PracticeUpdate Conference Series_WORLDSymposium 2019

Biochemical Change Corresponds With Clinical Manifestation of Neurologic Response in Patients With MPS I-H This is the first evidence of a link between a biomarker and intelligence.

R epresenting the frst evidence of a link between a biomarker and intelligence in patients with mucopolysaccharidosis (MPS) I-H, a biochemical change has been found to correspond with a clinical manifestation of neurologic response. This fnding of a prospective study was reported at the WORLDSymposium 2019. Troy C. Lund, MD, PhD, of the University of Minnesota in Minneapolis, and colleagues set out to determine whether intrathecal enzyme replacement therapy + intravenous enzyme replacement therapy and hematopoietic stem cell transplantation is associated with attenuation of cerebrospinal fluid abnormalities and whether this change exhibits clinical correlates. A total of 24 patients with MPS I-H received intrathecal enzyme replacement therapy at four time points in the peritransplant period. At these times, cerebrospinal fluid opening pressure, heparin sulfate, non-reducing ends (NRE I0S0 and I0S6), heparin cofactor II thrombin complex, and in ammatory markers were measured. Neurocognitive functioning (that is, infant IQ) was quantified at baseline, and 1 and 2 years after hematopoietic stem cell transplantation. No adverse events due to the administration of intrathecal enzyme replacement therapy were observed. An association between attenuated cerebrospinal fluid biomarkers and IQ change following transplant was examined. Significant reductions in cerebrospinal fluid abnormalities were seen between time points 1 and 2, that is, prior to hematopoietic stem cell transplantation, for cerebrospinal fluid opening pressure, NRE I0S0 and I0S6, and heparin cofactor II thrombin complex (P = .036, .001, .006, and 0.026, respectively). Reductions were seen across time points 1 through 4 for NRE I0S0 and I0S6, heparin sulfate, and heparin cofactor II thrombin complex (P < .001 for all four biomarkers). Percent decrease in non-reducing ends from the first to fourth dose was significantly associated with a percent increase in IQ from baseline to 2 years post-hematopoietic stem cell transplantation (mean ft slope 0.703; 95% CI 0.232–1.175; P = .003). Intrathecal enzyme replacement therapy is associated with attenuation of abnormal cerebrospinal fluid biomarkers in MPS I-H, with maximal attenuation following the combination of intrathecal/intravenous enzyme replacement therapy and hematopoietic stem cell transplantation. Dr. Lund explained that abnormal cerebrospinal uid characteristics have been reported in children with severe MPS I-H (Hurler syndrome), a progressive lysosomal storage disease associated with rapid neurocognitive decline, worsening multisystem organ dysfunction, and early death. MPS I-H is the most severe form of MPS I. MPS I-H is characterized by high concentrations of the mucopolysaccharides dermatan and heparan sulfates in the urine. Symptoms frst become evident at 6 months to 2 years of age with developmental delay, recurrent urine and upper respiratory infections, noisy breathing, and persistent nasal discharge. Hydrocephalus is common after age 2–3 years. Other physical manifestations may include clouding of the cornea, an unusually large tongue, misaligned teeth, the devel- opment of a curved spine, and severe joint stiffness with claw-like hands. Mental development usually reaches a peak at approximately 2 years of age with progressive mental retardation thereafter. Dr. Lund concluded that the results offer the first evidence of a biochemical change that corresponds with a clinical manifestation of neurologic response, specifically, improvement in IQ, in patients with MPS I-H.

" Significant reductions in cerebrospinal fluid abnormalities were seen… prior to hematopoietic stem cell transplantation for cerebrospinal fluid opening pressure, NRE I0S0 and I0S6, and heparin cofactor II thrombin complex. "

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PRACTICEUPDATE CONFERENCE SERIES • WORLDSymposium 2019 4