Amniotic fluid homocysteine levels, 5,10-methylenetetrahydrafolate reductase genotypes, and neural tube closure sites

A specific gene mutation leading to altered homocysteine metabolism has bee n identified in parents and fetuses with neural tube defects (NTDs). In add ition, current animal and human data indicate that spine closure occurs sim ultaneously in five separate sites that then fuse. me sought to determine w hether either this mutation or abnormal amniotic fluid homocysteine levels are associated with all five neural tube closure sites. me retrieved stored amniotic fluid from cases of isolated fetal neural tube defect diagnosed f rom 1988 to 1998 (n = 80) and from normal controls matched for race, month and year of amniocentesis, and maternal age. Cases were categorized accordi ng to defect site by using all available medical records. The presence or a bsence of the 677C-->T mutation of 5,10-methylenetetrahydrafolate reductase (MTHFR) gene was determined, and homocysteine levels were measured; case a nd controls were compared. Significantly more cases than controls were hete rozygous or homozygous for the 677C-->T MTHFR mutation (44% vs. 17%, P less than or equal to 0.001). Likewise, cases were significantly more likely th an controls to have amniotic fluid homocysteine levels > 90th centile (> 1. 85 mu mol/L), 27% vs. 10%, P = 0.02. Most (83%) of control cases had both n ormal MTHFR alleles and normal amniotic fluid homocysteine levels (normal/n ormal), whereas only 56% of NTD case were normal/normal (P = 0.001). When e valuated by defect site, only defects involving the cervical-lumbar spine, lumbosacral spine, and occipital encephalocele were significantly less like ly to be normal/normal than controls (P = 0.007, 0.0003, and 0.007, respect ively), suggesting a strong association with the 677C-->T allele. In contra st, anencephaly, exencephaly, and defects confined to the sacrum included m any cases that had both normal MTHFR alleles and normal homocysteine and we re not significantly different from controls. The 677C-->T MTHFR mutation a nd elevated homocysteine levels appear to be disproportionately associated with defects spanning the cervical-lumbar spine, lumbosacral spine, and occ ipital encephalocele. In contrast, anencephaly, exencephaly, and defects co nfined to the sacrum may not be related to altered homocysteine metabolism. Am. J. Med. Genet. 90:6-11, 2000. (C) 2000 Wiley-Liss, Inc.