Mucopolysaccharidosis III: Molecular basis and treatment

Abstract

Mucopolysaccharidoses (MPSs) are known as rare genetic diseases which are caused by mutation in the enzyme heparin sulfate, which normally leads to degradation and accumulation of glycosaminoglycans in the cells. There are 11 types of MPSs, whereby neuropathy may occur in seven of them (MPS I, II, IIIA, IIIB, IIIC, IIID and VII). Accumulation of degraded heparin sulfate in lysosomes causes cellular dysfunction and malfunction of several organs. However, the exact molecular mechanism how protein degradation and storage leads to cellular dysfunction is not understood, yet. Nonetheless, several genetic and biochemical methods for diagnosis of MPSs are available nowadays. Here we provide an overview on known molecular basis of MPS in general, including enzyme defects and symptoms of MPS; however, the main focus is on MPS type III together with potential and perspective therapy-options.

Keywords: clinical diagnosis.; glycosaminoglycan; lysosomal storage diseases (LSDs); therapy for mucopolysccharidosis; mucopolysaccharidosis III (MPS III).

Figure 1

Synthesis and degradation of HS (Heparan Sulfate) is presented schematically including cell organelles (Lysosome) and enzymes which are responsible for each MPSs; also modification of residues is shown

Figure 2

Potential therapy attempts to treat MPS. Schematic representations of: A) enzyme replacement therapy (ERT) to replace mutated form of protein; B) substrate reduction therapy (SRT), reduction of storage of undegraded substrate; C) pharmacological chaperone to correct substrate miss-folding; D) stem cell therapy (SCT) used for replacement of diseased cells; E) gene therapy to provide correct form of a mutated gene