Brain white matter volume abnormalities in Lesch-Nyhan disease and its variants

Abstract

Objective: We sought to examine brain white matter abnormalities based on MRI in adults with Lesch-Nyhan disease (LND) or an attenuated variant (LNV) of this rare, X-linked neurodevelopmental disorder of purine metabolism.

Methods: In this observational study, we compared 21 adults with LND, 17 with LNV, and 33 age-, sex-, and race-matched healthy controls using voxel-based morphometry and analysis of covariance to identify white matter volume abnormalities in both patient groups.

Results: Patients with classic LND showed larger reductions of white (26%) than gray (17%) matter volume relative to healthy controls. Those with LNV showed comparable reductions of white (14%) and gray (15%) matter volume. Both patient groups demonstrated reduced volume in medial inferior white matter regions. Compared with LNV, the LND group showed larger reductions in inferior frontal white matter adjoining limbic and temporal regions and the motor cortex. These regions likely include such long association fibers as the superior longitudinal and uncinate fasciculi.

Conclusions: Despite earlier reports that LND primarily involves the basal ganglia, this study reveals substantial white matter volume abnormalities. Moreover, white matter deficits are more severe than gray matter deficits in classic LND, and also characterize persons with LNV. The brain images acquired for these analyses cannot precisely localize white matter abnormalities or determine whether they involve changes in tract orientation or anisotropy. However, clusters of reduced white matter volume identified here affect regions that are consistent with the neurobehavioral phenotype.

Figure 1. Axial slice view showing group differences in white matter volume

Statistical parametric maps showing clusters of reduced white matter volume in adults with LND compared to healthy adults (A), adults with LNV compared to healthy adults (B), and adults with LND compared to those with LNV (C). Images are shown following neurologic convention (left hemisphere appears on the left side), with a cluster-forming threshold of p < 0.0005 and a cluster-level family-wise error correction of p < 0.05. Areas of significance are overlaid on the average fractional anisotropy maps from the Illinois Institute of Technology human brain atlas. LND = Lesch-Nyhan disease; LNV = Lesch-Nyhan variant.