Folate metabolism, inborn errors

Allen, R., S. Stabler, and J. Lindenbaum (1993). Serum betaine, A,A-dimethylglycine and N-methylglycine levels in patients with cobalamin and folate deficiency and related inborn errors of metabolism. Metabolism 42 1448-1460. 

Measurement of blood tHcy is usually performed for one of three reasons (1) to screen for inborn errors of methionine metabolism (2) as an adjunctive test for cobalamin deficiency (3) to aid in the prediction of cardiovascular risk. Hyperhomocysteinemia, defined as an elevated level of tHcy in blood, can be caused by dietary factors such as a deficiency of B vitamins, genetic abnormalities of enzymes involved in homocysteine metabolism, or kidney disease. All of the major metabolic pathways involved in homocysteine metabolism (the methionine cycle, the transsulfuration pathway, and the folate cycle) are active in the kidney. It is not known, however, whether elevation of plasma tHcy in patients with kidney disease is caused by decreased elimination of homocysteine in the kidneys or by an effect of kidney disease on homocysteine metabolism in other tissues. Additional factors that also influence plasma levels of tHcy include diabetes, age, sex, lifestyle, and thyroid disease (Table 21-1). 

Indirect indicators of vitamin B12 deficiency include measurements of the metabolites homocysteine and methylmalonic acid (MMA) in serum and MMA in urine (see the Biochemical Perspectives section). Whereas the serum homocysteine concentration increases during folate or vitamin B12 deficiencies, the serum and urine MMA concentrations increase only in vitamin B12 deficiency. Therefore, MMA determinations can be used to differentiate vitamin B12 deficiency from folate deficiency. The normal concentration of MMA in serum ranges from 0.08 to 0.28 pmol/L. MMA is quantified using gas-liquid chromatography and mass spectrometry. Elevated concentrations of MMA and homocysteine in serum may precede the development of hematological abnormalities and reductions in serum vitamin B12 concentrations. One should be aware that other conditions, including renal in sufficiency and inborn errors of metabolism, can also result in elevated serum levels of MMA. 

Transamination Products of the Amino Acids Vitamin Be-Responsive Inborn Errors of Metabolism Indices of Vitamin Be Nutritional Status Reference Intakes of Vitamin Be Adverse Effects of Hyperhomocysteinemia Indices of Folate and Vitamin B12 Nutritional Status Reference Intakes of Folate Reference Intakes of Vitamin B12... 

There are several vitamin Bg-responsive inborn errors of metabolism that include (1) cases of infantile convulsions in which the apoenzyme for glutamate decarboxylase has a poor affinity for the coenzyme (2) a type of chronic anemia in which the number but not morphological abnormality of erythrocytes is improved by pyridoxine supplementation (3) xanthurenic aciduria in which affinity of the mutant kynureninase for PLP is decreased (4) primary cystathion-inuria caused by similarly defective cystathionase and (5) homocystinuria in which there is less of the normal cystathionine synthetase. In these cases increased levels (200 to lOOOmg/day) of administered vitamin Bg are required for life. Low vitamin Bg status (together with low vitamin B12 and folate status) in humans has been linked to hyperho-mocysteinemia and as an independent risk factor for cardiovascular disease. ... 

What appeared to be a new inborn error of metabolism was described by Branda in 1978 (B19). The patient was a young man who came from a family in which hematological disease had contributed to, or caused the death of 18 of 34 affected members of the family. He was found to have a severe anemia and an aplastic bone marrow and required regular transfusions. A further bone marrow biopsy 2 years later showed continuing severe aplasia but a megaloblastic change was noted in the few remaining erythrocyte precursors. His serum vitamin normal but his serum folate was minimally... 

Pancytopenia-thrombocytopenia-leukopenia in organic acidurias hemolytic anemia in galactosemia, congenital erythropoietic porphyria, glycolytic and pentose-phosphate enzymes deficiencies macrocytic anemia in inborn errors of cobalamin and folate metaboUsm Metabolic acidosis in organic acidurias (anion gap) respiratory alkalosis in hyperammonemias... 

Inborn errors of folate metabolism also shed light on the role of folates and products of folate metabolism in neurological function. Disorders that result in decreased levels of 5-CH3-THF in the central nervous system are frequently associated with development of seizures e.g. MTHFR deficiency, DHFR deficiency, MTHFDl deficiency, and autoimmune or genetic cases of cerebral folate deficiency due to malfunction of folate receptor alpha). Adult onset cases of MTHFR deficiency have in some cases been associated with psychosis. 

Mild hyperhomocysteinemia due to inadequate intake of folate and vitamin Bi2 is associated with an increased risk of cardiovascular disease [7]. The number of persons at risk vastly exceeds the number of patients with inborn errors of metabolism, and public health policy recommendations for screening and intervention in patients with mild hyperhomocysteinemia await ongoing clinical trials. 

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See also in sourсe #XX -- [ ]

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