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PKU (PHENYLKETONURIA)
PKU (phenylketonuria) is an inherited disorder of body chemistry that, if untreated, causes mental retardation. Fortunately, through routine newborn screening, almost all affected newborns are diagnosed and treated early, allowing them to grow up with normal intelligence. At least 1 baby in 25,000 is born with PKU in the United States [1]. The disorder occurs in all ethnic groups, although it is more common in individuals of Northern European and Native American ancestry than in those of African-American, Hispanic and Asian ancestry.
Individuals with PKU cannot process a part of protein called phenylalanine, which is present in most foods. Because of a genetic abnormality, affected individuals lack or have very low levels of an enzyme (phenylalanine hydroxylase or PAH) that converts phenylalanine to other substances the body needs. Without treatment, phenylalanine builds up in the bloodstream and causes brain damage and mental retardation.
Children born with PKU appear normal for the first few months. If untreated, by 3 to 6 months they begin to lose interest in their surroundings. By the time they are 1 year old, they appear obviously developmentally delayed. Children with untreated PKU often are irritable and have behavioral problems. They may have a musty odor about them, and they may have dry skin, rashes or seizures. They usually are physically well developed and tend to have blonder hair than their siblings.
Genes come in pairs. To inherit PKU, a child must receive two abnormal PAH genes (that regulate the production of the enzyme), one from each parent who has a mutation (change) in one PAH gene. A parent who has one abnormal PAH gene is called a "carrier." A carrier has one normal PAH gene and one PAH gene that contains a mutation. A carrier's health is not affected in any known way.
When both parents are carriers, there is:
- A 1-in-4 (25 percent) chance that both will pass one abnormal PAH gene on to a child, causing the child to be born with PKU.
- A 2-in-4 (50-50) chance that the baby will inherit one abnormal PAH gene from one parent and the normal gene from the other, making it a carrier like its parents.
- A 1-in-4 (25 percent) chance that both parents will pass on the normal gene. The baby will neither have the disease nor be a carrier.
These chances are the same for each pregnancy.
TESTING INFANTS FOR PKU
All states and U.S. territories screen for PKU. Babies are tested before they leave the hospital. The PKU test was the nation's first newborn screening test. Developed with the help of the March of Dimes, the test has been routinely administered since the 1960s, sparing thousands of children from mental retardation [2].
INFANT PKU TESTING PROCEDURE
The baby's heel is pricked, and a few drops of blood are taken. (The same blood sample can be used to screen for a number of other inborn errors of body chemistry.) The blood sample generally is sent to a regional medical laboratory to find out if it has more than a normal amount of phenylalanine. Findings are sent to the health care professional responsible for the baby's care. If results are abnormal, more tests are done to determine whether the baby has PKU or if there is some other cause of high phenylalanine levels.
Occasionally, a case of PKU can be missed when the test is performed before 24 hours of age. For this reason, some experts recommend that infants whose initial test was taken within the first 24 hours of life be tested again at 1-2 weeks of age [3].
PKU SYMPTOM PREVENTION
Mental retardation can be prevented if the baby is treated with a special diet that is low in phenylalanine. This diet should be started as soon as possible after birth, ideally within the first seven to 10 days of life [2].
At first, the baby is fed a special formula that contains protein but no phenylalanine. Breast milk or infant formula is used sparingly to supply only as much phenylalanine as the baby needs and can tolerate. Later, certain vegetables, fruits, some grain products (for example, certain cereals and noodles) and other low-phenylalanine foods are added to the diet. No regular milk, cheese, eggs, meat, fish and other high protein foods are ever allowed. Because protein is essential for normal growth and development, the child must continue to have one of the special formulas that is high in protein and essential nutrients, but contains little or no phenylalanine. Diet drinks and foods that contain the artificial sweetener aspartame (which contains phenylalanine and is sold as Nutrasweet or Equal) must be strictly avoided.
