Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal storage disease that seriously affects the brain. Severity of neurocognitive symptoms in attenuated MPS subtype (MPS IA) broadly varies partially, due to restricted permeability of blood-brain barrier (BBB) which limits treatment effects of intravenously applied α-L-iduronidase (rhIDU) enzyme. Intrathecal (IT) rhIDU application as a possible solution to circumvent BBB improved brain outcomes in canine models; therefore, our study quantifies effects of IT rhIDU on brain structure and function in an MPS IA patient with previous progressive cognitive decline. Neuropsychological testing and MRIs were performed twice prior (baseline, at 1 year) and twice after initiating IT rhIDU (at 2nd and 3rd years). The difference between pre- and post-treatment means was evaluated as a percentage of the change. Neurocognitive performance improved particularly in memory tests and resulted in improved school performance after IT rhIDU treatment. White matter (WM) integrity improved together with an increase of WM and corpus callosum volumes. Hippocampal and gray matter volume decreased which may either parallel reduction of glycosaminoglycan storage or reflect typical longitudinal brain changes in early adulthood. In conclusion, our outcomes suggest neurological benefits of IT rhIDU compared to the intravenous administration on brain structure and function in a single MPS IA patient.© 2017 Wiley Periodicals, Inc.

Los Angeles Biomedical Institute at Harbor UCLA Torrance California

Multimodal and Functional Neuroimaging Research Group CEITEC Central European Institute of Technology Masaryk University Brno Czech Republic

Ryan Foundation Carrollton Texas

University of Minnesota Minneapolis Minnesota

University of Texas Southwestern Medical Center Dallas Texas

Zobrazit více v PubMed

Alexander AL, Lee JE, Lazar M, Field AS. 2007. Diffusion tensor imaging of the brain. Neurotherapeutics 4:316–329. PubMed PMC

Dickson PI, Chen AH. 2011. Intrathecal enzyme replacement therapy for mucopolysaccharidosis I: Translating success in animal models to patients. Curr Pharm Biotechnol 12:946–955. PubMed

Dierenfeld AD, McEntee MF, Vogler CA, Vite CH, Chen AH, Passage M, Le S, Shah S, Jens JK, Snella EM, Kline KL, Parkes JD, Ware WA, Moran LE, Fales‐Williams AJ, Wengert JA, Whitley RD, Betts DM, Boal AM, Riedesel EA, Gross W, Ellinwood NM, Dickson PI. 2010. Replacing the enzyme alpha‐L‐iduronidase at birth ameliorates symptoms in the brain and periphery of dogs with mucopolysaccharidosis type I. Sci Transl Med 2:60ra89. PubMed PMC

Felice BR, Wright TL, Boyd RB, Butt MT, Pfeifer RW, Pan J, Ruiz JA, Heartlein MW, Calias P. 2011. Safety evaluation of chronic intrathecal administration of idursulfase‐IT in cynomolgus monkeys. Toxicol Pathol 39:879–892. PubMed

Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, Frackowiak RS. 2001. A voxel‐based morphometric study of ageing in 465 normal adult human brains. Neuroimage 14:21–36. PubMed

Kakkis ED, Muenzer J, Tiller GE, Waber L, Belmont J, Passage M, Izykowski B, Phillips J, Doroshow R, Walot I, Hoft R, Neufeld EF. 2001. Enzyme‐replacement therapy in mucopolysaccharidosis I. N Engl J Med 344:182–188. PubMed

Liu RSN, Lemieux L, Bell GS, Sisodiya SM, Shorvon SD, Sander JWAS, Duncan JS. 2003. A longitudinal study of brain morphometrics using quantitative magnetic resonance imaging and difference image analysis. Neuroimage 20:22–33. PubMed

Muenzer J, Wraith JE, Clarke LA. 2009. International consensus panel on management and treatment of mucopolysaccharidosis I. Pediatrics 123:19–29. PubMed

Peters C, Balthazor M, Shapiro EG, King RJ, Kollman C, Hegland JD, Henslee‐Downey J, Trigg ME, Cowan MJ, Sanders J, Bunin N, Weinstein H, Lenarsky C, Falk P, Harris R, Bowen T, Williams TE, Grayson GH, Warkentin P, Sender L, Cool VA, Crittenden M, Packman S, Kaplan P, Lockman LA, Anderson J, Krivit W, Dusenbery K, Wagner J. 1996. Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome. Blood 87:4894–4902. PubMed

Shapiro EG, Nestrasil I, Rudser K, Delaney K, Kovac V, Ahmed A, Yund B, Orchard PJ, Eisengart J, Niklason GR, Raiman J, Mamak E, Cowan MJ, Bailey‐Olson M, Harmatz P, Shankar SP, Cagle S, Ali N, Steiner RD, Wozniak J, Lim KO, Whitley CB. 2015. Neurocognition across the spectrum of mucopolysaccharidosis type I: Age, severity, and treatment. Mol Genet Metab 116:61–68. PubMed PMC

Tisserand DJ, Visser PJ, Van Boxtel MPJ, Jolles J. 2000. The relation between global and limbic brain volumes on MRI and cognitive performance in healthy individuals across the age range. Neurobiol Aging 21:569–576. PubMed

Van Petten C. 2004. Relationship between hippocampal volume and memory ability in healthy individuals across the lifespan: Review and meta‐analysis. Neuropsychologia 42:1394–1413. PubMed

Vite CH, Nestrasil I, Mlikotic A, Jens JK, Snella EM, Gross W, Shapiro EG, Kovac V, Provenzale JM, Chen S, Le SQ, Kan S, Banakar S, Wanng RY, Haskins ME, Ellinwood NM, Dickson PI. 2013. Features of brain MRI in dogs with treated and untreated mucopolysaccharidosis type I. Comp Med 63:163–173. PubMed PMC

Yap QJ, Teh I, Fusar‐Poli P, Sum MY, Kuswanto C, Sim K. 2013. Tracking cerebral white matter changes across the lifespan: Insights from diffusion tensor imaging studies. J Neural Transm 120:1369–1395. PubMed

Yund B, Rudser K, Ahmed A, Kovac V, Nestrasil I, Raiman J, Mamak E, Harmatz P, Steiner R, Lau H, Vekaria P, Wozniak JR, Lim KO, Delaney K, Whitley C, Shapiro EG. 2015. Cognitive, medical, and neuroimaging characteristics of attenuated mucopolysaccharidosis type II. Mol Genet Metab 114:170–177. PubMed PMC