Am Fam Physician. 1999;60(5):1462-1466
The blood sample for phenylketonuria (PKU) screening should be obtained at least 12 hours after the infant's birth. Newborn screening for PKU has largely eliminated mental retardation caused by this disease. If the first phenylalanine test demonstrates positive results, a repeat test should be performed. Treatment to prevent sequelae from this disorder is best carried out in cooperation with an experienced PKU center. Dietary care is expensive, and financial assistance may be necessary for many families. A phenylalanine-restricted diet should be started as soon as possible. Occasionally, cases of PKU are missed by newborn screening. Thus, a repeat PKU test should be performed in an infant who exhibits slow development.
Phenylketonuria (PKU) is caused by an autosomal recessive defect in the enzyme phenylalanine hydroxylase, which is required for converting phenylalanine to tyrosine. (Five percent of natural protein is composed of phenylalanine.) The mutation that causes PKU is located on chromosome 12. The specific type of mutation varies, resulting in variable severity in the clinical course of the disorder.
Untreated, PKU results in severe mental retardation, but the exact pathogenesis of the mental defect is still not clear.1–3 Progressive neurologic damage occurs as the child grows older. Because treatment with a phenylalanine-restricted diet prevents the development of mental retardation, it seems likely that an increased concentration of phenylalanine in the blood is associated in some way with progressive neurologic deterioration if PKU remains untreated.
The symptoms of untreated PKU develop gradually, so they may not be noticed until irreversible mental retardation has occurred. Hence, newborn screening is essential for prevention of harmful effects. When PKU is identified in the first few weeks of life and a phenylalanine-restricted diet is instituted, intellectual development is substantially better than when the disorder is diagnosed at three to five years of age. When PKU is not diagnosed until this late age, serious damage has usually already occurred.4
Initial estimates of the frequency of PKU (one per 25,000 live births) were based on institutionalized populations with profound mental retardation caused by defects that completely prevented the production of phenylalanine hydroxylase.5 The frequency of PKU in the United States is currently considered to be one per 10,000 to one per 12,000 live births.6 The frequency varies in different ethnic groups. For example, it is one per 2,500 live births in Turkey and one per 4,000 live births in Ireland. In the United States, the frequency of PKU is one per 20,000 live births in California, compared with a frequency of one per 12,000 live births in Massachusetts. The large population of Americans of Irish ancestry in Massachusetts may explain the increased frequency in that state.
PKU Screening Procedure
Newborn PKU screening in the United States is performed with the Guthrie inhibition assay7 or the McCamon-Robins fluorometric test.8 Both tests can be performed on blood spotted on filter paper, and both are highly accurate. The laboratory that performs the PKU test has the responsibility of reporting the results to the physician and to the facility where the infant was born. Some laboratories also notify the parents.
The blood specimen for PKU screening must be obtained at least 12 hours after birth,9 but in recent years this has proved rather difficult because of changing obstetric practices in which patients are sometimes discharged a few hours after delivery. The American Academy of Pediatrics recommends that a PKU screening test be repeated by two weeks of age if it was performed before the newborn was 24 hours of age. However, a second test is not necessary if the initial PKU screening is performed with the McCamon-Robins fluorometric test8 when the newborn is between 12 and 24 hours of age. With either the McCamon-Robins test or the Guthrie test, the test should be repeated if it was performed when the newborn was less than 12 hours of age (Table 1).
|Infant's age at initial testing||Follow-up testing|
|<12 hours||Repeat the test regardless of the results on initial screening.|
|12 to 24 hours||Repeat the test if McCamon-Robins fluorometric assay was used.|
|If Guthrie inhibition assay was used, repeat the test if the results were positive; repeat testing is not required if the results were negative.|
|>24 hours||Repeat the test if the results were positive; repeat testing is not required if the results were negative.|
NORMAL AND ABNORMAL PHENYLALANINE LEVELS IN INFANTS
The blood phenylalanine concentration in newborns is normally 0.5 mg to 1 mg per dL (30 to 60 μmol per L). In general, few infants with PKU will remain unidentified when a phenylalanine cut-off value of 2 mg per dL (121 μmol per L) in the first 24 hours is used. Not all states, however, use 2 mg per dL as the cut-off value. Forty states and jurisdictions use 4 mg per dL (242 μmol per L) as the screening cut-off value for PKU, six states use 3 mg per dL (182 μmol per L) and seven states use 2 mg per dL.10 Some newborns without PKU have transiently elevated phenylalanine levels of more than 6 mg per dL (363 μmol per L) related to delayed maturation of enzymes required for amino acid metabolism. Blood phenylalanine levels are generally slightly lower in breast-fed infants than in bottle-fed infants. Breast milk contains only 12 to 14 mg of phenylalanine per ounce, compared with 24 to 28 mg per ounce in formula.
Because PKU is a heterogeneous disorder, phenylalanine levels vary greatly in infants with the disease. However, treatment is usually not necessary in infants who persistently demonstrate blood phenylalanine concentrations of less than 10 mg per dL (605 μmol per L). Such cases are mild and permit production of phenylalanine hydroxylase, which converts phenylalanine to tyrosine, as in the normal person.11 Persons with severe mutations have much higher phenylalanine levels. To be completely certain of the diagnosis, follow-up testing is recommended in male infants with initial phenylalanine levels between 3 and 10 mg per dL and in female infants with values between 4 and 10 mg per dL.12 Affected females should be followed through their reproductive years to prevent impaired fetal neurologic development as a result of maternal PKU.13
Although initial PKU screening demonstrates positive results in 1 percent of infants, there is only a 10 percent chance that an infant with an initial positive result has the disorder (false-positive rate of 90 percent).6 A repeat test must be performed if the initial test is positive. False-negative results are rare. Infants should be given a normal diet until a definitive diagnosis is made.