Children and adults with PKU require follow-up care at a medical center or clinic that specializes in this disorder. The diet for each person must be individualized, depending upon how much phenylalanine can be tolerated. All affected persons need regular blood tests to measure phenylalanine levels. Testing for babies may be as frequent as once a week for the first year of life, and then once or twice a month throughout childhood.
Individuals with PKU must remain on a restricted diet throughout childhood and adolescence and generally for life (although some relaxation of the diet may be possible as the person ages) [2]. Until the 1980s, health care providers believed that children with PKU could safely discontinue their special diet around age 6 when brain growth was completed. However, studies since then have found that discontinuance of the diet before age 8 can lead to a decrease in IQ, and discontinuance after age 12 may lead to learning disabilities and behavioral problems [2, 4].
Parents of children with PKU and affected adults should discuss their diet and treatment questions with health care professionals at a PKU clinic.
MATERNAL PKU
There are an estimated 3,000 women of childbearing age with successfully treated PKU in the United States [5]. Most discontinued their special diet in childhood because, at that time, most health care providers believed it was safe to do so.
If these young women are eating a normal diet, their blood phenylalanine levels are very high when they become pregnant. During pregnancy, high blood levels of phenylalanine in the mother can cause serious problems in the fetus. About 90 percent of their babies will have mental retardation, and about 70 percent will have a small head size (microcephaly) [6]. Many will have heart defects and low birthweight. Because most of these babies do not inherit PKU, but are suffering from brain damage caused by their mothers' high phenylalanine levels during pregnancy, they cannot be helped by the PKU diet.
Fortunately, there is a way to help prevent mental retardation and other problems in babies of women with PKU. Women with PKU need to resume their special diets at least three months before pregnancy and continue the diet throughout pregnancy. The Maternal PKU International Study found that women whose blood phenylalanine levels were under control before conception, or by 8 to ten weeks of pregnancy at the latest, were as likely to have healthy babies as women without PKU [7]. At age 7, the IQs of their children did not differ from those of children of women without PKU [7]. Women with PKU need at least weekly blood tests throughout pregnancy to make sure blood phenylalanine levels are not too high.
The March of Dimes urges all women who know or suspect that they were treated for PKU as children to contact their health care provider or clinic before they attempt to conceive, so that their blood phenylalanine levels can be measured and they can begin the special diet, if necessary.
Occasionally, a woman has undiagnosed PKU that can pose a risk to her baby. These women, who generally were not screened as newborns, usually are slightly affected, and may be diagnosed only following the birth of a baby with PKU-related birth defects. In order to help prevent these birth defects, some health care providers recommend screening women who may be at risk of PKU, such as those with a family history of the disorder, so that affected women can start the PKU diet before pregnancy.
PKU DRUG MANAGEMENT
In December 2007, the Food and Drug Administration (FDA) approved Kuvan (sapropterin dihydrocholoride), the first drug to help manage PKU [8]. The drug helps reduce blood phenylalanine levels in individuals with PKU by increasing the activity of the PAH enzyme.
Kuvan is effective only in individuals who have some PAH activity. Individuals who take this drug must continue to follow a phenylalanine-restricted diet and have blood tests to measure phenylalanine levels.
PKU RESEARCH
Researchers continue to study the long-term outcome for children who were born from treated maternal PKU pregnancies to determine whether there is an increased risk of learning disabilities, especially among children whose mothers' blood phenylalanine levels were not well controlled in the early weeks of pregnancy.
Researchers also are studying the benefits of a nutritional supplement called BH4 in individuals with PKU. Others are developing a genetically engineered version of the missing enzyme. Both approaches eventually may allow affected individuals to eat a diet that approximates normal. Researchers also are exploring the possibility of treating PKU using gene therapy.
For more information:Children's PKU Network
3790 Via De La Valle, Suite 120
Del Mar, CA 92014
Phone: (800) 377-6677
E-mail: pkunetwork@aol.com
REFERENCES
[1] American College of Medical Genetics. Newborn Screening: Toward a Uniform Screening Panel and System. Final Report, 3/8/05.
