The pattern of malformations observed in individuals with Miller syndrome is similar to those of individuals with fetal exposure to methotrexate (Figure 1c,d). Methotrexate is a well-established inhibitor of de novo purine biosynthesis, and its anti-proliferative actions are thought to be due to its inhibition of dihydrofolate reductase and folate-dependent transmethylations. Accordingly, defects of both purine and pyrimidine biosynthesis appear to be capable of causing a similar pattern of birth defects. However, at low doses methotrexate also decreases plasma levels of pyrimidines as well as purines. This observation raises the possibility that methotrexate embryopathy might indeed be caused by its effects on pyrimidine rather than purine metabolism. Given that not all embryos exposed to methotrexate manifest birth defects, functional polymorphisms in DHODH or other genes in the de novo pyrimidine biosynthesis pathway could influence susceptibility to methotrexate embryopathy.
