Long-Term Cognitive and Functional Outcomes in Children with Mucopolysaccharidosis (MPS)-IH (Hurler Syndrome) Treated with Hematopoietic Cell Transplantation

Abstract

The long-term cognitive and functional outcomes of children with mucopolysaccharidosis type I (MPS-IH) post-hematopoietic cell transplant (HCT) are not well documented, and the role of genetic and treatment factors in these outcomes has yet to be defined. In this multi-site, international study, we (1) characterize the cognitive and functional status of 47 individuals (ages 2-25, mean of 10.6 years) with MPS-IH who are 1-24 years post HCT (mean ¼ 9 years) and (2) examine contributions of genotype, transplant characteristics, and sociodemographic factors to cognitive ability, adaptive behavior, and quality of life. The overall cognitive ability of our sample was mildly impaired, more than two standard deviations below general population norms. Parent reported adaptive behaviors (i.e., communication, daily living, and motor skills) were similarly impaired with a relative strength in socialization. Quality of life, as reported by parents, fell more than two standard deviations below population norms for physical functioning; however, psychosocial quality of life (emotional well-being) approximated population norms. In linear regression analysis, adjusted for demographic and treatment factors, mutation severity was associated with lower cognitive ability (p ¼ 0.005) and adaptive functioning (p ¼ 0.004), but not parent ratings of children's quality of life. Older age at HCT was associated with poorer physical quality of life (p ¼ 0.002); lower socioeconomic status (p ¼ 0.028) and unrelated bone marrow HCT (p ¼ 0.010) were associated with poorer psychosocial quality of life. Implications for screening and early intervention for children at risk for poorer cognitive and functional outcomes are described.

Genotype‐phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry

“…ERT has been shown to alter somatic disease symptoms and progression but as current recombinant enzyme does not cross the blood‐brain barrier this treatment approach does not address the progressive central nervous system (CNS) disease characteristic of Hurler patients . HSCT particularly when initiated early, has been shown to preserve cognition and lead to improved developmental outcomes and is thus considered the standard of care for patients with severe MPS I . The recent initiation of newborn screening for MPS I as well as other programs to identify individuals with MPS I at an age when CNS and somatic involvement may be minimal, highlight the need for accurate delineation of patients so effective therapies can be initiated early.…”

Mucopolysaccharidosis Type I Newborn Screening: Best Practices for Diagnosis and Management

“…2 Available disease modifying therapies include hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) with laronidase. 4 Because early intervention with HSCT has been demonstrated to stabilize neurocognitive function in MPS I, [5][6][7] it is currently recommended as standard for patients who are predicted to have severe disease. 4,6 ERT with laronidase is used for treating nondirect CNS manifestations of MPS I.…”

“…4 Because early intervention with HSCT has been demonstrated to stabilize neurocognitive function in MPS I, [5][6][7] it is currently recommended as standard for patients who are predicted to have severe disease. 4,6 ERT with laronidase is used for treating nondirect CNS manifestations of MPS I. Clinical trials and follow-up studies of ERT in MPS I have demonstrated improvements in some somatic manifestations and functional outcomes in patients with attenuated MPS I.…”

Elevated cerebral spinal fluid biomarkers in children with mucopolysaccharidosis I-H

“…HCT leads to an increase in IDUA enzyme activity and concomitant reductions in substrate levels as well as stabilization of neurodegeneration567. HCT does not arrest the progression of joint and bone disease891011, nor does it reverse the characteristic changes in the heart valves1213.…”