[2] National Institutes of Health Consensus Development Statement. Phenylketonuria: Screening and Management. Washington, D.C., October 16-18, 2000.
[3] Kaye, C.I. and the American Academy of Pediatrics Committee on Genetics. Newborn Screening Fact Sheets. Pediatrics, volume 118, 2006, e934-963.
[4] Mitchell, J.J. and Scriver, C.R. Phenylalanine Hydroxylase Deficiency. Gene Reviews, updated 3/29/07.
[5] American College of Obstetricians and Gynecologists (ACOG) Committee on Genetics. Maternal Phenylketonuria. Committee Opinion, number 230, January 2000, reaffirmed 2004.
[6] Koch, R., and de la Cruz, F. The Maternal Phenylketonuria Collaborative Study: New Developments and the Need for New Strategies—Preface. Pediatrics, volume 112, number 6, part 2, December 2003, page 1513.
[7] Koch, R., et al. The Maternal Phenylketonuria International Study: 1984-2002. Pediatrics, volume 112, number 6, part 2, December 2003, pages 1523-1529.
[8] Food and Drug Administration (FDA). FDA Approves Kuvan for Treatment of Phenylketonuria (PKU), December 13, 2007.
PHENYLKOTONURIA (PKU) BLOOD TEST
Number: 003491
CPT: 84030
Synonyms: Phenylalanine Test ; PKU ; PKU Test
Special Instructions: State patient's exact age on the request form.
Specimen: Blood
Container: Filter paper
Collection Procedure: Do a finger or heelstick and thoroughly saturate the circles on the filter paper (Schleicher and Scheull No 903). Label the card with the patient's name and exact age. The prompt and accurate collecting and processing of infant blood samples is crucial to early detection of these disorders when the infant is 48-120 hours of age. Specimens must be collected on filter paper kits. Specimens should be mailed on the day of collection. The method for collecting specimens is relatively simple but care must be taken to ensure the sample is collected properly in order to avoid inaccurate test results. Steps for collection are as follows: Stimulate blood flow by warming the foot and/or massaging the leg. Clean the puncture site with an alcohol swab, then dry with a sterile sponge to remove alcohol. Hold the infant's heel securely and puncture the medial aspect of the heel with a sterile lancet at least 2.5 mm in length. Wipe away the first drop of blood and absorb the next drops on the filter paper. Be sure to allow large drops of blood to form. Lightly touch the filter paper to the drops and allow them to flow onto the filter paper and diffuse through the circles. Apply a bandaid or similar sterile covering to the site.
Storage Instructions: Maintain specimen at room temperature.
Causes for Rejection: Filter paper not thoroughly saturated; cord blood.
Reference Interval: 0-4 mg/dL
Use: Evaluate patients for phenylketonuria; monitor therapy with phenylalanine restricted diet.
Limitations: Cases have been missed because blood phenylalanine was not increased, even after the third day of life. Identification of non-PKU forms of hyperphenylalaninemia require additional testing for tetrahydrobiopterin pathway enzyme defects. Not all individuals with increased blood phenylalanine have phenylketonuria. When the infant is tested for PKU before 24 hours of age, there is a 16 percent chance of missing a positive case. When tested between 24 and 48 hours of birth, there is a 2.2 percent chance of missing a positive, between 48 and 72 hours, 0.3 percent chance.
Methodology: Enzyme immunoassay (EIA)
Additional Information: Successful detection of phenylketonuria by testing newborns for hyperphenylalaninemia has as its goal the identification of infants subject to central nervous system damage (in particular mental retardation) due to excessive levels of phenylalanine. Once identified, harmful CNS effects can be largely avoided by dietary measures, notably a semisynthetic diet low in phenylalanine. Widespread institution of PKU testing programs, worldwide, is an outstanding public health triumph of the 20th century. Incidence is 1:10,000 to 1:25,000 in the United States. For blacks in Maryland the reported incidence is 1:50,000.[1]
State laws require PKU testing of infants within 28 days or less prior to hospital discharge regardless of age. Disease caused by lack of phenylalanine hydroxylase leads to mental retardation if not treated. A second test should be considered but is not universally mandated in infants whose first test occurred within the first 24 hours of life. Every effort must be made to ensure that immediate diagnosis and treatment is provided for infants with abnormal results.
