Maternal Phenylketonuria Deﬁne the Child Health System And/Or Improve the Health of All Children Committee on Genetics

POLICY STATEMENT

Organizational Principles to Guide and Maternal Phenylketonuria Deﬁne the Child Health System and/or Improve the Health of All Children Committee on Genetics

ABSTRACT Elevated maternal phenylalanine concentrations during pregnancy are teratogenic and may result in growth retardation, microcephaly, significant developmental www.pediatrics.org/cgi/doi/10.1542/ peds.2008-1485 delays, and birth defects in the offspring of women with poorly controlled phenylketonuria during pregnancy. Women of childbearing age with all forms of doi:10.1542/peds.2008-1485 phenylketonuria, including mild variants such as mild hyperphenylalaninemia, All policy statements from the American Academy of Pediatrics automatically expire should receive counseling concerning their risks for adverse fetal effects, optimally 5 years after publication unless reaffirmed, before conceiving. The best outcomes occur when strict control of maternal revised, or retired at or before that time. phenylalanine concentration is achieved before conception and continued Key Words throughout pregnancy. Included are brief descriptions of novel treatments for phenylketonuria, maternal phenylketonuria. Pediatrics 2008;122:445–449 phenylketonuria, pregnancy, birth defect prevention Abbreviations PKU—phenylketonuria Phe—phenylalanine BACKGROUND PAH—phenylalanine hydroxylase BH4—tetrahydrobiopterin Phenylketonuria (PKU) is an autosomal recessive disorder of phenylalanine (Phe) PAL—phenylalanine ammonia lyase metabolism associated with deficient activity of Phe hydroxylase (PAH) and ele- PEDIATRICS (ISSN Numbers: Print, 0031-4005; vated concentrations of Phe and Phe metabolites. Untreated PKU is characterized Online, 1098-4275). Copyright © 2008 by the by severe to profound intellectual disability, seizures, autistic-like behaviors, mi- American Academy of Pediatrics crocephaly, rashes, hypopigmentation, and a musty body odor (phenylacetic acid). Hyperphenylalaninemia may be defined as having a blood Phe concentration above the reference range (31–110 ␮mol/L [0.51–1.8 mg/dL], depending on age). Different schemes exist for classifying subtypes of PKU on the basis of the severity of the clinical or biochemical and/or molecular phenotype.1–4 Patients have been classified as having mild hyperphenylalaninemia if their blood Phe concentration without dietary therapy is elevated but less than 600 ␮mol/L (10 mg/dL).2 Classic PKU is characterized by a Phe concentration higher than 1200 ␮mol/L (20 mg/dL) while receiving a normal dietary intake of protein.3 “Variant” or “atypical” forms of PKU (600–1200 ␮mol/L [10–20 mg/dL] that do not fit the mild or classic descriptions also exist, although there is not yet a universally accepted definition of these variant forms. In rare cases, an elevated blood Phe concentration may be caused by inherited disorders of the biosynthesis or recycling of tetrahydrobiopterin (BH4), a cofactor in the PAH reaction. Since the 1960s, newborn screening for PKU has allowed early detection and treatment of the disorder, preventing untoward consequences. Standard current treatment consists of selectively restricting intake of Phe and supplement- ing tyrosine (the product of normal PAH activity) by using special medical foods that are devoid of or low in Phe while providing enough additional protein, vitamins, and minerals to support normal growth. With good control of Phe concentrations during early childhood, most affected children have normal development measured at 5 years of age. Recommendations for dietary therapy have evolved as experience with different regimens and durations of therapy have accumulated. In earlier therapeutic protocols, treatment was only continued through the first few years of life, theoretically corresponding to the age at which brain myelination is complete. As developmental data accumulated, it became evident that treatment throughout childhood and adolescence was the best course for preserving intelligence. In more recent studies, it has been shown that brain MRI abnormalities and electrophysiologic testing abnormalities referable to the central nervous system are observed in adults who are on unrestricted Phe intake. Accordingly, it is reasonable to continue treatment into adulthood, and most centers recommend lifelong treatment. Strict adherence to the PKU diet is especially important for women during their reproductive years because of the risks to the fetus. Adults with classic PKU who had good control as children typically have normal intelligence or mild degrees of intellectual deficit. Careful psychometric testing of well-treated individuals has detected instances and degrees of impairment in visual motor skills, abstract reasoning, problem solving, specific aspects of executive control, attention, verbal memory, expressive naming, and verbal fluency,5 although overall IQ may still be within the reference range. One possible explanation for these neuropsychologic impairments invokes mid-dorsolateral prefrontal cortex dys-

