Neuropsychological profile and neuroimaging in patients with 22Q11.2 Deletion Syndrome: a review.

22q11.2 Deletion Syndrome is associated with cognitive, behavioural, and psychiatric problems and is known to affect brain structure. Recently, 22q11.2 Deletion Syndrome has been proposed as a disease model for a genetic subtype of schizophrenia. In this paper we discuss the currently available literature on neurocognitive functioning and brain anatomy in patients with 22q11.2 Deletion Syndrome, and how this contributes to our understanding of the neurobiology of schizophrenia. Research on cognitive functioning in 22q11.2 Deletion Syndrome patients suggests a specific cognitive profile with impairments on arithmetical, visuo-spatial, and executive tasks and relatively preserved language skills. Prominent findings of neuroimaging studies in 22q11.2 Deletion Syndrome patients are: reduction of overall brain volume, midline defects, structural alterations of cerebellum and frontal lobe, white matter abnormalities, and decreased grey matter volumes in parietal and temporal areas. We describe how brain abnormalities in patients with 22q11.2 Deletion Syndrome may contribute to the understanding of the clinical syndrome including cognitive impairments, psychotic symptoms, and social and communication problems.     

22q11.2 deletion syndrome: genetics, neuroanatomy and cognitive/behavioral features keywords.

This paper presents a conceptual review of the genetic underpinnings of 22q11.2 Deletion Syndrome. The neuroanatomical, neuropsychological, behavioral, and psychiatric phenotype associated with 22q11.2 Deletion Syndrome is also explored, including variables that are thought to affect symptom expression. The history of the deletion syndrome is described, and future directions for continued research are discussed.     

Effects of Comt Genotype on Behavioral Symptomatology in the 22q11.2 Deletion Syndrome

The 22q11.2 Deletion Syndrome (DiGeorge/velocardiofacial syndrome) is associated with elevated rates of psychosis, and is also characterized by severe attentional difficulties and executive dysfunction. Behavioral manifestations of this syndrome could result from haploinsufficiency of the catechol-O-methyltransferase (COMT) gene, located within the 22q11 region. The goal of the present study was to examine COMT genotype in relation to behavioral symptomatology in this syndrome. Val^158/108Met was genotyped in 38 patients (16 Met/-, 22 Val/-) with confirmed 22q11.2 deletions who had received the Child Behavior Checklist (CBCL) as part of a comprehensive evaluation. Results indicated that the Val genotype was associated with significantly greater internalizing and externalizing behavioral symptomatology in children with 22q11.2 deletions. Val allele status was associated with a greater-than-four-fold increase in risk for clinically significant behavior problems in children with this syndrome. These data are consistent with previous findings of increased psychopathology associated with the Val genotype in normal individuals and suggest that a functional genetic polymorphism in the 22q11 region may influence behavior in individuals with COMT haploinsufficiency.     

Selective and sustained attention in children with spina bifida myelomeningocele

This study examined memory functioning in children and adolescents with 22q11.2 Deletion Syndrome (DS; velocardiofacial syndrome). An overall verbal better than nonverbal memory pattern was evident on the Test of Memory and Learning (TOMAL), with children with 22q11.2 DS performing significantly below their siblings and children with low average IQ but similar to children with autism on facial memory. Children with 22q11 DS also performed significantly below their siblings on tests of verbal working memory. Children with autism performed significantly poorer than the siblings of children with 22q11.2 DS only on their recall of stories. Delayed recall was significantly poorer in children with 22q11.2 DS and children with autism, compared to sibling controls. Although there were no significant group differences on tests of multiple trial verbal or visual learning, a relative weakness was noted with multiple trial visual learning in children with 22q11.2 DS and their siblings, suggesting that an alternative or interactive factor other than the deletion may account for the relatively better verbal compared to nonverbal memory abilities. Deficits in facial memory in children with both 22q11.2 DS and autism suggest disruptions in ventral temporal pathways such as between fusiform gyrus and parahippocampal/hippocampal regions whereas deficits in verbal working memory in children with 22q11.2 DS implicates dorsolateral prefrontal regions, both intimating aberrant white matter pathways.     

