Severe Mthfr Deficiency

Severe MTHFR deficiency, with less than 20% of control enzyme activity, is the most common inborn error of folate metabolism (8). These patients have dramatic elevations of plasma homocysteine with homocystinuria, and low or low-normal levels of plasma methionine. This relatively rare condition can have devastating consequences. Some patients die in the first year of life; others have variable clinical features, including developmental delay, motor and gait disturbances, seizures, and psychiatric manifestations. Pathological findings have included demyelination and vascular changes (8). Over 20 different mutations in MTHFR have been reported in this group of patients (3,9-12). Some of these mutations have been expressed in vitro and confirmed to impact enzyme function (13).

The early-onset clinical symptoms in these homocystinuric patients emphasize the important role of MTHFR and folate metabolism in normal development, particularly in the development of the central nervous system. Other enzyme deficiencies, the most common being a deficiency of cys-tathionine-^-synthase (CBS), can cause homocystinuria through a disruption of homocysteine trans-sulfuration, but, in contrast to MTHFR-deficient patients, CBS deficiency is associated with high methionine levels in plasma (14). This is the result of the fact that MTHFR deficiency results in a disruption of the homocysteine remethylation pathway, whereas CBS-deficient patients have normal remethylation, with a block in the first enzyme of the trans-sulfuration pathway. Although CBS-deficient patients also have some CNS problems, such as mental retardation, MTHFR deficiency appears to be associated with additional significant neurological features. Because

MTHFR-deficient patients are likely to be compromised with respect to SAM synthesis, it is possible that some of their distinct neurological problems are related to a decrease in methylation reactions in the CNS, such as decreased phospholipid synthesis or decreased neurotransmitter synthesis.

Common to both types of homocystinuria are vascular changes, presumably reflecting the increased levels of homocysteine in the circulation. With the recognition of hyperhomocysteinemia as a risk factor for cardiovascular disease, many studies have addressed the nature of the pathogenic effects of homocysteine on the vasculature. These include toxicity to the vascular endothelium, enhanced proliferation of smooth muscle cells, thrombogenic effects and an increase in oxidative stress (15). However, because most studies have been performed in vitro, the physiologic relevance of these findings requires confirmation.

A mouse model for severe MTHFR deficiency has recently been generated (16). Mice that are homozygous for a knockout of the MTHFR gene have severe hyperhomocysteinemia with reduced survival or delayed development and cerebellar pathology. Additional investigations of these mice should provide important information regarding the pathogenicity of hyperhomocysteinemia and the role of folate in normal development.


Based on the presence of thrombotic episodes in patients with severe hyperhomocysteinemia and homocystinuria, several investigators suggested that milder elevations in homocysteine could also be a risk factor for cardiovascular disease (17). The observation that some patients with cardiovascular disease had a mild deficiency of MTHFR, with a thermolabile enzyme (18), led to molecular genetic studies that identified a C to T mutation at bp 677 (an alanine to valine substitution) (4). This mutation was expressed in vitro and shown to encode a thermolabile enzyme. Individuals who were homozygous mutant also had reduced enzymatic activity at 37°C (approx 35% of control values). These individuals are at risk for mild hyperhomocysteinemia, particularly when their plasma folate is low (19). Folate supplementation has been demonstrated to lower homocysteine in these individuals (20). These clinical observations are supported by biochemical studies that have demonstrated that the mutant human enzyme can be stabilized by both folate and its cofactor flavin adenine dinucleotide (FAD) (1). Thus, supplemental folate might prevent hyperhomocysteinemia in mutant individuals by improving enzyme function. Studies with the mutagenized bacterial enzyme have yielded similar results to those of the human enzyme and have predicted, on the basis of crystal structure informa tion, that the mutant valine residue may indirectly affect FAD binding and/ or increase the dissociation of the active bacterial tetramer into a dimer (1).

The mutation has been shown to decrease total plasma folate (21), as 5-methylTHF is the primary circulatory form of folate. It has also been shown to affect the distribution of folates in red blood cells (22). Individuals with the mutation have decreased amounts of methylTHF and increased amounts of the formylated derivatives. Because 5,10-methylene THF conversion to 5-methylTHF is compromised by reduced MTHFR activity, there is an increased amount of 5,10-methylene THF available for conversion to formyltetrahydrofolate. The decreased 5-methylTHF accounts for hyperhomocysteinemia because of the reduced conversion of homocysteine to methionine by methionine synthase; this reduction could also affect me-thylation reactions. The increased amount of other folate derivatives might improve thymidine and purine availability for DNA synthesis (see Fig. 1). Although total folate in red blood cells was not different in mutant individuals in this study (22), others have suggested decreased (23) or increased (24) total folate in erythrocytes. The discrepancy could be the result of the variable methodologies employed in different laboratories.

The 677C^T mutation is common in North American, European, and many Asian countries, with homozygosity frequencies ranging from 5% to 25% (25). The highest frequencies of this variant have been reported in southern Mediterranean populations and Hispanic populations in North America. The mutation is relatively infrequent in African-Americans (26).

The initial identification of this polymorphism was made on the basis of its role in the elevation of homocysteine, a risk factor for cardiovascular disease. However, because severe MTHFR deficiency is associated with a wide variety of developmental and neurologic problems, it is not too surprising that mild MTHFR deficiency might also have an impact on disorders involving the central nervous system (CNS).


