Genetic Predisposition to Neural Tube Defects?A review of: Christensen B, Arbour L, Tran P,et al. 1999 Genetic polymorphisms in methylenetetrahydrofolate

reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects. Am J Med Genet84:151–157.

RESEARCH IN THE last few years nowsuggests that the “thermolabile”

methylene tetrahydrofolate reductase(MTHFR) associated C677T polymor-phism leads to an increased risk ofoffspring with neural tube defects(NTDs). In a study of 56 Canadianpatients with spina bifida, 62 mothersof patients, 97 children without NTDs(controls) and 90 mothers of controls,Christensenet al. (1) observed that18–20% of patients with NTDs andtheir mothers were homozygous for theC677T MTHFR polymorphism, com-pared to 11% for controls and controlmothers, implying an increased risk ofNTD associated with the “thermo-labile” MTHFR polymorphism. Hav-ing an RBC folate concentration in thelowest quartile, in conjunction withhomozygosity for the C677T polymor-phism, further enhanced risk forNTDs, providing evidence for a “ge-netic-nutrient” interaction in risk asso-ciation for NTDs. In the Irish, Shieldsand coworkers (2) produced data thatled to similar conclusions. However,their patient population (n5271 NTDcases and n5218 NTD family mem-bers, predominantly parents) was con-siderably larger, providing enhancedstatistical significance. These investi-gators detected the homozygousC677T MTHFR polymorphism in 19%of NTD cases vs. 8% of controls(p50.0005), indicating that the ho-mozygous MTHFR polymorphismwas a key genetic determinant inMTHFR-derived NTD risk. These au-thors correctly noted that the majorityof NTDs, even those which may bepotentially preventable by folate ther-apy, must be associated with factors

unrelated to MTHFR since mostC677T homozygotes do not haveNTDs (suggesting low penetrance ofthe MTHFR polymorphism as a riskfactor for NTDs, or perhaps adequatefolic acid intake), and most womencarrying fetuses with NTDs do notmanifest clinically deficient folate lev-els in plasma or RBCs (although thisdoes not preclude the possibility thataffected fetuses may have a biochemi-cal abnormality requiring higher folicacid concentrations themselves). Datathat conflicted with these conclusionswere presented from a study of SouthAfrican Blacks by Ubbinket al. (3).Folate, homocysteine (HCys) levels,and presence of the “thermolabile”MTHFR polymorphism, were deter-mined in 107 healthy rural blackwomen, 54 rural black women with ahistory of pregnancy complicated byNTDs, and 101 apparently healthy ur-ban black women. Ubbinket al. (3)found that homozygosity for the “ther-molabile” MTHFR polymorphism didnot contribute a genetic risk factor forNTDs in this population; moreover, noabnormality in HCys metabolism wasdetected in women with NTD affectedpregnancies although they may havehad higher plasma folic acid levels.

Although controversial, the emerg-ing model features a “genetic-nutrient”interaction leading to increased risk forNTDs. Maternal hyperhomocysteine-mia (with or without the C677T allele)has been associated with increased riskof NTD in the fetus; “thermolabile”

MTHFR homozygotes are at risk ofhyperhomocysteinemia when plasmafolate is decreased, and decreasedMTHFR activity may further depressalready low folate concentrations. Asobserved by Shieldset al. (2), consen-sus may only come with studies ofmuch larger mother-child pairs associ-ated with NTDs, or through applica-tion of transmission disequilibriumtests (TDT) to three-generation fami-lies to include MTHFR heterozygousmaternal grandparents of NTD off-spring. Clearly, we have a lot to learnabout the role of folic acid, and theenzymes responsible for its metabo-lism, in human embryogenesis anddevelopment.

1. Christensen B, Arbour L, Tran P, Leclerc D, Sab-baghian N, Platt R, Gilfix BM, Rosenblatt DS,Gravel RA, Forbes P, Rozen R 1999 Genetic poly-morphisms in ethylenetetrahydrofolate reductaseand methionine synthase, folate levels in red bloodcells, and risk of neural tube defects. Am J MedGenet 84:151–157

2. Shields DC, Kirke PN, Mills JL, Ramsbottom D,Molloy AM, Burke H, Weir DG, Scott JM, White-head AS 1999 The “thermolabile” variant of meth-ylenetetrahydrofolate reductase and neural tube de-fects: an evaluation of genetic risk and the relativeimportance of the genotypes of the embryo and themother. Am J Hum Genet 64:1045–1055

3. Ubbink JB, Christianson A, Bester MJ, Van AllenMI, Venter PA, Delport R, Blom HJ, van derMerwe A, Potgieter H, Hayward Vermaak WJ1999 Folate status, homocystein metabolism, andmethylene tetrahydrofolate reductase genotype inrural south African Blacks with a history of preg-nancy complicated by neural tube defects. Metab-olism 48:269–274

K. Michael GibsonOregon Health Sciences UniversityMolecular and Medical Genetics and PediatricsPortland, OR 97201 USA

Teodoro BottiglieriBaylor University Medical CenterInstitute of Metabolic DiseaseDallas, TX 75246 USA

K. MICHAEL GIBSON AND

TEODORO BOTTIGLIERI

RESEARCH NEWS

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0031-3998/00/4802-0135PEDIATRIC RESEARCH Vol. 48, No. 2, 2000Copyright © 2000 International Pediatric Research Foundation, Inc. Printed in U.S.A.