Methionine homocystinuria

Methionine Homocystinuria Mental retardation common several eye diseases and thromboembolism common osteoporosis and faulty bone structures Cystathionine-j8-synthase... 

Figure 32, Chromatograms of plasma and urine samples with various abnormalities, A, Phenylalaninemia B, tyrosinemia C, elevated plasma methionine seen in homocystinuria D, glycinemia E, normal urine F, argininosuccinic aciduria G, homocystinuria H, hyperglycinuria I, hyperlysinuria.

Patients with homocystinuria are at risk for cerebrovascular and cardiovascular disease and thromboses 676 Prognosis is more favorable in the pyridoxine-responsive patients 677 Homocystinuria can occur when homocysteine is not remethylated back to form methionine 677... 

Methionine synthase deficiency (cobalamin-E disease) produces homocystinuria without methylmalonic aciduria 677 Cobalamin-c disease remethylation of homocysteine to methionine also requires an activated form of vitamin B12 677 Hereditary folate malabsorption presents with megaloblastic anemia, seizures and neurological deterioration 678... 

Homocystinuria Usually a failure of cystathionine synthase (Fig. 40-2 reaction 6). Rarely associated with aberrant vitamin B12 metabolism (Fig. 40-2) Thromboembolic diathesis, marfanoid habitus, ectopia lentis. Mental retardation is frequent. Diet low in methionine Vitamin B6 in pyridoxine-responsive syndromes Vitamin B12 in responsive syndromes Anticlotting agents... 

Homocystinuria can be treated in some cases by the administration of pyridoxine (vitamin Bs), which is a cofactor for the cystathionine synthase reaction. Some patients respond to the administration of pharmacological doses of pyridoxine (25-100 mg daily) with a reduction of plasma homocysteine and methionine. Pyridoxine responsiveness appears to be hereditary, with sibs tending to show a concordant pattern and a milder clinical syndrome. Pyridoxine sensitivity can be documented by enzyme assay in skin fibroblasts. The precise biochemical mechanism of the pyridoxine effect is not well understood but it may not reflect a mutation resulting in diminished affinity of the enzyme for cofactor, because even high concentrations of pyridoxal phosphate do not restore mutant enzyme activity to a control level. 

In cobalamin-E (cblE) disease there is a failure of methyl-B12 to bind to methionine synthase. It is not known if this reflects a primary defect of methionine synthase or the absence of a separate enzyme activity. Patients manifest megaloblastic changes with a pancytopenia, homocystinuria and hypomethioninemia. There is no methylmalonic aciduria. Patients usually become clinically manifest during infancy with vomiting, developmental retardation and lethargy. They respond well to injections of hydroxocobalamin. 

Cobalamin-c disease remethylation of homocysteine to methionine also requires an activated form of vitamin B12. In the absence of normal B12 activation, homocystinuria results from a failure of normal vitamin B12 metabolism. Complementation analysis classifies defects in vitamin B12 metabolism into three groups cblC (most common), cblD and cblF. Most individuals become ill in the first few months or weeks of life with hypotonia, lethargy and growth failure. Optic atrophy and retinal changes can occur. Methylmalonate excretion is excessive, but less than in methylmalonyl-CoA mutase deficiency, and without ketoaciduria or metabolic acidosis. 

Figure 9-5. Pathway for formation of cysteine from methionine. Only the enzymes involved in known diseases of this pathway are shown. Cystathionase is deficient in cysthioninuria, which leads to accumulation of cystathionine without producing frank symptoms. Cystathionine p-synthase deficiency causes homocystinuria.

A large elevation of Hey in body fluids and tissues is found in several genetic enzyme deficiencies, the homocystinurias. These include cystathionine /3-synlhase deficiency [9], the remethylation defects due to deficiency of MTHF reductase [10], methionine synthase and methionine synthase reductase deficiencies, as well as defects of intracellular cobalamin metabolism [11], namely the cblF, cblC and cblD defects. It is noteworthy that low levels of total Hey (tHcy) have been described in sulphite oxidase deficiency [12]. 