Presence of hyperphenylalaninemia implies a disorder of phenylalanine hydroxylation (to tyrosine). PKU, due to phenylalanine hydroxylase (PAH) deficiency is the common example. However, in addition to PAH, hydroxylation requires oxygen and tetrahydrobiopterin (BH4) as a cofactor. A defect in the metabolism of BH4 that results in BH4 deficiency will impair the hydroxylation and result in increased plasma phenylalanine levels. In the past 15 years three types of inborn errors of BH4 metabolism (“atypical PKU”) have been identified. Defects in BH4 synthesis are guanosine triphosphate cyclohydrolase I deficiency and pyruvoyl tetrahydropterin synthase deficiency. The third type of defect involves the regeneration of BH4 catalyzed by the enzyme dihydropteridine reductase. Experience with treatment of PKU over the past 25 years has shown that some 3 percent (variable between different populations) fail to respond.[2] These are largely cases of BH4 cofactor deficiency. There are important differences in therapy between classical PKU and the various BH4 cofactor deficiencies. “PKU positive” cases (identified as the result of phenylalanine tests) should be additionally tested for BH4 deficiency. Clinical features; urine, blood and enzyme analyses; prenatal diagnosis; and therapy of BH4 deficiencies have been recently reviewed.[2]
Classical PKU is an autosomal recessive disorder. Relatives (eg, siblings) of a PKU homozygote or heterozygote have a 50% to 66.7% probability of being heterozygous for PKU. DNA hybridization techniques are undergoing evaluation for the identification of PKU heterozygotes.[3]
Intrauterine fetal injury results from exposure of the developing fetus to increased intrapartum maternal plasma phenylalanine levels. There is a high incidence of resultant fetal damage including microcephaly, intrauterine growth retardation, mental retardation, and congenital heart disease, as a result of maternal hyperphenylalaninemia.[4] Dietary management of mothers identified by newborn testing programs has as its goal the maintenance of near normal maternal phenylalaninemia throughout pregnancy.[5] In order to retain the achievements of over three decades of early detection and treatment of PKU, increasing attention is being turned to control of maternal hyperphenylalaninemia.
FOOTNOTES
Hofman KJ, Steel G, Kazazian HH, et al, “Phenylketonuria in U.S. Blacks: Molecular Analysis of the Phenylalanine Hydroxylase Gene,” Am J Hum Genet, 1991, 48(4):791-8.
Matalon R, Michals K, Blau N, et al, “Hyperphenylalaninemia Due to Inherited Deficiencies of Tetrahydrobiopterin,” Adv Pediatr, eds, Barness LA, DeViro DC, Morrow G, et al, Chicago, IL: Year Book Medical Publishers, 1989, 36:67-89.
Lehmann WD, “Progress in the Identification of the Heterozygote in Phenylketonuria,” J Pediatr, 1989, 114(6):915-24 (review).
Brenton DP, “Cardiac Defects in the Children of Mothers With High Concentrations of Plasma Phenylalanine,” Br Heart J, 1990, 63(3):143-4.
Thompson GN, Francis DEM, Kirby DM, et al, “Pregnancy in Phenylketonuria: Dietary Treatment Aimed at Normalizing Maternal Plasma Phenylalanine Concentration,” Arch Dis Child, 1991, 66(11):1346-9
REFERENCES
American Academy of Pediatrics Committee on Genetics, “Newborn Screening Fact Sheets: Phenylketonuria,” Pediatrics, 1989, 83(3):449-64.
Morris AF, Holton JB, Burman D, et al, “Phenylalanine and Tyrosine Levels in Newborn Screening Blood Samples,” Arch Dis Child, 1983, 58(4):271-5.
