The mucopolysaccharidoses are lysosomal disorders that progressively affect most organ systems in the body usually beginning in childhood. Recent treatment advances have produced some amelioration, but notably brain and bone have been difficult to treat. The long-term objectives of this research are to identify abnormalities of central nervous system (CNS) structure and function over time using quantitative neuropsychological, behavioral, and MRI techniques; to identify, those measures that are most sensitive to change; and to identify the impact of biological, environmental, and disease factors on outcomes. Findings in the current research have suggested 1) white matter is abnormal in both structure and function; 2) significant psychosocial problems as MPS children age; and 3) need for better measurements. Our specific aims are 1) to study corpus callosum and white matter volumes, diffusion tensor imaging (DTI) and a new MRI technique, resting state fMRI, by disease subtype over time compared to normal controls and in relationship to neuropsychological functions such as attention. 2) We will examine the impact of biological, environmental, and disease related factors on emotional and social function. 3) We will develop more precise outcome measures. In particular, we will develop an MPS-specific and sensitive quality-of-life measure that will measure both physical and psychosocial difficulties. Measurement of gait, physical symptom severity, pain, and disability will also be considered in relationship to emotional/social function and quality-of-life. Methods: We will accomplish this with 120+ patients, recruited in the past 4 years from 6 centers (70 MPS I, 30 MPS II, and 20 MPS VI). Each patient will be seen for a total of 3 or 4 follow-up visits with quantitative neuroimaging (volumetrics/DTI for all; fMRI for older patients) and neuropsychological tests (IQ, attention, memory, visual spatial) as well as adaptive behavior, quality-of-life and emotion including behavior, temperament, and self-esteem. Data will be analyzed for 1) age changes in white matter and psychological adjustment, 2) the sensitivity of measures to disease progression, and 3) variables that contribute to outcomes. These results will enable prevention and interventions to enhance long-term functional outcomes.