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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 ≥1,200 μM (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. © 1996 Wiley‐Liss, Inc.
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 ≥1,200 μM (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. © 1996 Wiley‐Liss, Inc.
Maternal phenylketonuria (PKU) has serious consequences for the fetus as a result of elevated phenylalanine levels during pregnancy. An international survey of untreated maternal PKU pregnancies documented a 92% risk of mental retardation, 73% risk of microcephaly, 40% risk of low birth weight, and 12% risk of congenital heart disease in the offspring. Although the precise mechanism for fetal damage in maternal PKU is still unknown, it is clear that the fetus is harmed by the abnormal intrauterine environment. Treatment with a phenylalanine‐restricted diet significantly reduces the risks, however, especially if initiated before pregnancy and maintained carefully throughout pregnancy. Nonetheless, despite the apparent simplicity of treatment, few women begin treatment before conception and maintain metabolic control during pregnancy. Therefore, even in treated pregnancies, developmental and neuropsychological outcome is extremely variable. In addition, genetic and psychosocial factors also contribute to the developmental and neuropsychological outcome in maternal PKU. This review summarizes the studies of children born to mothers with PKU and discusses factors affecting outcome. In addition, the similarities between maternal PKU, fetal alcohol syndrome, and other maternal conditions are presented. The predominant neuropsychological deficits that occur when the fetus is exposed to a teratogen are in the areas of language and memory. Thus, the hypothesis that maternal PKU represents a generic response to a teratogen is supported by these findings and by the characteristics of the developing brain. MRDD Research Reviews 1999;5:125–131. © 1999 Wiley‐Liss, Inc.
An effective treatment is now available to prevent the masculinization of female fetuses with congenital adrenal hyperplasia. Some vitamin-responsive inborn errors of metabolism can be treated prenatally by cofactor administration. Maternal phenylketonuria and maternal diabetes mellitus and the prevention of recurrent neural tube defects are also areas where therapeutic advances are being made. It may be possible to carry out chorionic villi sampling before 8 weeks menstrual age if appropriate catheters and guidance systems (probably transvaginal ultrasound) are used. First trimester diagnosis and treatment of fetal cardiac arrhythmias could prove to be very important, as they are later in pregnancy. Future possibilities for progress include gene microinjection into zygotes, classification and treatment of fresh embryos, biopsy and frozen storage of genetically at risk embryos, and therapy of preimplantation embryos by chimera formation or gene introduction by retroviruses.
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