Congenital Anomalies Associated with Low MTHFR RBC Levels
Neural tube defects (NTDs) are the primary congenital anomalies associated with low methylenetetrahydrofolate reductase (MTHFR) RBC levels, including anencephaly, spina bifida, and encephalocele.
Neural Tube Defects (NTDs)
Neural tube defects are the most well-established congenital anomalies linked to MTHFR deficiency and low folate levels:
- Anencephaly: Partial or complete absence of skull bones with brain remnant, almost always fatal before or shortly after birth 1
- Spina bifida: Failure of vertebral arches to close over an open neural tube defect, exposing the spinal cord and nerves 1
- Encephalocele: Protrusion of brain and/or covering membranes through the skull, most often in the occipital region 1
The risk of NTDs is approximately three-fold higher (OR 3.3) for mothers heterozygous for MTHFR mutations and six-fold higher (OR 6.3) for homozygous mothers when not taking periconceptional folate supplements 2.
Other Congenital Anomalies
Evidence suggests that low MTHFR activity and folate deficiency may also be associated with:
- Cardiac anomalies: Ventricular septal defects, atrial septal defects, and other structural heart defects 1, 2
- Orofacial defects: Particularly cleft lip and palate 3
- Limb abnormalities: Various skeletal malformations 2
- Renal anomalies: Structural kidney defects 2
Severe MTHFR Deficiency Manifestations
In cases of severe MTHFR deficiency (autosomal recessive), additional clinical features may include:
- Developmental delay: Varying degrees of developmental abnormalities 4
- Motor and gait abnormalities: Movement disorders 4
- Seizures: Neurological manifestations 4
- Thrombosis: Vascular complications 4
- Homocystinuria: Biochemical abnormality 4
Mechanism of MTHFR Deficiency and Congenital Anomalies
MTHFR is a key enzyme in folate metabolism that catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (the primary circulating form of folate) 2. Deficiency leads to:
- Impaired DNA methylation and gene regulation due to reduced methionine production 5
- Hyperhomocysteinemia, which may contribute to vascular complications 5
- Disrupted cell division during critical embryonic development 6
- Potential epigenetic reprogramming defects 6
Clinical Implications
The relationship between MTHFR deficiency and congenital anomalies has important clinical implications:
- Periconceptional folic acid supplementation can reduce NTD incidence by up to 80% 2
- All women of childbearing age should receive folic acid supplementation (0.4 mg daily) 2
- Women with previous NTD-affected pregnancies should receive higher doses (4 mg daily) 2
- Folate supplementation should begin before conception, as neural tube closure occurs within 28 days of conception 1
- Prenatal diagnosis is possible through linkage analysis and enzymatic assays in high-risk families 4, 7
Special Considerations
- Maternal MTHFR genotype appears more significant than fetal genotype in determining risk 3
- Certain medications, particularly antiepileptic drugs like valproate, may significantly increase the risk of congenital anomalies in mothers with MTHFR polymorphisms 3
- Despite biochemical evidence of MTHFR deficiency, clinical expression can be highly variable, with some individuals remaining asymptomatic 7
- Population-based fortification of grain products with folic acid has reduced NTD rates by approximately 31% for spina bifida and 16% for anencephaly 2
Understanding these associations is critical for genetic counseling, preconception care, and prenatal management in affected families.