Please note: In 2003, the CTF updated its Grades of Recommendations to include an "I Recommendation" for situations where insufficient evidence exists to allow a recommendation to be made. (Formerly, these situations were captured under a "C Recommendation".) This change is not retroactive, and all "C Recommendations" made prior to 2003 have not been reevaluated in light of the new "I" recommendation grade. For a discussion of these recommendation grades, please link to the 2003 article in the Canadian Medical Association Journal here.
Overview
There is good evidence for universal newborn
screening and treatment for phenylketonuria (PKU). (A Recommendation) Since
such programs have been implemented, mental handicap due to PKU has virtually
disappeared. Screening for PKU is recommended for all newborns prior to
discharge from the nursery. Infants who are tested before 24 hours of age
should receive a repeat screening test between 2-7 days of age. There is
insufficient evidence to recommend for or against prenatal screening for
maternal PKU. (C Recommendation)
Burden of Suffering
Phenylketonuria is an inborn error of phenylalanine
metabolism that occurs in 1 out of every 12,000 births in North America.<1>
In the absence of treatment during infancy, most persons with this disorder
develop severe, irreversible mental retardation. Many also experience neurobehavioral
symptoms such as seizures, tremors, gait disorders, athetoid movements,
and psychotic episodes with behaviors resembling autism.<2> These clinical
manifestations of PKU have rarely developed in children born after the
mid-1960s, when routine screening was legislated and early treatment for
PKU became common. This has resulted in a cohort of healthy phenylketonuric
women have entered childbearing age. If dietary restriction of phenylalanine
is not maintained during pregnancy, these women are at increased risk of
giving birth to a child with mental retardation, microcephaly, congenital
heart disease, and low birthweight.<3> The incidence of this maternal
PKU syndrome is 1 out of every 30,000-40,000 pregnancies.<4> In the
absence of dietary control in women with PKU who become pregnant, it has
been estimated that exposure of the fetus to the teratogenic effects of
maternal hyperphenylalaninemia could result in an increase in the incidence
of PKU-related mental retardation to the level seen before PKU screening
was established.<5>
Efficacy of Screening Tests
Blood phenylalanine determination by the Guthrie
test has been the principal screening test for PKU for three decades.<6>
Although well-designed evaluations of the sensitivity and specificity of
the Guthrie test have never been performed,<5> sensitivity estimates
and international experience with its use in millions of newborns suggests
that false negative results are rare. Most missed cases of PKU do not appear
to be due to false negative results of the screening tests, but rather
to submission of an inadequate sample, clerical error involving the sample,
infants who have failed to have a blood specimen drawn for screening, e.g.
as a result of early discharge, or failure to follow up positive results.
Fluorometric assays, that can detect differences in blood phenylalanine
levels as low as 6 mmol/L (0.1 mg/dl), are alternative forms of testing
that also offer excellent sensitivity.<5> False positive and false negative
results can occur in PKU screening. In certain situations and population
conditions, the ratio of false positives to true positives is as high as
32 to 1.<5> Although false positives have been viewed for many years
as less important than false negative results because they can be corrected
easily by repeating the test, it should be noted that recalling patients
for a second PKU test generates significant parental anxiety.
