Genetic contributions to white matter architecture revealed by diffusion tensor imaging in Williams syndrome

Abstract

Little is known about genetic regulation of the development of white matter. This knowledge is critical in understanding the pathophysiology of neurodevelopmental syndromes associated with altered cognition as well as in elucidating the genetics of normal human cognition. The hemideletion of Ϸ25 genes on chromosome 7q11.23 that causes Williams syndrome (WS) includes genes that regulate cytoskeletal dynamics in neurons, especially LIMK1 and CYLN2, and therefore offers the opportunity to investigate the role of these genes in the formation of white matter tracts. We used diffusion tensor imaging to demonstrate alteration in white matter fiber directionality, deviation in posterior fiber tract course, and reduced lateralization of fiber coherence in WS. These abnormalities are consistent with an alteration of the late stages of neuronal migration, define alterations of white matter structures underlying dissociable behavioral phenotypes in WS, and provide human in vivo information about genetic control of white matter tract formation.development ͉ LIMK1 ͉ neuronal growth cone ͉ neuronal migration ͉ tractography

The Williams syndrome chromosome 7q11.23 hemideletion confers hypersocial, anxious personality coupled with altered insula structure and function

“…Such vulnerabilities may lead to malformations in transmodal nodes, and their connections, during critical developmental periods of cortical organization. Our present findings of alterations in the uncinate fasciculus, along with previous demonstrations of abnormalities in white-matter tracts connecting other transmodal regions in WS (25,26), provide support for this proposed neurogenetic mechanism.…”

“…These mouse studies also documented alterations in fear response [for both LIMK1 and GTF2IRD1 (20,22)] and reduced aggression [for GTF2IRD1 (22)]. In parallel with these preclinical observations, research on the neural mechanisms underlying WS-specific behavioral characteristics has identified functional and structural alterations of the intraparietal sulcus (12,(23)(24)(25)(26), hippocampal formation (27), amygdala, and orbitofrontal cortex (OFC) (12,17,28), and aberrant orbitofrontal circuitry has been associated with the syndrome's distinctive pattern of emotional processing: remarkable lack of social fear coupled with a high incidence of nonsocial anxieties and phobias (17,29,30).…”

“…These include the hippocampal formation, IPL, amygdala, and OFC (12,14,17,20,(23)(24)(25)(26)(27)(28)30). Such transmodal cortical systems (51) are composed of subregionally specialized and highly interconnected heteromodal, paralimbic, and limbic cortices (51)(52)(53).…”

“…Thirty-seven participants (14 with WS, seven female; 23 healthy controls, 10 female) participated in structural MRI scanning; 14 control subjects (five female) from the larger cohort and all 14 participants with WS underwent PET scanning. Five participants with WS (one female) completed DTI scans and were matched pairwise with five control participants for age, sex, and IQ (25). Parents of 11 participants with WS completed the parent report form of the MPQ (16).…”

“…To assess white-matter integrity, specifically the anatomical connectivity of the AI with the amygdala and OFC via the uncinate fasciculus, we used single-shot echo-planar imaging (six gradient directions with b value ∼1,100 s/mm 2 plus one acquisition with b value ∼0 s/mm 2 , 2-mm isotropic resolution, echo time of 82.7 ms, repetition time >10 s, cardiacgated, gradient strength 5 G/cm, eight repetitions) on a Signa 1.5-T scanner (GE) (25). DTI Studio software (41) was used to perform tractography as described earlier (25).…”