Prediction of phenotypic severity in mucopolysaccharidosis type IIIA

Abstract

ObjectiveMucopolysaccharidosis 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.MethodsFifty‐three patients were included for 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.ResultsSulfamidase 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 rapidly progressing patients by increase in sulfamidase activity when cultured at 30 °C (p < 0.001, sensitivity = 96%, specificity = 93%).InterpretationPhenotypic 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 health care and life planning decisions. Ann Neurol 2017;82:686–696

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

“…Enzyme activity levels in patient's cells generally cannot predict phenotype severity or progression [174,[190][191][192]. However, a recent study was able to differentiate slow progressing cases of MPS IIIA by an increase of sulfaminidase activity in patient's skin fibroblasts cultured at lower temperature (30 • C) [193].…”

Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

“…Molecular characterization of LSDs has shown that in most of the cases the disease is caused by missense mutations [37,38]. Pathophysiological studies in different LSDs have suggested that in some cases, the amino acid change leads to loss of protein stability due to changes in their processing, folding, glycosylation, and pH stability, which promotes aggregation and can induce ER or Golgi apparatus retention and/or increased degradation, or defective transport to the lysosomes [37][38][39][40][41][42][43][44][45][46][47][48]. In this sense, the use of PCs as an alternative to restore the folding and trafficking of the mutated lysosomal proteins has been proposed [19,20].…”

Early prediction of phenotypic severity in Citrullinemia Type 1

“…Based on a systematic data collection, currently more than 100 disease‐causing ASS1 genetic variants are known; however, the impact of the genotype on the phenotypic presentation remains insufficiently understood . Given that residual enzymatic activities have already been reported to predict disease severity and survival rates in other inborn errors of metabolism, such as Farber disease and mucopolysaccharidosis type IIIA and VII, we hypothesized that ASS1 enzyme activity may correlate with disease severity in CTLN1.…”