VERIFICATION OF POSITIVE RESULTS
When the initial newborn screening test and the second test show positive results, a confirmatory quantitative test, such as the McCamon-Robins fluorometric test, should be performed by a laboratory at a referral metabolic center. The infant should be referred to a center capable of providing the required medical, nutritional and laboratory services for infants with PKU. While the phenylalanine-restricted diet requires the assistance of health care professionals experienced in the management of PKU, the family physician should continue to provide routine care, including immunizations. Follow-up developmental testing before kindergarten is recommended.
If a positive test is overlooked and the infant is subsequently found to have PKU, a malpractice lawsuit is almost certain to follow. To be sure that the results of all PKU tests are noted, charts for newborns should be stamped on the cover or first page with a notation as to the results of newborn screening tests. In this way, the test results are readily available at the first office visit. If the PKU test result has not been recorded in the chart by the time the infant is two months of age, systematic follow-up should be instituted to be certain that newborn screening was performed and that the result was negative. Newborn PKU screening may not have been performed in infants born at home or out of the United States, or in infants who required transfer to another facility soon after birth.
If it becomes evident during regular follow-up of an infant that the infant's development is delayed, it is useful to examine the report of PKU screening, and consideration may be given to repeating the test. There may be instances in which the blood specimen was obtained during the first six hours after the infant's birth.
Nutritional Therapy for Infants
Mothers of infants with PKU should be encouraged to breast feed, along with giving the infant the special phenylalanine-free formula product. Treatment to prevent mental retardation and other neurologic sequelae from PKU is based on restriction of the dietary intake of phenylalanine while adequate protein and caloric intake is maintained. The diet is planned to provide a sufficient amount of phenylalanine and other amino acids to allow normal growth and development. The diet must be calculated to assure adequate nutrient intake and bioavailability. In additon, consideration may need to be given to the total fat content and the sources of essential fatty acids, because of the absence of lipids in some products and the specific fatty acids included in others.
The phenylalanine-restricted diet for infants utilizes a phenylalanine-restricted commercial product in combination with breast milk or infant formula. The acceptable range of plasma phenylalanine levels during treatment is 2 to 10 mg per dL (121 to 605 μmol per L). Tolerance of phenylalanine varies from infant to infant,7 so the content of the diet may need to be adjusted by monitoring the blood phenylalanine concentration and assessing the level in light of the intake of phenylalanine and other nutrients. In general, the child may eat all fruits and vegetables (except legumes).
Table 2 lists the recommended dietary prescriptions during the first year in infants with PKU. Protein recommendations are adjusted for the protein source. (Dietary guidelines for older children are beyond the scope of this article.)
Discontinuation of the Diet
The results of dietary therapy in children with PKU are impressive. The phenylalanine-restricted diet can prevent mental retardation as well as the other neurodegenerative effects of untreated PKU. While discontinuation of dietary therapy by the age of six to 10 years was once considered safe, this approach is no longer advocated.12 Although most PKU clinics recommend treatment into adulthood, some patients may prematurely discontinue the dietary restrictions. Phenylalanine-restricted diets are difficult to administer and maintain, especially during adolescence. Adherence is understandably difficult, and teenagers sometimes resist treatment. In other cases, physicians operating under earlier treatment recommendations may prematurely discontinue therapy.
In the Maternal PKU Collaborative Study,14 nearly 80 percent of the women were not adhering to the diet at the time they were pregnant and enrolled in the study. Their mean IQ on the Wechsler Adult Intelligence Scale was 83, probably because some were not identified on newborn screening and did not receive the benefit of early intervention and because the majority had discontinued dietary therapy between six to 10 years of age.
Women with a history of PKU must continue dietary therapy during pregnancy to prevent fetal damage. With current awareness of the need to adhere to dietary therapy during pregnancy, women are more likely to continue treatment.5,14 Adults who have severe mutations in the phenylalanine hydroxylase gene should definitely remain on dietary therapy for life.
Disagreement exists as to the ideal blood phenylalanine concentration that should be maintained. In Europe, the general recommendation is a level of 2 to 6 mg per dL (121 to 363 μmol per L) in children. For adults, it is 2 to 12 mg per dL (121 to 605 μmol per L). In the United States, a level of 2 to 10 mg per dL (121 to 605 μmol per L) is usually recommended for children; in adults, it is 2 to 12 mg per dL (121 to 726 μmol per L).
Counseling and Follow-up
With early diagnosis of PKU and institution of the phenylalanine-restricted diet, the prognosis for intellectual development in affected children is excellent. The child's eventual intellectual development is usually similar to that of his or her siblings.2
The annual cost of dietary care ranges from approximately $4,000 for infants to $5,000 for adults. Because phenylalanine-restricted food products are expensive, the family may need to be referred to the local health department for financial assistance, which is available in all states.
Blood phenylalanine concentrations are usually determined weekly during the first year of life, the period of maximal cerebral growth. Thereafter, blood tests can be done quarterly. Plasma amino acid concentrations are determined once or twice a year to be certain that tyrosine levels are adequate.
Two additional points are important. A few phenylalanine-restricted food products are insufficiently fortified with vitamins and minerals. If these products are used, blood selenium and vitamin B12 levels should be checked annually. Multivitamin and mineral supplements are often prescribed for patients with PKU.
The usual protein requirement to maintain growth in infants is about 2 to 3 g per kg per day. After growth patterns have stabilized, the requirement decreases gradually to 1 g per kg per day. The adequacy of the diet is guided best by regularly determining blood phenylalanine and tyrosine levels, and assessing the infant's growth and development.2 A nutritionist, usually one affiliated with a PKU center, should be consulted regularly. With a comprehensive approach, affected persons can be expected to develop normally.