Homocystinuria <0.5 Methionine degradation Cystathionine )8-synthase Faulty bone development mental retardation... 

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. 

Homocysteine is a nonprotein-building amino acid formed as a metabolite in the methionine cycle. It was first associated with disease in 1962 (1,2). Individuals with a mutation in cystathionine-(3-synthase (CBS) develop classical homocystin-uria with extremely elevated plasma tHcy (> 100 xmol/L) (3). Homocystinuria is characterized by early atherosclerosis and thromboembolism as well as mental retardation and osteoporosis and is ameliorated by vitamin supplementation aimed at reducing the blood concentration of homocysteine (4). 

Homocystinuria may result from one or several abnormalities in the mechanism whereby homocysteine is methylated to form methionine. About half of the patients respond to treatment with pyridoxine and it is thought that the vitamin overcomes a block at the homocysteine/cystathionine level by mass action (C23). However, Schuh et al. (S22) have recently described a patient who responded to vitamin B12. The infant presented with severe developmental delay, homocystinuria, and a megaloblastic anemia. Treatment with cyanocobalamin was without effect but treatment with hydroxocobalamin resulted in a rapid clinical improvement, and the homocystinuria disappeared. Methionine synthetase activity in cell extracts was normal, while cultured fibroblasts showed an absolute growth requirement for methionine. The defect appeared to be limited to methyleobalamin accumulation and an inability to transfer the methyl group from 5-methyltetrahydrofolate to homocysteine. 

Figure 20.17 Metabolism of methionine. FH4 indicates tetrahydrofolate. A and B indicate defects in homocystinuria and cystathioninuria, respectively, and the asterisk indicates the fate of the methionine carbon skeleton.

Mild hyperhomocysteinemia is defined as a plasma tHcy concentration of 10-30 (tmol/L moderate hyperhomocysteinemia is classified as 30-100 tmol/L. A very severe form of hyperhomocysteinemia, which produces plasma tHcy concentrations greater than 100 tmol/L, can be caused by one of several inborn errors of methionine metabolism. Patients with these disorders also have high levels of tHcy in their urine, a condition known as homocystinuria. 

The transsulfuration pathway involves conversion of homocysteine to cysteine by the sequential action of two pyridoxal phosphate (vitamin B6)-dependent enzymes, cystathionine- 5-synthase (CBS) and cystathionine y-lyase (Fig. 21-2). Transsulfuration of homocysteine occurs predominantly in the liver, kidney, and gastrointestinal tract. Deficiency of CBS, first described by Carson and Neill in 1962, is inherited in an autosomal recessive pattern. It causes homocystinuria accompanied by severe elevations in blood homocysteine (>100 (iM) and methionine (>60 (iM). Homocystinuria due to deficiency of CBS occurs at a frequency of about 1 in 300,000 worldwide but is more common in some populations such as Ireland, where the frequency is 1 in 65,000. Clinical features include blood clots, heart disease, skeletal deformities, mental retardation, abnormalities of the ocular lens, and fatty infiltration of the fiver. Several different genetic defects in the CBS gene have been found to account for loss of CBS activity. 

Deficiency of MTHFR can produce severe hy-perhomocysteinemia and homocystinuria but is distinguishable from CBS deficiency in that blood levels of methionine are not elevated. The first case of homocystinuria caused by deficiency of MTHFR was described by Mudd et al. in 1972. The case was a patient who presented with homocystinuria without elevation of blood levels of methionine. Since then, several... 

In 1969, McCully made an important observation when he noticed severe vascular pathology caused by defects in homocysteine remethylation in children with homocystinuria (McCully, 1969). Like patients with CBS deficiency, these children had markedly elevated levels of tHcy in their blood and urine, but their blood levels of methionine were lower than... 

Figure 7-10. Amino acids that can be converted to succinyl CoA. The amino acids methionine, threonine, isoleucine, and valine, which form succinyl CoA via methylmalonyl CoA, are all essential. The carbons of serine are converted to cysteine and do not form succinyl CoA by this pathway. A defect in cystathionine synthase (M) causes homocystinuria. SAM= S-adenosylmethionine PLP = pyridoxal phosphate.

