Mucopolysaccharidosis IVA: correlation between genotype, phenotype and keratan sulfate levels

Abstract

Mucopolysaccharidosis IVA (MPS IVA) is caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), leading to systemic skeletal dysplasia because of excessive storage of keratan sulfate (KS) in chondrocytes. In an effort to determine a precise prognosis and personalized treatment, we aim to characterize clinical, biochemical, and molecular findings in MPS IVA patients, and to seek correlations between genotype, phenotype, and blood and urine KS levels. Mutation screening of GALNS gene was performed in 55 MPS IVA patients (severe: 36, attenuated: 13, undefined: 6) by genomic PCR followed by direct sequence analysis. Plasma and urine KS levels were measured by ELISA method. Genotype/phenotype/KS correlations were assessed when data were available. Fifty-three different mutations including 19 novel ones (41 missense, 2 nonsense, 4 small deletions, 1 insertion, and 5 splice-site) were identified in 55 patients and accounted for 93.6% of the analyzed mutant alleles. Thirty-nine mutations were associated with a severe phenotype and ten mutations with an attenuated one. Blood and urine KS concentrations in MPS IVA patients were age-dependent and markedly higher than those in age-matched normal controls. Plasma and urine KS levels in MPS IVA patients with the severe phenotype were higher than in those with an attenuated form. This study provides evidence for extensive allelic heterogeneity of MPS IVA. Accumulation of mutations as well as clinical descriptions and KS levels allows us to predict clinical severity more precisely and should be used for evaluation of responses to potential treatment options.

Keywords: Biomarker; C6S; CDC; Centers for Disease Control and Prevention; Chondroitin-6-sulfate; Cr; Creatinine; DMB; DMSO; GAGs; GALNS; Genotype; Glycosaminoglycans; IMO; IVA Mucopolysaccharidosis IVA; International Morquio Organization; KS; Keratan sulfate; LSD; Lysosomal storage disorder; MPS; Mucopolysaccharidosis IVA; N-acetylgalactosamine-6-sulfate sufatase; Phenotype; dimethylmethylene blue; dimethylsulfoxide.

Figure 1. Comparison of initial and current clinical symptoms in MPS IVA patients

Distribution of clinical symptoms among the 55 patients who responded to the questionnaire. Dark gray bars show initial symptoms while light gray bars show current symptoms.

Figure 2. KS concentration in blood and urine

A. Concentrations of blood KS in MPS IVA patients and normal individuals. Blood samples taken from 38 MPS IVA subjects (mean age, 9.8 years; range, 0.5–46.9 years) and 234 control subjects (mean age, 18.6 years; 0–50 years). KS levels ranged between 97 ng/ml and 1,192 ng/ml (mean, 526 ± 263 ng/ml) for MPS IVA patients and 3 and 323 ng/ml (122 ± 73 ng/ml) for control subjects. B. Concentrations of urine KS in MPS IVA patients and normal individuals. Urine KS results taken from 33 MPS IVA subjects (mean age, 8.6 years; 0.5– 24 years) and 178 control subjects (mean, 9.7 years; range, 0–50 years). C. Concentrations of urine GAGs in MPS IVA patients and normal individuals. Urine GAG results taken from 36 MPS IVA subjects (mean, 8.8 years; 0.5–24 years) and 165 control subjects (mean, 9.9 years; range, 0–50 years).