PEDIATRICS Volume 122, Number 2, August 2008 445 Downloaded from www.aappublications.org/news by guest on October 2, 2021 function caused by abnormal catecholamine concentra- lines for the management of pregnancy in women with tions.6 Another theory suggests that abnormal brain my- PKU. The study has provided essential information re- elination and deficiency of brain large neutral amino garding the effective treatment of women with PKU. acids may play a role in impaired cognition.7–9 This information is now available for clinicians to impart In addition, emotional disorders (depression, anxiety, to their patients with PKU to ensure that women with phobias), as well as hyperactive behaviors, are encoun- PKU know their risk and how they may be able to have tered more frequently in individuals treated for classic healthy children with timely and appropriate interven- PKU than in the general population.10 However, people tion.18 with untreated mild hyperphenylalaninemia do not The effects of uncontrolled maternal PKU occur re- seem to be at risk of developing neuropsychologic im- gardless of whether the fetus has PKU. The best observed pairment.11 outcomes occur when strict control of maternal blood Poor dietary adherence leads to blood Phe concen- Phe concentration is instituted before pregnancy or by 8 trations above the current recommended therapeutic weeks of gestation at the latest.19,21,22 Women with PKU range.4 High blood Phe concentrations in people who who have their blood Phe concentration in good control have discontinued their special diets often results in a before conception have an excellent chance for normal decrease in IQ, learning disabilities, behavioral problems, pregnancies and neonatal outcome. The achievement of and even neurologic complications. White matter abnor- preconceptional and periconceptional dietary control malities may develop in people with PKU who have poor with a Phe-restricted diet significantly decreases the risk dietary control. MRI of the brain may detect dysmyeli- of microcephaly, intrauterine growth retardation, con- nation, especially T2 enhancement in the periventricular genital heart disease, and developmental delays in the white matter in individuals with PKU who are under offspring of women with hyperphenylalaninemia.19 poor dietary control. Abnormal areas of white matter Normal pregnancy and neonatal outcome have been may also demonstrate restricted diffusion of water, pos- achieved in women with PKU who have blood Phe sibly indicative of increased myelin turnover.12 These concentrations between 120 and 360 ␮mol/L before findings are potentially reversible once proper dietary conception or by 8 weeks of gestation at the latest.22 therapy is reinstituted.13 Before conception, counseling and early entrance During pregnancy, Phe crosses the placenta by active into a prenatal care program are essential for achieving transport, resulting in 70% to 80% increased fetal con- optimal fetal outcome for women with PKU, variant centration of Phe compared with maternal concentra- PKU, and mild hyperphenylalaninemia. It is acknowl- tion.14 An elevated Phe concentration is toxic and tera- edged that reinstitution of a Phe-restricted diet and sup- togenic to a developing fetus.15 Abnormalities in the plements is difficult.23 Because many pregnancies are children of women with uncontrolled PKU during preg- unintended, dietary control throughout the childbearing nancy were first reported by Dent16 in 1957 and Mabry years is essential for preventing an adverse effect on the et al17 in 1963. The international survey of women with fetus.24 The currently recommended Phe concentrations PKU, the results of which were published in 1980, doc- during pregnancy (120–360 ␮mol/L [2–6 mg/dL] in the umented an increased risk of spontaneous miscarriage United States)3 are consistent with those currently rec- (24%), intrauterine growth retardation (40%), micro- ommended for PKU treatment during early childhood. cephaly (73%), global developmental delays (92%), and Achieving this degree of control requires a major com- congenital heart defects (12%) in their offspring.18 Post- mitment by the woman and support by her treating natal growth retardation, abnormal neurologic findings, professionals. The recommendations for maternal con- and mild craniofacial dysmorphic features also have trol are based on maternal Phe concentration, as op- been reported.18 The frequency of abnormalities seems posed to the genotype or severity of the mother’s met- to be directly correlated with maternal Phe concentra- abolic condition. In 1 study, the IQs of offspring exposed tion during pregnancy.19 Poor fetal growth, microceph- to high concentrations of maternal Phe during preg- aly, and structural heart defects also are more likely to nancy (Ͼ750 ␮mol/L) were low (mean IQ: 56) and occur if there was “lack of control” of maternal Phe similar whether the mother had PKU or hyperpheny- concentrations during critical periods of embryogenesis lalaninemia and regardless of the genotype, whereas early in pregnancy.19 offspring had normal cognitive development (mean IQ: The Maternal Phenylketonuria Collaborative Study, 105) when their average exposure to Phe concentration sponsored by the National Institute of Child Health and during pregnancy was less than 360 ␮mol/L.25 Human Development, began in the United States in Dietary control for adults with PKU is challenging. 