The Maternal Phenylketonuria Project: A Summary of Progress and
Challenges for the Future
Joe T.R. Clarke, MD, PhD
ABSTRACT. The results of the International Collabo-rative Study of Maternal phenylketonuria have shown that dietary phenylalanine restriction of women with hyperphenylalaninemia during pregnancy decreases the incidence of mental retardation, microcephaly, congeni-tal heart disease, and intrauterine growth retardation in their offspring. The best results are achieved when treat-ment is initiated before conception. Psychosocial prob-lems are the most pervasive obstacle to the achievement of optimum dietary treatment. Novel, nondietary ap-proaches to the treatment of maternal phenylketonuria are under development. Pediatrics 2003;112:1584 –1587; maternal PKU, hyperphenylalaninemia, embryopathy, birth defects, health policy.
ABBREVIATIONS. PKU, phenylketonuria; Phe, phenylalanine; HPA, hyperphenylalaninemia; PAH, phenylalanine hydroxylase; ADHD, attention-deficit/hyperactivity disorder; BH4, tetrahydro-biopterin.
T
he proceedings of this conference summarizethe results of a multicenter, international, col-laborative study, spearheaded by Richard Koch, of unprecedented size, spanning a period of almost 18 years.1–13During the conference, we heard
presentations of papers covering a wide range of subjects directly relevant to our current understand-ing of phenylketonuria (PKU) in general and mater-nal PKU in particular. Harvey Levy set the stage with an overview of the history of our awareness of ma-ternal PKU embryopathy, including a review of a seminal article on the problem, which appeared⬎20 years ago.14 Besides reviewing data derived from
observations on the biology of PKU, we have heard about and discussed various psychological and be-havioral observations, social concerns, novel ap-proaches to treatment, and even public policy issues related to the management of the disease.
BIOLOGICAL OBSERVATIONS
The results of the International Maternal PKU Col-laborative Study have shown unambiguously that carefully monitored and controlled dietary phenylal-anine (Phe) restriction of women with hyperpheny-lalaninemia (HPA) during pregnancy decreases the
incidence of mental retardation, microcephaly, con-genital heart disease, and intrauterine growth retar-dation in their offspring. Moreover, the results of treatment are influenced by the time of initiation of therapy, the quality of the metabolic control achieved and maintained during the pregnancy, the intelli-gence of the mother, the mother’s general nutrition during pregnancy, and the maternal Phe hydroxy-lase (PAH) genotype. The outcome of treatment is best when optimum dietary control of plasma Phe levels is achieved before conception and maintained throughout the pregnancy. When treatment or the achievement of good dietary control of the disease is delayed until 20 weeks of gestation or later, the out-come for the offspring deteriorates rapidly.6,10,15,16
The impact of maternal intelligence is complex, not simply as a predictor of the skill of the woman in maintaining good dietary control. Not surprising, the outcome of therapy is better for the offspring of women who maintain good general nutrition throughout pregnancy, assuming good dietary Phe restriction. The offspring of women who have “se-vere”PAHmutations also tend to have poorer out-comes, in part because of the increased difficulty experienced maintaining good control of plasma Phe levels.
Platt et al10 summarized and updated earlier
re-ports of the obstetric implications of maternal PKU. No differences were found between women with HPA and control subjects with respect to method of delivery, multiple births, sex of the offspring, or Ap-gar scores. However, the rate of spontaneous abor-tion was higher for women with HPA, and their infants were smaller than those of the control women. Widaman reported the results of some ele-gant statistical analyses of the data derived from the International Maternal PKU Collaborative Study showing that Phe exposure during pregnancy seems to mediate the effects of many of the background variables, such as the severity of the maternal PKU. It also seems to have strong direct as well as indirect effects on cognitive outcomes.
