Multifactorial causation of spina bifida and its prevention: The role of maternal folic acid intake involves epigenetic component

Abstract

Neural tube defects (NTD) involve both genetic and non-genetic factors in their etiology. The recurrence risk for siblings of index cases is approximately 50-fold more than in the general population, which indicates a genetic basis. On the other hand the fact that maternal use of anti-epileptic drugs such as valproic acid and carbamazepine were proven as risk factors for NTD suggests a non-genetic or environmental causation basis. Most human NTDs could therefore be multifactorial which involve gene-gene, gene-environmental and gene-nutrient interaction. Following the startling news that a clinical trial with folic acid (FA) provided by the Medical Research Council resulted in a 72 % reduction in NTD recurrence, mandatory FA fortification of high consumption staples has expanded globally whereas Japan does not yet have such a policy. One of the major FA responsive mouse models, Splotch of Pax3 mutants, shows an approximately 30% preventative effect by maternal intake of folic acid, which strongly indicates an epigenetic component in the homozygous phenotype. And in vitro FA stimulates stem cell proliferation in mouse neural crest via epigenetic manner such as microRNAs expression and chromatin remodeling. The intrauterine repair of fetal spina bifida is currently under development in order to minimize fetal hindbrain herniation and the need of shunt surgery for subsequent hydrocephalus. A recent randomized clinical trial revealed some problems in that prenatal surgery was associated with an increased risk of preterm delivery and uterine dehiscence at delivery.