The Motor Profile of Primary School-Age Children with a 22q11.2 Deletion Syndrome (22q11.2DS) and an Age- and IQ-Matched Control Group

In the early publications on the 22q11.2 Deletion Syndrome (22q11.2DS) motor abnormalities have been frequently reported. However, systematic studies on the motor performance of children with the 22q11.2DS, and especially of school-age children, are scarce. In this study the motor performance of primary school-age children with a 22q11.2DS (n = 28) was compared with an age- and IQ-matched control group (n = 28) using the Movement Assessment Battery for Children (MABC), the Körperkoordinationstest für Kinder (KTK) and the Beery-Buctenica test of Visual-Motor Integration (Beery). Children with a 22q11.2DS scored significantly lower than the age- and IQ-matched control group on the subsection Manual Dexterity (MABC) and the Visual Perception and Motor Coordination subtests of the Beery. When investigating the correlations between Intelligence quotient (IQ) and motor performance, a specific profile was found in the 22q11.2DS group when compared with the age- and IQ-matched control group. Because an IQ-matched control group was adopted, the deficits in visual-perceptual and visuomotor integration skills cannot fully be attributed to a general developmental delay and thus may be specific for the 22q11.2DS. Future studies that investigate the specificity of the visual-perceptual problems — both on the behavioral and brain level (functional Magnetic Resonance Imaging [fMRI] and Diffusion Tensor Imaging [DTI]) — are necessary to answer this question. Nonetheless, the importance of incorporating motor functioning into the study of the neuropsychological profile of children with a 22q11.2DS has to be stressed.     

Gender-Moderated Dorsolateral Prefrontal Reductions in 22q11.2 Deletion Syndrome: Implications for Risk for Schizophrenia

To investigate the impact of the microdeletion on morphology of the prefrontal cortex in 22q11.2 Deletion Syndrome (22q11.2 DS), high-resolution, anatomic magnetic resonance imaging was performed on 19 children and adolescents with 22q11.2 DS (11 females, 8 males) and 18 unaffected controls (10 females, 8 males). Tissue volumes of the dorsolateral, dorsomedial, orbitolateral, and orbitomedial prefrontal cortex were measured. Tasks of executive function and working memory were administered to investigate the association between anatomy and function. Whole brain volume and frontal lobe tissue volume were preserved in girls but reduced in boys with 22q11.2 DS relative to age-matched controls. Dorsolateral prefrontal cortex (DLPFC) volumes were reduced in participants with 22q11.2 DS, although the gender-by-diagnosis effect found for frontal lobe was not as robust for DLPFC. DLPFC volumes were associated with performance on tasks of planning and emotional facial recognition. Longitudinal studies are needed to clarify whether gender differences in frontal lobe and DLPFC persist with development, and whether the volumes of the DLPFC are associated with eventual deterioration in adaptive/psychosocial function that may presage the onset of schizophrenia, for which individuals with 22q11.2 DS are at a disproportionately high risk.     

Gender-moderated dorsolateral prefrontal reductions in 22q11.2 Deletion Syndrome: implications for risk for schizophrenia.

To investigate the impact of the microdeletion on morphology of the prefrontal cortex in 22q11.2 Deletion Syndrome (22q11.2 DS), high-resolution, anatomic magnetic resonance imaging was performed on 19 children and adolescents with 22q11.2 DS (11 females, 8 males) and 18 unaffected controls (10 females, 8 males). Tissue volumes of the dorsolateral, dorsomedial, orbitolateral, and orbitomedial prefrontal cortex were measured. Tasks of executive function and working memory were administered to investigate the association between anatomy and function. Whole brain volume and frontal lobe tissue volume were preserved in girls but reduced in boys with 22q11.2 DS relative to age-matched controls. Dorsolateral prefrontal cortex (DLPFC) volumes were reduced in participants with 22q11.2 DS, although the gender-by-diagnosis effect found for frontal lobe was not as robust for DLPFC. DLPFC volumes were associated with performance on tasks of planning and emotional facial recognition. Longitudinal studies are needed to clarify whether gender differences in frontal lobe and DLPFC persist with development, and whether the volumes of the DLPFC are associated with eventual deterioration in adaptive/psychosocial function that may presage the onset of schizophrenia, for which individuals with 22q11.2 DS are at a disproportionately high risk.     

