Characteristic Metabolites for Inborn Errors of Lipid Metabolism

Hereditary disorders in lipid metabolism include Tay-Sachs disease, Gaucher disease, Niemann-Pick disease, metachromatic leucodystrophy, Fabry disease, Refsum disease, and Tangier disease. These lipidoses are characterized by dysfunctional lipid metabolism and result in abnormal metabolite accumulations. One of the first disorders recognized as an inborn error of lipid metabolism was Refsum disease, which produces toxic levels of phytanic acid if untreated.

Gaucher disease is a progressive sphingolipid-degradation disease characterized by genetic mutations in the lysosomal enzyme glucocerebrosidase, which leads to decreased enzymatic activity. Measurements of the metabolites methylcholine, phosphatidylcholine, and sphingomyelin are important for studying the pathophysiology of Gaucher disease. The main therapy used to treat Gaucher disease is enzyme-replacement therapy in order to normalize sphingolipid degradation and to prevent tissue damage caused by sphingolipid accumulation. Another promising therapeutic approach to Gaucher disease is to decrease the tissue glucocerebrosidase level to a concentration which can be cleared by the existing glucocerebrosidase.

A deficiency of the lysosomal enzyme a-galactosidase A results in the progressive accumulation of the glycosphingolipids globotriaosylceramide Gb3 and digalactosyl-ceramide in Fabry disease, which can cause early death from cardiac, renal, and cerebrovascular events.

Dimethylglycine dehydrogenase (DMGDH) deficiency is an inborn error of choline metabolism caused by a mutation in the gene hDMGDH and results in increased N,N-dimethylglycine concentrations of 100-fold in serum and 20-fold in urine.

Nine inborn errors of bile acid metabolism have been identified that result in enzyme deficiencies and damaged bile acid biosynthesis in infants, children, and adults. Since bile acids have several important physiological functions, such as emulsifying fats and fat-soluble vitamins, and involvement in cholesterol, bilirubin, xenobiotics, and drug metabolites elimination, a failure in the multistep enzymatic conversion of cholesterol to bile acids will accumulate unusual bile acids and metabolic intermediates.


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