Cystathionine P-synthase deficiency

Biochemical findings are variable. The blood cobala-min and folate levels often are normal. Patients often have homocysteinemia with hypomethioninemia, the latter finding discriminating this group from homocystinuria secondary to cystathionine- P-synthase deficiency. Urinary excretion of methylmalonic acid may be high, reflecting the fact that vitamin B12 serves as a cofactor for the methyl-malonyl-CoA (coenzyme A) mutase reaction. 

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.

The answer is A. The constellation of symptoms exhibited by this patient is characteristic of homocystinuria. The impairment of her cognitive function could be attributed to many conditions, but the key findings are ectopia lentis with downward lens dislocation and osteoporosis in a female of this age. Homocystinuria is produced by inherited deficiency of one of the enzymes in the pathway of Met conversion to Cys. The most common form is cystathionine P-synthase deficiency, which results in accumulation of all upstream components of the pathway, including homocysteine, which is responsible for the toxic effects, and Met, which becomes elevated in the blood. Cystathionine and cysteine, which are both downstream of the block in the pathway caused by cystathionine P Synthase deficiency, would be decreased. Metabolic pathways for lactate and urea are not involved in this disease mechanism. 

These studies are detailed in what follows. Although the severe increases in plasma homocysteine that occur with homozygous cystathionine P-synthase deficiency can be clearly treated with vitamin Bs, the moderate increases of homocysteine (which are widespread in the population and do not lead to mental retardation) can be treated best with folate. 

If the blood levels of methionine and homocysteine are very elevated and cystine is low, cystathionine p-synthase could be defective, but a cystathionase deficiency is also a possibility. With a deficiency of either of these enzymes, cysteine could not be synthesized, and levels of homocysteine would rise. Homocysteine would be converted to methionine by reactions that require B12 and tetrahydrofolate (see Chapter 40). In addition, it would be oxidized to homocystine, which would appear in the urine. The levels of cysteine (measured as its oxidation product cystine) would be low. A measurement of serum cystathionine levels would help to distinguish between a cystathionase or cystathionine p-synthase deficiency. 

Patients with this most common form of homocystinuria show evidence of involvement of the eye, the skeletal system, the vascular system, and the brain. It is important to note that individuals with cystathionine P-synthase deficiency do not manifest any abnormalities at birth and that the affected pregnancies are uneventful. Thus, this disorder, as opposed to the more rare remethylation defect variants of homocystinuria (described below), is not usually part of the differential diagnosis of the catastrophically ill newborn. Ectopia lentis does not usually appear before the age of 3 years, but most patients have some manifestations by the age of 10. The initial recognition of ocular abnormahties may be an observation by parent or physician that the iris shakes, when the head is moved rapidly. While a predilection for... 

The complication of cystathionine P-synthase deficiency that is of most concern is the prodensity to thromembolism. This involves vessels of all diameters and is unpredictable as to when, where, and if it occurs. The malar flush and erythemous mottling of the extremities are also vascular manifestations of homocystinuria. 

As the name implies, renal clearance of abnormal levels of homocystine in the plasma causes excessive excretion of the amino acid in the urine. In cystathionine P-synthase deficiency, plasma methionine concentrations are elevated as well -this serves as a point of distinction from the remethylation defects. At present, it appears that the pyridoxal phosphate response may be explained by the fact that this vitamin increases the steady-state concentration of the active enzymes by decreasing the rate of apoenzyme degradation and possibly by increasing the rate of holoenzyme formation. The explanation is not entirely satisfactory, however, since in vitro studies have shown detectable levels of enzyme activity in mutant fibroblasts that have no response, while in other mutant lines without detectable enzyme activity, response has occurred. Once again, a distressing lack of correspondence between in vivo observations and in vitro experiments forces investigators to probe the secrets of these diseases more deeply. 

Vanzin CS, et al. Homocysteine contribution to DNA damage in cystathionine P-synthase-deficient patients. Gene. 2014 539(2) 270-4. 

Smolin L. A. and Benevenga N. J. (1982) Accumulation of homocysteine in vitamin B-6 deficiency A model for the study of cystathionine p-synthase deficiency / Nutr 112, 1264 1272. 

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. 

Genetic conditions of vitamin Bg dependency which respond to high dose PN supplementation include certain idiopathic sideroblastic anaemias (30) and disturbed amino acid metabolism, e.g., cystathionine P-synthase deficiency (31). 

The most common cause of homocystinuria is a congenital deficiency of cystathionine-p-synthase, a pyridoxine-dependent enzyme that condenses homocysteine and... 

Figure 22.7 Homocysteine formation from methionine and formation of thiolactone from homocysteine. The homocysteine concentration depends upon a balance between the activities of homocysteine methyltransferase (methionine synthase) and cystathionine p-synthase. Both these enzymes require vitamin B12, so a deficiency can lead to an increase in the plasma level of homocysteine. (For details of these reactions, see Chapter 15.) Homocysteine oxidises spontaneously to form thiolactone, which can damage cell membrane.

