Maternal phenylketonuria: A metabolic teratogen

Abstract

The maternal phenylketonuria (PKU) syndrome refers to the teratogenic effects of PKU during pregnancy. These effects include mental retardation, microcephaly, congenital heart disease, and intrauterine growth retardation. In untreated pregnancies wherein the mother has classic PKU with a blood phenylalanine level > or = 1,200 microM (20 mg/dl), the frequencies of these abnormalities in offspring are exceedingly high, approaching 75-90% for microcephaly and mental retardation and 15% for congenital heart disease. There is a dose response relationship with progressively lower frequencies of these abnormalities at lower phenylalanine levels, both in the pregnancies of women with variants of PKU and in treated classic PKU pregnancies. The pathogenesis of this syndrome is unknown; it may be related to inhibition by phenylalanine of large neutral amino acid transport across the placenta or to direct toxicity of phenylalanine and/or a phenylalanine metabolite in certain fetal organs. A mouse model for PKU now exists, and studies of maternal PKU in this model are in progress. The treatment of maternal PKU consists of biochemical control through a phenylalanine restricted diet during pregnancy. The best results are obtained with diet initiation before conception or no later than the earliest weeks of pregnancy. Women with PKU and their families require much psychosocial support to meet the strict requirements of a maternal PKU pregnancy, including compliance with a difficult diet. With such compliance, however, it seems that bearing normal or near normal offspring is possible.

Environmental Risk Factors for Congenital Heart Disease

“…Transcriptomic analysis of the chick model suggests that phenylalanine teratogenicity may act through dysregulation of RA signaling (Watson and Seagraves 2019). This is supported by the observation that the characteristic facial phenotype of PKU-affected patients is often very similar to those of FASD (Levy and Ghavami 1996), which has also been associated with perturbed RA signaling (see above). Exactly how elevated Phe levels might affect RA signaling or metabolism awaits further investigation.…”

Executive Function Across Syndromes Associated with Intellectual Disabilities: A Developmental Perspective

“…Maternal PKU (MPKU) arises when mothers with PKU are not treated adequately during pregnancy, and leads to ID in 97% of offspring, with microcephaly (73%), low birth weight (40%), and congenital heart disease (12%) being the most common comorbid problems (Lenke & Levy, 1980;Levy & Ghavami, 1996). Although the toxic elements of PKU and maternal PKU (MKU) are the same, differences in the timing of children"s exposure to this toxicity in turn lead to differences in the expression of cognitive strengths and weaknesses (Antshel & Waisbren, 2003).…”

Maternale Phenylketonurie: Diätetische Behandlung einer Zweitgenerationserkrankung1

“…Dennoch wurde bereits 1980 in einer groûen retrospektiven Analyse von 524 Schwangerschaften bei 155 Frauen mit nicht mehr behandelter Phenylketonurie klar, dass die hohen Phe-Spiegel der Mutter zu schweren intrauterinen Schädigungen des Kindes und in der Folge zu kongenitalem Mikrozephalus, mentaler Retardierung, Herzfehlbildungen und intrauteriner Wachstumsretardierung führen [5]. Die Schädigung erfolgt im Sinne einer Phenylalanin-Embryofetopathie durch transplazentaren Übergang von Phenylalanin in den embryonalen/fetalen Kreislauf [6,7]…”