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

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.

Keywords: Age equivalent; Cognitive decline; Developmental quotient; Mucopolysaccharidosis type I; Natural history; Neurodegenerative disease; Newborn screening.

Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the University of Minnesota IRB and patients signed a consent form, approved by the IRB, at the time of enrollment.

Competing interests

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.

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Figures

Fig. 1

Developmental Growth Curves for Untreated Hurler Syndrome; Seen between 1983 and 1995. Developmental growth curves depict the patients’ mental ages as compared with their chronological ages at the time of testing. At younger chronological ages, most patients are measuring closer to the curve of normal development. With age, their mental functions depart from the normal developmental trajectory, revealing a plateauing in development and eventual decline, illustrated with a second order polynomial curve fit to the data

Fig. 2

Comparison of slopes of decline using Standard Score versus Developmental Quotient (DQ). When plotted against chronological age, Standard Scores reveal the floor effect, with many data points clustered at a score of 50 (left), which affects calculation of slope of decline. By contrast, use of DQ scores eliminates the floor effect and shows many data points lower than 50 (right). With more comprehensive representation of DQs, the slope of decline is more accurately calculated as steeper