Scriver CR and Clow CL, “Phenylketonuria: Epitome of Human Biochemical Genetics,” N Engl J Med, 1980, 303(23):1336-42, 1394-1400 (review).
Scriver CR, Kaufman S, and Woo SLC, “The Hyperphenylalaninemias,” The Metabolic Basis of Inherited Disease, 6th ed, Volume 1, Scriver CR, Beaudet AL, Sly WS, et al, eds, New York, NY: McGraw-Hill Information Services Co, 1989, 495-546.
Tessari P, Inchiostro S, Vettore M, et al, “A Fast High-Performance Liquid Chromatographic Method for the Measurement of Plasma Concentration and Specific Activity of Phenylalanine,” Clin Biochem, 1991, 24(5):425-8.
PKU SCREENING & TREATMENT
Article By Canadian Task Force on Preventive Health Care
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 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 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 percent for the first day of life, but decreased to 0.6 to 2 percent on the second day and to 0.3 percent 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 & 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 percent of patients had an intelligence quotient (IQ) less than 40, and 37 percent had IQ scores below 10; less than 1 percent had scores above 70.[2] Since dietary phenylalanine restriction was introduced, however, over 95 percent 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.
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 percent of these children will have mental retardation, 75 percent microcephaly, 40-50 percent intrauterine growth retardation, and 10-25 percent 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 & 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:1. If chemical tests such as the fluorometric test are found to have better measurement and predictive properties than the Guthrie test when done within the first 24 hours of life, can follow-up testing be safely eliminated in infants discharged within that time period?
2. Controlled clinical trials of varying protein, mineral and vitamin diets given before conception or early in pregnancy to women with PKU are required to answer questions regarding routine prenatal or preconception screening of females of child bearing age.
EVIDENCE
The literature was identified with a MEDLINE search using the MESH headings phenylketonuria, culminating in January 1993. This review was initiated in August 1993 and the recommendations of the Canadian Task Force were finalized in October, 1993.
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.
Reprinted in modified format by the Canadian Task Force on Preventive Health Care (CTFPHC) with permission. Original Copyright © 1994 Minister of Supply and Services Canada. Last modified March 30, 1998.
TETRAHYDROBIOPTERIN & MATERNAL PKU
Article By Richard Kocha, Kathryn Moseleya and Flemming Guttlerb
Department of Pediatrics, Keck School of Medicine
University of Southern California, Los Angeles, CA, USA
J.F. Kennedy Child Study Institute, Glostrup, Denmark
Received 25 April 2005; revised 15 September 2005; accepted 15 September 2005.
Available online 12 December 2005.
ABSTRACT
A 29-year-old woman with PKU is presented, who was successfully treated with phenylalanine restriction as well as oral BH4 during this pregnancy, with a normal outcome. Her PAH mutation was R408W/F39L. Remarkably, the blood phenylalanine control was easily accomplished during this pregnancy. The lack of nausea and vomiting during the first trimester suggests that the occurrence of CHD in babies born to women with PKU may be reduced with BH4.
KEYWORDS
Phenylketonuria; BH4; Tetrahydrobiopterin; Maternal phenylketonuria; Biopterin; PKU
RESULTS FROM THE INTERNATIONAL MATERNAL PKU STUDY
By Virginia Schuett
From the Fall 2002 issue of National PKU News
Last update: 3/03
National PKU News: www.pkunews.org
E-mail: schuett@pkunews.org
This spring (April 11-12, 2002), more than 150 people from all over the world met in Bethesda, Maryland to discuss research findings of the most important study of maternal PKU that has ever been done: The Maternal PKU International Collaborative Study. The study, which began in 1984, has provided us with reams of data and an emerging understanding of the syndrome that was first suggested 45 years ago. At one time, PKU clinicians wondered if the benefits of newborn screening for PKU might be overshadowed by the mental retardation and birth defects associated with maternal PKU. Fortunately, with good diet treatment throughout pregnancy, we now know that the "Maternal PKU Syndrome" can be largely eliminated.
