QJM, Vol 90, Issue 8 505-510, Copyright © 1997 by Oxford University Press
NM van der Put, CM Thomas, TK Eskes, FJ Trijbels, RP Steegers-Theunissen, EC Mariman, A De Graaf-Hess, JA Smeitink and HJ Blom
Folic acid intake reduces the risk of neural tube defects (NTDs). Although
the 677C-->T mutation in the 5,10-methylenetetrahydrofolate reductase
(MTHFR) gene is a risk factor for NTDs, it only partly explains the
elevated homocysteine levels in mothers of children with NTDs. We measured
vitamin B12, folate and homocysteine in patients with spina bifida (SB),
their parents, and in controls, to investigate which other enzymes of
homocysteine metabolism might be defective. Because homozygosity for the
677C-->T mutation causes decreased plasma folate and increased red-cell
folate (RCF) and plasma homocysteine levels, we excluded individuals
homozygous for that mutation. The remaining SB patients and their parents
still had lowered plasma folate and elevated total homocysteine levels, and
a small subset had decreased vitamin B12 levels. Red-cell folate was the
same in all groups, suggesting that dietary folate intake and its uptake
was normal. Risk of SB was increased at the 25th percentile of plasma
folate and at the 75th percentile of homocysteine values in SB patients and
their parents, and at the 5th and 25th percentiles of vitamin B12 in
mothers with SB- affected offspring. This underlines the functional
importance of homocysteine remethylation to methionine. There was no
correlation between vitamin B12 and homocysteine or RCF. In combination
with the lowered plasma folate (80-90% 5-methyltetrahydrofolate), our data
do not support a major involvement of methionine synthase in the aetiology
of SB. Our data rather favour the involvement of genetic variation at loci
coding for the formation of 5-methyltetrahydrofolate, such as MTHFR,
methylenetetrahydrofolate dehydrogenase or serine hydroxymethyltransferase.
ORIGINAL PAPERS
Altered folate and vitamin B12 metabolism in families with spina bifida offspring
Department of Pediatrics, University Hospital Nijmegen, The Netherlands.
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