The biochemical phenotype of homocystinuria is characterized by increased plasma concentrations of methionine, free homocysteine and cysteine-homocysteine disulfide, together with low cystine (Figure 55-6, C). Determination of total homocysteine after treatment of the sample with... 

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. 

Folic acid/cobalamin/pyridoxine hydrochloride are nutritional combinations. Folic acid and cobalamin reduce homocysteine by metabolizing it to methionine. Pyridox-ine facilitates breakdown of homocysteine to cysteine and other by-products. They are indicated for nutritional requirement of patients with end-stage renal failure, dialysis, hyperhomocysteinemia, homocystinuria, nutrient malabsorption or inadequate dietary intake, particularly for patients with or at risk for cardiovascular disease, cerebrovascular disease, peripheral vascular disease, arteriosclerotic... 

Cystathionine (made by cystathionine synthase from homocysteine and serine) plays a central role both in the biosynthesis of methionine in plants and bacteria and in the biosynthesis of cysteine in animals. In humans, deficiency of cystathionine synthase leads to a condition called homocystinuria, in which homocysteine overaccumulates. The condition results in severe mental retardation and dislocation of the lens of the eye. 

Leclerc, D., A. Wilson, R. Dumas, C. Gafuik, D. Song, D. Watkins et al. (1998). Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria. Proc. Natl. Acad. Sci. USA 95, 3059-3064. 

Homocystinuria is caused by deficiencies in the enzymes cystathionine p-synthase and cystathionase as well as by deficiencies of methyltetrahy-drofolate (CH3-FH4) or of methyl-B12. The deficiencies of CH3-FH4 or of methyl-B12 are due either to an inadequate dietary intake of folate or B12 or to defective enzymes involved in joining methyl groups to tetrahy-drofolate (FH4), transferring methyl groups from FH4 to B12, or passing them from B12 to homocysteine to form methionine (see Chapter 40). 

In the type of homocystinuria in which the patient is deficient in cystathione 13-synthase, the elevation in serum methionine levels is presumed to be the result of enhanced rates of conversion of homocysteine to methionine, caused by increased availability of homocysteine (see Fig. 39.14). In type II and type HI homocystinuria, in which there is a deficiency in the synthesis of methyl cobalamin and of N -methyltetrahydrofolate, respectively (both required for the methylation of homocysteine to form methionine), serum homocysteine levels are elevated but serum methionine levels are low (see Fig. 39.14). 

Classical homocystinuria is a rare inherited disorder, caused by the deficiency of cystathione beta-synthase resulting in accumulation of methionine it can cause mental retardation, eye problems and thrombosis. Dietary management aims to prevent accumulation of methionine by means of a low-methionine diet and by supplementing the diet with a methionine amino acid mixture. 

Homocystinuria is a biochemical abnormality caused either by a deficiency of cystathionine P-syn-thase or impaired activity of N -methyltetrahydrofolate-homocysteine methyltransferase. The classical homocystinuria occurs when the conversion of homocysteine to cystathionine is limited by a deficiency of cystathionine P-synthase, with accumulation of methionine and homocysteine and a decrease in cysteine. 

Methionine is an essential amino acid with a unique role in the initiation of protein synthesis, hi addition, by conversion to 5 -adenosyhnethionine, it serves as the major methyl group donor involved in the formation of creatinine and choline, in the methylation of bases in RNA, and as the source of the aminopropyl group in the formation of polyamines. Finally, in relationship to classical homocystinuria, it is converted by way of homocysteine and cystathionine in a series of reactions termed as the transsulfuration pathway (Fig. 20.3). 

Elevated homocysteine (Hey) blood levels but also the presence of Homocystine in urine is the biochemical hallmark of these disorders and can be detected by a positive urinary cyanide nitroprnsside reaction. As other disulfides, including cystine and P-mercaptolactate cystine, also react, amino acid paper thin layer chromatography will be reqnired to distingnish these componnds from homocystine. Since there are two other forms of homocystinuria (disenssed later) in which plasma methionine is decreased, plasma amino acid evalnation is also in order. 

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