Activator protein deficiency

Niemann-Pick disease C type 2 Gmj activator protein deficiency Sphingolipid activator protein deficiency... 

GM2 gangliosidosis is a family of autosomal recessive disorders characterized by accumulation of GM2 ganglioside and its related glycolipids in the neuronal lysosome. It comprises GM2 activator protein deficiency, Tay-Sachs and Sandhoff disease, the latter of which are caused by a deficiency in the a-subunit or B-subunit of B-hexosaminidase, respectively (Gravel et ah, 1995). 

Colsch et al., 2007). Because the diagnosis may be complicated in cases of arylsulfatase A pseudodeficiency and sphingolipid activator protein deficiency, this measurement of sulfatide in the urinary sediment of affected individuals by a rapid, sensitive, and specific mass spectrometric method has been long wanted (Whitfield et al., 2001). Urinary sulfatides are now commonly detected using electrospray ionization-tandem mass spectrometry by means of the precursor ion scan 97. Levels are considerably increased to X20-30 folds as compared to controls which allows the rapid screening of a large number of samples. 

Substances influencing drug and xenobiotic metabolism (other than enzyme inducers) include lipids, proteins, vitamins, and metals. Dietary lipid and protein deficiencies diminish microsomal drug-metabolizing activity. Protein deficiency leads to a reduction in hepatic microsomal protein and lipid deficiency oxidative metabolism is decreased because of an alteration in endoplasmic reticulum (ER) membrane permeability affecting electron transfer. In terms of toxicity, protein deficiency would increase the toxicity of drugs and xenobiotics by reducing their oxidative microsomal metabolism and clearance from the body. 

In addition to an enzyme, the presence of the GM2-activator protein in vivo or of a detergent in vitro is required for the digestion of ganglioside GM2. Mutations in the gene of the P-hexosaminidase a-chain in human patients leads to Tay-Sachs disease, and mutations in the P-chain lead to Sandhoff disease. Together with GM2-activator protein deficiency, these diseases belong to the GM2-gangUosidoses. 

Sphingolipid-activator protein deficiencies GM2-activator, pSAP, SAP-B, or SAP-C Different types... 

Suzuki, K., 1994b, Molecular basis of genetic sphingolipid activator protein deficiencies. Trends Glycosci. Glycotechnol. 6 215-227. 

Bifunctional protein deficiency. The enzyme defect involves the D-bifunctional protein. This enzyme contains two catalytic sites, one with enoyl-CoA hydratase activity, the other with 3-hydroxyacyl-CoA activity [13]. Defects may involve both catalytic sites or each separately. The severity of clinical manifestations varies from that of a very severe disorder that resembles Zellweger s syndrome clinically and pathologically, to somewhat milder forms. Table 41-6 shows that biochemical abnormalities involve straight chain, branched chain fatty acids and bile acids. Bifunctional deficiency is often misdiagnosed as Zellweger s syndrome. Approximately 15% of patients initially thought to have a PBD have D-bifunctional enzyme deficiency. Differential diagnosis is achieved by the biochemical studies listed in Table 41-7 and by mutation analysis. 

Hypercoagulable states include malignancy activated protein C resistance deficiency of protein C, protein S, or antithrombin factor VIII or XI excess antiphospholipid antibodies and other situations. Estrogens and selective estrogen receptor modulators have been linked to venous thrombosis, perhaps due in part to increased serum clotting factor concentrations. Although a thrombus can form in any part of the venous circulation, the majority of thrombi begin in the lower extremities. Once formed, a venous... 

Protein S The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors Villa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH]... 

Antithrombin and activated protein C concentrates are available for the appropriate indications that include thrombosis in the setting of antithrombin deficiency and sepsis respectively. 

In case of a deficiency of arylsulfatase A, at least one other sulfatase should be measured to exclude multiple sulfatase deficiency (see Chap. 4.1 for the assays of arylsulfatase and other sulfatases). Sulfatide excretion in urine should be measured (see assay below) and/or mutation analysis should to performed to confirm the diagnosis, especially if the clinical symptoms are atypical and in order to exclude a pseudodeficiency of arylsulfatase A. The enzyme should always be measured in the parents to check for the presence of compound heterozygosity of a metachromatic leukodystrophy and a pseudodeficiency allele. This is very important for the interpretation of the results of arylsulfatase A assays, especially when performed in asymptomatic or presymptomatic siblings or in the context of a prenatal diagnosis. Sulfatide should also be measured in case a normal arylsulfatase A activity is found in a patient with symptoms characteristic of (juvenile) metachromatic leukodystrophy. Increased urinary sulfatide excretion is indicative of an activator protein/saposin deficiency (Fig. 4.4.1). 

The carcinogenicity of af la toxin is reduced by protein deficiency, presumably because of reduced metabolic activation to the epoxide intermediate, which may be the ultimate carcinogen, which binds to DNA (Fig. 5.14). A deficiency in dietary fatty acids also decreases the activity of the microsomal enzymes. Thus, ethylmorphine, hexobarbital, and aniline metabolism are decreased, possibly because lipid is required for cytochromes P-450. Thus, a deficiency of essential fatty acids leads to a decline in both cytochromes P-450 levels and activity in vivo. 

Diet. The constituents and amount of food (deficiency/starvation) may influence disposition and hence toxicity of chemicals. Food constituents may be enzyme inducers or inhibitors. Lack of food or specific constituents (e.g., protein or vitamins) may decrease metabolic capability, for example, a protein-deficient diet decreases cytochrome P-450 activity. Lack of sulfur amino acids decreases glutathione level. The effect on toxicity will depend on the role of metabolism. 

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