Advances in research on the neurological and neuropsychiatric phenotype of Klinefelter syndrome.

Department of Clinical Neuroscience, Karolinska Institute, Solna, Stockholm, Sweden.
Current opinion in neurology (Impact Factor: 5.73). 04/2012; 25(2):138-43. DOI: 10.1097/WCO.0b013e32835181a0
Source: PubMed

ABSTRACT Klinefelter syndrome, 47,XXY is the most common chromosomal aberration among men. It represents a naturally occurring human model for studies of both X-chromosome gene expression and potential androgen effects on brain development and function. The aim of this review is to combine available brain imaging and behavioral data to provide an overview of what we have learned about the neural underpinnings of cognitive, emotional and behavioral dysunctions in Klinefelter syndrome.
The behavioral phenotype of 47,XXY is characterized by language, executive and psychomotor dysfunction, as well as socioemotional impairment. The prevalence of schizophrenia, attention deficit hyperactivity disorder, autism spectrum disorders and affective regulation problems is increased. Neuroimaging studies of children and adults with Klinefelter syndrome syndrome show characteristic structural changes from typical individuals. There are increases in the grey matter volume of the sensorimotor and parietooccipital regions, as well as significant reductions in amygdala, hippocampal, insular, temporal and inferior-frontal grey matter volumes. Widespread white matter abnormalities have been revealed, with reductions in some areas (including anterior cingulate, bilaterally) but increases in others (such as left parietal lobe). Mechanisms underlying these developmental anomalies could include imbalance in gene dosage relative to typical men or women, as well as the potential consequence of endocrinological deficits.
Studies of Klinefelter syndrome could generate important information about the impact of anomalies in sex chromosome gene regulation on the development of cerebral grey and white matter and, ultimately, on human behavior.

  • Source
    Frontiers in Endocrinology 01/2014; 5:242. DOI:10.3389/fendo.2014.00242
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Whilst many studies show sex differences in cerebral asymmetry, their mechanisms are still unknown. This report describes the potential impact of sex hormones and sex chromosomes by comparing MR data from 39 male and 47 female controls and 33 men with an extra X-chromosome (47,XXY). Regional asymmetry in gray and white matter volumes (GMV and WMV) was calculated using voxel based moprhometry (SPM5), by contrasting the unflipped and flipped individual GMV and WMV images. In addition, structural volumes were calculated for the thalamus, caudate, putamen, amygdala, and hippocampus, using the FreeSurfer software. Effects of plasma testosterone and estrogen on the GMV and WMV, as well on the right/left ratios of the subcortical volumes were tested by multi-regression analysis. All three groups showed a leftward asymmetry in the motor cortex and the planum temporale, and a rightward asymmetry of the middle occipital cortex. Both asymmetries were more pronounced in 46,XY males than 46,XX females and 47,XXY males, and were positively correlated with testosterone levels. There was also a rightward asymmetry of the vermis and leftward GMV asymmetry in the cerebellar hemispheres in all groups. Notably, cerebellar asymmetries were larger in 46,XX females and 47,XXY males, but were not related to sex hormone levels. No asymmetry differences between 46,XX females and 47,XXY males, and no overall effects of brain size were detected. The asymmetry in the planum temporale area and the occipital cortex seem related to processes associated with testosterone, whereas the observed cerebellar asymmetries suggest a link with X-chromosome escapee genes. Sex differences in cerebral asymmetry are moderated by sex hormones and X-chromosome genes, in a regionally differentiated manner.
    Frontiers in Neuroscience 11/2014; 8:329. DOI:10.3389/fnins.2014.00329
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The Klinefelter syndrome (KS), with an incidence of 1 to 2 per 1000 male neonates, is one of the most frequent congenital chromosome disorders. The 47,XXY karyotype causes infertility, testosterone deficiency and a spectrum of further symptoms and comorbidities. In recent years, significant progress has been made in the elucidation of the pathophysiology and the treatment of the KS. It became clear that, to a large extent, the clinical picture is determined by gene dosage effects of the supernumerary X-chromosome. The origin of the extra X-chromosome from either the father or the mother influences behavioural features of patients with KS. The CAGn polymorphism of the androgen receptor, located on the X-chromosome, has a distinct impact on the KS phenotype. KS predisposes to the metabolic syndrome and its cardiovascular sequelae, contributing to the increased mortality of patients with KS. Neuroimaging studies have correlated anomalies in brain structures with psychosocial problems. The unexpected possibility to produce pregnancies and live birth with either ejaculated sperm - about 8% of KS men have a few sperm in semen - or with sperm extracted from individual tubules obtained by testicular biopsy can be considered a breakthrough. Testosterone substitution requires further optimisation in terms of when to initiate therapy and which preparations and dosages to use. Recently developed animal models help to further elucidation the genetic and pathopysiological basis and may lead to new therapeutic approaches to KS.
    Annales d Endocrinologie 04/2014; 75(2). DOI:10.1016/j.ando.2014.03.007 · 0.66 Impact Factor