Prediction of phenotypic severity in mucopolysaccharidosis type IIIA

Objective: Mucopolysaccharidosis IIIA or Sanfilippo disease type A is a progressive neurodegenerative disorder presenting in early childhood, caused by an inherited deficiency of the lysosomal hydrolase sulfamidase. New missense mutations, for which genotype-phenotype correlations are currently unknown, are frequently reported, hampering early prediction of phenotypic severity and efficacy assessment of new disease-modifying treatments. We aimed to design a method to determine phenotypic severity early in the disease course. Methods: Fifty-three patients were included of whom skin fibroblasts and data on disease course and mutation analysis were available. Patients were phenotypically characterized on clinical data as ‘rapidly progressing' or ‘slowly progressing'. Sulfamidase activity was measured in fibroblasts cultured at 37°C and at 30°C. Results: Sulfamidase activity in fibroblasts from patients homozygous or compound heterozygous for a combination of known severe mutations remained below the limit of quantification under both culture conditions. In contrast, sulfamidase activity in fibroblasts from patients homozygous or compound heterozygous for a known mild mutation increased above the limit of quantification when cultured at 30°C. With division on the basis of the patients phenotype, fibroblasts from ‘slowly progressing' patients could be separated from ‘rapid progressing' patients by increase in sulfamidase activity when cultured at 30°C (p<0.001, sensitivity 96%, specificity 93%). Interpretation: Phenotypic severity strongly correlates with the potential to increase sulfamidase activity in fibroblasts cultured at 30°C, allowing reliable distinction between patients with ‘rapidly progressing' or ‘slowly progressing' phenotypes. This method may provide an essential tool for assessment of treatment effects and for healthcare and life planning decisions. This article is protected by copyright. All rights reserved.