Longitudinal Natural History of Pediatric Subjects Affected with Mucopolysaccharidosis IIIB

Ilyas Okur, Fatih Ezgu, Roberto Giugliani, Nicole Muschol, Anja Koehn, Hernan Amartino, Paul Harmatz, Maria J. de Castro Lopez, Maria Luz Couce, Shuan Pei Lin, Spyros Batzios, Maureen Cleary, Martha Solano, Heidi Peters, Joy Lee, Igor Nestrasil, Adam J. Shaywitz, Stephen M. Maricich, Bernice Kuca, Joseph KovalchinEric Zanelli

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

OBJECTIVE: To characterize the longitudinal natural history of disease progression in pediatric subjects affected with mucopolysaccharidosis (MPS) IIIB.

STUDY DESIGN: Sixty-five children with a confirmed diagnosis of MPS IIIB were enrolled into 1 of 2 natural history studies and followed for up to 4 years. Cognitive and adaptive behavior functions were analyzed in all subjects, and volumetric magnetic resonance imaging analysis of liver, spleen, and brain, as well as levels of heparan sulfate (HS) and heparan sulfate nonreducing ends (HS-NRE), were measured in a subset of subjects.

RESULTS: The majority of subjects with MPS IIIB achieved an apex on both cognition and adaptive behavior age equivalent scales between age 3 and 6 years. Development quotients for both cognition and adaptive behavior follow a linear trajectory by which subjects reach a nadir with a score <25 for an age equivalent of 24 months by age 8 years on average and by 13.5 years at the latest. All tested subjects (n = 22) had HS and HS-NRE levels above the normal range in cerebrospinal fluid and plasma, along with signs of hepatomegaly. Subjects lost an average of 26 mL of brain volume (-2.7%) over 48 weeks, owing entirely to a loss of cortical gray matter (32 mL; -6.5%).

CONCLUSIONS: MPS IIIB exists along a continuum based on cognitive decline and cortical gray matter atrophy. Although a few individuals with MPS IIIB have an attenuated phenotype, the majority follow predicted trajectories for both cognition and adaptive behavior.

TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT02493998, NCT03227042, and NCT02754076.

Original languageEnglish (US)
Pages (from-to)50-58.e2
JournalJournal of Pediatrics
Volume249
DOIs
StatePublished - Oct 2022

Bibliographical note

Funding Information:
These studies were funded by Allievex Corporation . B.K., J.K. and E.Z are employees of Allievex Corporation, and S.M.M. is a former employee of Allievex Corporation. The other authors declare no conflicts of interest.

Publisher Copyright:
© 2022 The Author(s)

Keywords

  • Sanfilippo syndrome Type III
  • adaptive behavior
  • cognition
  • natural history
  • organ MRI
  • Brain/diagnostic imaging
  • Magnetic Resonance Imaging
  • Mucopolysaccharidosis III/diagnosis
  • Gray Matter
  • Heparitin Sulfate
  • Humans
  • Atrophy/pathology

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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