will greatly facilitate the investigation of the role of LCR variation as a driver of 22q11 rearrangements and the phenotypic variability among 22q11DS patients.

Resilience and quality of life in young adults with a 22q11.2 deletion syndrome: a patient's perspective.

In the transition period between adolescence and young adulthood, individuals with 22q11.2DS are at an increased risk of developing severe psychiatric disorders. Various studies have focused on detecting risk factors, but until now protective factors are still understudied in 22q11.2DS. The current case-control study focuses on the role of resilience and quality of life (QoL) in young adults with 22q11.2DS and behavioural problems, in comparison with persons with an intellectual disability (ID) without a known genetic disorder. Self-report (and caregiver report) standardized questionnaires were used. Predictive general linear models were constructed to compare the resilience and quality of life across both groups (22q11.2DS vs ID-group) and to analyse the association between personal characteristics in both groups. Young adults with a 22q11.2DS show less resilience compared with both the general population norms and young adults with ID. Only a subscale of resilience (Acceptance of self and life) contributes to the reported level of QoL. Reported health problems are not related to resilience, but have an important effect on QoL. Our results suggest different factors are underlying resilience and the relation with QoL in 22q11.2DS and ID in general. These factors deserve more research and are important to take into account in clinical practice.

Atypical chromosome 22q11.2 deletions are complex rearrangements and have different mechanistic origins.

The majority (99%) of individuals with 22q11.2 deletion syndrome (22q11.2DS) have a deletion that is caused by non-allelic homologous recombination between two of four low copy repeat clusters on chromosome 22q11.2 (LCR22s). However, in a small subset of patients, atypical deletions are observed with at least one deletion breakpoint within unique sequence between the LCR22s. The position of the chromosome breakpoints and the mechanisms driving those atypical deletions remain poorly studied. Our large-scale, whole genome sequencing study of >1500 subjects with 22q11.2DS identified six unrelated individuals with atypical deletions of different types. Using a combination of whole genome sequencing data and fiber-fluorescence in situ hybridization, we mapped the rearranged alleles in these subjects. In four of them, the distal breakpoints mapped within one of the LCR22s and we found that the deletions likely occurred by replication-based mechanisms. Interestingly, in two of them, an inversion probably preceded inter-chromosomal 'allelic' homologous recombination between differently oriented LCR22-D alleles. Inversion associated allelic homologous recombination (AHR) may well be a common mechanism driving (atypical) deletions on 22q11.2.

Stressed parents, happy parents. An assessment of parenting stress and family quality of life in families with a child with Phelan-McDermid syndrome.

BACKGROUND: Individuals with Phelan-McDermid syndrome (PMS) are characterised by phenotypical traits that can be experienced as challenging by their environment. This study assessed parenting stress and Family Quality of Life (FQOL) in parents of individuals with PMS and identified potential contributing variables. METHOD: Mothers (n = 14) and fathers (n = 13) of individuals with PMS (n = 14; 6 females, 8 males; age 2-37, M = 20, SD = 11.92) completed questionnaires on parenting stress, FQOL, adaptive behaviour and background characteristics. RESULTS: Mothers and fathers experienced high, similar and related levels of parenting stress and FQOL satisfaction. Parenting stress and FQOL satisfaction were inversely related. High and low ratings were retrieved for subscales measuring feelings of parental role restriction and emotional well-being, respectively. The adaptive skills of the individuals with PMS were related to fathers' parenting stress and FQOL satisfaction. CONCLUSIONS: Clinical practice is encouraged to be attentive to family dynamics and grasp opportunities to interact with these dynamics.

Nested Inversion Polymorphisms Predispose Chromosome 22q11.2 to Meiotic Rearrangements.

Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have been uncovered as of yet. Using fiber-FISH, we demonstrate that parents transmitting the de novo 3 Mb LCR22A-D 22q11.2 deletion, the reciprocal duplication, and the smaller 1.5 Mb LCR22A-B 22q11.2 deletion carry inversions of LCR22B-D or LCR22C-D. Hence, the inversions predispose chromosome 22q11.2 to meiotic rearrangements and increase the individual risk for transmitting rearrangements. Interestingly, the inversions are nested or flanking rather than coinciding with the deletion or duplication sizes. This finding raises the possibility that inversions are a prerequisite not only for 22q11.2 rearrangements but also for all NAHR-mediated genomic disorders.

