Molecular markers for the follow‐up of enzyme‐replacement therapy in mucopolysaccharidosis type VI disease

Abstract

MPS VI (mucopolysaccharidosis type VI) is a lysosomal storage disease in which deficient activity of the enzyme N-acetylgalactosamine 4-sulfatase [ASB (arylsulfatase B)] impairs the stepwise degradation of the GAG (glycosaminoglycan) dermatan sulfate. Clinical studies of ERT (enzyme replacement therapy) by using rhASB (recombinant human ASB) have been reported with promising results. The release of GAG into the urine is currently used as a biomarker of disease, reflecting in some cases disease severity and in all cases therapeutic responsiveness. Using RNA studies in four Italian patients undergoing ERT, we observed that TNFalpha (tumour necrosis factor alpha) might be a biomarker for MPS VI responsive to therapy. In addition to its role as a potential biomarker, TNFalpha expression could provide insights into the possible pathophysiological mechanisms underlying the mucopolysaccharidoses.

Differential Expression of Matrix Metalloproteinases in the Serum of Patients with Mucopolysaccharidoses

“…Common characteristic of all these studies is the altered expression of enzymes studied, such as MMP-1 and MMP-13 (Simonaro et al 2008), MMP-12 (Ma et al 2008), as well as the two members of gelatinase family, MMP-2 and MMP-9 (Richard et al 2008;Simonaro et al 2005). Despite all this work, MMPs have not been sufficiently studied in human tissues, with the exception of one study, conducted by Di Natale et al, which revealed a downregulation of MMP-9 in patients with MPS VI (Di Natale et al 2008). Apart from the expression of MMPs, enzyme activity of these proteins is also a promising study field.…”

Biomarkers for the mucopolysaccharidoses: Discovery and clinical utility

“…These findings have yet to be confirmed in humans. Although one study has shown evidence of increased TNF-α gene expression in RNA from peripheral blood of a patient with MPS VI that subsequently decreased during ERT, direct measurement of serum levels was not performed [62]. It should be noted that increased levels of circulating cytokines or other inflammation-based markers could potentially reflect more broadly upon MPS disease burden rather than being biomarkers of only bone and joint disease.…”

Large Deletion Involving Exon 5 of the Arylsulfatase B Gene Caused Apparent Homozygosity in a Mucopolysaccharidosis Type VI Patient

“…At the age of 4 years he underwent enzyme replacement therapy with Naglazyme. On that occasion, a mutation analysis showed the presence of the nonsense mutation p.R315X (c.943C>T) in apparent homozygosity (Di Natale et al, 2008). At that time, however, the DNA of the parents was not available; only after 2 years from the initial molecular diagnosis did the family members ask for their carrier status to be defined.…”

“…The patient was previously diagnosed as being apparently homozygous for the p.R315X mutation found on exon 5 of the ARSB gene (Di Natale et al, 2008). Subsequently, the availability of DNA from his parents allowed us to reexamine the case.…”

“…Very recently, in an attempt to identify molecular markers for the follow-up of enzyme replacement therapy, four Italian patients were tested at the DNA level; among these, one patient showed the nonsense mutation p.R315X in apparent homozygosity (Di Natale et al, 2008). Subsequently, when the genetic test was performed on parents' DNA, we found (this study) that the patient carried a second mutation (g.99367-102002del) resulting in the deletion of the entire exon 5 of the gene as well as a part of introns 4 and 5.…”