MTHFR and isolated spina bifida: MTHFR gene polymorphisms cause enzyme thermolability and involve C-to-T substitution at nucleotide 667 and A-to-C at nucleotide 1298; these MTHFR mutations have been associated with homocystinuria, neural tube defects, preeclampsia, cleft lip and cleft palate, cerebrovascular disease, and psychiatric disorders including susceptibility to depression and schizophrenia [39,40].