X-chromosome effects on female brain: a magnetic resonance imaging study of Turner's syndrome

doi:10.1016/0140-6736(93)92184-U

The Lancet

Volume 342, Issue 8881, 13 November 1993, Pages 1197-1200

https://doi.org/10.1016/0140-6736(93)92184-U Get rights and content

Abstract

Summary

Many neuropsychiatric disorders differ between the sexes in incidence, symptoms, and age at onset. To investigate the effects of X-chromosome aneuploidy and of sex steroid deficiency during childhood on brain structure and function, we used neuropsychological tests and quantitative magnetic resonance imaging (MRI) to study the brains of eighteen women with Turner's syndrome (TS) and nineteen healthy control women of similar age.

Nine TS subjects had mosaic 45,X karyotypes, and 9 had non-mosaic 45,X. The TS group had significantly lower scores than the controls for all the Wechsler adult intelligence scale tests, except verbal comprehension and reading level. The greatest difference was in visuospatial construction (mean 90 [SD 12] vs 118 [13], p < 0·0001). The TS subjects also had a greater discrepancy than controls between verbal and performance intelligence quotients (9 [8] vs -5 [9], p<0 001). We found that TS subjects had significantly smaller values than controls in MRI-measured volumes of hippocampus, caudate, lenticular, and thalamic nuclei, and parieto-occipital brain matter, on both sides. Women with mosaic TS had values between the full TS and control groups for cerebral hemisphere and lenticular and thalamic nuclei volume and for verbal ability. Within the mosaic TS group, visuospatial ability was significantly correlated with the percentage of lymphocytes that had the 45,X karyotype. Hippocampal volume and memory test scores were significantly lower in mosaic and non-mosaic 45,XTS subjects than in controls.

We postulate that in human beings the X chromosome plays an important part in the development and ageing of grey matter in striatum, diencephalon, and cerebral hemispheres.

