Development and Testing of New Screening Method for Keratan Sulfate in Mucopolysaccharidosis IVA

Abstract

Mucopolysaccharidosis IVA (MPS IVA), a progressive lysosomal storage disease, causes skeletal dysplasia through excessive storage of keratan sulfate (KS). We developed an ELISA-sandwich assay that used a MAb specific to KS. Forty-five blood and 59 urine specimens from MPS IVA patients (ages 1-65 y) were analyzed to determine whether KS concentration is a suitable marker for early diagnosis and longitudinal assessment of disease severity. Blood specimens were obtained from patients categorized as phenotypically severe (n ϭ 36) and milder (n ϭ 9). Urine specimens were also analyzed from patients categorized as severe (n ϭ 56) and milder (n ϭ 12), respectively. Blood KS levels (101-1525 ng/mL) in MPS IVA patients were two to eight times higher than those in age-matched controls (15-323 ng/mL). It was found that blood KS level varied with age and clinical severity. Blood KS levels in both MPS IVA and controls peaked between 5 and 10 y of age (mean, 776 versus 234 ng/mL, respectively). Blood levels in severe MPS IVA were 1.5 times higher than in the milder form. In contrast to blood, urine KS levels in both MPS IVA and controls peaked between 1 and 5 y (15.3 versus 0.26 mg/g creatinine), and thereafter declined with age. Urine KS level also varied with age and clinical severity, and the severe MPS IVA phenotype was associated with 6.7 times greater urine KS excretion than the milder one.

Measurement of Elevated Concentrations of Urine Keratan Sulfate by UPLC-MSMS in Lysosomal Storage Disorders (LSDs): Comparison of Urine Keratan Sulfate Levels in MPS IVA Versus Other LSDs

“…Therefore, urine KS appears to correlate with the severity of skeletal involvement, as patients with MPS IVA and ML II or ML II/III have the highest urine KS levels of all patients analyzed in this study. A correlation between urine KS level and clinical severity has already been reported in MPS IVA patients (Tomatsu et al 2004). The explanation for elevated urine KS levels in patients with MPS I, MPS II, and fucosidosis is less clear.…”

Identification of a common mutation in mucopolysaccharidosis IVA: correlation among genotype, phenotype, and keratan sulfate

“…Values in patients under 15 years were higher than those in age-matched controls (mean 807 ng/ml versus 195 ng/ ml for MPS IVA patients and controls, respectively), while those in patients over 15 years were nearly normal (mean 187 ng/ml versus 166 ng/ml for MPS IVA patients and controls, respectively) ( Table 1). Urine KS concentrations in MPS IVA patients (0.5-7.9 mg/g creatinine) were also significantly higher than those of agematched controls (mean in all ages, 0.21 mg/g creatinine) (Tomatsu et al 2004). Plasma KS concentrations in severe MPS IVA patients (n=9) were 3.5 times higher than those in attenuated patients (n=4) (mean, 569 ng/ ml versus 156 ng/ml).…”

“…Haplotype analyses were done by using six restriction enzyme sites as previously described (Iwata et al 1995;Tomatsu et al 1998). Plasma and urine KS concentrations were measured using the ELISA-sandwich method, and the reagents were obtained from Seikagaku (Tokyo, Japan) (Tomatsu et al 2004). …”

A Rare Case of Mucopolysaccharidosis

“…• Urine spot tests Urine spot tests are forerunners for screening mucopolysaccharides (GAG) [11]. However; these tests are associated with false-positive and falsenegative results.…”