Multimodal MRI reveals structural connectivity differences in 22q11 deletion syndrome related to impaired spatial working memory.

INTRODUCTION: Impaired spatial working memory is a core cognitive deficit observed in people with 22q11 Deletion syndrome (22q11DS) and has been suggested as a candidate endophenotype for schizophrenia. However, to date, the neuroanatomical mechanisms describing its structural and functional underpinnings in 22q11DS remain unclear. We quantitatively investigate the cognitive processes and associated neuroanatomy of spatial working memory in people with 22q11DS compared to matched controls. We examine whether there are significant between-group differences in spatial working memory using task related fMRI, Voxel based morphometry and white matter fiber tractography. MATERIALS AND METHODS: Multimodal magnetic resonance imaging employing functional, diffusion and volumetric techniques were used to quantitatively assess the cognitive and neuroanatomical features of spatial working memory processes in 22q11DS. Twenty-six participants with genetically confirmed 22q11DS aged between 9 and 52 years and 26 controls aged between 8 and 46 years, matched for age, gender, and handedness were recruited. RESULTS: People with 22q11DS have significant differences in spatial working memory functioning accompanied by a gray matter volume reduction in the right precuneus. Gray matter volume was significantly correlated with task performance scores in these areas. Tractography revealed extensive differences along fibers between task-related cortical activations with pronounced differences localized to interhemispheric commissural fibers within the parietal section of the corpus callosum. CONCLUSIONS: Abnormal spatial working memory in 22q11DS is associated with aberrant functional activity in conjunction with gray and white matter structural abnormalities. These anomalies in discrete brain regions may increase susceptibility to the development of psychiatric disorders such as schizophrenia. Hum Brain Mapp 37:4689-4705, 2016. © 2016 Wiley Periodicals, Inc.

Craniofacial dysmorphology in 22q11.2 deletion syndrome by 3D laser surface imaging and geometric morphometrics: illuminating the developmental relationship to risk for psychosis.

Persons with 22q11.2 deletion syndrome (22q11.2DS) are characterized inter alia by facial dysmorphology and greatly increased risk for psychotic illness. Recent studies indicate facial dysmorphology in adults with schizophrenia. This study evaluates the extent to which the facial dysmorphology of 22q11.2DS is similar to or different from that evident in schizophrenia. Twenty-one 22q11.2DS-sibling control pairs were assessed using 3D laser surface imaging. Geometric morphometrics was applied to 30 anatomical landmarks, 480 geometrically homologous semi-landmarks on curves and 1720 semi-landmarks interpolated on each 3D facial surface. Principal component (PC) analysis of overall shape space indicated PC2 to strongly distinguish 22q11.2DS from controls. Visualization of PC2 indicated 22q11.2DS and schizophrenia to be similar in terms of overall widening of the upper face, lateral displacement of the eyes/orbits, prominence of the cheeks, narrowing of the lower face, narrowing of nasal prominences and posterior displacement of the chin; they differed in terms of facial length (increased in 22q11.2DS, decreased in schizophrenia), mid-face and nasal prominences (displaced upwards and outwards in 22q11.2DS, less prominent in schizophrenia); lips (more prominent in 22q11.2DS; less prominent in schizophrenia) and mouth (open mouth posture in 22q11.2DS; closed mouth posture in schizophrenia). These findings directly implicate dysmorphogenesis in a cerebral-craniofacial domain that is common to 22q11.2DS and schizophrenia and which may repay further clinical and genetic interrogation in relation to the developmental origins of psychotic illness.

Relationship between reaction time, fine motor control, and visual-spatial perception on vigilance and visual-motor tasks in 22q11.2 Deletion Syndrome.

22q11.2 Deletion Syndrome (22q11DS) is a common microdeletion disorder associated with mild to moderate intellectual disability and specific neurocognitive deficits, particularly in visual-motor and attentional abilities. Currently there is evidence that the visual-motor profile of 22q11DS is not entirely mediated by intellectual disability and that these individuals have specific deficits in visual-motor integration. However, the extent to which attentional deficits, such as vigilance, influence impairments on visual motor tasks in 22q11DS is unclear. This study examines visual-motor abilities and reaction time using a range of standardised tests in 35 children with 22q11DS, 26 age-matched typically developing (TD) sibling controls and 17 low-IQ community controls. Statistically significant deficits were observed in the 22q11DS group compared to both low-IQ and TD control groups on a timed fine motor control and accuracy task. The 22q11DS group performed significantly better than the low-IQ control group on an untimed drawing task and were equivalent to the TD control group on point accuracy and simple reaction time tests. Results suggest that visual motor deficits in 22q11DS are primarily attributable to deficits in psychomotor speed which becomes apparent when tasks are timed versus untimed. Moreover, the integration of visual and motor information may be intact and, indeed, represent a relative strength in 22q11DS when there are no time constraints imposed. While this may have significant implications for cognitive remediation strategies for children with 22q11DS, the relationship between reaction time, visual reasoning, cognitive complexity, fine motor speed and accuracy, and graphomotor ability on visual-motor tasks is still unclear.

Candidate genes and the behavioral phenotype in 22q11.2 deletion syndrome.

There is an overwhelming evidence that children and adults with 22q11.2 deletion syndrome (22q11.2DS) have a characteristic behavioral phenotype. In particular, there is a growing body of evidence that indicates an unequivocal association between 22q11.2DS and schizophrenia, especially in adulthood. Deletion of 22q11.2 is the third highest risk for the development of schizophrenia, with only a greater risk conferred by being the child of two parents with schizophrenia or the monozygotic co-twin of an affected individual. Both linkage and association studies of people with schizophrenia have implicated several susceptibility genes, of which three are in the 22q11.2 region; catechol-o-methyltransferase (COMT), proline dehydrogenase (PRODH), and Gnb1L. In addition, variation in Gnb1L is associated with the presence of psychosis in males with 22q11.2DS. In mouse models of 22q11.2DS, haploinsufficiency of Tbx1 and Gnb1L is associated with reduced prepulse inhibition, a schizophrenia endophenotype. The study of 22q11.2DS provides an attractive model to increase our understanding of the development and pathogenesis of schizophrenia and other psychiatric disorders in 22q11.2DS and in wider population.

Pseudophaeochromocytoma associated with clozapine treatment.

We describe a 44 year old man with treatment resistant schizophrenia who developed pseudophaeochromocytoma on clozapine with high blood pressure, tachycardia and elevated 24 hour urinary catecholamines. All resolved on discontinuing clozapine. We reviewed the literature and found five other cases. We suggest that this is a common side effect, transient in some patients. Elevated plasma noradrenaline does not appear to be relevant to the unique benefits of clozapine.