Deficiency cystathionine 3-synthase

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. 

Homer Sistine. The most characteristic biochemical featnres of the disor-J der affecting Homer Sistine, a cystathionine 3-synthase deficiency, are the — presence of an accnmnlation of both homocyst(e)ine and methionine in the blood. Becanse renal tnbnlar reabsorption of methionine is highly efficient, this... 

Treatment is directed toward early reduction of the elevated levels of homocysteine and methionine in the blood. In addition to a diet low in methionine, very high oral doses of pyridoxine (vitamin B6) have significantly decreased the plasma levels of homocysteine and methionine in some patients with cystathionine 3-synthase deficiency. (Genetically determined responders to pyridoxine treatment make up approximately 50% of type I homocystinurics.) PLP serves as a cofactor for cystathionine (3-synthase however, the molecular properties of the defective enzyme that confer the responsiveness to B6 therapy are not known. 

Answer C Only methionine is degraded via the homocysteine/cystathionine pathway and would be elevated in the plasma of a cystathionine synthase-deficient patient via activation of homocysteine methyl-transferase by excess substrate. 

Correct answer = B. Alkaptonuria is a rare metabolic disease involving a deficiency in homogentisic acid oxidase, and the subsequent accumulation of homogentisic acid in the urine, which turns dark upon standing. The elevation of methylmalonate (due to methylmalonyl CoA mutase deficiency), phenylpyruvate (due to phenylalanine hydroxlyase deficiency), a-ketoisovalerate (due to branched-chain a-ketoacid dehydrogenase deficiency), and homocystine (due to cystathionine synthase deficiency) are inconsistent with a healthy child with darkening of the urine. 

E-S) Hypermetbioninuria (decrease in methionine adenosyl transferase) at this step. The condition is relatively benign, whereas cystathionine synthase deficiency (see above) is not benign. 

H omocy steine-c y ste-ine disulfide B T H Cystathionine 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 major type is caused by cystathionine fi-synthase deficiency, leading to accumulation of upstream intermediates in the pathway, especially homocysteine. 

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. 

Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE, et al. The natural history of homo-cystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet 1985 37 1-31. 

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. 

Homocystinurla A deficiency of the enzyme cystathionine synthase leads to the accumulation of sulphur-containing amino acids. Affected children are normal at birth but develop eye problems, osteoporosis and mental retardation... 

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. 

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. 

Furthermore, in vitro classical homocystinuria showed an elevation of rat hippocampal acetylcholinesterase (AChE) activity, whereas the other types of homocystinuria had no effect on the enzyme (Schulpis et al., 2006). These preliminary results may lead to the suggestion that homocystinuria due to cystathionine-6-synthase deficiency may partly implicate high Hey levels with neurodegeneration. 

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