STUDIES OF THE MOLECULAR BASIS OF CONGENITAL MALFORMATIONS

With recent advances in treatment of many acute and chronic diseases, the problems associated with congenital malformations in children have assumed a greater importance in pediatrics. Previous to the work of Warkany and Nelson in 19401, it was recognized that many congenital defects were genetically determined and hereditary. The finding by Warkany and co-workers1-3 that modification of the prenatal environment by severe states of riboflavin deficiency produced congenital malformations in mammals demonstrated clearly the importance of the prenatal environment in the development of the fetus and gave impetus to searches for other environmental factors of importance to the developing organism. The syndrome resulting from severe maternal riboflavin deficiency in rats is characterized mainly by micrognathia and reduction type of defects in the distal extremities of the fetuses, and by a wide number of other anomalies such as cleft palate and hydronephrosis. More recently, Nelson and co-workers4 demonstrated that galactoflavin, a synthetic analog of riboflavin, produced a rapid riboflavin deficiency syndrome in pregnant rats. The addition of galactoflavin to a riboflavin-deficient diet materially shortened the time required to produce riboflavin deficiency, and permitted much better regulation of the experimental model. In other studies of riboflavin deficiency, Miller and co-workers5 showed a lower flavin content in fetuses from riboflavindeficient rats than in control fetuses, suggesting the possibility that there may be corresponding deficiencies in the activities of flavin-dependent enzymes such as the terminal electron transport systems (ETP). Other investigators6 have reported studies of enzymatic activities in liver mitochondria of adult rats fed a riboflavin-deficient diet with added galactoflavin, but with varying results.