Effects of COMT genotype on behavioral symptomatology in the 22q11.2 Deletion Syndrome.

The 22q11.2 Deletion Syndrome (DiGeorge/velocardiofacial syndrome) is associated with elevated rates of psychosis, and is also characterized by severe attentional difficulties and executive dysfunction. Behavioral manifestations of this syndrome could result from haploinsufficiency of the catechol-O-methyltransferase (COMT) gene, located within the 22q11 region. The goal of the present study was to examine COMT genotype in relation to behavioral symptomatology in this syndrome. Val158/108Met was genotyped in 38 patients (16 Met/-, 22 Val/-) with confirmed 22q11.2 deletions who had received the Child Behavior Checklist (CBCL) as part of a comprehensive evaluation. Results indicated that the Val genotype was associated with significantly greater internalizing and externalizing behavioral symptomatology in children with 22q11.2 deletions. Val allele status was associated with a greater-than-four-fold increase in risk for clinically significant behavior problems in children with this syndrome. These data are consistent with previous findings of increased psychopathology associated with the Val genotype in normal individuals and suggest that a functional genetic polymorphism in the 22q11 region may influence behavior in individuals with COMT haploinsufficiency.     

Memory and learning in children with 22q11.2 deletion syndrome: evidence for ventral and dorsal stream disruption?

This study examined memory functioning in children and adolescents with 22q11.2 Deletion Syndrome (DS; velocardiofacial syndrome). An overall verbal better than nonverbal memory pattern was evident on the Test of Memory and Learning (TOMAL), with children with 22q11.2 DS performing significantly below their siblings and children with low average IQ but similar to children with autism on facial memory. Children with 22q11 DS also performed significantly below their siblings on tests of verbal working memory. Children with autism performed significantly poorer than the siblings of children with 22q11.2 DS only on their recall of stories. Delayed recall was significantly poorer in children with 22q11.2 DS and children with autism, compared to sibling controls. Although there were no significant group differences on tests of multiple trial verbal or visual learning, a relative weakness was noted with multiple trial visual learning in children with 22q11.2 DS and their siblings, suggesting that an alternative or interactive factor other than the deletion may account for the relatively better verbal compared to nonverbal memory abilities. Deficits in facial memory in children with both 22q11.2 DS and autism suggest disruptions in ventral temporal pathways such as between fusiform gyrus and parahippocampal/hippocampal regions whereas deficits in verbal working memory in children with 22q11.2 DS implicates dorsolateral prefrontal regions, both intimating aberrant white matter pathways.     

22q11.2 Deletion Syndrome: Attitudes towards Disclosing the Risk of Psychiatric Illness

22q11.2 Deletion Syndrome (22q11.2DS) is a common microdeletion syndrome with multisystem features. There is a strong association with psychiatric disorders. One in every four to five patients develop schizophrenia. Despite studies showing that early diagnosis and treatment are likely to lead to improved outcome, genetic counselors may be reluctant to discuss the risk of psychiatric illness. The aim of this research was to explore parental attitudes and genetic counselors’ perspectives and practice regarding disclosure of the clinical manifestations of 22q11.2DS, particularly the risk of psychiatric illness. We delivered a questionnaire to genetic counselors via established list-serves, 54 of which were completed. We also conducted interviews with four parents of adults with 22q11.2DS and schizophrenia. The majority of counselors and parents felt that the increased risk to develop a psychiatric illness is important to disclose. However, in the initial counseling session when the diagnosis was made in infancy genetic counselors were significantly less likely to discuss the risk of psychiatric disorders compared to other later onset features such as hypothyroidism (41?% vs. 83?%, p?=?0.001). When the diagnosis of 22q11.2DS was made in infancy, counselors’ responses in regard to timing of disclosure about psychiatric illnesses were fairly evenly divided between infancy, childhood and adolescence. In contrast, for other major features of 22q11.2DS, disclosure would predominantly be in infancy. The respondents reported that the discussion of psychiatric issues with parents was challenging due to the stigma associated with mental illness. Some also noted limited knowledge about psychiatric illness and treatment. These results suggest that genetic counselors could benefit from further education regarding psychiatric illness in 22q11.2DS and best strategies for discussing this important subject with parents and patients.     

