Quantitative brain MRI morphology in severe and attenuated forms of mucopolysaccharidosis type I

Victor Kovac, Elsa G. Shapiro, Kyle D. Rudser, Bryon A. Mueller, Julie B. Eisengart, Kathleen A. Delaney, Alia Ahmed, Kelly E. King, Brianna D. Yund, Morton J. Cowan, Julian Raiman, Eva G. Mamak, Paul R. Harmatz, Suma P. Shankar, Nadia Ali, Stephanie R. Cagle, Jeffrey R. Wozniak, Kelvin O. Lim, Paul J. Orchard, Chester B. WhitleyIgor Nestrasil

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Objective: To assess our hypothesis that brain macrostructure is different in individuals with mucopolysaccharidosis type I (MPS I) and healthy controls (HC), we conducted a comprehensive multicenter study using a uniform quantitative magnetic resonance imaging (qMRI) protocol, with analyses that account for the effects of disease phenotype, age, and cognition. Methods: Brain MRIs in 23 individuals with attenuated (MPS IA) and 38 with severe MPS I (MPS IH), aged 4–25 years, enrolled under the study protocol NCT01870375, were compared to 98 healthy controls. Results: Cortical and subcortical gray matter, white matter, corpus callosum, ventricular and choroid plexus volumes in MPS I significantly differed from HC. Thicker cortex, lower white matter and corpus callosum volumes were already present at the youngest MPS I participants aged 4–5 years. Age-related differences were observed in both MPS I groups, but most markedly in MPS IH, particularly in cortical gray matter metrics. IQ scores were inversely associated with ventricular volume in both MPS I groups and were positively associated with cortical thickness only in MPS IA. Conclusions: Quantitatively-derived MRI measures distinguished MPS I participants from HC as well as severe from attenuated forms. Age-related neurodevelopmental trajectories in both MPS I forms differed from HC. The extent to which brain structure is altered by disease, potentially spared by treatment, and how it relates to neurocognitive dysfunction needs further exploration.

Original languageEnglish (US)
Pages (from-to)122-132
Number of pages11
JournalMolecular Genetics and Metabolism
Volume135
Issue number2
DOIs
StatePublished - Feb 2022

Bibliographical note

Funding Information:
Kelly King, Consultant for Passage Bio, RTI Health Solutions, has received research support from Alexion Pharmaceuticals, Inc., bluebird bio, Magenta Therapeutics, Sanofi Genzyme, Shire/Takeda, and was previously a consultant for Shire Plc, and has done previous contract work for Shapiro Neuropsychology Consulting.Nadia Ali, Research support from Sanofi Genzyme, Shire Takeda, BioMarin, Amicus, and Pfizer, as well as lecturers' honoraria from Sanofi Genzyme, BioMarin, Amicus, and Vitaflo.Chester B Whitley, Research support from National Institutes of Health including Lysosomal Disease Network (RDCRN) NIH U54NS065768.Igor Nestrasil, Consultant for ICON, Bioclinica, and Quantims and received research support from Million Dollar Bike Ride - University of Pennsylvania, National MPS Society, Biomarin, Sanofi Genzyme, and Shire/Takeda.We thank the children and their parents and/or caretakers, and adults with mucopolysaccharidosis for their participation in this study. In addition, we thank Dr. Bruce Fischl from MGH-NMR Center, Harvard University, for his guidance and support in the processing of complicated cases. The authors also thank Brenda Diethelm-Okita, Ashley Schneider (née Wiesenburger), David Erickson, and Evelyn Redtree in the Lysosomal Disease Network office at the University of Minnesota for administrative assistance. Study data were collected and managed with REDCap electronic data capture tools hosted at the University of Minnesota. The study was funded by the Sanofi Genzyme (GZ-2014-11270), the National MPS Society, Million Dollar Bike Ride from the University of Pennsylvania (MDBR-16-125-MPS, 303052MPSI-16-003-02), the Ryan Foundation, the Rare Diseases Clinical Research Network, Lysosomal Disease Network, NIH U54NS065768, and the resources of the Center for Magnetic Resonance Research (supported by NIBIB P41 EB027061, P30 NS076408, and 1S10OD017974-01), the Center for Neurobehavioral Development, and the Minnesota Supercomputing Institute. Control data were supported by the NIH (5P41RR008079, 5K12RR023247, P30-NS057091, and MO1-RR00400; K24 MH071434, K24 DA028773, RO1-MH61744, R01-AA12479, and RO1-MH63407 to Master Drug Data Base), Medical Investigation of Neurodevelopmental Disorders Institute, and Gillette Children's Research Fund, Shire/Takeda (4-7-year-old study), and Clinical and Translational Science Institute grant support (UL1TR000114 from the National Center for Advancing Translational Sciences [NCATS] of the NIH). This publication was also supported in part by the NIH NCATS through UCSF-CTSI grant UL1TR000004. Its contents are solely the authors' responsibility and do not necessarily represent the official views of the NIH.

Funding Information:
Control data were supported by the NIH ( 5P41RR008079 , 5K12RR023247 , P30-NS057091 , and MO1-RR00400 ; K24 MH071434 , K24 DA028773 , RO1-MH61744 , R01-AA12479 , and RO1-MH63407 to Master Drug Data Base), Medical Investigation of Neurodevelopmental Disorders Institute, and Gillette Children's Research Fund, Shire/Takeda (4-7-year-old study), and Clinical and Translational Science Institute grant support ( UL1TR000114 from the National Center for Advancing Translational Sciences [NCATS] of the NIH). This publication was also supported in part by the NIH NCATS through UCSF-CTSI grant UL1TR000004 . Its contents are solely the authors' responsibility and do not necessarily represent the official views of the NIH.

Funding Information:
Kelly King, Consultant for Passage Bio, RTI Health Solutions, has received research support from Alexion Pharmaceuticals, Inc., bluebird bio, Magenta Therapeutics, Sanofi Genzyme , Shire/Takeda, and was previously a consultant for Shire Plc , and has done previous contract work for Shapiro Neuropsychology Consulting.

Funding Information:
Chester B Whitley, Research support from National Institutes of Health including Lysosomal Disease Network (RDCRN) NIH U54NS065768 .

Funding Information:
The study was funded by the Sanofi Genzyme ( GZ-2014-11270 ), the National MPS Society , Million Dollar Bike Ride from the University of Pennsylvania ( MDBR-16-125-MPS , 303052MPSI-16-003-02 ), the Ryan Foundation, the Rare Diseases Clinical Research Network , Lysosomal Disease Network , NIH U54NS065768 , and the resources of the Center for Magnetic Resonance Research (supported by NIBIB P41 EB027061 , P30 NS076408 , and 1S10OD017974-01 ), the Center for Neurobehavioral Development , and the Minnesota Supercomputing Institute.

Publisher Copyright:
© 2022 Elsevier Inc.

Keywords

  • Brain MRI
  • Cortex
  • Hurler Scheie syndrome
  • Mucopolysaccharidosis
  • Quantitative brain volumetry
  • Ventricle

Center for Magnetic Resonance Research (CMRR) tags

  • ANDI

PubMed: MeSH publication types

  • Journal Article
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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