A BRIEF HISTORY OF MPKU
In 1957, a London physician who was a pioneer in identifying metabolic diseases through urine amino acid analysis, first mentioned "maternal PKU." He described a mentally retarded woman with PKU who had 3 severely retarded children, all without PKU, and speculated that the mother's high blood phenylalanine levels had caused brain damage to the developing fetus. Several years later, Dr. Charlton Mabry and his colleagues in Kentucky described an additional 14 children, who were mentally retarded but did not have PKU-but were the offspring of 3 women with PKU. The Maternal PKU Syndrome was more fully characterized in the following years to include intrauterine growth retardation, small heads, and a variety of congenital abnormalities (most notably heart defects). In 1980, Dr. Harvey Levy and Dr. Roger Lenke of Boston reported the results of an international survey of maternal PKU cases. This seminal study of more than 500 pregnancies served to focus worldwide medical attention on the problem.
Shortly afterwards, in 1984, Dr. Richard Koch at Children's Hospital of Los Angeles became the principal investigator of the Maternal PKU Collaborative Study (MPKUCS). This multi-center study was funded by the National Institute of Child Health and Human Development (NICHD). The study was designed to thoroughly research important aspects of maternal PKU and sought to prevent the problems described in offspring of women with PKU.
ORGANIZATION OF THE STUDY
Coordinated by Children's Hospital of Los Angeles under the direction of Dr. Richard Koch, this large study has drawn participants from all over the U.S. as well as several other countries. It has been a massive and intense effort.
The study began with four coordinating centers in Boston, Chicago, Texas and Los Angeles. In 1985, Canada joined the group. In 1992, Germany, Austria, and Switzerland entered the study to increase the number of pregnancies that would be treated preconceptually (since by 1988 it was clear that about 80 percent of enrollees in the study were not on the PKU diet when they became pregnant). These countries were selected since they provided the diet for all adults. The idea was to enroll and follow all pregnancies occurring in women with PKU and hyper-phenylalaninemia in these countries during the study time period. Any woman of childbearing age with blood phe levels above 4 mg/dl (240 µmol/L) was eligible, as long as she had the intellectual capacity to follow diet treatment recommendations.
Enrollment began in 1984 and ended in 1995. The study followed 574 pregnancies in women with PKU or hyperphenylalaninemia, and 100 non-PKU control women matched on a number of important characteristics. The sample included 416 live births. Extensive evaluations of the babies began at birth and continued each year thereafter. These included medical, physical, psychosocial, intelligence, and behavior assessments.
TREATMENT PLAN
To prevent the devastating effects of high blood phe levels during pregnancy, treatment in the study with a low phe diet and medical food was designed to include adequate general nutrition and supplementation with tyrosine and trace elements as needed. The diet was offered to any woman with a blood phe level over 10 mg/dl (600 µmol/L). Every effort was made to help the women keep their blood phe levels in the range of 2-10 mg/dl (120-600 µmol/L). As the study progressed, data showed that outcome for the babies was dependent on the degree of blood phe control in the mother, so the goal for metabolic control was reduced to 2-6 mg/dl (120-360 µmol/L). The ideal would be for the pregnancy to be planned and for the women to be on diet prior to conception. Only 21 percent of women enrolled in the study had stayed on the diet into adulthood.
STUDY RESULTS
Overall Results: This study has clearly shown us that the major factor affecting outcome in maternal PKU is the mother's blood phe level during pregnancy. This comes as no surprise. Rather, it reaffirms our original assumption that high blood phe levels are what damage the babies of untreated mothers with PKU.
To our dismay, in only 148 of the 574 pregnancies were the mothers treated before conception. Of the total group, 206 were treated before 8 weeks of pregnancy, 109 were treated between 9 and 26 weeks, and 4 were treated between 27 and 40 weeks. Of the women with mild hyperphe, 57 were not on treatment due to blood phe levels that were already mainly within treatment range; however 9 women were on a phe-restricted diet at some time during their pregnancy.
