Purpose: Early treatment is critical for mucopolysaccharidosis type I (MPS I), justifying its incorporation into newborn screening. Enzyme replacement therapy (ERT) treats MPS I, yet presumptions that ERT cannot penetrate the blood–brain barrier (BBB) support recommendations that hematopoietic cell transplantation (HCT) treat the severe, neurodegenerative form (Hurler syndrome). Ethics precludes randomized comparison of ERT with HCT, but insight into this comparison is presented with an international cohort of patients with Hurler syndrome who received long-term ERT from a young age. Methods: Long-term survival and neurologic outcomes were compared among three groups of patients with Hurler syndrome: 18 treated with ERT monotherapy (ERT group), 54 who underwent HCT (HCT group), and 23 who received no therapy (Untreated). All were followed starting before age 5 years. A sensitivity analysis restricted age of treatment below 3 years. Results: Survival was worse when comparing ERT versus HCT, and Untreated versus ERT. The cumulative incidences of hydrocephalus and cervical spinal cord compression were greater in ERT versus HCT. Findings persisted in the sensitivity analysis. Conclusion: As newborn screening widens treatment opportunity for Hurler syndrome, this examination of early treatment quantifies some ERT benefit, supports presumptions about BBB impenetrability, and aligns with current guidelines to treat with HCT.
Bibliographical noteFunding Information:
J.B.E. has received honoraria, consulting fees, and/or research support from ArmaGen, Sangamo, Regenexbio, and Sanofi Genzyme, and has done contract work for Shapiro Neuropsychology Consulting; Y.X. is an employee of Sanofi Genzyme; P.O. has received research support and honoraria from Sanofi Genzyme; W.M. will be employed by Sangamo Therapeutics in January 2018; T.L. has received research support from Sanofi Genzyme; S. J. has received research support and consulting fees from Sanofi Genzyme; S.G. has received travel support from Alexion, Sanofi Genzyme, and Shire. N.G. has received research support from Sanofi Genzyme and Biomarin, and consulting fees from Sanofi Genzyme; R.G. has received speaker honoraria, travel grants, and investigator fees from ArmaGen, BioMarin and Sanofi Genzyme; C.F.M.D. has received speaker honoraria, travel grants, and investigator fees from BioMarin and Sanofi Genzyme; E.G.S. is a Partner in Shapiro Neuropsychology Consulting; and C.B.W. has received consulting fees and research support from ArmaGen, Sangamo, BioMarin, and Sanofi Genzyme.
The Lysosomal Disease Network (U54NS065768) is a part of the Rare Diseases Clinical Research Network, an initiative of the Office of Rare Diseases Research, and the National Center for Advancing Translational Sciences. This consortium is funded through a collaboration between the National Center for Advancing Translational Sciences, the National Institute of Neurological Disorders and Stroke, and the National Institute of Diabetes and Digestive and Kidney Diseases. Research reported in this publication was also supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health award UL1TR000114. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The University of Minnesota’s Center for Neurobehavioral Development, the Center for Magnetic Resonance Research, and the Minnesota Supercomputer Center provided infrastructure for this research. We are indebted to the patients who enabled this research.
© 2018, American College of Medical Genetics and Genomics.
- enzyme replacement therapy
- hematopoietic cell transplantation
- newborn screening