Further to this, the enzyme cystathionine P-synthase is involved in the catabolism of homocysteine, so that a deficiency of this enzyme also results in an elevated level of homocysteine in the blood. Consequently, patients with a deficiency, even a partial deficiency, could also suffer an increased risk of coronary artery disease. 

A couple comes to the physician s office after having had two sons affected with a similar disease. The first-born son is tall and thin and has dislocated lenses and an IQ of 70. He has also experienced several episodes of deep vein thromboses. The chart mentions deficiency of the enzyme cystathionine-P-synthase, but a diagnosis is not given. The second son was treated from an early age with pyridoxine (vitamin Bg) and is less severely affected. No other family members are affected. While taking a family history, the physician discovers that the parents are first cousins. The 38-year-old mother is pregnant, and amniocentesis has demonstrated that the fetus has a 46,XY karyotype. The risk that the fetus will be affected with the same disease is... 

When present in excess methionine is toxic and must be removed. Transamination to the corresponding 2-oxoacid (Fig. 24-16, step c) occurs in both animals and plants. Oxidative decarboxylation of this oxoacid initiates a major catabolic pathway,which probably involves P oxidation of the resulting acyl-CoA. In bacteria another catabolic reaction of methionine is y-elimination of methanethiol and deamination to 2-oxobutyrate (reaction d, Fig. 24-16 Fig. 14-7). Conversion to homocysteine, via the transmethylation pathway, is also a major catabolic route which is especially important because of the toxicity of excess homocysteine. A hereditary deficiency of cystathionine P Synthase is associated with greatly elevated homocysteine concentrations in blood and urine and often disastrous early cardiovascular disease. ° ° About 5-7% of the general population has an increased level of homocysteine and is also at increased risk of artery disease. An adequate intake of vitamin Bg and especially of folic acid, which is needed for recycling of homocysteine to methionine, is helpful. However, if methionine is in excess it must be removed via the previously discussed transsulfuration pathway (Fig. 24-16, steps h and The products are cysteine and 2-oxobutyrate. The latter can be oxidatively decarboxylated to propionyl-CoA and further metabolized, or it can be converted into leucine (Fig. 24-17) and cysteine may be converted to glutathione. ... 

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). 

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. 

Deficiency of cystathionine P-synthase may be demonstrated in cnltnred fibroblasts, bnt it is not essential to the clinical diagnosis (Stabler et al., 1988). 

Homocystinuria is caused by a deficiency in the enzyme, cystathionine-P-synthase (CBS), and results in the accumulation of homocysteine and methionine. 

Homocystinurla Homocysteine Is excreted In the urine when cystathionine P-synthase or methionine synthase activities are deficient... 

Classical homocystinuria is caused by defective activity of cystathionine P-synthase. However, methionine synthase deficiency causes hyperhomocysteinaemia. 

Yap, S., Boers, G.H., Wilcken, B., Wilcken, D.E., Brenton, D.P., Lee, P.J., Walter, J.H., Howard, P.M., and Naughten, E.R., 2001. Vascular outcome in patients with homocystinuria due to cystathionine beta-synthase deficiency treated chronically a multicenter observational study. Arteriosclerosis, Thrombosis, and Vascular Biology. 21 2080-2085. 

Corticosterone methyl oxidase II deficiency Costeff optic atrophy syndrome Coupling state defect Creatine deficiency Creatine transporter deficiency Cu-binding P-type ATPase deficiency y-Cystathionase deficiency Cystathionine gamma-lyase deficiency Cystathionine y -synthase deficiency Cystathioninuria... 

Homocysteine is markedly elevated in different inborn errors of homocysteine metabolism such as cystathionine p-synthase, methionine synthase deficiencies,... 

Homocyslinuiia is an autosomal recessive condition caused by a deficiency of the enzyme, cystalhionine-p-synthase (CBS), which results in the accumulation of homocysteine and methionine and a deficiency of cystathionine and cysteine. There are other disorders to consider when an elevated homocysteine concentration is identified. These disorders include vitanun Bn uptake or activation defects, which may or may not have associated elevated methylmalonic acid, severe 5,10-methylenetetrahydrofolate reductase deficiency, and 5-methyl-THF-homocysteine meth-yltransferase deficiency. The latter two are typically associated with an elevated homocysteine, but low methionine concentrations, so it is relatively easy to disaiminate these conditions from homocystinuria. It is also important to consider that nongenetic causes of hyperhomocyste-inemia exist, such as dietary deficiencies, end-stage renal disease, and administration of several drugs [6]. 

Transsulfuration is facilitated by the action of two vitamin Be-dependent enzymes, cystalhionine-p-synthase (CBS), the enzyme deficient in homocystinuria, and cystathionine-Y-lyase (CTH). CBS catalyzes the condensation of homocysteine and serine to cystathionine, and CTH subsequently catalyzes the hydrolysis of cystathionine to cysteine and a-ketobutyrale. Cysteine is important in protein synthesis and taurine synthesis and is a precursor to glutathione, a strong antioxidant and essential compound in detoxification of many xenobiotics [8,10,11]. 

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