Diffusion tensor imaging with free‐water correction reveals distinctions between severe and attenuated subtypes in Mucopolysaccharidosis type I

Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal storage disorder leading to deleterious brain effects. While animal models suggested that MPS I severely affects white matter (WM), whole‐brain diffusion tensor imaging (DTI) analysis was not performed due to MPS‐related morphological abnormalities. 3T DTI data from 28 severe (MPS IH, treated with hematopoietic stem cell transplantation—HSCT), 16 attenuated MPS I patients (MPS IA) enrolled under the study protocol NCT01870375, and 27 healthy controls (HC) were analyzed using the free‐water correction (FWC) method to resolve macrostructural partial volume effects and unravel differences in DTI metrics accounting for microstructural abnormalities. FWC analysis in MPS IH compared to HC revealed higher free‐water fraction (FWF) in all WM regions with increased radial (RD) and mean diffusivity (MD). Higher RD, MD, and FWF in cingulate and FWF in temporal WM were observed in MPS IA relative to HC. FWF and RD in the corpus callosum (CC) were higher in MPS IH than in MPS IA. Reaction time was correlated with fractional anisotropy (FA) in frontal and parietal WM in MPS IH. FA in temporal and central WM correlated with d‐prime in MPS IA. The HSCT age was related to FA in parietal WM and FWF in frontal WM in MPS IH. FWC delineated subtype‐specific WM microstructural abnormalities linked to myelination that were more extensive in MPS IH than IA, with CC findings being a key differentiator between subtypes. Earlier age at HSCT was related to preserved WM microstructure in the brain of MPS IH patients. Free water‐corrected DTI distinguishes severe and attenuated MPS I patients and reveals a relationship between attention, age at HSCT, and white matter microstructure.