Atypical Neuropsychological Profile in a Boy with 22q11.2 Deletion Syndrome Keywords:

In this article the general and specific cognitive impairments of the boy R.H. with a de novo deletion 22q11.2 are described. His full-scale IQ was 73, and he obtained only slightly better verbal than non-verbal subtest scores. Neuropsychological assessment revealed specific impairments in perceptual categorization of objects presented suboptimal, matching of unfamiliar faces, and verbal learning and memory. In contrast, he performed in accordance with his intelligence level on other visual perceptual tasks, on non-verbal learning and memory tasks, and on attention tasks. Voxel-wise statistical comparison of a high-resolution T1-weighted magnetic resonance image of R.H’s brain with similar images obtained from 14 normal control children revealed as major abnormalities a reduction of the right inferior parietal and superior occipital lobe, and a bilateral reduction of deep white matter behind the inferior frontal gyrus. These cognitive impairments and MRI abnormalities are not commonly described in 22q11.2 Deletion Syndrome and may indicate a larger heterogeneity in the neurocognitive phenotype than currently evidenced. At least in this boy the microdeletion seems to have interfered with the development and functioning of particular neural subsystems, while the structure and functioning of other subsystems was left intact.     

Neuropsychological characteristics of children with the 22q11 Deletion Syndrome: a descriptive analysis.

Previous reports of cognitive functioning in children with the 22q11 Deletion Syndrome have reported marked variability in IQ and achievement subtest scores. Studies have begun to explore neuropsychological function in 22q11 DS however results are inconsistent and the profile incomplete. We assessed 40 children ages 5-12 with 22q11 DS. Consistent with past results, visual-spatial memory was significantly lower than verbal memory. Differentially lowered scores were found only in visual attention, working memory and motor function. Contrary with some past results quantitative, verbal ability, and visual spatial memory scores were within 1 SD from the standardization sample mean. Motor behavior, not typically discussed with regard to 22q11 DS school-age children, may be critical to incorporate in neurocognitive studies of children with 22q11 DS. Implications of these findings are considered with regard to past results.     

Social cognition and real-life functioning in patient samples with 22q11.2 deletion syndrome with or without psychosis,compared to a large sample of patients with schizophrenia only and healthy controls

Patients with the 22q11.2 deletion syndrome (DS) show an increased risk of developing a psychotic illness lifetime. 22q11.2DS may represent a reliable model for studying the neurobiological underpinnings of schizophrenia. The study of social inference abilities in a genetic condition at high risk for psychosis, like 22q11.2DS, may shed light on the relationships between neurocognitive processes and patients' daily general functioning. The study sample consisted of 1736 participants, divided into four groups: 22q11.2DS patients with diagnosis of psychotic disorder (DEL SCZ, N = 20); 22q11.2DS subjects with no diagnosis of psychosis (DEL, N = 43); patients diagnosed with schizophrenia without 22q11.2DS (SCZ, N = 893); and healthy controls (HC, N = 780). Social cognition was assessed through The Awareness of Social Inference Test (TASIT) and general functioning through the Specific Levels of Functioning (SLoF) scale. We analysed data through regression analysis. The SCZ and DEL groups had similar levels of global functioning; they both had significantly lower SLoF Total scores than HC (p < .001); the DEL SCZ group showed significantly lower scores compared to the other groups (SCZ, p = .004; DEL, p = .003; HC, p < .001). A significant deficit in social cognition was observed in the three clinical groups. In the DEL SCZ and SCZ groups, TASIT scores significantly predicted global functioning (p < .05). Our findings of social cognition deficit in psychosis-prone patients point to the possible future adoption of rehabilitation programmes, like Social Skills Training and Cognitive Remediation, during premorbid stages of psychosis.     

