Differences in MPS I and MPS II Disease Manifestations

Int J Mol Sci. 2021 Jul 23;22(15):7888. doi: 10.3390/ijms22157888.

PMID: 34360653

Christiane S Hampe, Brianna D Yund, Paul J Orchard

Highlights: While enzyme replacement therapy (ERT) has beneficial effects on respiratory and cardiopulmonary function and extends the lifespan of MPS II patients, it does not significantly affect CNS manifestations. Therefore, many experimental therapies aim to prevent neurocognitive decline in these patients.

Abstract

Background: The lysosomal storage diseases mucopolysaccharidosis (MPS) type I and type II are connected by defective glycosaminoglycan catabolism. Iduronate 2-sulfatase (IDS) (a lysosomal enzyme) deficiency blocks the first phase of the breakdown of heparan sulfate (HS) and dermatan sulfate (DS) in MPS II, whereas iduronidase deficiency blocks the second step in MPS I. (IDUA). The subsequent accumulation of HS and DS affects cellular processes like cell adhesion, endocytosis, intracellular trafficking of various molecules, intracellular ionic balance, and inflammation by causing lysosomal hypertrophy and an increase in the number of lysosomes in cells. Skeletal disease, reflected in short stature, inguinal and umbilical hernias, hydrocephalus, hearing loss, coarse facial characteristics, protruding abdomen with hepatosplenomegaly, and neurological involvement with various functional issues are some of the distinctive phenotypical signs of both MPS I and II. The severity and form of some manifestations, such as corneal clouding in MPS I, epidermal manifestations in MPS II, and changes in behavioral issues, are disease-specific. These phenotypic variations seem to be connected to various DS/HS ratios and sulfation levels. Higher DS/HS ratios and lower sulfation levels are characteristics of MPS I, but in MPS II, HS levels predominate over DS levels and sulfation levels are higher. Corneal clouding may be more common in MPS I than MPS II due to the high concentration of DS in the cornea and its role in the positioning of collagen fibrils. Due to HS's role in neurological development, the disparities in neurological involvement may be caused by MPS II's elevated HS levels. Enzyme replacement therapy is currently the only available treatment for MPS II patients (ERT).

Objective: The fact that ERT does not significantly alter CNS symptoms is likely due to the enzyme's inability to cross the blood-brain barrier at sufficient levels, even though it has positive effects on respiratory and cardiac function and increases patient lifespan. In an effort to stop patients' neurocognitive decline, numerous investigational medicines target IDS delivery to the CNS.

Keywords: dermatan sulfate, glycosaminoglycans, heparin sulfate, mucopolysaccharidosis type I, mucopolysaccharidosis type II