Spina bifida, meaning “split spine” in Latin, is a type of neural tube defect (NTD) resulting from the incomplete closing of the spine and the membranes around the spinal cord during early pregnancy. It is not caused by a single gene inherited in a straightforward manner. Instead, it results from a complex mix of genetic predispositions and environmental factors. This birth defect is considered a multifactorial condition, meaning its development involves a network of influences that converge during a critical phase of fetal development.
Understanding Multifactorial Inheritance
Spina bifida does not follow the predictable patterns of inheritance seen in conditions caused by a single gene. It is governed by multifactorial inheritance, meaning multiple genes (polygenic factors) inherited from both parents combine with external, non-genetic elements to cause the condition. The genetic component creates a susceptibility, rather than a guarantee of the defect. Environmental triggers then interact with this underlying genetic risk, pushing the individual past a “threshold” required for the defect to manifest. This explains why most cases occur in families with no prior history of the disorder.
Specific Genetic Contributions to Spina Bifida Risk
Folate Metabolism and MTHFR
The genetic susceptibility for spina bifida is often traced to variants within genes that regulate specific metabolic processes. Primary among these are variants involved in the folate metabolic pathway, which processes the B-vitamin folate. Folate is necessary for cell division and DNA synthesis, processes fundamental to the rapid development of the neural tube in early pregnancy.
The most well-known example is the MTHFR gene, which provides instructions for making the enzyme methylenetetrahydrofolate reductase. Variations in this gene, particularly the C677T polymorphism, decrease the enzyme’s activity. A less active MTHFR enzyme impairs the body’s ability to process folate into its active form, leading to lower active folate concentrations.
The C677T variant alone does not cause spina bifida, but it increases vulnerability, especially if dietary folate intake is low. Other genes in this pathway, such as MTRR and MTHFD1, also increase susceptibility. These genetic differences effectively raise the requirement for folate, making the individual highly dependent on sufficient environmental intake.
Essential Environmental and Maternal Factors
The non-genetic factors that interact with inherited susceptibilities often relate to the mother’s health and environment during the periconceptional period. Folate deficiency is the single most common environmental factor, as the neural tube closes between days 17 and 30 of gestation, often before a woman realizes she is pregnant. Inadequate levels of this nutrient during this precise window significantly increase the likelihood of a defect.
Several maternal health conditions also act as environmental triggers, compounding the underlying genetic risk. Poorly controlled pre-existing diabetes is associated with a two- to six-fold increase in risk, and maternal obesity is a recognized risk enhancer.
Exposure to certain medications is another major factor, notably the anti-seizure drug valproic acid, which can increase risk up to tenfold, even with standard folic acid supplements. Environmental toxins, including solvents, pesticides, and heavy metals like arsenic, also elevate risk, particularly when combined with a genetic predisposition. These external factors synergistically impair the neurulation process.
Assessing Recurrence Risk and Preventive Measures
For couples who have had one child affected by an NTD, the risk of recurrence in a subsequent pregnancy is substantially higher than the general population risk. While the general population prevalence is about 1 in 1,000 live births, the recurrence risk after one affected child is approximately 3% to 4%.
The most effective preventive measure is periconceptional folic acid supplementation. Women of childbearing age are advised to take a daily supplement of 400 micrograms (0.4 mg) of folic acid starting at least one month before conception and continuing through the first three months of pregnancy. This timing is crucial because the protective effect must be in place before the neural tube closes.
For women considered high-risk, a much higher dosage is recommended. High-risk individuals include those who have previously had an affected pregnancy, have a first-degree relative with an NTD, or are taking anti-seizure medication. These mothers are advised to take a high-dose supplement of 4 to 5 milligrams (4,000 to 5,000 micrograms) of folic acid daily. This regimen should ideally begin three months prior to conception and continue for the first trimester, offering a significant reduction in the chance of recurrence.