The emergence of psychotic experiences in the early adolescence of 22q11.2 Deletion Syndrome.
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ABSTRACT:
SUBMITTER: Chawner SJRA
PROVIDER: S-EPMC6331974 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Chromosome 22q11.2 deletion syndrome (22q11DS) confers 25% risk for psychosis and is an invaluable window for understanding the neurobiological substrate of psychosis risk. The Structured Interview for Prodromal Syndromes (SIPS) is well validated in nondeleted populations for detecting clinical risk but has only recently been applied to 22q11DS. We assessed the largest 22q11DS cohort to date and report on SIPS implementation and symptoms elicited.The SIPS, including its 19 subscales, was administered to 157 individuals with 22q11DS aged 8 to 25 years. Youth and caregiver interviews were conducted and rated separately, then compared for agreement. Implementation of the SIPS in 22q11DS was challenging because of the prevalence of developmental delay and comorbid conditions. However, by explaining questions and eliciting examples, we were able to help youths and caregivers understand and respond appropriately. Consensus ratings were formulated and analyzed with itemwise and factor analysis.Subthreshold symptoms were common, with 85% of individuals endorsing 1 or more. The most commonly rated items were ideational richness (47%) and trouble with focus and attention (44%). Factor analysis revealed a 3-factor solution with positive, negative, and disorganized components. Youth-caregiver comparisons suggested that youths report greater symptoms of perceptual abnormalities, suspiciousness, trouble with emotional expression, and bizarre thinking. Caregivers reported more impaired tolerance to normal stress, poor hygiene, and inattention.The SIPS was adapted for 22q11DS through comprehensive and semi-structured administration methods, yielding a high prevalence of subthreshold psychotic symptoms. The significance and predictive validity of these symptoms require future longitudinal analysis.
| S-EPMC4159384 | biostudies-literature
Project description:22q11.2 deletion syndrome (22q11DS) is a recurrent genetic mutation that is highly penetrant for psychosis. Behavioral research suggests that 22q11DS patients exhibit a characteristic neurocognitive phenotype that includes differential impairment in spatial working memory (WM). Notably, spatial WM has also been proposed as an endophenotype for idiopathic psychotic disorder, yet little is known about the neurobiological substrates of WM in 22q11DS. In order to investigate the neural systems engaged during spatial WM in 22q11DS patients, we collected functional magnetic resonance imaging (fMRI) data while 41 participants (16 22q11DS patients, 25 demographically matched controls) performed a spatial capacity WM task that included manipulations of delay length and load level. Relative to controls, 22q11DS patients showed reduced neural activation during task performance in the intraparietal sulcus (IPS) and superior frontal sulcus (SFS). In addition, the typical increases in neural activity within spatial WM-relevant regions with greater memory load were not observed in 22q11DS. We further investigated whether neural dysfunction during WM was associated with behavioral WM performance, assessed via the University of Maryland letter-number sequencing (LNS) task, and positive psychotic symptoms, assessed via the Structured Interview for Prodromal Syndromes (SIPS), in 22q11DS patients. WM load activity within IPS and SFS was positively correlated with LNS task performance; moreover, WM load activity within IPS was inversely correlated with the severity of unusual thought content and delusional ideas, indicating that decreased recruitment of working memory-associated neural circuitry is associated with more severe positive symptoms. These results suggest that 22q11DS patients show reduced neural recruitment of brain regions critical for spatial WM function, which may be related to characteristic behavioral manifestations of the disorder.
| S-EPMC3930118 | biostudies-literature
Project description:BackgroundPathways leading to psychosis in 22q11.2 deletion syndrome (22q11.2DS) have been the focus of intensive research during the last two decades. One of the common clinical risk factors for the evolution of psychosis in 22q11.2DS is the presence of positive and negative subthreshold psychotic symptoms. The gold standard for measuring subthreshold symptoms is the Structured Interview for Prodromal Syndromes (SIPS) and its accompanying Scale of Prodromal Symptoms (SOPS) ratings. Although the scale has been used by many centers studying 22q11.2DS, the inter-site reliability of the scale in this population has never been established.MethodsIn the present study, experienced clinical assessors from three large international centers studying 22q11.2DS independently rated video recordings of 18 adolescents and young adults with 22q11.2DS.ResultsThe intraclass correlations coefficients (ICCs) among three raters for the SOPS total scores, as well as for the positive, negative, and disorganization subscale scores, were good-to-excellent (ICCs range 0.73-0.93). The raters were also able to reliably determine the subjects' subthreshold syndrome status (ICC = 0.71). The reliability of individual items was good-to-excellent for all items, ranging from 0.61 for motor disturbances [G3] to 0.95 for bizarre thinking.ConclusionsOur results show that trained clinicians can reliably screen for subthreshold psychotic symptoms in individuals with 22q11.2DS. To increase assessment reliability, we suggest specific clarifications and simplifications to the standard SIPS interview for future studies.
