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Objective: 22q11.2 Deletion Syndrome (22q11DS) results in physical, cognitive, and behavioral issues. Although it is the most common microdeletion syndrome, there remains a high prevalence of delayed diagnosis. Its heterogeneous phenotypic presentation lead to differing considerations for early diagnostic identification. If initial symptomatology includes behavioral and cognitive disturbance, it is likely for such individuals to be referred first for neuropsychological testing before genetic testing. This case will expand upon diagnostic identification of 22q11DS. Method: A 12-year-old, 5-years educated, white female was seen for tele-neuropsychological evaluation due to COVID-19 restrictions in December 2020. Patient's mother reported concern regarding sudden and worsening behavioral changes including hallucinations, unusual affects, odd beliefs, academic decline, illegible handwriting, attention and memory issues, and behavioral problems in school to the point of removal. Results: Overall performance on the Meyers Neuropsychological Battery was severely impaired. See uploaded image file for specific test findings. Speech, affect, and behavior were notable during examination. Diagnoses included schizophrenia (provisional) and specific learning disorder with reading impairment (historical). Immediate neurology consultation was recommended. Later EEG, brain MRI, and CSF were unremarkable. Acute metabolic etiology was ruled out. Subsequent genetic testing revealed 22q11DS. Conclusions: Diagnostic identification of 22q11DS and resulting access to care management heavily depends on initial symptom presentation. In this specific case, the COVID-19 lockdown created barrier to sufficient services. This case expands upon knowledge of the cognitive profile of 22q11DS and calls upon increased awareness. Targeted improvement of neurocognition potentially protects against cognitive decline related to psychotic symptoms, and thus neuropsychologists play a vital role in referral to such resources. [ABSTRACT FROM AUTHOR]

Schizophrenia is a chronic and disabling mental illness characterized by a disordered sense of self. Current theories suggest that deficiencies in the sense of control over one's actions (Sense of Agency, SoA) may underlie some of the symptoms of schizophrenia. However, it is not clear if agency deficits are a precursor or a result of psychosis. Here, we investigated full body agency using virtual reality in a cohort of 22q11 deletion syndrome participants with a genetic propensity for schizophrenia. In two experiments employing virtual reality, full body motion tracking, and online feedback, we investigated SoA in two separate domains. Our results show that participants with 22q11DS had a considerable deficit in monitoring their actions, compared to age-matched controls in both the temporal and spatial domain. This was coupled with a bias toward erroneous attribution of actions to the self. These results indicate that nonpsychotic 22q11DS participants have a domain general deficit in the conscious sensorimotor mechanisms underlying the bodily self. Our data reveal an abnormality in the SoA in a cohort with a genetic predisposition for schizophrenia, but without psychosis, providing evidence that deficits in delineation of the self may be a precursor rather than a result of the psychotic state. [ABSTRACT FROM AUTHOR]

The 22q11.2 deletion syndrome (22q11.2 DS), one of the highest genetic risk for the development of schizophrenia, offers a unique opportunity to understand neurobiological and functional changes preceding the onset of the psychotic illness. Reduced auditory mismatch negativity response (MMN) has been proposed as a promising index of abnormal sensory processing and brain pathology in schizophrenia. However, the link between the MMN response and its underlying cerebral mechanisms in 22q11.2 DS remains unexamined. We measured auditory-evoked potentials to frequency deviant stimuli with high-density electroencephalogram and volumetric estimates of cortical and thalamic auditory areas with structural T1-weighted magnetic resonance imaging in a sample of 130 individuals, 70 with 22q11.2 DS and 60 age-matched typically developing (TD) individuals. Compared to TD group, the 22q11.2 deletion carriers reveal reduced MMN response and significant changes in topographical maps and decreased gray matter volumes of cortical and subcortical auditory areas, however, without any correlations between MMN alteration and structural changes. Furthermore, exploratory research on the presence of hallucinations (H+\H−) reveals no change in MMN response in 22q11.2DS (H+ and H−) as compared to TD individuals. Nonetheless, we observe bilateral volume reduction of the superior temporal gyrus and left medial geniculate in 22q11.2DSH+ as compared to 22q11.2DSH− and TD participants. These results suggest that the mismatch response might be a promising neurophysiological marker of functional changes within the auditory pathways that might underlie elevated risk for the development of psychotic symptoms. [ABSTRACT FROM AUTHOR]