Compared to the 1980 findings of Lenke and Levy for untreated pregnancies, in the MPKUCS we found that diet treatment during pregnancy, even when started late, resulted in dramatically improved outcome for the babies. For example, for women with classical PKU in the MPKUCS only 23 percent of babies had a small head, compared to 73 percent in the Lenke/Levy study. The rate of spon-taneous abortion (13 percent) was similar to the rate for normal pregnancies. Heart disease occurred in only 7 percent of the sample, compared to 12 percent in the 1980 study of untreated women (but the rates of heart defects were only improved when the mother was in good diet control before 10 weeks of pregnancy). The overall rate of mental retardation was reduced to 28 percent, compared to 92 percent in the 1980 study.
TREATMENT BEFORE PREGNANCY
The good news is that for women who were in optimal diet control prior to 10 weeks, their babies did not differ from normal on any tests performed at ages 4 and 7 years. Optimal control is defined as no blood phe levels above 6 mg/dl (360 µmol/L) after 10 weeks of pregnancy, and average blood phe levels throughout pregnancy of 6 mg/dl (360 µmol/L) or lower. Women in the MPKUCS who met these criteria had babies whose intelligence test (I.Q.) scores ranged from 70 to 124 at 4 and 7 years of age. This was comparable to women with mild hyperphe whose blood phe levels were in the same range during pregnancy without treatment. Only one child had heart disease (0.7 percent) among the pregnancies treated preconcep-tually, comparable to a 1-2 percent rate of defects seen in normal pregnancies.
Women in the study who started the diet before pregnancy were more likely to achieve early blood phe control and to maintain levels in the target range throughout the pregnancy. Early diet control was then associated with babies who had larger birth measurements and higher developmental and cognitive test scores. When the mother had blood phe levels in the range of 2-6 mg/dl (120-360 µmol/L), the outcome for the baby was better than when the blood phe levels were 6-10 (360-600 µmol/L).
TREATMENT AFTER 10 WEEKS OF PREGNANCY
A surprising finding is that the average measured I.Q. of children born to mothers who did not achieve good diet control until 10-20 weeks of pregnancy was 92 (range 45-124); we expected a much lower average I.Q. The relatively higher I.Q.s might be related to the fact that some of the women were actually on the phe-restricted diet before 10 weeks of pregnancy, but were not in optimal control after that.
Still, the outcome was very unpredictable for women treated late, reflected in a large range in I.Q. scores for their children, from the mentally retarded range and on up. The average measured I.Q. of the children became progressively lower with increasing delay of the mother starting the diet. Besides having mental retardation, many of these children also had small heads, poor growth, and a variety of birth defects.
EFFECT OF GENE MUTATIONS ON OUTCOME
The study also found that if a woman had 2 "severe" gene mutations for PKU (resulting in zero phenylalanine hydroxylase enzyme activity) and had stopped the diet, she had an average I.Q. of only 83. Those women off the diet with one severe and one moderate mutation had an average I.Q. of 84; and those with one severe and one mild mutation had an average I.Q. of 96. The longer a woman was treated into the adolescent and teen years, the higher the average I.Q. The I.Q. differences due to mutation effects and being off the diet indirectly affected the outcome of the babies, but only when diet treatment during pregnancy was not good.
OVERALL COGNITIVE & BEHAVIORAL DEVELOPMENT
The MPKUCS documented increasing effects from maternal PKU with each week's delay in achieving good metabolic control. Only 16 percent of the women were in metabolic control before conception, though more than twice that number started the diet before conceiving. Starting the diet for pregnancy clearly does not ensure good control.
The children in the lower I.Q. groups had deficits in memory, all aspects of language, and behavior (with a greater tendency toward acting out behavior, hyperactivity, and attention deficit disorder). They also had lower achievement in all academic subjects and in visual motor skills at 4, 7 and 10 years of age. The findings suggest that the problems associated with poorly treated maternal PKU are real and long-lasting. Dr. Susan Waisbren, Coordinator of Psychology for the MPKUCS, did a tremendous job of organizing data and ensuring a high rate of compliance with psychological testing (80 percent), enabling us to feel confident about the research findings.