The deleterious effects of maternal HPA are dose related: the better the dietary control, as assessed by serial measurements of plasma Phe levels, the fewer stigmata of maternal PKU embryopathy encountered in the offspring. A great deal of information has emerged relating genotype to phenotype in children with PKU.17–21 To the extent that women with
“se-vere”PAHmutations tend to have poorer outcomes of treatment during pregnancy than women who From the Division of Clinical and Metabolic Genetics, Hospital for Sick
Children, and University of Toronto, Toronto, Ontario, Canada. Reprint requests to (J.T.R.C.) Division of Clinical and Metabolic Genetics, Hospital for Sick Children, 555 University Ave, Toronto, Ontario M5G 1X8, Canada. E-mail: [email protected]
have PKU with other mutations, genotyping has some predictive value. However, it is only 1 variable influencing outcome, and an understanding of the full significance of genotyping for the individual pa-tient requires additional study.
Data were presented from magnetic resonance spectroscopy studies of adults with PKU that may explain, at least in part, why some individuals with the condition seem to tolerate HPA in later life better than others. Although the studies are still small in scale, the results suggest that individuals with PKU differ with respect to the permeability of the blood-brain barrier to Phe and that this may explain the seeming resistance of some adults to the chronic neurotoxic effects of the amino acid.22–26
BEHAVIORAL AND PSYCHOLOGICAL OBSERVATIONS
Elegant longitudinal studies on the behavior of children who are born to mothers with PKU, treated by dietary Phe restriction during pregnancy, showed an increased risk for developmental problems.27 In
some respects, the offspring of mothers with PKU resemble children with PKU. Notably, Waisbren re-ported that maternal PKU children and children who are affected with PKU show significant deficits in executive function. Similarly, both groups of chil-dren showed an increased incidence of attention-deficit/hyperactivity disorder (ADHD) that was in-dependent of IQ. However, unlike children who are affected with PKU, who exhibit an inattention type of ADHD, the offspring of mothers with PKU tend to display the full spectrum of behavioral problems associated with ADHD.
SOCIAL ISSUES
Some of the most important observations to issue from the International Maternal PKU Collaborative Study relate to factors that affect compliance with therapy. The data presented by Brown and her col-leagues showed that the outcome of the treatment of maternal PKU is affected by a number of nonbiologi-cal variables, such as socioeconomic status, the edu-cation of the mother, the health belief of the woman on treatment, and the quality of emotional support for the woman, before as well as during pregnancy.28
Following up on previous studies describing psycho-social factors that affect compliance with dietary therapy during pregnancy,29,30Waisbren reported on
experience with a pilot project linking women with PKU with “resource mothers” to facilitate compli-ance with dietary treatment during pregnancy. The results indicated that the psychological and social needs of women with maternal PKU play an impor-tant role in the outcome of treatment during preg-nancy; however, the needs are complex and require additional study. Brown also identified a number of barriers to successful dietary control of women with PKU during pregnancy. These include access to treatment, the cost of maintaining the therapeutic diet, and the medical expertise available to the pa-tient. The results include no surprises: the same is true of a wide range of chronic, although treatable, illnesses.
PUBLIC POLICY ISSUES
Hanley reported on the observation that some women with untreated PKU are near normal in in-telligence. Those who were born before the wide-spread introduction of newborn screening are often not recognized until they have had 2 or more off-spring with maternal PKU embryopathy. He raised the question of whether screening for PKU should be extended to women of childbearing age who are old enough to have escaped detection by newborn screening,31 a question with important implications
for the development of screening policies.
We saw how the outcome of the treatment of ma-ternal PKU is influenced by various systemic vari-ables, such as the nature and the amount of resources provided for specialized care. However, other char-acteristics of the environment in which care is pro-vided have an impact on the results. Sites participat-ing in the International Maternal PKU Collaborative Study in countries or centers with state-supported, unobstructed access to medical care generally had better outcomes.32 Similarly, the results were better
when the organization of health care was centralized, with most of the medical care provided, without interruption, by a relatively small group of physi-cians and other health care professionals with expe-rience and demonstrated interest and expertise in the overall management of PKU. A potent obstacle to access to care in some cases was the absence of comprehensive financial support for special dietary products, medical care, and dietary counseling.