Maladaptive conflict monitoring as evidence for executive dysfunction in children with chromosome 22q11.2 deletion syndrome

Using an adaptation of the Attentional Networks Test, we investigated aspects of executive control in children with chromosome 22q11.2 deletion syndrome (DS22q11.2), a common but not well understood disorder that produces non-verbal cognitive deficits and a marked incidence of psychopathology. The data revealed that children with DS22q11.2 demonstrated greater difficulty than controls in locating and processing target items in the presence of distracters. Importantly, children with DS22q11.2 showed a deficit in the ability to monitor and adapt to stimulus conflict. These data provide evidence of inadequate conflict adaptation in children with DS22q11.2, a problem that is also present in schizophrenia. The findings of specific executive dysfunction in this group may provide a linkage between particular genetic abnormalities and the development of psychopathology.     

Domain specific attentional impairments in children with chromosome 22q11.2 deletion syndrome

One of the defining cognitive characteristics of the chromosome 22q deletion syndrome (DS22q11.2) is visuospatial processing impairments. The purpose of this study was to investigate and extend the specific attentional profile of children with this disorder using both an object-based attention task and an inhibition of return task. A group of children with the disorder was compared in these tasks with a group of age-matched typically developing children. The children with DS22q11.2 demonstrated impaired spatially based orienting which is consistent with previous findings in this group. Strikingly, the children with DS22q11.2 also demonstrated an improved ability to use object-based cues, relative to the typically developing group. Finally, the children with DS22q11.2 demonstrated an intact inhibition of return system, however, it appears to be delayed developmentally.     

Atypical neuropsychological profile in a boy with 22q11.2 Deletion Syndrome.

In this article the general and specific cognitive impairments of the boy R.H. with a de novo deletion 22q11.2 are described. His full-scale IQ was 73, and he obtained only slightly better verbal than non-verbal subtest scores. Neuropsychological assessment revealed specific impairments in perceptual categorization of objects presented suboptimal, matching of unfamiliar faces, and verbal learning and memory. In contrast, he performed in accordance with his intelligence level on other visual perceptual tasks, on non-verbal learning and memory tasks, and on attention tasks. Voxel-wise statistical comparison of a high-resolution T1-weighted magnetic resonance image of R.H's brain with similar images obtained from 14 normal control children revealed as major abnormalities a reduction of the right inferior parietal and superior occipital lobe, and a bilateral reduction of deep white matter behind the inferior frontal gyrus. These cognitive impairments and MRI abnormalities are not commonly described in 22q11.2 Deletion Syndrome and may indicate a larger heterogeneity in the neurocognitive phenotype than currently evidenced. At least in this boy the microdeletion seems to have interfered with the development and functioning of particular neural subsystems, while the structure and functioning of other subsystems was left intact.     

Communication of Psychiatric Risk in 22q11.2 Deletion Syndrome: A Pilot Project

Individuals with 22q11.2 deletion syndrome (22q11.2DS) have an increased chance of developing a psychiatric disorder. While parents of children affected by 22q11.2DS typically receive counseling about risk for non-psychiatric health concerns, genetic counselors may be reluctant to discuss psychiatric risk. Further education of genetic counselors may be necessary to encourage discussion of psychiatric risk with these families. The goal of this project was to develop recommendations for genetic counselors to provide psychiatric risk information to families affected by 22q11.2DS. The recommendations were developed by synthesizing resources in the literature about risk communication. These recommendations were refined following an online focus group meeting with five health care professionals who were recruited for participation from 22q11.2DS clinics across the U.S.A. The focus group data revealed three themes related to discussion of psychiatric risk: 1) Stepwise approach, 2) Discussing treatment options and reducing risks, and 3) Addressing stigma. These recommendations may be used as a foundation for a future clinical protocol to encourage discussion about the risk for psychiatric illness at an earlier point in the diagnostic process for 22q11.2DS and to provide improved information, support and resources to affected families.     