SUMMARY
The most important message of this study is that achieving good metabolic control (2-6 mg/dl or 120-360 µmol/L) before or very early in pregnancy is critically important. This will give the baby the best chance to be born free of birth defects, and to have the best chance for optimal development.
FOLLOW-UP OF OFFSPRING OF WOMEN WITH MATERNAL PHENYLKETOURIA
Article From Nutrition Research Newsletter, March, 2000
Phenylketonuria (PKU) in women increases the risk for adverse outcomes in their offspring. Children of women with untreated PKU have a 92 percent chance of mental retardation, a 73 percent risk for microcephaly, a 40 percent risk for low birth weight, and 12 percent risk for congenital heart disease. Treatment of PKU with a phenylalanine-restricted diet begun prior to pregnancy reduces these risks. The extent to which these risks are reduced in late or inadequately treated pregnancies has not been clearly established. The Maternal PKU Collaborative Study is an ongoing, longitudinal prospective study that began in 1984 in a total of 78 metabolic clinics in obstetrical offices in the United States, Canada, and Germany. The outcomes at age four years in offspring were reported in the February 9, 2000, issue of the Journal of the American Medical Association.
Project Management Standard Program Women with PKU were offered a low-phenylalanine diet prior to or during pregnancy with the aim of maintaining metabolic control (plasma phenylalanine = 10 mg/dL). Women with mild hyperphenylalaninemia (MHP) were also invited to participate in the study, and they remained on a normal diet as treatment was not recommended. The final study included 572 pregnancies, of which 412 were completed. Eight children died of complications associated with PKU. At the time of the report, 368 children from the United States and Canada had reached their four-year birthday. Four offspring were excluded from the study after being diagnosed with PKU or MHP and the children in Germany were excluded because a different test battery was used. Of the 253 offspring receiving the preschool psychological test battery, 149 were born to mothers with PKU, 33 had mothers with untreated MHP, and 71 had mothers in a comparison group. All of the children received the McCarthy Scales of Children's Abilities test, 183 received the full battery of tests to assess language, behavior, and adaptive behavior, and the IQ of the mothers was also measured.
The majority of women with PKU attained metabolic control after 10 gestational weeks. Maternal IQ was lower in these women, their assigned plasma phenylalanine level was higher, and their education and level of social position was lower. The children's scores on the McCarthy Scales declined as the number of weeks to metabolic control increased. A group of 10 children had mothers who attained metabolic control after pregnancy but within six weeks of gestation. These children did not perform as well as those whose mothers had been treated prior to conception. Treatment at any time during pregnancy appears to reduce the risks of cognitive impairment and developmental delay associated with untreated PKU. The children are best protected when metabolic control is achieved prior to pregnancy. There is no evidence for a "safe zone" once pregnancy begins that would mark a period in which the fetus is fully protected. It is well documented that maternal phenylalanine levels higher than 10 mg/dL during pregnancy affect the fetus. The developmental profile of maternal PKU offspring shows a distinct trend toward lower scores on tests of language, memory, and quantitative abilities, while motor skills and behavior are relatively less affected.
This cohort of women with PKU had difficulty complying with dietary restrictions and monitoring metabolic status. Adhering to the diet did not become easier with successive pregnancies. The women were often less able to maintain metabolic control because of lack of resources, time, motivation, support, or organization. This finding underscores the relevance of psychosocial factors in maternal PKU. Interventions directed at reducing the risks at each step in the maternal PKU cycle may prove to be the most effective. In terms of outcome, every week counts.
S. Waisbren, W. Hanley, H. Levy, et al., Outcome at Age 4 Years in Offspring of Women with Maternal Phenylketonuria, JAMA 283 (6): 756-762 (February 2000) [Correspondence: Susan E. Waisbren, PhD, Genetic Services, Childrens Hospital, 300 Longwood Ave., 1C-107, Boston, MA 02115. E-mail: waisbren@al.tch.harvard.edu.]
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