Neural tube defects have a birth incidence of approximately 1 in 1,000 in American Caucasians and are the second most common type of birth defect after congenital heart defects. The most common NTDs are open spina bifida (myelomeningocele) ... Neural tube defects have a birth incidence of approximately 1 in 1,000 in American Caucasians and are the second most common type of birth defect after congenital heart defects. The most common NTDs are open spina bifida (myelomeningocele) and anencephaly (206500) (Detrait et al., 2005). Women with elevated plasma homocysteine, low folate, or low vitamin B12 (cobalamin) are at increased risk of having a child with a neural tube defect (O'Leary et al., 2005). Motulsky (1996) cited evidence from the Centers for Disease Control ( Anonymous, 1992) that folic acid given before and during the first 4 weeks of pregnancy can prevent 50% or more of neural tube defects. Botto et al. (1999) and Detrait et al. (2005) provided reviews of neural tube defects. De Marco et al. (2006) provided a detailed review of neurulation and the possible etiologies of neural tube defects.
Van der Put et al. (1995) found an increased frequency of the 677C-T thermolabile MTHFR polymorphism (607093.0003) among 55 Dutch patients with spina bifida and their parents compared to controls. Sixteen percent of mothers, 10% of fathers, and ... Van der Put et al. (1995) found an increased frequency of the 677C-T thermolabile MTHFR polymorphism (607093.0003) among 55 Dutch patients with spina bifida and their parents compared to controls. Sixteen percent of mothers, 10% of fathers, and 13% of patients were homozygous for the variant compared to 5% of controls. Van der Put et al. (1995) concluded that the 677C-T variant is a genetic risk factor for spina bifida. Ou et al. (1996) studied fibroblast cultures from 41 NTD-affected fetuses and compared their genotypes with 109 blood specimens from the general population. They demonstrated that 677C-T homozygosity was associated with a 7.2-fold increased risk for NTD (p = 0.001). Ou et al. (1996) concluded that the 677C-T polymorphism of MTHFR may provide a partial biologic explanation for the prevention of neural tube defects by folic acid. Christensen et al. (1999) assessed genotypes and folate status in 56 patients with spina bifida, 62 mothers of patients, 97 children without NTDs (controls), and 90 mothers of controls to determine the impact of these factors on NTD risk. In 20% of patients and 18% of mothers of patients, they found homozygosity for the MTHFR 677C-T polymorphism, compared to 11% of controls and 11% of control mothers, indicating that the mutant genotype conferred an increased risk for NTDs. The risk was further increased if both mother and child had this genotype. RBC folate was lower in patients and in mothers of patients compared to their respective controls. The combination of homozygous mutant MTHFR genotype and RBC folate in the lowest quartile conferred an odds ratio for being an NTD case of 13.43 and an odds ratio for having a child with NTD of 3.28. Christensen et al. (1999) proposed that the genetic-nutrient interaction, i.e., MTHFR polymorphism and low folate status, is associated with a greater risk for NTDs than either variable alone. Among 56 patients with spina bifida and 58 mothers of children with spina bifida, Wilson et al. (1999) found that patients and mothers of patients were almost twice as likely to be homozygous for a 66A-G polymorphism in the MTRR gene (602568.0003) compared to controls. When combined with low levels of serum B12, the risk for mothers increased nearly 5 times (odds ratio of 4.8); the OR for children with this combination was 2.5. In the presence of combined MTHFR 677C-T and MTRR 66A-G homozygous mutant genotypes, children and mothers had a 4- and 3-fold increase in risk, respectively. Doolin et al. (2002) analyzed data on the MTR 2756A-G polymorphism (156570.0008) and the MTRR 66A-G polymorphism and concluded that both variants influence the risk of spina bifida via the maternal rather than the embryonic genotype. For both variants, the risk of having a child with spina bifida appeared to increase with the number of high-risk alleles in the maternal genotype. Relton et al. (2004) conducted a case-control association study in families affected by NTD to determine the contribution of polymorphic variation in genes involved in the folate-dependent homocysteine pathway. They investigated 7 polymorphisms in 6 genes: 2 in MTHFR and 1 each in MTRR, SHMT1 (182144), CBS (613381), GCP2 (600934), and RFC1 (600424). Both independent genetic effects and gene-gene interactions were observed in relation to NTD risk. Maternal-fetal interaction was also detected when offspring carried the MTHFR 677C-T variant and mothers carried the MTRR 66A-G variant. Hol et al. (1998) identified a heterozygous mutation in the MTHFD1 gene (172460.0001) in 2 brothers with spina bifida, 1 with spina bifida aperta and 1 with spina bifida occulta. The unaffected maternal grandmother, mother, and a third brother also carried the mutation. Brody et al. (2002) and De Marco et al. (2006) both observed an association between an R653Q polymorphism in the MTHFD1 gene (172460.0002) and neural tube defects in an Irish and Italian population, respectively. Parle-McDermott et al. (2006) analyzed the MTHFD1 gene in an independent sample of 245 Irish mothers with a history of NDT-affected pregnancy and 770 controls and found a significant excess of QQ homozygote mothers of NTD cases compared to controls (OR, 1.49; p = 0.019). Parle-McDermott et al. (2006) concluded that the R653Q polymorphism has a significant role in influencing a mother's risk of having an NTD-affected pregnancy in the Irish population. O'Leary et al. (2005) found no association between the MTRR 66A-G polymorphism and neural tube defects in an Irish population comprising 470 patients and 447 mothers of patients. A dominant paternal effect was observed (OR, 1.46). Mildly elevated maternal plasma homocysteine levels have been observed in some NTD pregnancies. In the NTD population in Ireland, Ramsbottom et al. (1997) examined the frequency of relatively common mutations in the gene encoding cystathionine beta-synthase (236200), one of the main enzymes that controls homocysteine levels. Neither the severely dysfunctional G307S CBS allele (236200.0001) nor the allele with the 68-bp insertion in exon 8 in association with the I278T CBS mutation (236200.0004) was observed in increased frequency in the cases relative to controls. Ramsbottom et al. (1997) concluded that loss-of-function CBS alleles do not account for NTD in Ireland.