Nearly one-third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop a psychotic disorder during life, most of them by early adulthood. Importantly, a full-blown psychotic episode is usually preceded by subthreshold symptoms. In the current study, 760 participants (aged 6-55 years) with a confirmed hemizygous 22q11.2 microdeletion have been recruited through 10 medical sites world-wide, as part of an international research consortium. Of them, 692 were nonpsychotic and with complete measurement data. Subthreshold psychotic symptoms were assessed using the Structured Interview for Prodromal Syndromes (SIPS). Nearly one-third of participants met criteria for positive subthreshold psychotic symptoms (32.8%), less than 1% qualified for acute positive subthreshold symptoms, and almost a quarter met criteria for negative/disorganized subthreshold symptoms (21.7%). Adolescents and young adults (13-25 years) showed the highest rates of subthreshold psychotic symptoms. Additionally, higher rates of anxiety disorders and attention deficit/hyperactivity disorder (ADHD) were found among the study participants with subthreshold psychotic symptoms compared to those without. Full-scale IQ, verbal IQ, and global functioning (GAF) scores were negatively associated with participants' subthreshold psychotic symptoms. This study represents the most comprehensive analysis reported to date on subthreshold psychosis in 22q11.2DS. Novel findings include age-related changes in subthreshold psychotic symptoms and evidence that cognitive deficits are associated with subthreshold psychosis in this population. Future studies should longitudinally follow these symptoms to detect whether and how early identification and treatment of these manifestations can improve long-term outcomes in those that eventually develop a psychotic disorder. [ABSTRACT FROM AUTHOR]

The recurrent 22q11.2 deletion is a genetic risk factor for early-onset Parkinson's disease. Adults with the associated 22q11.2 deletion syndrome (22q11.2DS) may exhibit phenotypes that could help identify those at highest risk and reveal disease trajectories. We investigated clinical and neuroimaging features relevant to Parkinson's disease in 26 adults: 13 with 22q11.2DS at genetic risk of Parkinson's disease (mean age = 41.5 years, standard deviation = 9.7), 12 healthy age and sex-matched controls, and a 22q11.2DS patient with l-DOPA-responsive early-onset Parkinson's disease. Neuroimaging included transcranial sonography and positron emission tomography using 11C-dihydrotetrabenazine (11C-DTBZ), a radioligand that binds to the presynaptic vesicular monoamine transporter. The 22q11.2DS group without Parkinson's disease demonstrated significant motor and olfactory deficits relative to controls. Eight (61.5%) were clinically classified with parkinsonism. Transcranial sonography showed a significantly larger mean area of substantia nigra echogenicity in the 22q11.2DS risk group compared with controls (P = 0.03). The 22q11.2DS patient with Parkinson's disease showed the expected pattern of severely reduced striatal 11C-DTBZ binding. The 22q11.2DS group without Parkinson's disease however showed significantly elevated striatal 11C-DTBZ binding relative to controls (∼33%; P < 0.01). Results were similar within the 22q11.2DS group for those with (n = 7) and without (n = 6) psychotic illness. These findings suggest that manifestations of parkinsonism and/or evolution to Parkinson's disease in this genetic at-risk population may include a hyperdopaminergic mechanism. Adequately powered longitudinal studies and animal models are needed to evaluate the relevance of the observed clinical and imaging phenotypes to Parkinson's disease and other disorders that are more prevalent in 22q11.2DS, such as schizophrenia. [ABSTRACT FROM AUTHOR]

