Biomedical subjects

David H Skuse

Publications and source records attributed to David H Skuse.

5 recordsLinked to original sources

PubMed2005

Influence of X chromosome and hormones on human brain development: a magnetic resonance imaging and proton magnetic resonance spectroscopy study of Turner syndrome.

BACKGROUND: Women with Turner syndrome (TS; 45,X) lack a normal second X chromosome, and many are prescribed exogenous sex and growth hormones (GH). Hence, they allow us an opportunity to investigate genetic and endocrine influences on brain development. METHODS: We examined brain anatomy and metabolism in 27 adult monosomic TS women and 21 control subjects with volumetric magnetic resonance imaging and magnetic resonance spectroscopy. RESULTS: In TS women, regional gray matter volume was significantly smaller in parieto-occipital cortex and caudate nucleus and larger in cerebellar hemispheres. White matter was reduced in the cerebellar hemispheres, parieto-occipital regions, and splenium of the corpus callosum but was increased in the temporal and orbitofrontal lobes and genui of corpus callosum. Women with TS had a significantly lower parietal lobe concentration of N-acetyl aspartate, and higher hippocampal choline. Also, among women with TS, there were significant differences in regional gray matter volumes and/or neuronal integrity, depending upon parental origin of X chromosome and oxandrolone and GH use. CONCLUSIONS: X chromosome monosomy, imprinting and neuroendocrine milieu modulate human brain development-perhaps in a regionally specific manner.

Adult↗

PubMed2005

X-linked genes and mental functioning.

The X-chromosome has played a crucial role in the development of sexually selected characteristics for over 300 million years. During that time it has accumulated a disproportionate number of genes concerned with mental functions. Evidence is emerging, from studies of both humans and mice, for a general influence upon intelligence (as indicated by the large number of X-linked mental retardation syndromes). In addition, there is evidence for relatively specific effects of X-linked genes on social-cognition and emotional regulation. Sexually dimorphic processes could be influenced by several mechanisms. First, a small number of X-linked genes are apparently expressed differently in male and female brains in mouse models. Secondly, many human X-linked genes outside the X-Y pairing pseudoautosomal regions escape X-inactivation. Dosage differences in the expression of such genes (which might comprise at least 20% of the total) are likely to play an important role in male-female neural differentiation. To date, little is known about the process but clues can be gleaned from the study of X-monosomic females who are haploinsufficient for expression of all non-inactivated genes relative to 46,XX females. Finally, from studies of both X-monosomic humans (45,X) and mice (39,X), we are learning more about the influences of X-linked imprinted genes upon brain structure and function. Surprising specificity of effects has been described in both species, and identification of candidate genes cannot now be far off.

Animals↗

PubMed2005

Adolescents and young adults with 22q11 deletion syndrome: psychopathology in an at-risk group.

BACKGROUND: 22q11 deletion syndrome is associated with high rates of psychiatric morbidity, especially schizophrenia. If common neurodevelopmental trajectories characterise 22q11 deletion syndrome and idiopathic schizophrenia, then similar'premorbid'features would be predicted. AIMS: To define psychopathologyin adolescents and young adults with 22q11 deletion syndrome. METHOD: Individuals with 22q11 deletion syndrome (n=25) and age- and IQ-matched comparison participants (n=25), along with their parents/carers, completed standardised semi-structured assessments. RESULTS: Psychiatric disorders were more prevalent among those with the syndrome and included attention deficit, depression and anxiety; nearly half reported transient psychotic experiences. Inappropriate emotionality and disrupted social behaviour were also common. Poor functional adjustment was associated with schizotypal symptoms and was more marked in older individuals. CONCLUSIONS: 22q11 deletion syndrome is associated with significant psychopathology prior to adulthood. Double the proportion expected to develop schizophrenia reported psychotic phenomena. These findings imply a continuum of developmental disruption in 22q11 deletion syndrome, associated with declining mental health in early adulthood.

Adaptation, Psychological↗

PubMed2005

Measuring autistic traits: heritability, reliability and validity of the Social and Communication Disorders Checklist.

BACKGROUND: Autistic traits are widely distributed in the general population, but the boundaries of the autistic spectrum are unclear. Whole-population surveys of unselected samples of children are hampered by the lack of appropriate screening instruments. AIMS: To assess whether the Social and Communication Disorders Checklist (SCDC) fulfils the need for a sensitive measure of autistic traits, which can be completed in a few minutes and which measures heritable characteristics in both males and females. METHOD: A12-item scale, the SCDC, was completed by three independent samples drawn from a twin register, a group with Turner syndrome and children with a diagnosis of autistic-spectrum disorder attending clinics. The data were used to establish the heritability, reliability and validity of the checklist. RESULTS: Traits measured by the SCDC were highly heritable in both genders (0.74). Internal consistency was excellent (0.93) and test - retest reliability high (0.81). Discriminant validity between pervasive developmental disorder and other clinical groups was good, discrimination from non-clinical samples was better; sensitivity (0.90), specificity (0.69). CONCLUSIONS: The SCDC is a unique and efficient first-level screening questionnaire for autistic traits.

Adolescent↗

PubMed2003

Dosage-sensitive X-linked locus influences the development of amygdala and orbitofrontal cortex, and fear recognition in humans.

The amygdala, which plays a critical role in emotional learning and social cognition, is structurally and functionally sexually dimorphic in humans. We used magnetic neuroimaging and molecular genetic analyses with healthy subjects and patients possessing X-chromosome anomalies to find dosage-sensitive genes that might influence amygdala development. If such X-linked genes lacked a homologue on the Y-chromosome they would be expressed in one copy in normal 46,XY males and two copies in normal 46,XX females. We showed by means of magnetic neuroimaging that 46,XY males possess significantly increased amygdala volumes relative to normal 46,XX females. However, females with Turner syndrome (45,X) have even larger amygdalae than 46,XY males. This finding implies that haploinsufficiency for one or more X-linked genes influences amygdala development irrespective of a direct or indirect (endocrinological) mechanism involving the Y-chromosome. 45,X females also have increased grey matter volume in the orbitofrontal cortex bilaterally, close to a region implicated in emotional learning. They are as poor as patients with bilateral amygdalectomies in the recognition of fear from facial expressions. We attempted to localize the gene(s) responsible for these deficits in X-monosomy by means of a deletion mapping strategy. We studied female patients possessing structural X-anomalies of the short arm. A genetic locus (no greater than 4.96 Mb in size) at Xp11.3 appears to play a key role in amygdala and orbitofrontal structural and (by implication) functional development. Females with partial X-chromosome deletions, in whom this critical locus is deleted, have normal intelligence. Their fear recognition is as poor as that of 45,X females and their amygdalae are correspondingly enlarged. This 4.96 Mb region contains, among others, the genes for monoamine oxidase A (MAOA) and B (MAOB), which are involved in the oxidative deamination of several neurotransmitters, including dopamine and serotonin. Abnormal activity of these neurotransmitters has been implicated in the aetiology of several neurodevelopmental disorders in which social cognitive deficits are prominent. These associated deficits include a specific lack of fear recognition from facial expressions. We show that the thrombocytic activity of MAOB is proportionate to the number of X-chromosomes, and hypothesize that haploinsufficiency of this enzyme in 45,X females predisposes to their deficits in social cognition.

Adolescent↗