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Turner syndrome (TS) and Noonan syndrome (NS) are distinct genetic conditions with highly similar physical and neurodevelopmental phenotypes. TS is caused by X chromosome absence, whereas NS results from genetic mutations activating the Ras–mitogen-activated protein kinase signaling pathway. Previous neuroimaging studies in individuals with TS and NS have shown neuroanatomical variations relative to typically developing individuals, a standard comparison group when initially examining a clinical group of interest. However, none of these studies included a second clinical comparison group, limiting their ability to identify syndrome-specific neuroanatomical phenotypes.
In this study, we compared the behavioral and brain phenotypes of 37 girls with TS, 26 girls with NS, and 37 typically developing girls, all ages 5 to 12 years, using univariate and multivariate data-driven analyses.
We found divergent neuroanatomical phenotypes between groups, despite high behavioral similarities. Relative to the typically developing group, TS was associated with smaller whole-brain cortical surface area (p ≤ .0001), whereas NS was associated with smaller whole-brain cortical thickness (p = .013). TS was associated with larger subcortical volumes (left amygdala, p = .002; right hippocampus, p = .002), whereas NS was associated with smaller subcortical volumes (bilateral caudate, p ≤ .003; putamen, p < .001; pallidum, p < .001; right hippocampus, p = .015). Multivariate analyses also showed diverging brain phenotypes in terms of surface area and cortical thickness, with surface area outperforming cortical thickness at group separation.
TS and NS have syndrome-specific brain phenotypes, despite their behavioral similarities. Our observations suggest that neuroanatomical phenotypes better reflect the different genetic etiologies of TS and NS and may be superior biomarkers relative to behavioral phenotypes.
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Since the inception of the organizational/activational hypothesis of development, researchers have been fascinated by the influences hormones have on the way the brain and body develop. This, since, has led to the investigation of the relationship between genetic and hormonal differences, as well as, environmental factors. The environment, as you will see in this and many other chapters, plays an important role in development and hormones can also be impacted in this process. All of these factors combine to shape the way the brain develops.
Mapping the effect of the X chromosome on the human brain: Neuroimaging evidence from Turner syndrome
2017, Neuroscience and Biobehavioral Reviews
Citation Excerpt :
Two studies have investigated this effect by comparing X-monosomy with mosaic TS individuals, in which mosaic TS was characterized by X-monosomy and another cell line presenting the second X chromosome, that is, the loss of the entire second X chromosome in only a proportion of their cells (Murphy et al., 1993; Xie et al., 2015). In their pioneering study, Murphy and colleagues reported significant volumetric differences in the left caudate nucleus and thalamus between mosaic and X-monosomy TS individuals (Murphy et al., 1993). More recently, Xie and colleagues identified a significant “dosage effect” (mosaic vs. X-monosomy) on cortical SA of the right angular gyrus and WM integrity of the left tapetum of the corpus callosum (Xie et al., 2015).
In addition to determining sex, the X chromosome has long been considered to play a crucial role in brain development and intelligence. Turner syndrome (TS) is caused by the congenital absence of all or part of one of the X chromosomes in females. Thus, Turner syndrome provides a unique “knock-out model” for investigating how the X chromosome influences the human brain in vivo. Numerous cutting-edge neuroimaging techniques and analyses have been applied to investigate various brain phenotypes in women with TS, which have yielded valuable evidence toward elucidating the causal relationship between the X chromosome and human brain structure and function. In this review, we comprehensively summarize the recent progress made in TS-related neuroimaging studies and emphasize how these findings have enhanced our understanding of X chromosome function with respect to the human brain. Future investigations are encouraged to address the issues of previous TS neuroimaging studies and to further identify the biological mechanisms that underlie the function of specific X-linked genes in the human brain.
White matter microstructural abnormalities in girls with chromosome 22q11.2 deletion syndrome, Fragile X or Turner syndrome as evidenced by diffusion tensor imaging
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Children with chromosome 22q11.2 deletion syndrome (22q11.2DS), Fragile X syndrome (FXS), or Turner syndrome (TS) are considered to belong to distinct genetic groups, as each disorder is caused by separate genetic alterations. Even so, they have similar cognitive and behavioral dysfunctions, particularly in visuospatial and numerical abilities. To assess evidence for common underlying neural microstructural alterations, we set out to determine whether these groups have partially overlapping white matter abnormalities, relative to typically developing controls. We scanned 101 female children between 7 and 14 years old: 25 with 22q11.2DS, 18 with FXS, 17 with TS, and 41 aged-matched controls using diffusion tensor imaging (DTI). Anisotropy and diffusivity measures were calculated and all brain scans were nonlinearly aligned to population and site-specific templates. We performed voxel-based statistical comparisons of the DTI-derived metrics between each disease group and the controls, while adjusting for age. Girls with 22q11.2DS showed lower fractional anisotropy (FA) than controls in the association fibers of the superior and inferior longitudinal fasciculi, the splenium of the corpus callosum, and the corticospinal tract. FA was abnormally lower in girls with FXS in the posterior limbs of the internal capsule, posterior thalami, and precentral gyrus. Girls with TS had lower FA in the inferior longitudinal fasciculus, right internal capsule and left cerebellar peduncle. Partially overlapping neurodevelopmental anomalies were detected in all three neurogenetic disorders. Altered white matter integrity in the superior and inferior longitudinal fasciculi and thalamic to frontal tracts may contribute to the behavioral characteristics of all of these disorders.

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ArticlesX-chromosome effects on female brain: a magnetic resonance imaging study of Turner's syndrome

Abstract

Psychoneuroendocrinology

Cortex

Neurosci Lett

Turner's syndrome: further demonstration of the presence of specific cognitional deficiencies

J Med Genet

ISCN (1985): an international system for human cytogenetic nomenclature

Wechsler adult intelligence scale

Old wine in new skins: grouping Wechsler subtests into new scales

J Consult Psychol

Articles
X-chromosome effects on female brain: a magnetic resonance imaging study of Turner's syndrome