Maternal Phenylketonuria (PKU)

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Phenylketonuria (PKU) is a recessive genetic condition —a condition that you have if you received two gene copies that cause the same defect, one copy from your mother and the other from your father. Consequently, it is often discussed a lot in terms of the risk that you will give birth to a child afflicted with PKU. Our focus today, however, is maternal PKU, the issues for the mother and for her pregnancy.

In North America, PKU occurs in approximately 1 person per 100,000, but the prevalence of the condition varies greatly around the planet. In Turkey, the prevalence of PKU is particularly high, at 1 case per 2,600. PKU is also fairly common in Ireland. It is extremely unlikely that you would have PKU and find out about it as an adult, because newborns have been screened for PKU since the 1960s. On the other hand, since management of PKU depends on a special diet, it is not uncommon for the condition to worsen in early adulthood, due to the individual going to live on her own and letting her diet lapse.

First, let’s talk some genetics. Normally, the two gene copies encode an enzyme called phenylalanine hydroxylase (PAH). This enzyme is needed to convert the amino acid (protein building block) phenylalanine into a different amino acid, called tyrosine. The latter can be utilized by the body to make proteins, and also converted into still other amino acids, by other enzymes. More than 500 mutations have been discovered that can make the gene for PAH defective. The combination of any two defective genes for this enzyme in the same person leads to PKU. However, depending on the particular mutations, the individual can have some amount of enzyme activity. If PKU is identified early in infancy, its effects can be minimized with a special diet that limits the amount of phenylalanine that the person with PKU ingests.

If you have reached adulthood and are now pregnant, this means that your PKU has been controlled for a long time. Also, if your partner does not carry a PKU gene, the fetus, although though a carrier for PKU on account of you, will not have the condition as you do. Nevertheless, the levels of phenylalanine in your blood have to be kept at a particularly low level during pregnancy (below 360 μmol/l). Otherwise, the concentration of phenylalanine will rise to dangerous levels in the blood of your fetus. If this happens, development of fetal organs, including the brain and heart, will be abnormal, leading to severe consequences that can even be fatal. If the blood concentration of phenylalanine is just a little too high, there may not be obvious effects on internal organs, but it is likely that there will be effects on mental function, because of subtle damage to the brain. Problems in mental function can show up as difficulties in reasoning or problem solving, hand-eye coordination, attention, communication ability, and overall IQ.

Nearly all cases of PKU are diagnosed very soon after birth, because newborns are screened for the condition. However, if you were diagnosed with PKU as a newborn, the condition will stay with you, if and when you become pregnant. Because there is a 100 percent chance that you will pass one copy of the abnormal PAH gene to your child, your doctor will recommend genetic counseling and referral to a medical genetics specialist. This may lead to further tests, both for you and the child’s father. First, it is important to determine whether the father is a carrier for PKU. Should he be a carrier, the fetus would then have a 50 percent chance of having two abnormal PAH genes and thus having PKU. Additionally, it will be very helpful to know which specific PAH mutations you and the father possess. The fetus can also be tested.

If the concentration of phenylalanine rises too high in the mother’s blood, she can develop mental difficulties. Such difficulties may include problems in concentration, memory, or reasoning. During pregnancy, such effects can interfere with an expectant mother’s ability to take care of herself, which ultimately can harm the pregnancy. Also, for proper development of the embryo and then the fetus, the mother’s blood concentration of phenylalanine must be kept within the range of 120–360 μmol/l. The reason for the lower limit of 120 μmol/l is that everybody needs some phenylalanine in order to build proteins. However, if the level of phenylalanine rises about 360 μmol/l, the fetus would be at high risk of developing what doctors called MPKU syndrome, which can include any or all of the following complications:

  • Microcephaly (small head and brain)
  • Poor fetal growth
  • Congenital heart defects (CHD — malformation of structures within the heart or the great vessels connected to it). The CHD risk is especially high, if blood levels of phenylalanine rise too high during the first 8–10 weeks of gestation.
  • Fetal growth retardation
  • Non-familial facial features (the baby’s face looks as if the baby were not biologically part of the family)
  • Intellectual disability

PKU is treated with a medicine called sapropterin, which is not harmful to the fetus. Sapropterin does not work for the most severe forms of PKU, namely those who do not produce any PAH enzyme at all. Most people with PKU have some amount of PAH activity, however. Along with the special diet, such patients are given a trial of sapropterin to see if it helps. Additionally, a treatment called large neutral amino acids (LNAA) has helped some people with PKU, but there is some concern about their effects on the fetus.

David Warmflash
Dr. David Warmflash is a science communicator and physician with a research background in astrobiology and space medicine. He has completed research fellowships at NASA Johnson Space Center, the University of Pennsylvania, and Brandeis University. Since 2002, he has been collaborating with The Planetary Society on experiments helping us to understand the effects of deep space radiation on life forms, and since 2011 has worked nearly full time in medical writing and science journalism. His focus area includes the emergence of new biotechnologies and their impact on biomedicine, public health, and society.

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