Neural Tube Defects

Clinical studies have clearly demonstrated that folate supplementation reduces the occurrence and recurrence of neural tube defects (NTD) (27,28). Mothers of children with NTD had been shown to have low folate levels and were suspected of having an altered folate metabolism (29). The observation that mothers of NTD cases had mild hyperhomocysteinemia (30,31) led to the investigation of the MTHFR variant as a genetic risk factor for this birth defect (24). Several studies have reported that the 677C^T variant in the homozygous state in the child or in the mother can increase the risk for NTD. A recent review of the literature indicated a pooled odds ratio of 1.8 (95% confidence interval [CI] = 1.4 - 2.2) and 2.0 (95% CI = 1.5 - 2.8) for children and mothers, respectively, with the homozygous mutant genotype (25); these values are quite similar to those reported in an earlier meta-analy-sis (32). The combination of the mutant genotype in both the mother and child could have an even greater risk, according to one report (33). As mentioned earlier for hyperhomocysteinemia, nutritional folate status is a critical determinant in the magnitude of the genetic risk conferred by this mutation. Low folate status combined with the homozygous mutant genotype may result in a higher risk than either variable alone (33). The lack of an association between NTD and the MTHFR variant in some studies may reflect the nutritional status of the study group during the critical period of development of the neural tube.

The mechanism by which this mutation increases risk is not clear. Homocysteine has been shown to be teratogenic in studies of chicken embryos (34). Alternatively, a decrease in methylation reactions or dysregulated DNA synthesis in critical cells could compromise neural tube closure.

Pregnancy Complications

Women with placental abruption (35) or recurrent pregnancy loss (36) have been reported to have mild hyperhomocysteinemia. These findings have culminated in several publications that have documented an increased frequency of the 677C^T variant in women with the aforementioned complications and with preeclampsia (36-38). A recent review of the relevant literature has reported pooled odds ratios of 2.3 (95% CI = 1.1 - 4.9), 3.3 (95% CI = 1.2 - 9.2), and 2.6 (95% CI = 1.4 - 5.1) for placental abruption, recurrent pregnancy loss, and preeclampsia, respectively, in women who were homozygous mutant for the 677-bp variant (38). The risk for these problems is also augmented in the presence of other thrombophilic risk factors, such as Factor V Leiden and the 20210-bp mutation in the prothrombin gene, either alone or in combination with the MTHFR mutation (39-41). These various types of pregnancy complication could be caused by homo-cysteine-mediated effects on the placental vasculature.

A few reports in the literature have alluded to genetic selection, with possible intrauterine losses, based on MTHFR genotypes. One study has suggested that the frequency of the homozygous mutant genotype is increased in the younger population in Spain, compared to an older group, because folate supplementation during pregnancy in the past two decades has im proved the nutritional status of pregnant women and decreased the number of losses of mutants in utero (42). Another study has suggested heterozygote advantage in families with NTD (43) and one publication has reported decreased amounts of control female newborns that are homozygous for this mutation (44).

Other Emerging Developmental Problems

Oral Clefts

Maternal use of multivitamins with folic acid has been reported to reduce the risk of a cleft lip with or without cleft lip palate (45). The first study of MTHFR in children with this congenital anomaly did not identify a statistically significant risk in a Hispanic California population, although there was an increased nonsignificant odds ratio for cleft lip (1.8, 95% CI = 0.3-7.9) in children of non-Hispanic white mothers who did not use vitamins (46). The same group reported the absence of an effect on an isolated cleft palate (47). In contrast, maternal hyperhomocysteinemia was observed in mothers of children with nonsyndromic orofacial clefts in the Netherlands (48), and a recent small study in Ireland reported a significantly higher frequency of mutant MTHFR in subjects with an isolated cleft palate (49).

Fetal Anticonvulsant Syndrome

One study has reported an increased frequency of this variant in women on anticonvulsant medication who had children with this syndrome (50). Three common anticonvulsants (carbamazepine, phenytoin, and sodium valproate) have been shown to interfere with folate metabolism; consequently, these women may have a higher requirement for folate during pregnancy. In a related study, epileptic women on anticonvulsants were shown to have hyperhomocysteinemia and low folate, particularly when they were homozygous for this variant (51).

Down Syndrome

Two studies (52,53) have reported an increase in the frequency of the MTHFR variant in mothers of children with Down syndrome. The postulated mechanism is an increase in DNA hypomethylation, which could promote nondisjunctional events by altering centromere methylation patterns or chromosome stability.


Abnormalities in methyl group metabolism have been observed in schizophrenics (54), and patients with severe MTHFR deficiency can have psychiatric disturbances (8). Consequently, a few studies have examined the common MTHFR variant as a risk factor for this condition. Positive associations (55,56) have been observed in some but not all studies. This discrepancy could be the result of the fact that the association may only be present in subgroups of patients (e.g., those who are good responders to neuroleptic medication) as reported in a recent study (56).

Congenital Heart Defects

Multivitamin supplementation has been shown to decrease the risk of congenital heart defects. Mothers of children with congenital heart defects have been reported to have higher homocysteine levels than control subjects (57). Although the MTHFR variant was not examined in this study, the association between vitamin responsiveness and hyperhomocysteinemia suggests that the MTHFR variant could be a candidate risk factor, particularly because neural-crest cells contribute to the formation of the septum.


The high frequency of a polymorphism that can affect genetic fitness in several different conditions raises the question of a possible selective advantage. One hypothesis relates to the fact that a mutation in MTHFR should increase DNA synthesis or repair through an elevation of 5,10-methylene THF levels for the synthesis of thymidine or purines. Several publications have reported a protective effect of the MTHFR variant in colorectal cancer (58,59), possibly through the aforementioned mechanism; a recent study has demonstrated a similar protective effect in adult acute lymphocytic leukemia (60). Although the age of onset of these disorders is in the adult period and therefore may have little impact on selection or early development, it is possible that enhanced DNA synthesis may be advantageous during early development or in the protection against early-onset childhood cancers.

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