Mucopolysaccharidosis type I: current knowledge on its pathophysiological mechanisms

• Published in: Metabolic brain disease 2012-06, Vol.27 (2), p.121-129
• Main Authors: Campos, Derbis, Monaga, Madelyn
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Apoptosis - physiology; Biochemistry; Biomedical and Life Sciences; Biomedicine; Gangliosides; Gangliosides - metabolism; Glycosaminoglycans - metabolism; Heparan sulfate; Homeostasis; Homeostasis - physiology; Humans; Inflammation; Inflammation - pathology; Intracellular signalling; Lysosomal Membrane Proteins - metabolism; lysosomal storage diseases; Lysosomes; Lysosomes - physiology; Macromolecules; Membrane permeability; Metabolic Diseases; Metabolic disorders; Metabolism; Morbidity; Mortality; Mucopolysaccharidosis; Mucopolysaccharidosis I - metabolism; Mucopolysaccharidosis I - physiopathology; Mutation; Neurology; Neurosciences; Oncology; Oxidative stress; Review Article; Signal transduction; Signal Transduction - physiology; Sulfate
• ISSN: 0885-7490; 1573-7365
• DOI: 10.1007/s11011-012-9302-1

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.