Severe hyperhomocysteinemia in its most frequent form, is caused by a homozygous 
enzymatic deficiency of cystathionine beta-synthase (CBS). A major complication 
in CBS deficiency is deep venous thrombosis or pulmonary embolism. A recent 
report by Mandel et al (N Engl J Med 334:763, 1996) postulated factor V Leiden 
(FVL) to be an absolute prerequisite for the development of thromboembolism in 
patients with severe hyperhomocysteinemia. We studied 24 patients with 
homocystinuria caused by homozygous CBS deficiency from 18 unrelated kindreds 
for FVL and for the 677C-->T mutation in the methylenetetrahydrofolate reductase 
(MTHFR) gene and investigated their possible interaction in the risk of venous 
thrombosis. Thrombotic complications were diagnosed in six patients, of whom 
only one was a carrier of FVL. On the contrary, thermolabile MTHFR caused by the 
677C-->T mutation, was frequently observed among homocystinuria patients, 
especially among those with thromboembolic complications: three of six 
homocystinuria patients who had suffered from a thromboembolic event had 
thermolabile MTHFR. These data indicate that FVL is not an absolute prerequisite 
and probably not even a major determinant of venous thrombosis in 
homocystinuria, but, interestingly, thermolabile MTHFR may constitute a 
significant risk factor for thromboembolic complications in this inborn error of 
methionine metabolism.