Executive functioning and its relation to ASD and ADHD symptomatology in 22q11.2 deletion syndrome*

Children with 22q11.2 deletion syndrome (22q11DS; velo-cardio-facial-syndrome) are at risk for the developmental disorders, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). In this study, the relation between executive functioning (EF) and the severity of ADHD and ASD symptoms is examined, since EF is known to be important in relation to emotional and behavioral problems. The participants consist of 58 children (38 females) with a mean age of 13.5 years (SD 2.6). Standardized assessment was used to evaluate the severity of ASD and ADHD symptomatology. The major aspects of EF, i.e., cognitive flexibility, inhibition, sustained attention, distractibility, working memory and reaction speed, were evaluated. The profile of EF in 22q11DS was found to be characterized by weaker performance compared to the norms on all subdomains of EF. Poor cognitive flexibility and inhibition, as well as high distractibility, were found to be related to more severe ASD symptoms, while poor quality of sustained attention and high distractibility were found to be related to more severe ADHD symptoms. It is concluded that children with 22q11DS experience impairments in EF, and that the degree of impairment on specific EF subdomains is related to the severity of ASD and/or ADHD symptomatology. These results may help in defining the mediating role of neurocognitive dysfunctions in the development of social and behavioral problems in 22q11DS.     

Catechol-O-methyltransferase polymorphism modulates cognitive control in children with chromosome 22q11.2 deletion syndrome

Dopamine plays a critical role in regulating neural activity in prefrontal cortex (PFC) and modulates cognition via a hypothesized inverse U function. We investigated PFC function in children with chromosome 22q11.2 deletion syndrome (22q11.2DS) in which one copy of catechol-O-methyltransferase (COMT) is deleted, thereby shifting them toward the lower end of dopamine turnover on the nonlinear function. A common polymorphism with valine to methionine substitution alters COMT activity that results in higher enzyme activity in the valine variant. Twenty-seven children with 22q11.2DS between 7 and 14 years old, and 21 age-matched typically developing children, performed a modified version of the Attention Network Test. Children with a single valine allele showed a reduction in response times when trials with incongruent flankers were repeated, whereas those who were hemizygous for the methionine allele did not show the same context-based response facilitation. Our results support that a single gene, COMT, could modulate PFC-dependent cognition.     

Socioeconomic Status and Psychological Function in Children with Chromosome 22q11.2 Deletion Syndrome: Implications for Genetic Counseling

The purpose of this study is to examine the association between parental socio-economic status (SES) and childhood neurocognition and behavior in children with chromosome 22q11.2 deletion syndrome (22q11DS). Although undoubtedly, the deletion of genes in the 22q11.2 interval is primarily responsible for the psychological manifestations, little is known about the role of the environment in either mitigating or contributing to these problems. We examined the association of parental socio-economic status (SES) with cognition and behavior in children with 22q11DS (n = 65) and matched healthy control subjects (n = 52), since SES is a component of family resources. We found that in children with 22q11DS, higher SES correlated with better overall functioning (p < .01) and social skills (p < .01), and less frequent oppositional defiant behavior (p < .001). These findings were in contrast to the control subjects in whom SES correlated with cognition and achievement, but not behavior. Our results indicate that environmental factors influence the behavioral phenotype in children with 22q11DS, providing a framework for developing appropriate interventions. As such, genetic counseling for families with 22q11DS may include consideration of family resources and inclusion of other health professionals, such as social workers, to explore with the family available social supports and resources.