2 research outputs found
Effect of Anti-Iduronate 2-Sulfatase Antibodies in Patients with Mucopolysaccharidosis Type II Treated with Enzyme Replacement Therapy
Objective To assess the relationship between anti-Iduronate 2-sulfatase (IDS) antibodies, IDS genotypes, phenotypes and their impact in patients with enzyme replacement therapy (ERT)-treated Mucopolysaccharidosis type II. Study design Dutch patients treated with ERT were analyzed in this observational cohort study. Antibody titers were determined by enzyme-linked immunosorbent assay. Neutralizing effects were measured in fibroblasts. Pharmacokinetic analysis of ERT was combined with immunoprecipitation. Urinary glycosaminoglycans were measured using mass spectrometry and dimethylmethylene blue. Results Eight of 17 patients (47%) developed anti-IDS antibodies. Three patients with the severe, neuronopathic phenotype, two of whom did not express IDS protein, showed sustained antibodies for up to 10 years of ERT. Titers of 1:5120 or greater inhibited cellular IDS uptake and/or intracellular activity in vitro. In 1 patient who was neuronopathic with a titer of 1:20 480, pharmacokinetic analysis showed that all plasma recombinant IDS was antibody bound. This finding was not the case in 2 patients who were not neuronopathic with a titer of 1:1280 or less. Patients with sustained antibody titers showed increased urinary glycosaminoglycan levels compared with patients with nonsustained or no-low titers. Conclusions Patients with the neuronopathic form and lack of IDS protein expression were most at risk to develop sustained anti-IDS antibody titers, which inhibited IDS uptake and/or activity in vitro, and the efficacy of ERT in patients by lowering urinary glycosaminoglycan levels. (J Pediatr 2022;248:100-7)
Can serial cerebral MRIs
OBJECTIVE: To advance the prediction of the neurocognitive development in MPS II patients by jointly analyzing MRI and neurocognitive data in mucopolysaccharidosis (MPS) II patients. METHODS: Cognitive ability scores (CAS) were obtained by neuropsychological testing. Cerebral MRIs were quantified using a diseaseâspecific protocol. MRI sumscores were calculated for atrophy, whiteâmatter abnormalities (WMA) and VirchowâRobin spaces (VRS). To distinguish between atrophy and hydrocephalus the Evans' index and the callosal angle (CA) were measured. A random effects repeated measurement model was used to correlate CAS with the three MRI sumscores. RESULTS: MRI (n = 47) and CAS scores (n = 78) of 19 male patients were analyzed. Ten patients were classified as neuronopathic and nine as nonâneuronopathic. Neuronopathic patients had normal cognitive development until age 3âyears. Mental age plateaued between ages 3 and 6, and subsequently declined with loss of skills at a maximum developmental age of 4âyears. MRIs of neuronopathic patients showed abnormal atrophy sumscores before CAS dropped below the threshold for intellectual disability (<70). Whiteâmatter abnormalities (WMA) and brain atrophy progressed. The calculated sumscores were inversely correlated with CAS (r = â.90 for atrophy and â.69 for WMA). This was not biased by the influence of hydrocephalus as shown by measurement of the Evans' and callosal angle. Changes over time in the VirchowâRobin spaces (VRS) on MRI were minimal. CONCLUSION: In our cohort, brain atrophy showed a stronger correlation to a decline in CAS when compared to WMA. Atrophyâscores were higher in young neuronopathic patients than in nonâneuronopathic patients and atrophy was an important early sign for the development of the neuronopathic phenotype, especially when observed jointly with whiteâmatter abnormalities