Cystathionine /?-synthase supplementation

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). 

Studies of plasma homocysteine and supplements with vitamins that are relevant to enzymes of the pathway of homocysteine breakdown. These enzymes are cystathionine 3-synthase (vitamin Bh), methionine synthase (vitamin Bi ), and 5,10-methylerie-H4folate reductase (folic acid). The associated vitamins are listed,... 

Singh RH, et al. Cystathionine beta-synthase deficiency effects of betaine supplementation after methionine restriction in B6-nonresponsive homocystinuria. Genet Med. 2004 6(2) 90-5. 

Homocystinuria (pyridoxine nonresponsive) Cystathionine 6-synthase Homocystine in blood and urine, increased methionine and decreased cystine in blood Dislocated lenses, marfanoid-fike skeletal changes, intravascular thromboses, intellectual disabUity, osteopenia Methionine restriction cystine, betaine, and folate supplementation Betaine 100 mg/kg/ day oraUy... 

Metabolism In a prospective controlled study in 74 patients taking isotretinoin for cystic acne, blood concentrations of homocysteine, vitamin B12, and folate were assessed before and after 45 days of isotretinoin therapy [39 ]. The control group consisted of 80 individuals. Homocysteine concentrations were significantly higher in those who took isotretinoin. The vitamins were unaffected, but serum lipids and liver enzymes increased significantly. These effects may have been due to inhibition of cystathionine-beta-synthase, an enzyme required for the metabolism of homocysteine by either the drug or liver dysfunction. Daily supplementation with vitamin B12 and folate can lower plasma concentrations of homocysteine, and the authors therefore recommended the use of these vitamins in patients taking isotretinoin. 

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). 

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