We propose to study the relationship of neuroimaging abnormalities and neuropathology in mucopolysaccharidosis I (MPS I), a lysosomal storage disease that strikes in infancy or childhood. Children with MPS I develop hydrocephalus, atrophy, cystic or cribriform changes, and white matter abnormalities including decreased volume and fractional anisotropy of the corpus callosum (a white matter structure). The cause of hydrocephalus is thought to be decreased reabsorption of cerebrospinal fluid from storage in the arachnoid granulations, and the cause of cystic or cribriform lesions is probably the accumulation of glycosaminoglycans in perivascular (Virchow-Robin) spaces. However, the underlying basis of atrophy, white matter hyperintensities, and reduced volume and fractional anisotropy in the corpus callosum (and probably other white matter structures) is not known. The basis of these latter findings is important to understand, because they have been found to correlate with cognitive impairment in MPS patients. We hypothesize that the underlying basis of white matter abnormalities on imaging studies is dysmyelination. We have found evidence of significant dysmyelination in the corpus callosum of an MPS I animal model which is consistent with the reduced volume and fractional anisotropy in that white matter structure. The hypothesis that dysmyelination underlies these imaging findings will be directly tested, and we will also test alternate hypotheses that gray matter disease or hydrocephalus is responsible. Methods employed will include high-resolution magnetic resonance imaging, volumetrics, diffusion tensor imaging, ultrastructural studies of white and gray matter, evaluations of myelin components, and other evaluations of gray and white matter pathology. Interventions tested will include treatment with intrathecal enzyme replacement therapy in the juvenile period and ventriculoperitoneal shunting for hydrocephalus. The results will lead to a new, central model to connect neuropathology and neuroimaging findings, which are the key to understanding the pathogenesis of MPS- related brain disease.

Public Health Relevance

Novel therapy development for brain disease due to mucopolysaccharidoses (MPS) has stalled, because we do not have sufficient understanding of its pathophysiology. This proposal will study the neuropathology that underlies neuroimaging findings in MPS type I, thus relieving a key bottleneck in the development of new treatments for this devastating disorder. In the process, we hope to learn something about myelination that may inform more common diseases in which abnormalities of white matter are a feature.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Program Officer
Morris, Jill A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
La Biomed Research Institute/ Harbor UCLA Medical Center
United States
Zip Code
Le, Steven Q; Kan, Shih-Hsin; Clarke, Don et al. (2018) A Humoral Immune Response Alters the Distribution of Enzyme Replacement Therapy in Murine Mucopolysaccharidosis Type I. Mol Ther Methods Clin Dev 8:42-51
Middleton, Dana M; Li, Jonathan Y; Chen, Steven D et al. (2018) Diffusion tensor imaging findings suggestive of white matter alterations in a canine model of mucopolysaccharidosis type I. Neuroradiol J 31:90-94
Li, Jonathan Y; Middleton, Dana M; Chen, Steven et al. (2017) Novel region of interest interrogation technique for diffusion tensor imaging analysis in the canine brain. Neuroradiol J 30:339-346
Middleton, Dana M; Li, Jonathan Y; Chen, Steven D et al. (2017) Quantitative diffusion tensor imaging analysis does not distinguish pediatric canines with mucopolysaccharidosis I from control canines. Neuroradiol J 30:454-460
Middleton, Dana M; Li, Jonathan Y; Lee, Hui J et al. (2017) Diffusion tensor imaging tensor shape analysis for assessment of regional white matter differences. Neuroradiol J 30:324-329
Dickson, Patricia I; Tolar, Jakub (2015) The individual (single patient) IND for inborn errors of metabolism. Mol Genet Metab 116:1-3
Provenzale, James M; Nestrasil, Igor; Chen, Steven et al. (2015) Diffusion tensor imaging and myelin composition analysis reveal abnormal myelination in corpus callosum of canine mucopolysaccharidosis I. Exp Neurol 273:1-10
Choi, Joshua; Dickson, Patricia; Calabrese, Evan et al. (2015) Predicting degree of myelination based on diffusion tensor imagining of canines with mucopolysaccharidosis type I. Neuroradiol J 28:562-73