Skip to main content
Open Access Publications from the University of California

Reduced microstructural white matter integrity in a genetic metabolic disorder: A diffusion tensor MRI study

  • Author(s): Bava, Sunita
  • Advisor(s): Trauner, Doris
  • et al.


Reduced microstructural white matter integrity in a genetic metabolic disorder:

A diffusion tensor MRI study


Sunita Bava

Doctor of Philosophy in Clinical Psychology

University of California, San Diego,

San Diego State University, 2007

Professor Doris Trauner, Chair

Infantile nephropathic cystinosis is a genetic metabolic disorder in which cystine accumulates continuously in lysosomes, forming intracellular crystals throughout various organs in the body, including the kidneys, liver, thyroid, and brain. Cognitive deficits are particularly evident in the visuospatial domain and are accompanied by impairments in arithmetic and tactile recognition. Though the genetic causes and behavioral expression of this disorder are well characterized, the underlying neuropathological features are only grossly defined. The available literature suggests that cerebral white matter may be preferentially affected in this group, as cystine crystals have been identified in oligodendrocytes and perivascular macrophages. Within this context, the current study used diffusion tensor MRI to investigate whether early processes in this disorder contribute to selective neuropathological changes. Accordingly, white matter integrity in the dorsal visual pathway (the "where" system) was examined in a young group (ages 3-7 years) of children with cystinosis (n = 24) and compared to an age-matched group of typically developing children (n = 24). A secondary aim of this study was to characterize the relationship between diffusion fractional anisotropy (FA), visuospatial functioning and white blood cell cystine level (an indicator of disease load).

Voxel-based analysis identified reduced FA primarily in bilateral inferior parietal white matter in children with cystinosis. Other areas bearing similar attenuations in anisotropy were found in the right mid-temporal and subgyral frontal regions. To expand this approach on a single-subject level, a region-of-interest (ROI) analysis was conducted focusing on parietal and temporal subregions, corresponding to the neuroanatomical visual pathways. In addition to changes in the inferior parietal lobule (IPL) as identified by voxel-level analysis, results of ROI analysis indicated bilaterally decreased FA in the superior parietal lobule (SPL). These findings occurred in the context of nonsignificant differences in FA in inferior temporal regions. A concomitant increase in the apparent diffusion coefficient (MD) in bilateral SPL and IPL was evident in the cystinosis group, with comparable MD values in inferior temporal white matter. Together, this pattern of findings is consistent with the hypothesized dissociation between the dorsal and ventral pathways in children with cystinosis.

Results of multiple regression analysis revealed an interaction between age and FA, which when decomposed into simple effects, indicated a stronger relationship between FA and visuospatial functioning for older cystinosis children. Specifically, decremented performance on a task of visual-motor integration was associated with reduced FA in the right IPL in school-aged children with cystinosis (age > 5 years, n = 13, r = .74). Spearman correlations between white blood cell cystine level and MD in the right IPL (r = .46) and SPL (r = .50) were evident across the entire cystinosis group. In addition, correlations between cystine level and bilateral parietal MD became apparent in school-aged children, suggesting a progressive effect of cystine accumulation in addition to early white matter changes.

Taken together, significant attenuations in FA suggest that the genetic deletion underlying cystinosis results in early and regionally selective neuropathological changes which may involve myelin-forming oligodendroglia or their precursors. Contrary to expectations, relationships between anisotropy, cognitive performance, and cystine level, were only present in the older children of our group. These findings suggest that the accumulation of cystine over time may constitute a secondary progressive effect that interferes with white matter maturation. Moreover, the extent of cognitive deficit observed in children with cystinosis may result from an interaction of both the static and progressive processes in this condition.

Main Content
Current View