Beneath the floor: Re-analysis of neurodevelopmental outcomes in untreated Hurler syndrome

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Abstract

Background: Hurler syndrome (MPS IH), the severe, neurodegenerative form of type one mucopolysaccharidosis, is associated with rapid neurocognitive decline during toddlerhood and multi-system dysfunction. It is now standardly treated with hematopoietic cell transplantation (HCT), which halts accumulating disease pathology and prevents early death. While norm-based data on developmental functioning in untreated children have previously demonstrated neurocognitive decline, advances in methodology for understanding the cognitive functioning of children with neurodegenerative diseases have highlighted that the previous choice of scores to report results was not ideal. Specifically, the lowest possible norm-based score is 50, which obscures the complete range of cognitive functioning at more advanced stages of neurodeterioration. To a set of cognitive data collected on a sample of untreated children, we applied a modern method of score analysis, calculating a developmental quotient based on age equivalent scores, to reveal the full range of cognitive functioning beneath this cutoff of 50, uncovering new information about the rapidity of decline and the profound impairment in these children. Results: Among 39 observations for 32 patients with untreated Hurler syndrome, the full array of cognitive functioning below 50 includes many children in the severely to profoundly impaired range. The loss of skills per time unit was 14 points between age 1 and 2. There was a very large range of developmental quotients corresponding to the norm-based cutoff of 50. Conclusions: This report enables clarification of functioning at levels that extend beneath the floor of 50 in previous work. At the dawn of newborn screening and amidst a proliferation of new therapies for MPS I, these data can provide crucial benchmark information for developing treatments, particularly for areas of the world where transplant may not be available.

Original languageEnglish (US)
Article number76
JournalOrphanet Journal of Rare Diseases
Volume13
Issue number1
DOIs
StatePublished - May 11 2018

Bibliographical note

Funding Information:
Original data collection supported by NIH grant # NS 29099, 1991–1996. “Value of Bone Marrow Transplant for Storage Diseases.” Analysis supported by NIH U54NS065768. The Lysosomal Disease Network (U54NS065768) 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.

Funding Information:
ES is a Partner in Shapiro Neuropsychology Consulting, LLC; CBW has received consulting fees and research support from ArmaGen, Sangamo, BioMarin and Sanofi Genzyme; JBE has received honoraria, consulting fees, and/or research support from ArmaGen, Regenxbio, Sangamo, Sanofi Genzyme and Shire, and has done contract work for Shapiro Neuropsychology Consulting, LLC.

Keywords

  • Age equivalent
  • Cognitive decline
  • Developmental quotient
  • Mucopolysaccharidosis type I
  • Natural history
  • Neurodegenerative disease
  • Newborn screening

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