| S-EPMC8204529 | biostudies-literature
Project description:Individuals with 22q11.2 Deletion Syndrome (22q11.2DS) are at substantially heightened risk for psychosis. Thus, prevention and early intervention strategies that target the antecedents of psychosis in this high-risk group are a clinical priority. Attention Deficit Hyperactivity Disorder (ADHD) is one the most prevalent psychiatric disorders in children with 22q11.2DS, particularly the inattentive subtype. The aim of this study was to test the hypothesis that ADHD inattention symptoms predict later psychotic symptoms and/or psychotic disorder in those with 22q11.2DS. 250 children and adolescents with 22q11.2DS without psychotic symptoms at baseline took part in a longitudinal study. Assessments were performed using well-validated structured diagnostic instruments at two time points (T1 (mean age?=?11.2, SD?=?3.1) and T2 (mean age?=?14.3, SD?=?3.6)). Inattention symptoms at T1 were associated with development of psychotic symptoms at T2 (OR:1.2, p?=?0.01) but weak associations were found with development of psychotic disorder (OR:1.2, p?=?0.15). ADHD diagnosis at T1 was strongly associated with development of psychotic symptoms at T2 (OR:4.5, p?<?0.001) and psychotic disorder (OR:5.9, p?=?0.02). Our findings that inattention symptoms and the diagnosis of ADHD are associated with subsequent psychotic outcomes in 22q11.2DS have important clinical implications. Future studies examining the effects of stimulant and other ADHD treatments on individuals with 22q11.2DS are warranted.
| S-EPMC6406019 | biostudies-literature
Project description:22q11.2 deletion syndrome (22qDS) is a genetic syndrome associated with a chromosome 22q11.2 deletion and variable phenotypic expression that commonly includes schizophrenia. Approximately 1% of patients with schizophrenia have 22qDS. The schizophrenia in 22qDS appears broadly similar to that found in the general population with respect to core signs and symptoms, treatment response, neurocognitive profile, and MRI brain anomalies. However, individuals with a 22qDS form of schizophrenia typically have distinguishable physical features, have a lower IQ, and may differ in auxiliary clinical features. IQ, length of 22q11.2 deletions, and COMT functional allele do not appear to be major risk factors for schizophrenia in 22qDS. Ascertainment biases and small sample sizes are limitations of most studies. Larger studies over the lifespan and continuing education about this underrecognized condition are needed. 22qDS-schizophrenia is an important genetic subtype and a valuable model of neurodevelopmental mechanisms involved in the pathogenesis of schizophrenia.
| S-EPMC3129332 | biostudies-other
Project description: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.
| S-EPMC7026075 | biostudies-literature
Project description:22q11.2 deletion syndrome (22q11DS) represents a homogeneous model of schizophrenia particularly suitable for the search of neural biomarkers of psychosis. Impairments in structural connectivity related to the presence of psychotic symptoms have been reported in patients with 22q11DS. However, the relationships between connectivity changes in patients with different symptomatic profiles are still largely unknown and warrant further investigations. In this study, we used structural connectivity to discriminate patients with 22q11DS with (N = 31) and without (N = 31) attenuated positive psychotic symptoms. Different structural connectivity measures were used, including the number of streamlines connecting pairs of brain regions, graph theoretical measures, and diffusion measures. We used univariate group comparisons as well as predictive multivariate approaches. The univariate comparison of connectivity measures between patients with or without attenuated positive psychotic symptoms did not give significant results. However, the multivariate prediction revealed that altered structural network architecture discriminates patient subtypes (accuracy = 67.7%). Among the regions contributing to the classification we found the anterior cingulate cortex, which is known to be associated to the presence of psychotic symptoms in patients with 22q11DS. Furthermore, a significant discrimination (accuracy = 64%) was obtained with fractional anisotropy and radial diffusivity in the left inferior longitudinal fasciculus and the right cingulate gyrus. Our results point to alterations in structural network architecture and white matter microstructure in patients with 22q11DS with attenuated positive symptoms, mainly involving connections of the limbic system. These alterations may therefore represent a potential biomarker for an increased risk of psychosis that should be further tested in longitudinal studies.
