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Maternal Phenylketonuria ("PKU")

From the Mountain States Regional Genetic Services Network

Phenylketonuria (PKU) is an autosomal recessive disorder of amino acid metabolism affecting approximately 1/10,000"-1"5,000 infants in North America. It is most often due to deficiency of the enzyme phenylalanine hydroxylase which causes the accumulation of harmful metabolites, including phenylketones. If untreated, PKU leads to mental retardation, seizures, psychoses, eczema and a distinctive "mousy" odor.

A diet low in phenylalanine has been proven to prevent neurological and intellectual deterioration, if initiated in early infancy. Historically, this diet was discontinued at age 6 since it was felt the brain was fully developed by that time and would not be susceptible to the effects of excess phenylalanine and its derivatives.

Currently, it is recommended that diet therapy be continued throughout an affected person's lifetime to prevent the decline in intellect that has been documented in some cases, as well as harm to fetuses of affected women.

In 1961, newborn screening for PKU was begun which enabled the initiation of dietary treatment before neurologic deterioration occurred. With successful dietary therapy, most people with PKU live normal lives, including having children.

Unfortunately, if women with successfully treated PKU are not on dietary therapy during pregnancy, their children are exposed to high levels of phenylalanine in utero, which causes embryologic/fetal brain (and other organ) injury.

Statistically, there are greater than 3,000 women of reproductive age in the United States who have PKU diagnosed after a positive newborn screen and are at risk of delivering infants with the effects of untreated maternal PKU. In addition, there are still women of reproductive age who were born prior to newborn screening for PKU, and those with variants of PKU who are also at risk to have children with maternal PKU syndrome.

Therefore, there are approximately 6,000 women in the United States who will potentially have one or more children affected by exposure to high phenylalanine levels during fetal development.

The characteristic features of maternal PKU syndrome include mental retardation, microcephaly, intrauterine growth retardation, and congenital heart defects. The risk for these defects is approximately 90%, 75%, 50% and 15% respectively, in infants of mothers with untreated classical or atypical PKU (maternal plasma phenylalanine levels >20 mg/dL).

The incidence of these anomalies is considerably lower (approximately 20%) in children of women treated with diet during pregnancy or those with milder forms of hyperphenylalaninemia (maternal plasma phenylalanine levels < 16 mg/dL), but still increased over the occurrence of these defects in the general population. In addition, many women with PKU commonly experience pregnancy loss.

The fetal nervous system is susceptible to nutritional variations, including deficiencies and excesses, as well as toxins. It has not been determined if an excess of phenylalanine and its metabolites, a deficiency of tyrosine due to the absence or inactivity of phenylalanine hydrolase, an amino acid imbalance, or a combination effect cause the disruption of normal development and fetal growth throughout pregnancy. There is also a fetal-maternal plasma gradient for phenylalanine across the placenta causing increased concentrations of phenylalanine in the fetal compartment. Unfortunately, diets low in phenylalanine also may not be ideal for appropriate fetal development because they may be deficient in important nutrients, including zinc, selenium and iron.

Various studies have shown that the best way to prevent fetal malformations and decrease fetal mortality is to initiate a strict, low phenylalanine diet prior to conception. Women who have uncontrolled phenylalanine levels prior to conception but initiate diet therapy after pregnancy is confirmed are still at increased risk of delivering a baby with malformations. This risk closely resembles the incidence of malformations in infants whose mothers received no dietary treatment throughout pregnancy. Current guidelines indicate that maternal plasma phenylalanine levels should be maintained by dietary control at 2-8 mg/dL and a supplement of L-tyrosine provided to achieve maternal blood tyrosine levels of >0.5 mg/dL.

Optimally, an extensive plan for women with PKU should be developed by a multidisciplinary team of physicians, nurses, nutritionists, genetic counselors, patients and their families, which provides counseling, information and support prior to, during and after pregnancy. In addition, an effort needs to be made to identify women who may not know they are at risk to have a child affected by exposure to excessive amounts of phenylalanine prenatally who would greatly benefit from the vast amount of information, treatment and support that is available. We suggest providers contact the clinical genetics unit in their area for advice in managing women with hyperphenylalaninemia.