NOVEL APPROACHES TO TREATMENT
The conference included reports on some exciting new developments in the treatment of HPA. Stevens and Trefz reported on experience with the treatment of HPA with tetrahydrobiopterin (BH4).33–35 BH4is
part of the standard treatment of inborn errors of biopterin biosynthesis, which account for only a small percentage of children with persistent HPA. The observation that children have HPA caused by
PAH mutations is relatively new. Some children, who are often identifiable by the demonstration of
the presence of specific PAH mutations, show a
marked increase in dietary Phe tolerance when treated with pharmacologic doses of oral BH4. Most of the responders seem to have atypical PKU, and determination of the role of BH4supplementation in the overall management of PKU requires additional study.
Other novel nondietary approaches to treatment include oral administration of Phe ammonia lyase, which has been shown to hydrolyze free Phe within the gut to cinnamic acid, which is excreted in the urine. This approach to treatment is still under in-vestigation. Stevens also reported on progress being made in investigation into methods for stabilizing recombinant human PAH to be useful in enzyme replacement therapy of PKU, including by oral ad-ministration of the enzyme. Preliminary studies on the possible role of treatment of PKU by administra-tion of large neutral amino acids was reported by Matalon. The results are interesting and certainly merit additional investigation.
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These novel therapeutic alternatives to dietary Phe restriction may make the management of PKU, in-cluding maternal PKU, much easier in the future. Determination of their ultimate utility will require the organization of extended, large-scale clinical tri-als, probably involving⬎1 PKU treatment center.
CHALLENGES
The results of the International Maternal PKU Col-laborative Study pose some serious and immediate challenges. One challenge is to work toward the achievement and maintenance of good dietary con-trol of HPA in women with PKU before they become pregnant. This is a formidable undertaking. It re-quires changes to our system of following individu-als with PKU to ensure that they are identified and receive appropriate counseling and support through-out adulthood, especially for women, who are likely to become pregnant. It will also require the identifi-cation and correction of a wide range of behavioral, social, and public policy obstacles to access to opti-mum treatment, whether the treatment is by dietary Phe restriction or some other strategy. The way is clear to achieve some of the changes necessary to improve access to and compliance with treatment. How the necessary resources will be found is a big-ger problem. Other proposed solutions to problems of access are almost certainly unrealistically simplis-tic and require additional sociological and public policy examination for realistic strategies to be de-veloped and implemented.
The development of novel, nondietary approaches to the treatment of PKU represents a longer range and continuing challenge. Experience with the frus-trations and dangers inherent in the dietary therapy of maternal PKU and the frequency with which it fails utterly or is only partly successful places added pressure on clinician scientists to develop alterna-tives to dietary treatment of the condition.
Another continuing and long-range challenge is clarification of the relationship betweenPAH
geno-type and clinical phenogeno-type in individuals with PKU. Although this is an important predictor, it is only 1 of a myriad of variables that affect the outcome of treat-ment. Understanding the source and magnitude of other genetic, environmental, behavioral, and social variables that affect the outcome of treatment of ma-ternal PKU (Fig 1) is perhaps the most daunting challenge facing clinical and basic scientists who are involved with efforts to improve the outcome of the treatment of PKU. The achievements of the Interna-tional Maternal PKU Collaborative Study are truly remarkable. However, in many respects they repre-sent 1 step—a critically important step—in a journey of a thousand miles.
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2003;112;1584
Pediatrics
Joe T.R. Clarke
for the Future
The Maternal Phenylketonuria Project: A Summary of Progress and Challenges
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2003;112;1584
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Joe T.R. Clarke
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The Maternal Phenylketonuria Project: A Summary of Progress and Challenges
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