Folate metabolism disorders

CFD is further associated with the following inherited metabolic disorders 5,10-methylen-tetrahydrofolate reductase (MTHFR) deficiency [7], 3-phos-phoglycerate dehydrogenase (PGDH) deficiency [8], dihydropteridine reductase (DHPR) deficiency [9], as well as with Rett syndrome [10], and Aicardi-Gou res Syndrome [11]. Furthermore, folate deficiency may be associated with congenital folate malabsorption, severe malnutrition, and formiminotransferase deficiency. 

Methotrexate, a folic acid antagonist, is used in the treatment of several disorders. Its major action is inhibition of dihydrofolate reductase, a critical enzyme in intracellular folate metabolism. Co-trimoxazole competes with methotrexate in inhibiting dihydrofolate reductase and further impairs DNA synthesis. 

Vitamin Bij (cyanocobalamin extrinsic factor) is required in folate metabolism for DNA synthesis, and a deficiency leads to pernicious anaemia. It is used to supplement the diet after certain operations that remove the site of production of intrinsic factor, such as total gastrectomy. Deficiency causes megaloblastic haemopoiesis in which there is a marked disorder of formation of erythroblasts, and can be rectified by giving hydroxocobalamin. 

Figure 30-17 L-ascorbic and dehydroascorbic acids. (Modified from Row PB Inherited disorders of folate metabolism. In Stanbury JB, Wyngaarden DS (eds) The metabolic bases of inherited disease, Sth edition, New York McGraw-Hill, 1983.)...

Deficiencies of methionine adenosyltransferase, cystathionine 8-synthase, and cystathionine )/-lyase have been described. The first leads to hypermethioninemia but no other clinical abnormality. The second leads to hypermethioninemia, hyperhomocysteinemia, and homo-cystinuria. The disorder is transmitted as an autosomal recessive trait. Its clinical manifestations may include skeletal abnormalities, mental retardation, ectopia lentis (lens dislocation), malar flush, and susceptibility to arterial and venous thromboembolism. Some patients show reduction in plasma methionine and homocysteine concentrations and in urinary homocysteine excretion after large doses of pyridoxine. Homocystinuria can also result from a deficiency of cobalamin (vitamin B12) or folate metabolism. The third, an autosomal recessive trait, leads to cystathioninuria and no other characteristic clinical abnormality. 

One patient has been found with this deficiency (All). Hie patient, an infant, was mentally retarded, had a megaloblastic anemia and abnormally high levels of serum and erythrocyte folate. In spite of the high serum folate concentration there was a marked rise in the reticulocyte count when the patient was treated with folate. It was thought that the patient had impaired utilization of -methyltetrahydrofolate. Assay of liver W -methyltetrahy-drofolate transferase showed it to be reduced. It was suggested that folate accumulated at the N -methyltetrahydrofolate block and could therefore not be further utilized. Treatment with pteroylglutamic acid provided a means of producing active folate up to the point of the block. Unfortunately this patient was also treated with pyridoxine, and it is not clear which vitamin was responsible for the reticulocyte response. Further studies are required to determine the precise nature of this metabolic disorder. 

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. 

Rowe, P.B. (1978), Inherited disorders of folate metabolism. In The Metabolic Basis of Inherited Disease (eds J.B. Stanbury, J.B. Wyngaarden and D.S. Fredrickson), 4th edn., McGraw-Hill Book Co., New York, Chapter 22, pp. 430-457. 

Rosenblatt DS, Erbe RW (2001) Inherited disorders of folate and cobalamin transport and metabolism. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease, 8th edn. McGraw-Hill, New York, NY, pp 3897-3933... 

The homocystinurias are a group of disorders involving defects in the metabolism of homocysteine. The diseases are inherited as autosomal recessive illnesses, characterized by high plasma and urinary levels of homocysteine and methionine and low levels of cysteine. The most common cause of homocystinuria is a defect in the enzyme cystathionine /3-synthase, which converts homocysteine to cystathionine (Figure 20.21). Individuals who are homozygous for cystathionine [3-synthase deficiency exhibit ectopia lentis (displace ment of the lens of the eye), skeletal abnormalities, premature arte rial disease, osteoporosis, and mental retardation. Patients can be responsive or non-responsive to oral administration of pyridoxine (vitamin B6)—a cofactor of cystathionine [3-synthase. Bg-responsive patients usually have a milder and later onset of clinical symptoms compared with B6-non-responsive patients. Treatment includes restriction of methionine intake and supplementation with vitamins Bg, B, and folate. 

