Klinefelter's syndrome (XXY) as a genetic model for psychotic disorders

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.

Genetic, hormonal, and metabolomic influences on social behavior and sex preference of XXY mice

“…These clinical and behavioral features of KS could be explained as genetic and/or hormonal (testosterone deficiency). Others have also suggested that KS is a useful model to dissect the genetic bases for complex cognitive and behavioral disorder and that brain-expressed genes that escape X inactivation are plausible candidates (7).…”

Case study of a patient presenting both type II bipolar affective disorder and Klinefelter syndrome

“…DeLisi et al (2005) investigated KS as a genetic model for psychotic disorders. It was hypothesized that, in KS, genes on the extra X chromosome escape inactivation and are expressed, altering both gray and white matter and development of the frontal and temporal lobes.…”

“…The downward shift in mean IQ seems to be driven by deficits in the verbal-conceptual domain (Boada et al, 2009). Increased incidences of anxiety, depression, substance abuse, and psychotic disorders have been reported in patients with KS (Hambert, 1964;Roy, 1981;DeLisi et al, 2005;Cederlöf et al, 2014). Our aim was to report the case of a man with untreated KS, who was also diagnosed with type II bipolar disorder (BD).…”

Sex chromosome trisomies are not associated with atypical lateralisation for language

“…The flow chart was produced using the DiagrammeR package 5 , the plot showing changes in MCA blood flow with ggplot2 6 , and the pirate plot with yarrr 7 . The R packages tidyverse 8 , stringr 9 , psych 10 , and xlsx 11 were also used in analysis.…”

“…http://dx.doi.org/10.1101/248286 doi: bioRxiv preprint first posted online Jan. 15, 2018; sided (left internal capsule, left arcuate and bilateral anterior cingulate) 11 . Cerebral torque (the typical pattern of greater anterior volume in the right hemisphere and greater posterior volume in the left) has been examined in 47,XXY individuals (n=10), but did not differ significantly from controls 12 .…”