Background: The 22q11.2 deletion syndrome is a neurogenetic disorder that is associated with both physical anomalies and neurocognitive impairments. Deletion carriers have a greatly elevated risk of developing schizophrenia (SCZ); as such, it offers a compelling ‘high-penetrance’ model to explore the neuropathology of SCZ risk. Indeed, widespread structural alterations of both gray and white matter have been reported for 22q11.2 deletion carriers. Interestingly, there are also cases of duplications at the same gene locus. While less is known about the phenotype associated with 22q11.2 duplication, carriers also present physical and neurodevelopmental abnormalities, although they may have reduced risk of developing SCZ compared to the general population. The only study to date which looked at brain structure in duplication carriers found reciprocal effects of 22q11.2 deletion and duplication on cortical thickness and surface measurements. In the present study, we apply diffusion magnetic resonance imaging (MRI) to examine the white matter microstructure in both 22q11.2 deletion and duplication carriers. Methods: Multi-shell diffusion-weighted images were acquired on a 3 Tesla MRI scanner from 13 healthy control individuals (HC), 25 deletion carriers, and 18 22q11.2 duplication carriers. Images were preprocessed utilizing the Human Connectome Project (HCP) Minimal Preprocessing Pipeline v4.0.0. Free Water imaging was applied, which differentiates the diffusion signal into a free-water compartment and a tissue compartment. The output parameters are the free-water fractional volume (FW) and a free-water corrected diffusion tensor from which fractional anisotropy of the tissue (FAT) is calculated. We compared FAT and FW maps between 1) HC and 22q11.2 deletion carriers and 2) HC and 22q11.2 duplication carriers using Tract-Based Spatial Statistics (TBSS) and voxel-wise, non-parametric statistics (5000 permutations, threshold-free cluster enhancement, corrected for age and sex). Lastly, white matter clusters that displayed significant differences between 22q11.2 deletion or duplication and HC were extracted. We averaged FAT and FW values over these significant clusters for each individual and correlated with the scores of the Structured Interview for Prodromal Syndromes (SIPS). Results: 22q11.2 deletion carriers showed significant (p<0.05) FW reductions (72% of white matter skeleton) and FAT increase (8%) when compared to HC. In contrast, 22q11.2 duplication carriers displayed the opposite effect, with significant (p<0.05) widespread FW increase (51%) and FAT decrease (50%) when compared to HC. Both 22q11.2 deletion and duplication carriers scored higher on the SIPS than HC, with negative symptom score differences being the most pronounced (mean for HC= 1.36, mean for 22q11.2 duplication = 7.0, mean for 22q11.2 deletion =9.96, F=6.68, df=2, p<.003). FAT and FW were not associated with SIPS scores in 22q11.2 deletion syndrome. However, FAT was negatively correlated with the negative symptom score in 22q11.2 duplication carriers (Spearman rho=-.61, p<.009). Discussion: We observed opposing effects of gene-dosage on FAT and FW. While we did not see an association between WM measurements and psychotic symptoms in 22q11.2 deletion, there was an association of WM structure with negative symptoms in 22q11.2 duplication carriers. These findings highlight the importance of studying the influence of reciprocal chromosomal imbalance on white matter architecture. Ongoing longitudinal studies may help advance understanding of the role of microstructural white matter abnormalities in the emergence of neuropsychiatric symptoms. [ABSTRACT FROM AUTHOR]

Background: 22q11.2 deletion syndrome (22q11.2DS; also known as DiGeorge syndrome or velo-cardio-facial syndrome) is characterized by increased vulnerability for neuropsychiatric symptoms, with approximately 30% of the individuals with the deletion developing schizophrenia. Clinically, deficits in executive function have been noted in this population, but the underlying neural processes are not well understood. Methods: Using high-density electrophysiology (EEG), we investigated the neural dynamics of inhibition of a prepotent response (a critical component of executive function) in individuals with 22q11.2DS with and without psychotic symptoms. Twenty-seven individuals with 22q11.2DS (14–35 years old, 14 with at least one psychotic symptom) and 27 age-matched neurotypical controls participated in a go/no-go task while EEG was recorded. Analyses were focused on the P3 go/no-go response and error-related positivity (Pe). Results: Behaviorally, individuals with 22q11.2DS were slower and unable to inhibit prepotent responses as the controls, with significantly more false alarms. Atypical inhibitory processing was confirmed by significantly reduced P3 no-go responses in the 22q11.2DS group. Such reductions were particularly marked in those with psychotic symptomatology. Pe was likewise significantly decreased (regardless of the presence of psychotic symptoms), suggesting impaired ability to register errors (i.e., false alarms) in 22q11.2DS. Both Pe and P3 correlated with clinical measures of inhibition (DKEFS and CPT). Discussion: To our knowledge, this is the first study looking at electrophysiological measures of response inhibition in 22q11.2DS. P3 and Pe reductions, which have also been shown in schizophrenia, suggest diminished error registration and awareness in 22q11.2DS and, possibly, a consequent difficulty in adjusting response strategies. [ABSTRACT FROM AUTHOR]