No abstract

Males with an extra-X chromosome (Klinefelter's syndrome) frequently, although not always, have an increased prevalence of psychiatric disturbances that range from attention deficit disorder in childhood to schizophrenia or severe affective disorders during adulthood. In addition, they frequently have characteristic verbal deficits. Thus, examining brain magnetic resonance imaging (MRI) scans of these individuals may yield clues to the influence of X chromosome genes on brain structural variation corresponding to psychiatric and cognitive disorders. Eleven adult XXY and 11 age matched XY male controls were examined with a structured psychiatric interview, battery of cognitive tests, and an MRI scan. Ten of eleven of the XXY men had some form of psychiatric disturbance, four of whom had auditory hallucinations compared with none of the XY controls. Significantly smaller frontal lobe, temporal lobe, and superior temporal gyrus (STG) cortical volumes were observed bilaterally in the XXY men. In addition, diffusion tensor imaging (DTI) of white matter integrity resulted in four regions of reduced fractional anisotropy (FA) in XXY men compared with controls, three in the left hemisphere, and one on the right. These correspond to the left posterior limb of the internal capsule, bilateral anterior cingulate, and left arcuate bundle. Specific cognitive deficits in executive functioning attributable to frontal lobe integrity and verbal comprehension were noted. Thus, excess expression of one or more X chromosome genes influences both gray and white matter development in frontal and temporal lobes, as well as white matter tracts leading to them, and may in this way contribute to the executive and language deficits observed in these adults. Future prospective studies are needed to determine which gene or genes are involved and whether their expression could be modified with appropriate treatments early in life. Brain expressed genes that are known to escape inactivation on extra-X chromosomes would be prime candidates.

Susceptibility to schizophrenia is considered familial, but the mechanism for transmission has not been found. Since widespread cognitive deficits have been found in patients with schizophrenia, several of these have been proposed as candidate familial endophenotypes that may or may not be predictive of who develops the illness. The current study examines these candidates in individuals from 32 families with at least 2 members having the diagnosis of chronic schizophrenia and normal comparison subjects using an extensive neuropsychological battery. Consistent with previous literature, family members with schizophrenia were significantly impaired on all measures compared with controls. Well relatives demonstrated significantly worse performance on a measure of verbal learning, delayed visual recall, perceptual-motor, and pure motor speed. Expressive and receptive language, but not other functions, were highly correlated within both concordant for schizophrenia and discordant sibling pairs, suggesting that they are familial vulnerability endophenotypes, but not predictive of whom becomes ill. On the other hand, some measures of perceptual-motor, pure motor speed, and frontal/executive functioning were significantly correlated in concordant, but not discordant pairs. These latter correlations suggest that some cognitive measures may be genetically related to the illness.

Direction and degree of handedness in humans are variable between individuals and thought to be in part inherited. Several studies have shown an increase in non-right handedness among patients with schizophrenia, and some have included unaffected relatives. The present study was designed to determine whether reduced right handedness is more frequent among individuals with schizophrenia as compared with their well relatives and whether it clusters within families having multiple ill members. A total of 259 families comprising 418 individuals diagnosed with schizophrenia or schizoaffective disorder, 54 individuals with other psychoses, 145 family members with depression and other minor diagnoses, and 288 unaffected individuals were included. Hand preference was assessed by the Annett Scale and right relative to left hand skill measured using the Tapley-Bryden test. For all assessments of hand preference and hand skill, females were significantly more lateralised towards the right than males. Those individuals with schizophrenia or schizoaffective disorder had significantly less right hand preference than their unaffected relatives when measured as a quantitative index of items from the Annett Scale (p = .019), but not categorically (right, left or mixed). In contrast, there was no difference in hand skill between diagnostic groups. Hand preference was significantly correlated among male-male affected sibling pairs (p = .01) and similar results were found for hand skill among the total group of affected pairs (p = .001). Although these results only partially support a relationship between handedness and schizophrenia, they nevertheless draw attention to sex differences in hand preference and the familial aspects of hand preference in this disorder. More direct approaches to the genetics of cerebral dominance and psychosis are required.