Diffusion tensor imaging and myelin composition analysis reveal abnormal myelination in corpus callosum of canine mucopolysaccharidosis I

James M. Provenzale, Igor Nestrasil, Steven Chen, Shih hsin Kan, Steven Q. Le, Jacqueline K. Jens, Elizabeth M. Snella, Kristen N. Vondrak, Jennifer K. Yee, Charles H. Vite, David Elashoff, Lewei Duan, Raymond Y. Wang, N. Matthew Ellinwood, Miguel A. Guzman, Elsa G. Shapiro, Patricia I. Dickson

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14 Scopus citations


Children with mucopolysaccharidosis I (MPS I) develop hyperintense white matter foci on T2-weighted brain magnetic resonance (MR) imaging that are associated clinically with cognitive impairment. We report here a diffusion tensor imaging (DTI) and tissue evaluation of white matter in a canine model of MPS I. We found that two DTI parameters, fractional anisotropy (a measure of white matter integrity) and radial diffusivity (which reflects degree of myelination) were abnormal in the corpus callosum of MPS I dogs compared to carrier controls. Tissue studies of the corpus callosum showed reduced expression of myelin-related genes and an abnormal composition of myelin in MPS I dogs. We treated MPS I dogs with recombinant alpha-L-iduronidase, which is the enzyme that is deficient in MPS I disease. The recombinant alpha-L-iduronidase was administered by intrathecal injection into the cisterna magna. Treated dogs showed partial correction of corpus callosum myelination. Our findings suggest that abnormal myelination occurs in the canine MPS I brain, that it may underlie clinically-relevant brain imaging findings in human MPS I patients, and that it may respond to treatment.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalExperimental Neurology
StatePublished - Nov 1 2015

Bibliographical note

Funding Information:
Catalina Guerra, Jenny Dancourt, and Amanda Todd at the Los Angeles Biomedical Research Institute at Harbor—UCLA Medical Center, and numerous undergraduate students at Iowa State University, provided assistance with animals. Daisy O'Brien and Shida Banakar operated the MRI scanner. Leonard White assisted with neuroanatomy. Funding was provided by NIH /NINDS NS085381 and NS05242 to P.I.D., T32 GM8243-28 to support S.-h.K., NIH/NCATS (UCLA CTSI) UL1TR000124 , NIH/NIBIB (Duke Center for In Vivo Microscopy) P41 EB015897 to G. Allan Johnson, NIH/OD P40 OD010939 to Mark Haskins and NIH/NIDDK R01 DK066448 to Katherine Ponder, and grants from the Ryan Foundation and the Gene Spotlight Charity Inc. to N.M.E. Lipid analysis was performed at the Kansas Lipidomics Research Center (KLRC). Mary Roth and Ruth Welti of the KLRC provided advice regarding data interpretation. Instrument acquisition and method development at KLRC was supported by NSF grants MCB 0455318 and 0920663 and DBI 0521587, and NSF EPSCoR grant EPS-0236913 with matching support from the State of Kansas through Kansas Technology Enterprise Corporation and Kansas State University. The KLRC is also supported by K-INBRE (NIH Grant P20 RR16475 from the INBRE program of the National Center for Research Resources). Canine care and housing was also supported in part by grants from the MPS1 Research Foundation and CHOC Pediatric Subspecialty Faculty to R.Y.W. Recombinant human alpha- l -iduronidase was provided by BioMarin Pharmaceutical Inc.

Publisher Copyright:
© 2015 Elsevier Inc..


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