Microstructural white matter abnormalities in Lesch-Nyhan disease

• Type of Material: Article
• Authors: Victor A Del Bene, Johns Hopkins University; Jeffrey L Crawford, Johns Hopkins University; Ainara Gómez-Gastiasoro, University of Deusto; Tracy D Vannorsdall, Johns Hopkins University; Alison Buchholz, Johns Hopkins University; Natalia Ojeda, University of Alabama Birmingham; James C Harris, Johns Hopkins University; Hyder Jinnah, Emory University; David J Schretlen, Johns Hopkins University
• Language: English
• Date: 2021-12-06
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 Federation of European Neuroscience Societies and John Wiley & Sons Ltd
• Final Published Version (URL): http://dx.doi.org/10.1111/ejn.15512
• Title of Journal or Parent Work: EUROPEAN JOURNAL OF NEUROSCIENCE
• Volume: 55
• Issue: 1
• Start Page: 264
• End Page: 276
• Grant/Funding Information: National Institute of Neurological Disorders and Stroke, Grant/Award Numbers: NH1009242, NS109242; National Center for Advancing Translational Sciences, Grant/Award Number: TR001456; National Institute of Child Health and Human Development, Grant/Award Number: RO1 HD053312
• Keywords: cognition; Neurosciences; GENETIC MOUSE MODEL; PATHOLOGY; Neurosciences & Neurology; STIMULATION; VOLUME ABNORMALITIES; Lesch-Nyhan disease; Science & Technology; NEURONS; diffusion tensor imaging; DISORDER; Lesch-Nyhan variant; CINGULUM BUNDLE; PHENOTYPE; magnetic resonance imaging; Life Sciences & Biomedicine; ATTENUATED VARIANTS; PATHOPHYSIOLOGY; white matter

Abstract

Lesch–Nyhan disease is a rare, sex-linked, genetic neurodevelopmental disorder that is characterized by hyperuricemia, dystonia, cognitive impairment and recurrent self-injury. We previously found reduced brain white matter volume in patients with Lesch–Nyhan disease compared with healthy adults using voxel-based morphometry. Here, we address the structural integrity of white matter via diffusion tensor imaging. We hypothesized that white matter integrity would be decreased in men with Lesch–Nyhan disease and to a lesser extent in men with a milder variant of the disease (Lesch–Nyhan variant) relative to healthy men. After acquiring diffusion-weighted brain images from Lesch–Nyhan disease (n = 5), Lesch–Nyhan variant (n = 6) and healthy participants (n = 10), we used both tract-based spatial statistics and a regions of interest approach to analyse between-group fractional anisotropy differences. We first replicated earlier findings of reduced intracranial, grey matter and white matter volumes in patients. We then discovered marked reductions of fractional anisotropy relative to the healthy control group. The Lesch–Nyhan disease group showed more pronounced reductions in white matter integrity than the Lesch–Nyhan variant group. In addition to whole brain fractional anisotropy group differences, reductions in white matter integrity were observed in the corpus callosum, corona radiata, cingulum, internal capsule and superior longitudinal fasciculus. Moreover, the variant group had attenuated dystonia severity symptoms and cognitive deficits. These findings highlight the need to better understand the role of white matter in Lesch–Nyhan disease.