Detection of hunter syndrome (mucopolysaccharidosis type II) in Taiwanese: Biochemical and linkage studies of the iduronate-2-sulfatase gene defects in MPS II patients and carriers

Background: Hunter syndrome (mucopolysaccharidosis type II) is an X-linked recessive lysosomal storage disease caused by a defect of the iduronate-2-sulfatase (IDS) gene. The result is impaired IDS enzyme function. Methods: To characterize the biochemical and molecular defects in IDS-deficient patients and their families, we measured IDS enzyme activity by fluorimetric enzyme assay and identified the IDS gene mutations in 14 unrelated Taiwanese patients with varying clinical phenotypes. In addition, haplotype analysis was also performed. Results: Three novel (IVS2 + 1G > C, 1055del12, and G489D) and 7 previously reported (N63K, P228L, K347E, R468Q, R468W, I485R, and 1241delAG) mutations were found. Together R468Q and R468W account for 42.8% mutations found in our patients. Haplotype analysis using IDS flanking markers DXS1113 and DXS1123 revealed that the unrelated R468Q alleles were independent in origin whereas the unrelated R468W alleles are probably of the same origin. The R468Q mutation in patient 1150 and I485R mutation in patient 710 occurred de novo in male meioses. Once the mutation in a family was identified, restriction analysis was also performed for rapid diagnosis of female carriers in 8 families. Leukocyte IDS measurement revealed significantly wide range of IDS activity in normal controls and MPS II carriers (19.2∼70.6 vs. 8.4∼26.6 nmol/h/mg cell protein). The average leukocyte IDS activity of normal controls (n = 43) was 43.9 ± 13.3 nmol/h/mg protein, whereas patients with MPS II (n = 14) had < 5% of mean normal IDS activity (0.9 ± 0.6 nmol/h/mg protein), and carriers (n = 13) had a mean activity of 17.5 (± 5.7) nmol/h/mg protein. The mean leukocyte IDS activity in female carriers was less than a half of the normal level. Conclusion: Due to a small overlapping range of normal and carriers, the level of enzyme activity cannot be used alone for carrier detection.