Low prevalence of substance use in people with 22q11.2 deletion syndrome.

BACKGROUND: 22q11.2 deletion syndrome (22q11DS), one of the most common recurrent copy number variant disorders, is associated with dopaminergic abnormalities and increased risk for psychotic disorders. AIMS: Given the elevated prevalence of substance use and dopaminergic abnormalities in non-deleted patients with psychosis, we investigated the prevalence of substance use in 22q11DS, compared with that in non-deleted patients with psychosis and matched healthy controls. METHOD: This cross-sectional study involved 434 patients with 22q11DS, 265 non-deleted patients with psychosis and 134 healthy controls. Psychiatric diagnosis, full-scale IQ and COMT Val158Met genotype were determined in the 22q11DS group. Substance use data were collected according to the Composite International Diagnostic Interview. RESULTS: The prevalence of total substance use (36.9%) and substance use disorders (1.2%), and weekly amounts of alcohol and nicotine use, in patients with 22q11DS was significantly lower than in non-deleted patients with psychosis or controls. Compared with patients with 22q11DS, healthy controls were 20 times more likely to use substances in general (P < 0.001); results were also significant for alcohol and nicotine use separately. Within the 22q11DS group, there was no relationship between the prevalence of substance use and psychosis or COMT genotype. Male patients with 22q11DS were more likely to use substances than female patients with 22q11DS. CONCLUSIONS: The results suggest that patients with 22q11DS are at decreased risk for substance use and substance use disorders despite the increased risk of psychotic disorders. Further research into neurobiological and environmental factors involved in substance use in 22q11DS is necessary to elucidate the mechanisms involved. DECLARATION OF INTEREST: None.

A pilot study on immuno-psychiatry in the 22q11.2 deletion syndrome: A role for Th17 cells in psychosis?

BACKGROUND: A growing body of evidence supports a role for immune alterations in Schizophrenia Spectrum Disorders (SSD). A high prevalence (25-40%) of SSD has been found in patients with 22q11.2 deletion syndrome (22q11.2DS), which is known for T-cell deficits due to thymus hypoplasia. This study is the first to explore the association between the T-cell subsets and psychotic symptoms in adults with 22q11.2DS. METHODS: 34 individuals (aged 19-38 yrs.) with 22q11.2DS and 34 healthy age- and gender matched control individuals were included. FACS analysis of the blood samples was performed to define T-cell subsets. Ultra-high risk for psychosis or diagnosis of SSD was determined based on CAARMS interviews and DSM-5 criteria for SSD. Positive psychotic symptom severity was measured based on the PANSS positive symptoms subscale. RESULTS: A partial T-cell immune deficiency in 22q11.2DS patients was confirmed by significantly reduced percentages of circulating T and T-helper cells. Significantly higher percentages of inflammatory Th1, Th17, and memory T-helper cells were found in adults with 22q11.2DS. Most importantly an increased Th17 percentage was found in adults with psychotic symptoms as compared to non-psychotic adults with 22q11.2DS, and Th17 percentage were related to the presence of positive psychotic symptoms. CONCLUSIONS: Given the literature on the role of T cells and in particular of Th17 cells and IL-17 in hippocampus development, cognition and behavior, these results support the hypothesis for a role of Th17 cells in the development and/or regulation of psychotic symptoms in 22q11.2DS. This pilot study underlines the importance to further study the role of T-cell defects and of Th17 cells in the development of psychiatric symptoms. It also supports the possibility to use 22q11.2DS as a model to study T-cell involvement in the development of SSD.

High prevalence of fatigue in adults with a 22q11.2 deletion syndrome.

The 22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome with high phenotypic variability, including somatic disorders like congenital heart disease and psychiatric disorders such as schizophrenia, anxiety disorders, and mood disorders. Clinical observations suggest that many patients with 22q11.2DS suffer from severe fatigue. However, to the best of our knowledge, no previous study has investigated the potential association between 22q11.2DS and fatigue. Twenty-nine patients (mean age 26.8, 18-38 y) with 22q11.2DS completed the multidimensional fatigue inventory (MFI) measuring severity of fatigue. The results of the study group were compared with published population norms. In addition, cross-sectional associations between fatigue, depression (Beck Depression Inventory-BDI), and a quality of life questionnaire (WHO) in patients with 22q11.2 DS were examined. Subscales and total MFI scores were significantly higher in adults with 22q11.2DS. Approximately 80% of the study group had a total MFI score above the mean of the norms. A significant correlation between depressive symptoms and fatigue was found. Fatigue was also significantly associated with quality of life scores, specifically the general score, psychological health, and environment. This is the first report of high levels of fatigue in adults with the 22q11.2DS. Fatigue is a frequent complaint in this age group and should get the necessary attention given its association with quality of life and depression severity. Taking into account the multisystem nature of the 22q11.2DS, we recommend a systematic clinical examination to exclude underlying somatic or psychiatric causes of fatigue. © 2017 Wiley Periodicals, Inc.