Anyone taking diuretics for longer than six months may experience a folate, or folic acid, deficiency. Folic acid plays a part in the health and reproduction of virtually every cell in the body. It is responsible for protein metabolism, the prevention of neural tube defects in pregnancy, blood cell production, and the synthesis of neurotransmitters. Individuals with folate deficiencies may suffer from anemia, depression and other mood disorders, and may give birth to babies with neural tube defects. Supplementation with folic acid may be useful in reversing these effects. 

Folic acid deficiency, unlike vitamin B12 deficiency, is often caused by inadequate dietary intake of folates. Alcoholics and patients with liver disease develop folic acid deficiency because of poor diet and diminished hepatic storage of folates. There is also evidence that alcohol and liver disease interfere with absorption and metabolism of folates. Pregnant women and patients with hemolytic anemia have increased folate requirements and may become folic acid-deficient, especially if their diets are marginal. Evidence implicates maternal folic acid deficiency in the occurrence of fetal neural tube defects, eg, spina bifida. (See Folic Acid Supplementation A Public Health Dilemma.) Patients with malabsorption syndromes also frequently develop folic acid deficiency. Folic acid deficiency is occasionally associated with cancer, leukemia, myeloproliferative disorders, certain chronic skin disorders, and other chronic debilitating diseases. Patients who require renal dialysis also develop folic acid deficiency, because folates are removed from the plasma each time the patient is dialyzed. 

Adverse effects include CNS symptoms (reversible blurring of vision, diplopia, dizziness and ataxia) and depression of cardiac AV conduction. Alimentary symptoms, skin rashes, blood disorders and liver and kidney dysfunction also occur. Osteomalacia by enhanced metabolism of vitamin D (enzyme induction) occurs over years so also does folate deficiency. Enzyme induction reduces the efficacy of combined and progestogen-only contraceptives. Carbamazepine impairs cognitive function less than phenytoin. 

Inherited disorders of folate transport and metabolism include defects in folate carrier (hereditary folate malabsorption, previously discussed), deficiency of N, N °-methylene FH4 reductase (Chapter 17), or functional deficiency of N -methyl FH4 methyltransferase due to defects... 

Deficiency of folate or vitamin Bn can cause hematological changes similar to hereditary orotic aciduria. Folate is directly involved in thymidylic acid synthesis and indirectly involved in vitamin Bn synthesis. Orotic aciduria without the characteristic hematological abnormalities occurs in disorders of the urea cycle that lead to accumulation of carbamoyl phosphate in mitochondria (e.g., ornithine transcarbamoylase deficiency see Chapter 17). The carbamoyl phosphate exits from the mitochondria and augments cytosolic pyrimidine biosynthesis. Treatment with allopurinol or 6-azauridine also produces orotic aciduria as a result of inhibition of orotidine-5 phosphate decarboxylase by their metabolic products. 

An increased plasma level of homocysteine is regarded as a risk factor for cardiovascular disease and the development of arteriosclerosis. Homocysteine concentrations in plasma are reduced by remethylation and transsulfuration (Komarnisky et al. 2003). The remethylation is catalyzed by methionine synthase, which in turn is influenced by vitamin B12 and folate. The transsulfura-tions depend on cystathionine 3-synthase. A dietary deficiency of vitamins B, B12 and folate, accompanied by a high protein intake, can cause hyperhomocystinemia in humans (Jacobsen 1998). Furthermore, a genetic disorder of enzymes involved in the metabolism of homocysteine leads to hypercystinuria (Mudd et al. 1989). 

Steinfeld, R., Grapp, M., Kraetzner, R., Dreha-Kulaczewski, S., Helms, G., Dechert, P., Wevers, R., Grosso, S., and Gartner J., 2009. FDolate receptor alpha defect causes cerebral folate transport deficiency a treatable neuro-degenerative disorder associated with disturbed myelin metabolism. American Journal of Human Genetics. 85 354-363. 

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