Homocystinuria clinical effect

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. 

Epidemiological studies indicate that elevated plasma tHcy increases the risk of venous thromboembolism (43,44), In homocystinuria, the presence of the factor V Leiden mutation further increases the risk of thromboembolism (45). It has been proposed that hyperhomocysteinemia might interfere with the inhibition of activated factor V by activated protein C, possibly via similar effects as those caused by the factor V Leiden mutation (46,47), However, one in vitro study (48) and one large clinical study failed to demonstrate an association between hyperhomocysteinemia and activated protein C resistance (49). 

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. 

Despite the strong evidence for the role of plasma Hey in cardiovascular risk prediction, clinical trials have consistently shown that Hey lowering strategies in either primary of secondary prevention are ineffective. However, Hey lowering treatment with folate and B vitamins is still considered to be an effective means to reduce vascular and thrombotic complications of homocystinuria, while folate fortification may be beneficial in selected groups of patients, such as those with reduced folate levels due to dietary or specific genetic characteristics. 

Because treatment is most effective if started in earliest infancy, it is necessary to make the diagnosis of phenylketonuria before any clinical signs appear, i.e. from the biochemical changes. Every newborn infant must be tested and, therefore, the test used must be inexpensive, simple and reliable [70, 71]. The available methods are determination of phenylalanine concentration in the blood, o-hydroxyphenyl-acetic acid in urine or phenylpyruvic acid in urine. The third method, once widely used, has now been largely abandoned the first and, to a lesser extent, the second are used on a very large scale in many countries. Sometimes tests for other conditions, such as homocystinuria, galactosaemia and maple syrup urine disease, are combined with the test for phenylketonuria. 

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