1984 to determine fetal outcomes with improved control Although low-Phe flour, pastas, cookies, and nutrition of maternal Phe concentrations during pregnancy.19,20 bars have increased dietary options for patients, the PKU This study became an international effort with partici- diet remains bland, so poor dietary adherence continues pating clinics in Canada and Germany since 1985 and to be a major problem. In addition to considerations 1991, respectively. The National Institutes of Health con- about the palatability of the PKU diet, economic and sensus conference on PKU in 2000 emphasized the im- health care system issues may contribute to barriers to portance of dietary control before conception. This in- dietary control. In 1 study that examined impediments ternational effort was completed in 2002 and culminated to successful dietary control, women with private insur- with the International Conference on Maternal Phe- ance identified infrequent assistance with the cost of nylketonuria in April 2002, which provided clear guide- medical food and beverages and low-protein foods as a

446 AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on October 2, 2021 barrier, despite the existence of US public law defining that such therapies may play in reducing the risk of the formula as medical foods.26 Public assistance pro- maternal PKU syndrome is still to be determined. grams provided more coverage for the cost of the medical foods, clinic visits, and low-protein foods.26 How- RECOMMENDATIONS ever, these women were less likely to achieve metabolic The recommendations of the American Academy of Pe- control before 10 weeks’ gestation. Brown et al26 be- diatrics reflect the guidelines of the Maternal Phenylke- lieved this may reflect that many women enrolled in tonuria Collaborative Study of the National Institutes of public assistance programs were younger and less edu- Health.3,19 These recommendations are to be applied to cated, which are factors associated with late control. individual patients and their particular care plan with Adolescent girls with PKU who become pregnant are at the guidance of their primary care physician in coordi- particular risk of not having dietary control until late in nation with the patient’s metabolic expert physician. their pregnancy, given their young age and the higher risk of unplanned pregnancy. 1. All girls and women of childbearing age with elevated The National Institutes of Health consensus guidelines Phe concentrations, including those with PKU and recommend that pregnant women with PKU have their milder forms of hyperphenylalaninemia, should be Phe concentrations monitored twice weekly.3 Frequent counseled concerning their risks of having an adverse visits to clinicians who specialize in treating PKU are also fetal outcome if they have uncontrolled blood Phe recommended for pregnant women with PKU. However, concentrations during pregnancy. Education regard- given the limited number of specialist centers, especially ing the risks of maternal PKU should begin when an centers skilled at caring for adults, there may be a need infant is diagnosed with PKU in the newborn period. to travel relatively long distances to obtain appropriate We recommend that the pediatrician include this in- management. Such barriers to access challenge patients formation again in anticipatory guidance counseling to comply with the frequency recommendations for PKU during preadolescence and adolescence for girls with monitoring. In addition, psychosocial, emotional, and PKU. All individuals, particularly women and girls of social factors contribute to the barriers for successful childbearing age, should be referred to an experi- control of PKU during pregnancy.26 enced PKU treatment center for genetic and nutri- All offspring of mothers with PKU will inherit at least tional evaluation and counseling throughout their 1 abnormal allele at the PAH locus from the affected lifetime. mother. Affected mothers have 2 PAH mutations, either 2. Women with hyperphenylalaninemia who are un- in a homozygous (2 identical mutations) or compound able or unwilling to maintain blood Phe concentra- heterozygous (2 different mutations) state. Depending tions in the range for optimum pregnancy outcome on the PKU carrier status of the father, approximately 1 should be counseled before conception regarding the in 120 offspring will also inherit an abnormal PAH gene risk of microcephaly, mental retardation, and fetal from the father and will have PKU. anomalies in their offspring. Emphasis should also be A number of novel therapies are being developed for placed on the education that structural defects, such treatment of PKU, including large neutral amino acid as congenital heart disease, are associated with poor supplementation, BH4 administration, and enzyme ther- control early in pregnancy. Dietary therapy should be apy using Phe ammonia lyase (PAL). Large neutral in place before conception to ensure optimal outcome amino