We describe a family illustrating the diagnostic difficulties occurring when
pyridoxine-responsive
cystathionine beta-synthase (
CBS) deficiency presents with thrombotic disease without associated ocular, skeletal, or CNS abnormalities, a situation increasingly recognized. This family had several thromboembolic episodes in two generations with apparently inconstant elevations of plasma total
homocysteine (tHcy). When taking (sometimes even low amounts) of
pyridoxine, the affected family members had low-normal tHcy and normal values for
cystathionine,
methionine, and
cysteine. Withdrawal of
vitamin therapy was necessary before lower
cystathionine, elevated
methionine, and decreased
cysteine became apparent, a pattern suggestive of
CBS deficiency, leading to the finding that the affected members were each compound heterozygotes for CBS p.G307S and p.P49L. To assist more accurate diagnosis of adults presenting with
thrombophilia found to have elevated tHcy, the patterns of
methionine-related metabolites in CBS-deficient patients are compared in this article to those in patients with
homocysteine remethylation defects, including inborn errors of
folate or
cobalamin metabolism, and untreated severe
cobalamin or
folate deficiency. Usually serum
cystathionine is low in subjects with
CBS deficiency and elevated in those with remethylation defects.
S-Adenosylmethionine and
S-adenosylhomocysteine are often markedly elevated in
CBS deficiency when tHcy is above 100 umol/L. We conclude that there are likely other undiagnosed, highly B6-responsive adult patients with
CBS deficiency, and that additional testing of
cystathionine, total
cysteine,
methionine, and
S-adenosylmethionine will be helpful in diagnosing them correctly and distinguishing
CBS deficiency from remethylation defects.