Methylenetetrahydrofolate reductase thermolabile variant and oral clefts

Abstract

Folic acid can prevent neural tube defects; in some cases the mechanism is probably a correction of a metabolic defect caused by thermolabile methylenetetrahydrofolate reductase (MTHFR) found in increased frequency in cases. It is less clear whether folic acid can prevent oral clefts, in part because it is not known whether thermolabile MTHFR is more common in those with oral clefts. This study examined the prevalence of the mutation (677 C-->T) that causes thermolabile MTHFR in subjects with oral clefts from a national Irish support group, and an anonymous control group randomly selected from a neonatal screening program covering all births in Ireland. Eighty-three of 848 control subjects were homozygous (TT) thermolabile MTHFR (9.8%). This defect was almost three times as common in the 27 subjects (25.9%) with isolated cleft palate (odds ratio 3.23, 95% confidence interval 1.32 -7.86, P = 0. 02) and somewhat more common in the 66 subjects with cleft lip with or without cleft palate (15.2%, odds ratio 1.65, 95% confidence interval 0.81-3.35, P = 0.20). When the two groups with different etiologies were combined, the overall odds ratio was 2.06 (95% confidence interval 1.16-3.66, P = 0.02). In the Irish population homozygosity for the common folate-related polymorphism associated with thermolabile MTHFR is significantly more frequent in those with isolated cleft palate, and could be etiologically important. Am. J. Med. Genet. 86:71-74, 1999. Published 1999 Wiley-Liss, Inc.

Folate‐related gene polymorphisms as risk factors for cleft lip and cleft palate

“…Some studies of MTHFR 677 C→T have shown no association with CLP in either cases or mothers while others have reported associations in mothers, or in mothers who did not use folic acid periconceptionally (Jugessur et al, 2003; Gaspar et al, 1999; Blanton et al, 2002; Martinelli et al, 2001; Prescott et al, 2002; Shotelersuk et al, 2003; Shaw et al, 1998; van Rooij et al, 2003; Mills et al, 1999). One recent study (Chevrier et al, 2007) found that the TT genotype was significantly protective in their case control analysis, although the authors noted that the sample size was small and that the TT rate in controls was higher than expected.…”

“…The majority (80%) of Irish patients with cleft lip and palate are treated through the Centre. Subjects were also recruited from the membership of the Cleft Lip and Palate Association of Ireland as previously described (Mills et al, 1999). Cleft subjects or their parents were either interviewed or completed the interview questionnaire themselves and, when necessary, had an interviewer review their answers with them in order to collect data on socio-demographic variables, obstetrical history, family history, and relevant data on the affected pregnancy including medication use, folic acid exposure, alcohol, and smoking.…”

“…Some studies have found a decline in cleft rates since food fortification with folic acid began (Canfield et al, 2005; Yazdy et al, 2007), although others have not found a change (Ray et al, 2003; Simmons et al, 2004). These observations have led investigators to look for associations between clefts and folate enzyme genes, including methylenetetrahydrofolate reductase ( MTHFR ) (Jugessur et al, 2003; Gaspar et al, 1999; Blanton et al, 2002; Martinelli et al, 2001; Prescott et al, 2002; Shotelersuk et al, 2003; Shaw et al, 1998; van Rooij et al, 2003; Vieira et al, 2005; Mills et al, 1999) and methylenetetrahydrofolate dehydrogenase—the trifunctional cytoplasmic enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase— MTHFD1 (Boyles et al, 2008; Mostowska et al, 2006). Because of the interrelationship between vitamin B12 and folate, the plasma vitamin B12 transporter, transcobalamin 2 ( TCII ), has also been investigated for a role in clefts (Boyles et al, 2008).…”

Maternal MTHFR genotype contributes to the risk of non-syndromic cleft lip and palate

“…Associations have only been found in small studies that lack corroboration when larger groups are tested. [7][8][9][10] We have established MTHFR genotypes in 243 CLP affected subjects and their parents (226 mothers and 210 fathers) in order to determine if genetic susceptibility to folate deficiency may play a role in the development of oral clefts. Families were recruited from the white UK population via the Great Ormond Street Children's Hospital, London.…”

Folate during reproduction: the Canadian experience with folic acid fortification

“…In contrast, Ray et al (2003) reported no change in the risk for orofacial clefts preand post-folic acid fortification of the food supply in Canada. There is epidemiological evidence that the offspring of mothers' homozygous for the 677C >T MTHFR variant may be at increased risk of orofacial clefts, especially among women with low folate intake in some (Mills et al, 1999; van Rooij et al, 2003), but not all studies (Jugessur et al, 2003; Shaw et al, 1998)…”