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

Abstract

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.

An Experiment of Nature: Brain Anatomy Parallels Cognition and Behavior in Williams Syndrome

“…Collectively, aberrant (augmented) gray matter in orbital and medial prefrontal cortices, amygdale, and insula is in accord with the WSassociated neurobehavioral phenotype that includes hyperarousal, anxiety, altered or enhanced social impulses, enhanced emotional reactivity, and relatively strong face recognition skills. Interestingly, enlargement of the amygdala and orbitofrontal cortex also was reported recently in Turner syndrome (Good et al, 2003), a neurogenetic disorder associated with impaired social cognition and significant visual-spatial deficits.…”

Current and lifetime psychiatric illness in women with Turner syndrome

“…However, the presence and impact of co-existing psychiatric morbidity has received little attention. Indeed, neuro-imaging studies in women with TS have identified abnormalities in several brain regions relative to controls including the dorsolateral prefrontal cortex, amygdala, and hippocampus 4,7,[30][31][32][33] . The function of these brain regions also has been reported to be altered in mood disorders 34,35 , and, therefore, the neuroimaging data would suggest that women with TS may have an increased risk for the development of affective disorders.…”

“…Anatomical features such as lymphedema, skeletal abnormalities and congenital heart and kidney defects are found in about 50% of affected individuals 1,2 . Brain development also may be affected in TS, with several neuroimaging studies reporting anatomical and functional differences between girls or women with TS and age-matched controls in the parietal and dorsolateral prefrontal cortices, superior temporal gyrus, hippocampal formation, amygdala, and temporal lobes [4][5][6][7][8] . Supporting the possibility of brain involvement, girls and women with TS Correspondence: Peter J. Schmidt, Behavioral Endocrinology Branch, Bldg.…”

Selective Alterations of White Matter Associated with Visuospatial and Sensorimotor Dysfunction in Turner Syndrome

“…Complementing the findings of atypical cerebral functioning seen in fMRI studies, neuroanatomic studies of TS have consistently found decreased gray matter volume in the bilateral parietal lobes, parieto-occipital region, and subcortical gray matter (Murphy et al, 1993;Reiss et al, 1995;Brown et al, 2002;Good et al, 2003;Kesler et al, 2003;Molko et al, 2003), as well as increased volume of the superior temporal gyrus (STG) (Kesler et al, 2003), amygdala (Kesler et al, 2004a,b), and orbitofrontal cortex (Good et al, 2003). Recent volumetric MRI localized parietal lobe findings to the bilateral superior parietal lobule and postcentral gyrus (Brown et al, 2004).…”