From homocysteinuria vascular phenotype to mild homocysteinemia

http://www.phlebolymphology.org/pdf/special/special_46/part_4.pdf

Homocysteinemia is a rare constitutive metabolic disease but is treatable. It is defined by a plasma homocysteine concentration above 100 μmol/L, combined with a urinary excretion of large amounts of homocysteine. Homocysteinemia is the result of an enzymatic defect in one of the methionine metabolism pathways. The most common cause is a cystathionine β synthase (CBS) deficiency in the transulfuration pathway. It is characterized by high methionine and low cysteine levels and chronic intoxication disease.

An impaired remethylation pathway may also occur, due to defects in methionine synthetase, in methylenetetrahydrofolate reductase (MTHFR), or in enzymes involved in the metabolism or transport of cobalamin. It is characterized by low methionine levels and an acute disturbance in stressful situations.

Histologic vascular abnormalities in patients with homocysteinuria are at the level of large and medium-sized arteries, with focal intimal and medial fibrosis and proliferation of perivascular connective tissues surrounding small arteries. The intima/media thickness measured by echography is much higher than in controls.

Hyperhomocysteinuria, whatever the type of enzymatic deficit, leads to an increased risk of venous and arterial thrombosis.

In a cohort of 629 patients with CBS homocystinuria, 25% had thrombosis before the age of 30 years, (49% arterial thrombotic events and 51% venous thrombotic events), In all the published cohorts, venous risk of thrombosis is high, even in patients without other risks of VTE, mutation of factor V for example. Treatment of homocysteinuria by vitamin B6 (pyridoxine) reduces the risk of thrombosis. In a cohort of 158 patients, 50% of them were responders to treatment with vitamin B6, and 50% were not. Only 17 thrombotic events were observed during follow-up instead of 112 expected without treatment. Despite effective treatment with vitamin B6, the thrombotic risk remains 5 fold superior to the risk observed in the general population.

The prevalence of homocystinuria is underestimated and is probably closer to 1/30,000 live born babies than the previous expected prevalence of 1/ 300,000. This may be due to mild phenotype with predominant vascular thrombotic phenotype diagnosed in the adulthood.
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http://en.wikipedia.org/wiki/Thrombosis

Thrombosis is the formation of a clot or thrombus within the lumen of a blood vessel, obstructing the flow of blood through the circulatory system. Thromboembolism is a general term describing both thrombosis and its main complication which is embolisation.

When a thrombus occupies more than 75% of surface area of the lumen of an artery, blood flow to the tissue supplied is reduced enough to cause symptoms because of decreased oxygen (hypoxia) and accumulation of metabolic products like lactic acid. More than 90% of obstruction can result in anoxia, the complete deprivation of oxygen, and infarction, a mode of death of cells.