Metabolic diseases lysosomal storage

Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein (2001) The metabolic molecular bases of inherited disease. Vol III Lysosomal storage disorders McGraw-Hill, New York, Chapters 134, 143,144-148, 150, 151, and 153... 

Dehydrogenase Deficiency, Biotinidase Deficiency, and Adrenoleukodystrophy. Catabolism of essential amino acid skeletons is discussed in the chapters Phenylketonuria and HMG-CoA Lyase Deficiency. The chapters Inborn Errors of Urea Synthesis and Neonatal Hyperbilirubinemia discuss the detoxification and excretion of amino acid nitrogen and of heme. The chapter Gaucher Disease provides an illustration of the range of catabolic problems that result in lysosomal storage diseases. Several additional chapters deal with key aspects of intracellular transport of enzymes and metabolic intermediates the targeting of enzymes to lysosomes (I-Cell Disease), receptor-mediated endocytosis (Low-Density Lipoprotein Receptors and Familial Hypercholesterolemia) and the role of ABC transporters in export of cholesterol from the cell (Tangier disease). 

Can include a variety of effects, but neurodegenerative disorders are primarily hereditary in nature (in-born errors of metabolism), for example lysosomal storage diseases. 

Mucolipidoses are characterized by a combined metabolic disorder of mucopolysaccharides, lipids, and glycoproteins. Lysosomal storage and foamy swollen Kupffer cells with hepatomegaly may be seen. In some of the numerous types, the underlying enzymatic defects have not yet been detected. Type II is also called Leroy syndrome (J.G. Leroy et al., 1967). Due to distinctive cytoplasmic inclusions in fibroblast cultures, this disorder is also known as inclusion cell disease (J.G. Leroy et al., 1971). Foamy altered stellate cells, macrophages and also epithelioid foam cell granulomas are found. 

Unlike lysosomal lipid-storage diseases (see below), very few metabolic diseases are known to be related to mutations of glycosyltransferases in ganglioside synthesis. The one new finding has been from that of Simpson et al. [45], who showed that a nonsense mutation of ST-I (GM3-synthase) is the cause of human autosomal recessive infantile-onset s)mptomatic epilepsy s)mdrome. Because ST-I is a key enz)me in the synthesis of all complex gangliosides, this report clearly indicates that the precise expression of complex gangliosides has critical biological functions in human nervous system development. 

Measurements of enzymes are used in medicine in two major ways Enzymes are measured in serum and other bodily fluids to detect injury to a tissue that makes the enzyme. Enzymes are also measured, often within a tissue, to identify abnormahties or absence of the enzyme, which may cause disease. In the first part of this chapter we discuss enzymes as markers of disease, and then describe conditions associated with abnormalities of enzymes in one readily available cell type, the erythrocyte or red blood cell. Many other abnormahties of enzymes exist, of course, and many are described in chapters of this book including Chapters 40 (Inherited Disease), 43 (Pharmacogenetics) and 55 (Inborn Errors of Amino Acid, Organic Acid, and Fastty Acid Metabolism). For descriptions of enzyme abnormalities associated with lysosomal storage disease, and tests for the related enzymes, readers are referred to the Chapter 40 Appendix that is located on this book s accompanying Evolve site, found at http //evolve.elsevier.com/Tietz/textbook/. 

Lysosomal accumulation of free sialic acid occurs in two phenotypically distinct inherited metabolic disorders, Salla disease and infantile sialic acid storage disease [1096]. Salla disease is an autosomal recessive lysosomal storage disorder and was first observed in patients of Fiimish ancestry, but also occurs outside Finland. The clinical symptoms are a slow progressive psychomotor retardation, impaired speech, ataxia and a prolonged course. Sialic acid accumulates in the lysosomes due to a defective efflux into the cytosol. The genetic defect affects the function of the specific transport protein for sialic acid and other acidic monosaccharides in the lysosomal membrane [1097]. The Salla disease locus... 

Each lysosomal storage disease (see p. 49) is caused by a hereditary deficiency of an enzyme required for the degradation of a specific metabolite. Several lysosomal storage diseases are associated with sphingolipid metabolism. Most of... 

Beutler E., Lysosomal storage diseases natural history and ethical and economic aspects. Molecular genetics and metabolism 88 (2006) 208-215. 

There are multitudes of namrally occurring diseases of the central nervous system, including degenerative, traumatic, neoplastic, and metabolic disorders. Naturally occurring diseases for which there are potential models include models for include Parkinson s disease (PD), Huntington s disease (HD), Alzheimer s disease (AD), cerebral ischemia, miscellaneous neoplastic conditions, and lysosomal storage diseases. Examples of selected animal models of human disease will be briefly suimnarized. 

Lysosomal storage diseases Inborn errors of metabolism (see), in which specific hydrolases are absent from the lysosomes, leading to accumulaticm... 

Bis(monoacylglycero)phosphate (BMP) species are isomeric to PG species. In BMP, two FA chains are acylated to different glycerol molecules, whereas these FA chains are located in one glycerol in PG species. BMP plays an important role in normal lysosomal/endosomal functions in cells [62]. It has become evident that BMP is involved in the pathology of lysosomal storage diseases such as Niemann-Pick C disease (cholesterol accumulation) and certain drug-induced lipidoses [63,64]. Dys-regulation of BMP metabolism and hence of cholesterol homeostasis may also be relevant to atherosclerosis [64]. 

There have been few discoveries of lysosomal storage diseases being related to a deficiency of a protease. Efficient lysosomal proteolysis could be such a crucial metabolic process that any defects in this system would be developmentally lethal and therefore never observed medically. For example, mice deficient in cathepsin D were generated by targeted disruption of the gene and the animals died in a state of anorexia by day 26 due to widespread intestinal necroses [42]. Since bulk lysosomal... 

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