Blood brain barrier permeability increases with age in individuals with 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.2DS) is characterised by high rates of psychotic disorders and immune abnormalities. Blood-brain barrier (BBB) permeability is known to be a risk factor for schizophrenia and immune aberrations. OBJECTIVE: To evaluate the relationship between psychosis and BBB permeability in this population. METHODS: We examined two biomarkers for BBB permeability, s100ß and neuron-specific enolase (NSE), in 22q11.2DS individuals with/without psychosis. The first cohort of this Israeli-Belgium study was comprised of 20 22q11.2DS adults (30.58 ± 9.42 years) afflicted with a psychotic disorder, another group of 69 non-psychotic 22q11.2DS adults (23.42 ± 8.36 years), and 58 healthy controls (26.39 ± 7.77 years). A second cohort was comprised of 18 non-psychotic 22q11.2DS Israeli children (5.83 ± 1.55 years) and 14 healthy controls (5.34 ± 1.43 years). NSE and s100ß serum levels were detected in all participants. RESULTS: Both factors were elevated in adults with 22q11.2DS compared to healthy controls, specifically in the non-psychotic sub-group. In contrast, there were no significant differences in their levels between the two groups of the paediatric cohort. CONCLUSIONS: Increased BBB permeability seems to be a trait of 22q11.2DS that evolves sometime in early adulthood. Our findings are in line with previous reports on non-syndromic schizophrenia, and suggest potential novel neural pathways to psychosis in 22q11.2DS.

Recent developments in Phelan-McDermid syndrome research: an update on cognitive development, communication and psychiatric disorders.

PURPOSE OF REVIEW: The purpose of this review is to summarize the literature on cognitive development, communication, behavioral or psychiatric aspects in Phelan-McDermid syndrome (PMS) and to discuss the clinical implications and recommendations of these summarized findings. RECENT FINDINGS: PMS is often associated with severe communication impairments, behavioral or psychiatric problems and regression. These challenges may adversely affect and impair the quality of life of the individual with PMS and his family. SUMMARY: Individuals with PMS experience intellectual disability, communication and behavioral/psychiatric challenges, such as catatonia, bipolar disorder and regression across the lifespan. Providing appropriate guidance and support to them and their families demands a better understanding of these challenges.

Cognitive deficits in childhood, adolescence and adulthood in 22q11.2 deletion syndrome and association with psychopathology.

22q11.2 Deletion Syndrome (22q11.2DS) is associated with high risk of psychiatric disorders and cognitive impairment. It remains unclear to what extent key cognitive skills are associated with psychopathology, and whether cognition is stable over time in 22q11.2DS. 236 children, adolescents and adults with 22q11.2DS and 106 typically developing controls were recruited from three sites across Europe. Measures of IQ, processing speed, sustained attention, spatial working memory and psychiatric assessments were completed. Cognitive performance in individuals was calculated relative to controls in different age groups (children (6-9 years), adolescents (10-17 years), adults (18+ years)). Individuals with 22q11.2DS exhibited cognitive impairment and higher rates of psychiatric disorders compared to typically developing controls. Presence of Autism Spectrum Disorder symptoms was associated with greater deficits in processing speed, sustained attention and working memory in adolescents but not children. Attention deficit hyperactivity disorder in children and adolescents and psychotic disorder in adulthood was associated with sustained attention impairment. Processing speed and working memory were more impaired in children and adults with 22q11.2DS respectively, whereas the deficit in sustained attention was present from childhood and remained static over developmental stages. Psychopathology was associated with cognitive profile of individuals with 22q11.2DS in an age-specific and domain-specific manner. Furthermore, magnitude of cognitive impairment differed by developmental stage in 22q11.2DS and the pattern differed by domain.

