Mucopolysaccharidosis type I: current knowledge on its pathophysiological mechanisms

Abstract

Mucopolysaccharidosis type I is one of the most frequent lysosomal storage diseases. It has a high morbidity and mortality, causing in many cases severe neurological and somatic damage in the first years of life. Although the clinical phenotypes have been described for decades, and the enzymatic deficiency and many of the mutations that cause this disease are well known, the underlying pathophysiological mechanisms that lead to its development are not completely understood. In this review we describe and discuss the different pathogenic mechanisms currently proposed for this disease regarding its neurological damage. Deficiency in the lysosomal degradation of heparan sulfate and dermatan sulfate, as well as its primary accumulation, may disrupt a variety of physiological and biochemical processes: the intracellular and extracellular homeostasis of these macromolecules, the pathways related to gangliosides metabolism, mechanisms related to the activation of inflammation, receptor-mediated signaling, oxidative stress and permeability of the lysosomal membrane, as well as alterations in intracellular ionic homeostasis and the endosomal pathway. Many of the pathogenic mechanisms proposed for mucopolysaccharidosis type I are also present in other lysosomal storage diseases with neurological implications. Results from the use of methods that allow the analysis of multiple genes and proteins, in both patients and animal models, will shed light on the role of each of these mechanisms and their combination in the development of different phenotypes due to the same deficiency.

Normalization and Improvement of CNS Deficits in Mice With Hurler Syndrome After Long-term Peripheral Delivery of BBB-targeted Iduronidase

“…1 Mucopolysaccharidosis type I (MPS I), one of the most common lysosomal storage disorders, is caused by mutations in the gene encoding a lysosomal enzyme, α-l-iduronidase (IDUA), and subsequent accumulation of dermatan sulfate and heparan sulfate. 2 The abnormal accumulation of these complex sugars known as glycosaminoglycans (GAG) in the lysosomes leads to progressive multiorgan damage. Patients with severe form of MPS I have an early-onset, rapidly progressive disease that is accompanied by CNS complications and premature death if untreated.…”

Proteomic analysis of mucopolysaccharidosis I mouse brain with two-dimensional polyacrylamide gel electrophoresis

“…An elevation of the pH in lysosome may severely compromise the activity of different lysosomal hydrolases and vesicle trafficking mechanisms (29). As a side effect, substrates and molecules not directly related to the primary enzyme deficiency may accumulate, as is the case with most lysosomal diseases (reviewed in 30). Further, elevation in pH and lower Ca 2+ concentration in lysosomes can inhibit the fusion between endosomes, autophagosomes and lysosomes, resulting in impaired endocytotic and autophagic pathways (31).…”

Chiari I malformation and syringomyelia in mucopolysaccharidosis type I (Hurler syndrome) treated with posterior fossa decompression: Case report and review of the literature

“…Intralysosomal accumulation of these substrates results in pathological processes that produce a progressive dysfunction resulting in multiorgan deterioration that includes hepatosplenomegaly, dysostosis multiplex, short stature, coarse facial features, corneal clouding, joint contractures, umbilical hernias, failure to thrive, intellectual disability, and developmental delay. [512] The extensive storage of these glycosaminoglycans is also known to cause meningeal thickening. [4] Intraoperatively, our patient was noted to have thickened arachnoid membrane, which was biopsied and sent for pathological assessment.…”