A Prospective Natural History Study of Mucopolysaccharidosis Type IIIA.

OBJECTIVES: To characterize the clinical course of mucopolysaccharidosis type IIIA (MPS IIIA), and identify potential endpoints for future treatment trials. STUDY DESIGN: Children with a confirmed diagnosis of MPS IIIA, functioning above a developmental age of 1 year, were followed for up to 2 years. Cognitive status and brain atrophy were assessed by standardized tests and volumetric magnetic resonance imaging, respectively. Liver and spleen volumes and cerebrospinal fluid and urine biomarker levels were measured. RESULTS: Twenty-five children, from 1.1 to 18.4 years old, were enrolled, and 24 followed for at least 12 months. 19 exhibited a rapidly progressing (RP) form of MPS IIIA, and 5, a more slowly progressing form. Children with RP plateaued in development by 30 months, followed by rapid regression after 40-50 months. In patients with RP, cognitive developmental quotients showed consistent steep declines associated with progressive cortical gray matter atrophy. Children with slowly progressing had a similar but more prolonged course. Liver and spleen volumes were approximately double normal size, and cerebrospinal fluid and urine heparin sulfate levels were elevated and relatively constant over time. CONCLUSION: Developmental quotient and cortical gray matter volume are sensitive markers of disease progression in MPS IIIA, and may have utility as clinical endpoints in treatment trials. For optimal outcomes, treatment may need to be instituted in children before the onset of steep cognitive decline and brain atrophy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01047306.

Enzyme replacement is associated with better cognitive outcomes after transplant in Hurler syndrome.

OBJECTIVE: To investigate whether intravenous enzyme replacement therapy (ERT) benefits cognitive function in patients with mucopolysaccharidosis type IH (Hurler syndrome) undergoing hematopoietic cell transplantation (HCT). STUDY DESIGN: Data were obtained for 9 children treated with HCT + ERT (ERT group) and 10 children treated with HCT only (no-ERT group) from neuropsychologic evaluations before HCT and at 1-year and 2-year post-HCT follow-up. RESULTS: At 2 years after HCT, children in the ERT group lost 9.19 fewer IQ points per year compared with children in the no-ERT group (P = .031). Furthermore, the ERT group improved in nonverbal problem solving and processing, whereas the no-ERT group declined, resulting in a difference of 9.44 points per year between the 2 groups (P < .001). CONCLUSION: ERT in association with HCT enhances cognitive outcomes, providing new evidence that ERT is a valuable addition to the standard transplantation protocol. Although the mechanism responsible for this improved outcome is unknown, both direct benefits and indirect effects must be considered.

Effective treatment of alpha-mannosidosis by allogeneic hematopoietic stem cell transplantation.

OBJECTIVES: To study the efficacy of hematopoietic stem cell transplantation (HCT) for ameliorating the clinical manifestations of alpha-mannosidosis. STUDY DESIGN: Four patients with alpha-mannosidosis underwent allogeneic HCT at the University of Minnesota. Diagnosis was established by assay of leukocyte alpha-mannosidase activity level. Physical features, donor engraftment, leukocyte alpha-mannosidase activity, neuropsychologic function, and hearing were monitored before and after transplantation, with follow-up ranging from 1 to 6 years. RESULTS: All 4 patients showed slowing of their neurocognitive development and sensorineural hearing loss before HCT. All patients are alive, with normalization of leukocyte enzyme activity after HCT. Intellectual function has stabilized, with improvement in adaptive skills and verbal memory function in 3 of 4 patients. Hearing has improved to normal or near normal for speech frequencies in 3 patients. No new skeletal abnormalities have developed. CONCLUSIONS: HCT can halt the progressive cognitive loss in patients with alpha-mannosidosis. Early diagnosis and treatment with HCT is critical for optimal results.