Lysosomal storage disorders

From LipidomicsWiki

Lysosomal storage disorders (LSD) represent a group of 40 distinct genetic diseases, resulting in most cases from a deficiency of particular lysosomal hydrolases and in a few cases from non-lysosomal enzymes. The deficiency of the enzymes leads to accumulation of undigested metabolites in lysosomes and is a cause of various polysystemic dysfunctions, including progressive neurologic deterioration, mental retardation, blindness and early death. Most lysosomal storage disorders are inherited in an autosomal recessive manner with the exception of Fabry disease and mucopolysaccharidosis type II, which are linked to the X chromosome (Meikle and Hopwood, 2003). With few exceptions, these disorders are a result of the deficiency of one or more glycosidases and they are classified according to the type and site of the primary accumulated products into mucopolysaccharidoses (MPC), mucolipidoses (ML), glycoproteinoses, sphingolipidoses and others (Tab.11). Sphingolipidoses are the most prevalent subgroup of the lysosomal storage disorders and are characterized by excessive accumulation of one or multiple (glyco)sphingolipids (Aerts et al. 2003). Niemann-Pick disease (NP) was initially characterized as a pathologic unit comprising hepatosplenomegaly, sphingomyelin storage in reticuloendothelial and peripherial tissues and neurodegeneration (Crocker and Farber, 1958). Niemann-Pick type A and B display sphingomyelin deficiency , while type C and D have normal sphingomyelinase level (Schneider and Kennedy, 1967). Studies of Niemann-Pick type C (NPC) delivered valuable insights into the mechanisms underlying regulation of cellular cholesterol homeostasis (Ory, 2004). This type of Niemann-Pick disorder is characterized by excessive cholesterol accumulation in the liver, spleen and central nervous system (Ory, 2000). The cells in NPC display a regular uptake of LDL and hydrolysis of cholesteryl esters, however, they are defective in the delivery of lysosomal cholesterol to the ER for esterification and in the movement of lysosomal cholesterol to the plasma membrane (Neufeld et al. 1996). Two genes NPC1 and NPC2 have been identified and mutations in these genes result in the clinical and biochemical NPC phenotype (Vanier et al. 1996). They appeared to be key participants in intracellular cholesterol trafficking and cells with mutations within NPC1 and NPC2 accumulate unesterified cholesterol in endosomal/lysosomal organelles and exhibit markedly impaired rates of esterification of LDL-derived cholesterol to form lipid droplets (Steinberg et al. 1996).


In NPC1-/- macrophages, ABCA1-mediated cholesterol efflux to ApoAI is impaired and accumulation of lipoprotein-derived cholesterol in the cells would promote differentiation into foam cells leading to progression of atherosclerosis (Chen et al. 2001). Only recently, Altmann et al (Altmann et al. 2004) identified a gene homologous to NPC1, which seems to be involved in the regulation of cholesterol and plant sterol (sitosterol) absorption. Human NPC1-like 1 (NPC1L1) gene, which is in 50% homologous to NCP1 gene and the target gene of the cholesterol absorption inhibitor Ezetrol (Ezetimibe), turned out to be critical for the uptake of cholesterol across the plasma membrane of the intestinal enterocyte. Treatment of some lipid storage disorders is possible. Till now, several therapies have been applied including substrate reduction therapy (Lachmann and Platt, 2001), enzyme replacement therapy (ERT), hematopoietic stem cell (HSC) transplantation and gene therapy (D’Azzo, 2003), which over the past three decades has moved from an academic pursuit to direct delivery of effective clinical care for affected patients and families. This success is based on understanding the complexities of lysosomal biogenesis, lysosomal hydrolase sorting and hydrolytic requirements, and the target sites of pathology of these diseases (Grabowski and Hopkin, 2003). However, despite the biochemical and genetic knowledge that has been accumulated upon years about the cause of most of the lysosomal storage disorders, it is still unclear how the storage leads to cellular dysfunction and how the dysfunctions lead to pathological symptoms of the disorders.

table to added Noragon 31 May 2011


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