The sensitivity of the Guthrie test is influenced by the age of the newborn when the sample is obtained. The current trend toward early discharge from the nursery (resulting in PKU screening being performed as early as 1 to 2 days of age) has raised concerns that test results obtained during this early period may be inaccurate. This is because the blood level of phenylalanine in affected neonates is typically normal at birth, and with the initiation of protein feedings, increases progressively during the first days of life. Using the conventional cutoff of 240 mmol/L (4 mg/dL), diagnostic levels of phenylalanine may not be present in some phenylketonuric newborns tested in the first 24 hours of life. Prospective, longitudinal evaluations of serum phenylalanine levels in infants known to be at risk for PKU have demonstrated a variable rate of false negative results when screening has occurred within the first 24 hours of life.<7,8> False negative rates ranged from 2% to 31% for the first day of life, but decreased to 0.6%-2% on the second day and to 0.3% on the third day.<5,7,8> Current rates may be lower due to the participation of many labs in a voluntary proficiency program run by the Centers for Disease Control. Fluorometric assays, provide more precise measurements of blood phenylanine levels than the Guthrie test and lower false negative rates as well.<5> Two additional solutions designed to improve sensitivity – repeat testing of all newborns after early discharge and lowering the cutoff value to reduce the false negative rate – have encountered criticism for several reasons. Repeat testing would have low yield and cost effectiveness;<9,10> it has been estimated that detecting even one case of PKU in this manner would require performing an additional 600,000 to perhaps 6 million tests.<5> Lowering the cutoff value, on the other hand, improves sensitivity at the expense of specificity, thereby increasing the ratio of false positives to true positives.<5> As of 1990, eight of the fifty-two screening programs in the U.S. use a cutoff level of 120 mmol/L (2 mg/dl). The majority of labs continue to use a cutoff of 240 mmol/L (4 mg/dl) or greater.
The development of a cloned phenylalanine hydroxylase gene probe has made possible the prenatal diagnosis of phenylketonuria in families with previously affected children by analyzing DNA isolated from cultured amniotic cells or samples of chorionic villi. Through the use of the polymerase chain reaction, thirty-one alleles of the phenylalanine hydroxylase gene have been identified. This may eventually permit the screening of the general population for carriers of these alleles, thereby detecting at-risk families prior to the birth of an affected child.
Routine screening of pregnant women for maternal PKU has been recommended as a means of preventing fetal complications.<1,4> This disorder is rare in the general population, however, and as a result of screening programs, many women with PKU are aware of their diagnosis. As the cohort of women born before implementation of routine newborn screening move out of their childbearing years, the yield from screening all pregnant women should be very low. In Massachusetts, routine screening of cord blood for 10 years detected only 22 mothers with previously undiagnosed hyperphenylalaninemia.<1,11>
Effectiveness of Prevention and
Treatment
Before treatment with dietary phenylalanine restriction
became common in the early 1960s, severe mental retardation was a common
outcome in children with PKU. A review in 1953 reported that 85% of patients
had an intelligence quotient (IQ) less than 40, and 37% had IQ scores below
10; less than 1% had scores above 70.<2> Since dietary phenylalanine
restriction was introduced, however, over 95% of children with PKU have
developed normal or near normal intelligence.<12-15> A large longitudinal
study has reported a mean IQ of 100 in children followed to age twelve
years<16> and other reports show that adolescent and young adult patients
are functioning well in society.<17> Although the efficacy of dietary
treatment has never been proven in a properly designed controlled trial,
the contrast between children receiving dietary treatment and historical
controls provides compelling evidence of its effectiveness. This prompted
most Western governments to require routine neonatal screening as early
as the late 1960s.
It is essential that phenylalanine restriction be instituted in early infancy to prevent the irreversible effects of PKU.<12,14,18> Traditionally, strict adherence to the diet was recommended for the first four to eight years of life after which it was felt that liberalization of protein intake could occur without damage to the developed central nervous system.<12,14,18> Recent data, however, suggest that discontinuation of the diet may result in some deterioration of cognitive functioning, leading many to recommend continuation of the diet through adolescence and into adulthood.<19,20,21> Even if such precautions are taken, dietary treatment may not offer full protection from subtle effects of PKU. Intelligence scores in treated persons with PKU, although often in the normal range for the general population, are somewhat lower than those of siblings and parents,<12> and mild psychological deficits, such as perceptual motor dysfunction, and attention and academic difficulties have been reported. For more information on screening for abnormal mental development, see Chapter 24.