acids compete with Phe for transport across the for the fetus. It is important that these women receive blood-brain barrier by the L-type amino acid carrier and assistance to obtain adequate means for access to consequently decrease the concentration of Phe in the reproductive services. central nervous system.27 Decreased brain Phe concentration, as measured by proton magnetic resonance spec- 3. Genetic counseling should be offered for all women troscopy, and increased blood concentrations of tyrosine with PKU before and after conception. Pregnant and tryptophan (the respective precursors for dopamine women with hyperphenylalaninemia should be and serotonin) were noted in 1 clinical trial using large counseled concerning the risks to the fetus and of- 28 fered detailed ultrasonographic examinations and fe- neutral amino acid supplements. Oral BH4, the natu- rally occurring cofactor to the PAH reaction, has been tal echocardiography to detect fetal abnormalities (eg, shown to decrease serum Phe concentrations, especially growth retardation, congenital heart defects). Consid- in patients with mild hyperphenylalaninemia.29,30 Re- eration should be given to maternal Phe concentrations during critical time periods of organogenesis. It sponse to BH4 has also been documented in patients with classic or variant PKU.30,31 Another novel therapeu- is equally important that these women obtain assis- tic approach uses the nonmammalian enzyme PAL. PAL tance in locating centers with skilled clinicians who converts Phe to transcinnamic acid, a harmless com- are able to provide medical care for pregnant women pound, and has been shown to reduce hyperphenylala- with PKU. ninemia in animal models of PKU.32 PAL therapy has the 4. Mothers who give birth to children with features theoretic potential to increase dietary Phe tolerance, but suggestive of maternal PKU, such as congenital heart significant practical hurdles need to be overcome (PAL is disease, microcephaly, and suggestive facial dysmor- destroyed by gastric acidic pH and intestinal proteolysis). phic features without a known cause, should undergo Although these are exciting developments, they are not blood testing for hyperphenylalaninemia. The Phe currently approved for use during pregnancy, so the role level of a newborn of a mother with PKU is usually

PEDIATRICS Volume 122, Number 2, August 2008 447 Downloaded from www.aappublications.org/news by guest on October 2, 2021 normal. Consideration should also be given to other maintenance versus manipulation-functions of working mem- teratogenic causes, such as maternal diabetes melli- ory. Neurosci Biobehav Rev. 2002;26(6):697–712 tus, alcohol abuse, or use of isotretinoin. In addition, 7. Bick U, Ullrich K, Sto¨ber U, et al. White matter abnormalities in mothers should be considered for PKU testing if their patients with treated hyperphenylalaninemia: magnetic reso- infants have an initial elevation of Phe concentration nance relaxometry and proton spectroscopy findings. Eur J Pe- on newborn screening that resolves. diatr. 1993;152(12):1012–1020 8. Pietz J, Kreis R, Rupp A, et al. Large neutral amino acids block 5. Pediatricians should work with the families of people transport into brain tissue in patients with phenylketonuria. with PKU to ensure access to social services, medical J Clin Invest. 1999;103(8):1169–1178 foods, and routine reliable visits to a center with exper- 9. Shulkin BL, Betz AL, Koeppe RA, Agranoff BW. Inhibition of tise in caring for people with metabolic disorders. neutral amino acid transport across the human blood-brain barrier by phenylalanine. J Neurochem. 1995;64(3):1252–1257 10. Smith I, Knowles J. Behaviour in early treated phenylketonuria: COMMITTEE ON GENETICS, 2007–2008 a systematic review. Eur J Pediatr. 2000;159(suppl 2):S89–S93 Howard M. Saal, MD, Chairperson 11. Weglage J, Ullrich K, Pietsch M, Funders B, Zass R, Koch HG. Stephen R. Braddock, MD Untreated non-phenylketonuric-hyperphenylalaninaemia: in- Marilyn J. Bull, MD tellectual and neurological outcome. Eur J Pediatr. 1996; *Gregory Enns, MB, ChB 155(suppl 1):S26–S28 Jeffrey R. Gruen, MD 12. Phillips MD, McGraw P, Lowe MJ, Mathews VP, Hainline BE. *Nancy J. Mendelsohn, MD Diffusion-weighted imaging of white matter abnormalities in Robert A. Saul, MD patients with phenylketonuria. AJNR Am J Neuroradiol. 2001; 22(8):1583–1586 LIAISONS 13. Cleary MA, Walter JH, Wraith JE, White F, Tyler K, Jenkins JP. Magnetic resonance imaging in phenylketonuria: reversal of Anthony Gregg, MD cerebral white matter change. J Pediatr. 1995;127(2):251–255 American College of Obstetricians and Gynecologists 14. Cetin I, Corbetta C, Sereni LP, et al. Umbilical amino acid James W. Hanson, MD concentration in normal and growth-retarded fetuses sampled American College of Medical Genetics in utero by cordocentesis. Am J Obstet Gynecol. 1990;162(1): National Institute of Child Health and Human 253–261 Development 15. Levy HL. Historical background for the maternal PKU syn- Michele A. Lloyd-Puryear, MD, PhD drome. Pediatrics. 2003;112(6 pt 2):1516–1518 Health Resources and Services Administration 16. 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