Objective: To evaluate the natural course of disease progression in patients with Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB), identify potential end points for future therapy trials, and characterize biomarkers related to the disease. Study design: A prospective, multicenter study was conducted. Baseline, 6-month, and 12-month assessments included neurodevelopmental status (Bayley Scales of Infant Development, Third edition), adaptive status (Vineland Adaptive Behavior Scales, Second Edition), volumetric brain magnetic resonance imaging, cerebrospinal fluid heparan sulfate, and urine glycosaminoglycan (GAG) measurements. Results: Nineteen patients aged 1.6-31.7 years were enrolled. Over 12 months, cognition, adaptive behavior, and cortical gray matter volume (GMV) declined in most patients. For patients diagnosed at <6 years, although there was no overall mean change over 12 months, there were 10%-48%, 3%-66%, and 1%-14% decreases in cognitive development quotient score, Vineland Adaptive Behavior Scales, Second Edition development quotient score, and cortical GMV in 8/12, 9/11, and 10/11 patients, respectively. Mean urine GAG and cerebrospinal fluid heparan sulfate levels were stable, but patients diagnosed at <6 years (n = 14) had higher levels than those ≥6 years at diagnosis (n = 4), which was likely associated with age as they also were generally younger. Conclusions: Cognition, adaptive behavior, and cortical GMV measures sensitively tracked deterioration in patients with mucopolysaccharidosis type IIIB aged ≤8.6 years. Biomarkers may have prognostic value, but their sensitivity to disease progression requires further investigation. These findings should help evaluate enzyme replacement and gene therapy agents for this rare, devastating, neurodegenerative disease. Trial registration: ClinicalTrials.gov: NCT01509768.
Bibliographical noteFunding Information:
Funded by Shire Human Genetic Therapies, Lexington, MA, USA. Although employees of the Sponsor were involved in the design, collection, analysis, interpretation, and fact checking of information, the content of this manuscript, the interpretation of the data, and the decision to submit the manuscript for publication in The Journal of Pediatrics was made by the authors independently. Shire International GmbH, Zug, Switzerland provided funding to Excel Medical Affairs for support in writing and editing all drafts of this manuscript. This work including quantification of magnetic resonance neuroimaging and selection and implementation of neurocognitive assessments was also supported, in part (to C.W., E.S., and I.N.) by a US federal grant, the Lysosomal Disease Network ( U54NS065768 ), which is a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), and NCATS. This consortium is funded through a collaboration between NCATS, NINDS, and NIDDK, the University of Minnesota's Center for Neurobehavioral Development (CNBD), and the Minnesota Supercomputing Institute (MSI). This publication was supported, in part (P.H., UCSF Benioff Children's Hospital Oakland), by the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), through UCSF- CTSI grant number UL1 TR000004 . Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
C.W. received honoraria, travel grants, and consulting fees from Shire. M.C. performed research for studies sponsored by BioMarin Pharmaceutical, Genzyme, and Shire; she received honoraria and travel support from BioMarin Pharmaceutical, Chiesi, Genzyme, and Shire for speaking and consulting. K.M. received consulting fees from BioMarin Pharmaceutical, Orphazyme, Actelion, Shire, and Sanofi Genzyme. P. Harmatz received consulting fees from Alexion, Armagen, BioMarin Pharmaceutical, Chiesi, Genzyme Sanofi, Inventiva, PTC Therapeutics, ReGenXBio, and Shire; he also received research funding from Alexion , Armagen , BioMarin Pharmaceutical , Genzyme Sanofi , Shire, Inventiva , Sangamo , and Ultragenyx . E.S. received honoraria and research grants from Shire, and consulting fees through Shapiro Neuropsychology Consulting LLC. I.N. served as a consultant for Armagen, BioMarin Pharmaceutical, Genzyme, ICON, and Lysogene. D.A. and D.W. are full-time employees of, and stockholders in, Shire. P. Haslett was an employee of Shire at the time of this study.
- disease progression
- mucopolysaccharidosis type III B
- prospective study