| S-EPMC5540832 | biostudies-other
Project description:The 22q11.2 deletion syndrome (22q11.2DS) is a congenital malformation and neuropsychiatric disorder caused by meiotic chromosome rearrangements. One of the goals of this review is to summarize the current state of basic research studies of 22q11.2DS. It highlights efforts to understand the mechanisms responsible for the 22q11.2 deletion that occurs in meiosis. This mechanism involves the four sets of low copy repeats (LCR22) that are dispersed in the 22q11.2 region and the deletion is mediated by nonallelic homologous recombination events. This review also highlights selected genes mapping to the 22q11.2 region that may contribute to the typical clinical findings associated with the disorder and explain that mutations in genes on the remaining allele can uncover rare recessive conditions. Another important aspect of 22q11.2DS is the existence of phenotypic heterogeneity. While some patients are mildly affected, others have severe medical, cognitive, and/or psychiatric challenges. Variability may be due in part to the presence of genetic modifiers. This review discusses current genome-wide efforts to identify such modifiers that could shed light on molecular pathways required for normal human development, cognition or behavior.
| S-EPMC6214629 | biostudies-literature
Project description:22q11.2 deletion syndrome (22q11.2 DS) is the most common microdeletion syndrome and is underdiagnosed in diverse populations. This syndrome has a variable phenotype and affects multiple systems, making early recognition imperative. In this study, individuals from diverse populations with 22q11.2 DS were evaluated clinically and by facial analysis technology. Clinical information from 106 individuals and images from 101 were collected from individuals with 22q11.2 DS from 11 countries; average age was 11.7 and 47% were male. Individuals were grouped into categories of African descent (African), Asian, and Latin American. We found that the phenotype of 22q11.2 DS varied across population groups. Only two findings, congenital heart disease and learning problems, were found in greater than 50% of participants. When comparing the clinical features of 22q11.2 DS in each population, the proportion of individuals within each clinical category was statistically different except for learning problems and ear anomalies (P < 0.05). However, when Africans were removed from analysis, six additional clinical features were found to be independent of ethnicity (P ≥ 0.05). Using facial analysis technology, we compared 156 Caucasians, Africans, Asians, and Latin American individuals with 22q11.2 DS with 156 age and gender matched controls and found that sensitivity and specificity were greater than 96% for all populations. In summary, we present the varied findings from global populations with 22q11.2 DS and demonstrate how facial analysis technology can assist clinicians in making accurate 22q11.2 DS diagnoses. This work will assist in earlier detection and in increasing recognition of 22q11.2 DS throughout the world.
| S-EPMC5363275 | biostudies-literature
Project description:Background22q11.2 deletion syndrome (22q11.2DS) is a multisystem condition associated with an increased risk of early-onset Parkinson's disease (PD).MethodsWe review the clinical, neuroimaging, and neuropathological observations, as well as diagnostic challenges, of PD in 22q11.2DS. We conducted a search of PubMed up until June 1, 2018 and personal files to identify relevant publications.Results22q11.2DS-associated PD is responsible for approximately 0.5% of early-onset PD. The hallmark motor symptoms and neuropathology of PD, and typical findings of reduced striatal dopamine transporter binding with molecular imaging, are present in 22q11.2DS-associated PD. Mean age at PD onset in 22q11.2DS is relatively young (∼40 years). Patients with 22q11.2DS-associated PD show a good response to levodopa.ConclusionsFurther recognition of 22q11.2DS and study of PD in people with 22q11.2DS could provide insights into the mechanisms that cause PD in the general population. 22q11.2DS may serve as an identifiable PD model to study prodromal PD and disease-modifying treatments.
| S-EPMC6335527 | biostudies-literature