Early detection of maternal PKU in pregnant women may also be beneficial. The incidence of maternal PKU is increasing with the growing number of healthy phenylketonuric females now entering childbearing age. Maternal hyperphenylalaninemia can produce teratogenic effects, even on normal fetuses who have not inherited PKU. If the mother does not follow a restricted phenylalanine diet during pregnancy, there is an overwhelming risk of birth of an abnormal child. This risk appears to increase as the average maternal levels of phenylalanine during pregnancy increase.<22,23> Over 90% of these children will have mental retardation, 75% microcephaly, 40-50% intrauterine growth retardation, and 10-25% other birth defects.<3,4> Uncertainties exist, however, as to whether these outcomes can be prevented by instituting treatment with dietary phenylalanine restriction.<3,24> Although some pregnant women under treatment have given birth to normal children, a number of investigators,<24-28> have found that dietary intervention fails to prevent fetal damage. Many believe dietary restrictions must be instituted prior to conception to be effective.<1,3,26-28> There are also concerns that the low phenylalanine diet may produce deficiencies in calories, protein, and other nutrients needed for proper fetal growth.<4,24> A major study examining the health effects of such diets during pregnancy is currently under way.
Recommendations of Others
In 1989, the U.S. Preventive Services Task Force
recommended screening for all newborns prior to discharge from the nursery,
repeat screening for infants discharged prior to 24 hours between 7-14
days and recommended against prenatal screening for maternal PKU.<29>
While there are no federal guidelines for metabolic programs, every Canadian province and U.S. state has mandated routine screening services for all newborns. Individual states vary regarding participation requirements with participation in three jurisdictions (District of Columbia, Maryland, and North Carolina) being completely voluntary. All Canadian provinces have universal screening programs. The American Academy of Pediatrics (AAP) and the American Academy of Family Physicians (AAFP) recommend that a capillary blood specimen be obtained from every neonate before leaving the nursery and as close as possible to discharge. Premature infants and those being treated for illness should be tested on or near the seventh day. The AAP recommends that infants who are tested before 24 hours of age receive a repeat screening test at 1 to 2 weeks of age. The AAP also recommends that if appropriate screening results cannot be documented for a patient transferring into a practice, the physician should obtain a specimen for screening, even if the patient is beyond the neonatal period. Routine prenatal screening for maternal PKU has been advocated by some authors, but most groups, including the AAP and the American College of Obstetricians and Gynecologists, have not recommended this approach due to concerns about cost-effectiveness.<4,10>
Conclusions and Recommendations
A capillary blood test for phenylalanine level
is recommended for all newborns before discharge from the nursery (A Recommendation).
Infants who were tested in the first 24 hours of age should receive a repeat
screening test at 2 – 7 days of age. We recommend earlier re-screening
than the U.S. Task Force because it is felt that the earlier a diagnosis
is established and therapy is begun, the better the outcome. Premature
infants and those with illnesses should be tested at or near 7 days of
age. All parents should be adequately informed regarding the indications
for testing and the interpretation of PKU test results, including the probability
of false positives and false negatives. There is no evidence to recommend
for or against routine prenatal screening for maternal PKU (C Recommendation).
We differ from the U.S. Task Force which recommends against routine prenatal
screening because there is no clear evidence either in favour of or against
such a policy.
Unanswered Questions (Research
Agenda)
The following have been identified as research
priorities:
Acknowledgements
The Task Force is grateful to William B. Hanley,
MD, FRCPC, Director, PKU Program, Division Clinical Genetics, Hospital
for Sick Children, Toronto, Ontario and Professor, University of Toronto,
Toronto, Ontario for his helpful contributions and Kent Dooley, PhD, BSc,
Director, Depts of Pathology and Laboratory Medicine, Izaak Walton Killam
Hospital, Halifax, Nova Scotia for reviewing the chapter.
Full Citation
Feldman W. Screening for phenylketonuria. In:
Canadian Task Force on the Periodic Health Examination. Canadian
Guide to Clinical Preventive Health Care. Ottawa: Health Canada,
1994;180-8.