Typical features of Parkinson disease and diagnostic challenges with microdeletion 22q11.2.

OBJECTIVE: To delineate the natural history, diagnosis, and treatment response of Parkinson disease (PD) in individuals with 22q11.2 deletion syndrome (22q11.2DS), and to determine if these patients differ from those with idiopathic PD. METHODS: In this international observational study, we characterized the clinical and neuroimaging features of 45 individuals with 22q11.2DS and PD (mean follow-up 7.5 ± 4.1 years). RESULTS: 22q11.2DS PD had a typical male excess (32 male, 71.1%), presentation and progression of hallmark motor symptoms, reduced striatal dopamine transporter binding with molecular imaging, and initial positive response to levodopa (93.3%). Mean age at motor symptom onset was relatively young (39.5 ± 8.5 years); 71.4% of cases had early-onset PD (<45 years). Despite having a similar age at onset, the diagnosis of PD was delayed in patients with a history of antipsychotic treatment compared with antipsychotic-naive patients (median 5 vs 1 year, p = 0.001). Preexisting psychotic disorders (24.5%) and mood or anxiety disorders (31.1%) were common, as were early dystonia (19.4%) and a history of seizures (33.3%). CONCLUSIONS: Major clinical characteristics and response to standard treatments appear comparable in 22q11.2DS-associated PD to those in idiopathic PD, although the average age at onset is earlier. Importantly, treatment of preexisting psychotic illness may delay diagnosis of PD in 22q11.DS patients. An index of suspicion and vigilance for complex comorbidity may assist in identifying patients to prioritize for genetic testing.

Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome.

OBJECTIVE: Chromosome 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. METHOD: Through 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. RESULTS: Rare 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. CONCLUSIONS: The 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.

A catalog of hemizygous variation in 127 22q11 deletion patients.

The 22q11.2 deletion syndrome is the most common microdeletion disorder, with wide phenotypic variability. To investigate variation within the non-deleted allele we performed targeted resequencing of the 22q11.2 region for 127 patients, identifying multiple deletion sizes, including two deletions with atypical breakpoints. We cataloged ~12,000 hemizygous variant positions, of which 84% were previously annotated. Within the coding regions 95 non-synonymous variants, three stop gains, and two frameshift insertions were identified, some of which we speculate could contribute to atypical phenotypes. We also catalog tolerability of 22q11 gene mutations based on related autosomal recessive disorders in man, embryonic lethality in mice, cross-species conservation and observations that some genes harbor more or less variants than expected. This extensive catalog of hemizygous variants will serve as a blueprint for future experiments to correlate 22q11DS variation with phenotype.

3 generation pedigree with paternal transmission of the 22q11.2 deletion syndrome: Intrafamilial phenotypic variability.

In this case report, we present a paternal transmission of a classic 3 Mb 22q11.2 deletion syndrome (22q11.2 DS) in a 3 generation family. In this family a young girl, her father, her uncle and her grandfather were diagnosed with this disorder. All carriers showed phenotypic expression, there were no unaffected siblings in the second or third generation. Presenting symptoms in the patient in first generation (grandfather) were psoriatic arthritis, thrombocytopenia and a right aortic arch. There was no intellectual disability. The second generation uncle was known with a severe intellectual disability, mild facial characteristics, a septal defect and a clubfoot, whereas the second generation father had a tetralogy of Fallot, no intellectual disability and minimal facial characteristics. The third generation daughter had a moderate intellectual disability, hypernasal speech, triphalangeal thumb, severe speech and language development delay, pronounced facial characteristics and a diagnosis of ADHD. It was notable that the expression in the two brothers of the second generation gives two very different clinical phenotypes with a severe intellectual disability in the oldest brother. This report describes a pronounced clinical variability in a 3 generation familial 22q11.2 deletion with paternal transmission. We can assume that several mechanisms play an important role in the heterogeneity and part of the answer should be found in the genetic background underlying the 22q11.2 deletion. In addition in this family the neuropsychiatric phenotype and intellectual disability seem to be associated with a lower level of social and occupational functioning while a congenital heart disease does not. This clinical report illustrates that a detailed description of these patients can be very informative and still increase the knowledge on this heterogeneous syndrome. For the clinicians working with these patients it emphasizes the need for a multidisciplinary approach that takes into account the individual needs.