Homocysteine metabolism disorders

Brain Damage in Phenylalanine, Homocysteine and Galactose Metabolic Disorders... 

As described above, phenylalanine, homocysteine, and galactose metabolic disorders affect brain function, the latter being profoundly or partially avoided by early diagnosis and proper treatment. As the ancient Greek doctor Hippocrates said, Prevention is better than treatment . 

Dudman NP, Wilcken DE, Wang J, Lynch JF, Macey D, Lundberg P. Disordered methionine/ homocysteine metabolism in premature vascular disease. Its occurrence, cofactor therapy and enzymology. Arterioscler Thromb 1993 13 1253-1260. 

Homocystinuria. An inherited autosomal recessive disorder of homocysteine metabolism (1/200000 births) caused by mutations in the cystathione beta synthase (CBS) gene that disrupts the normal activity of CBS. Homocystinuria patients have highly elevated plasma homocysteine levels and are at increased early risk of thrombotic/vascular events. Homocystinuria can be more rarely caused by mutations in other genes involved in homocysteine metabolic pathways. 

Figure 7.3. Scheme of the enzymatic synthesis of cobamides in the cell. AdoCbl and MeCbl are formed from the common precursor OHCbl via two reductive steps catalyzed by separate enzymes. Metabolic disorders due to enzyme defects may occur at the two reductions and additions of adenosyl or methyl residues. High urinary levels of methylmalonic acid (methylmalonic aciduria) indicate an impaired synthesis of AdoCbl, whereas high levels of urinary homocysteine (homocystinuria) indicate an impaired MeCbl synthesis. In patients with high urinary levels of both methylmalonic acid and homocysteine a defective reduction of cobalamin is likely (Rosenberg, 1983). 

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. 

This is another rare inherited disorder of vitamin B12 metabolism in which both coenzyme forms, adenosylcobalamin and methylcobalamin, are affected. Methylcobalamin is required for the transfer of the methyl group of 5-methyltetrahydrofolate to homocysteine to give methionine. Lack of methylcobalamin results in deficient activity of 2V5-methyltetrahydrofolate-homo-cysteine methyltransferase, resulting in a reduced ability to methylate homocysteine. A failure of methionine synthetase would produce a similar result. 

High homocysteine levels and vascular disease Section 24.2.9 Inherited disorders of porphyrin metabolism Section 24.4.4 Anticancer drugs that block the synthesis of thymidylate Section 25.3.3... 

A large number of disorders are associated with cobalamin deficiency in infancy or childhood. Of these, the most commonly encountered is the Imerslund-Graesbeck syndrome, a condition that is characterized by inability to absorb vitamin B,2, with or without IF, and proteinuria. It appears to be due to an inability of intestinal mucosa to absorb the vitamin B,2 IF complex. The second most common of these is congenital deficiency of gastric secretion of IF. Very rarely, congenital deficiency of vitamin B12 in a breast-fed infant is due to deficiency of vitamin B12 in maternal breast milk as a result of unrecognized pernicious anemia in the mother. This is rare because most women with undiagnosed and untreated pernicious anemia are infertile. Additionally, there are some rare methylmalonic acidemias (acidurias) caused by inborn errors in homocysteine and methionine metabolism that are responsible for disorders in vitamin B status. ... 

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. 

Several inherited disorders of methionine metabolism (Chapter 17) give rise to exeessive production of homocysteine, HS-CH2-CH2CH(NH3 )COO , and its excretion in urine. The most common form of homocystinuria is due to a deficiency of cystathionine synthase (Chapter 17). A major clinical manifestation of homocystinuria is connective tissue abnormalities that are probably due to the accumulation of homocysteine, which either inactivates the reactive aldehyde groups or impedes the formation of polyfunctional cross-links. 

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). 

The main function of vitamin B12 is thought to be in the metabolism of amino acids. Thus, B,2 is involved in the conversion of homocysteine to methionine and in the catabolism of some branched-chain amino acids. The neurological disorder that is usually associated with vitamin B12 deficiency is due to progressive demyelination of nervous tissue, thought to be owing to a build up of the vitamin Bj2 substrate, methylmalonyl CoA. This probably interferes with the formation of the myelin sheath. 

A second metabolic system similar to the first is shown in Figure 1, panel ii. In this schematic, the emphasis is a metabolite one or two steps proximal to the primary enzyme deficiency. For example, in normal individuals, metabolite C is converted by enzyme Y to metabolite A, which is subsequently converted by enzyme X to metabolite B. As described above, in individuals with an inherited deficiency of enzyme X, metabolite A accumulates. In this particular scenario, compounds that are converted to metabolite A, namely metabolite C, will increase as enzyme Y is inhibited by basic kinetics. An example of this enzyme system is homocystinuria. In this disorder, the metabolism of homocysteine to cystathionine by cystathionine S-synthase is blocked. An increase in homocysteine causes an accumulation of S-adenosyl homocysteine and S-adenosyl methionine. Due to an increase in these metabolites, the metabolism of methionine to S-adenosyl methionine by methionine adenosyl transferase is decreased. Hence, methionine increases in the blood of individuals with homocystinuria. Note that in this example there were two enzymatic steps before the metabolism of homocysteine. 

Cystathionine P-synthase deficiency is an autosomal recessive trait (Fig. 47.1). It is the most common cause of homocystinuria and is the second most treatable disorder of amino acid metabolism. Some patients respond to pyridoxine treatment but others are pyridoxine non-responsive. Orally administered betaine often lowers serum homocysteine concentrations. 

Nutrition Concentrations of homocysteine and the vitamins responsible for its metabolism have been investigated in patients with moderate to severe acne vulgaris on isotretinoin treatment, before and after treatment with isotretinoin homocysteine concentrations were increased after 2 months [69 ]. This suggests that isotretinoin may increase the risk of cardiovascular disorders by causing hyperhomocysteinemia. 

Diet and nutrition have been extensively investigated as risk factors for CHD. Many dietary factors have been linked directly to an increased or decreased risk of CHD or to major established risk factors of CHD like high blood pressure, disordered blood fats (dyslipidemia), diabetes and metabolic syndrome, overweight and obesity, and also to emerging risk factors like inflammatory markers and homocysteine. Nutrition influences atherogen-esis, thrombosis, and inflammation - all of which are interconnected pathways that lead to CHD. 

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