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By Virginia Schuett, MS, RD, Director and Editor, National PKU News
For a complete, unabridged version of the PKU Consensus Conference Statement, go to http://consensus.nih.gov
On October 16-18, 2000, approximately 200 professionals and a handful of parents and adults with PKU attended one of the most important U.S. conferences in the history of PKU treatment. Sponsored by the National Institute of Child Health and Human Development and the Office of Medical Applications of Research (Bethesda, MD), the "PKU Consensus Development Conference" was in planning for over two years. The outcome is a set of guidelines that everyone hopes will lead to greater uniformity of treatment and improved quality of care throughout the U.S. Conference participants reminded the group that the guidelines will have international importance as well.
These U.S. guidelines are the culmination of many years’ effort by a large number of people. This includes the work of the American Academy of Pediatrics Sub-Committee on Genetics, which did an extensive "subject review of PKU" beginning in 1994. Their review ultimately served as a major stimulus for the Consensus Conference. It also includes over two years of work by an independent panel of professionals from a wide variety of disciplines and one young adult with PKU.
This group of fourteen dedicated people worked very hard over the two years to become thoroughly knowledgeable about PKU through extensively searching and analyzing the medical literature. Their preparations allowed them to answer the questions posed by the meeting’s organizing committee. The panel’s final "consensus statement" was the outcome of their exhaustive literature review, expert presentations at the meeting, and discussion from national and international PKU experts and others in attendance at the meeting.
It was a truly extraordinary collaborative effort of which we in the PKU community can be proud. While there are still differences of opinion on some of the issues related to PKU screening and treatment, the new guidelines are based on the best information and experience that is currently available. Dr. Rodney Howell, panel chairperson and the meeting’s excellent moderator, reminded the group that the guidelines should be adjusted as we continue to gain new knowledge and experience.
The full consensus statement, a more much lengthy document than could be reproduced here, is available by calling: 1-888-NIH-CONSENSUS (1-888-644-2667) or by visiting the NIH Consensus Development Program web site at http://consensus.nih.gov. Also, an on-line video of the complete conference is available at http://videocast.nih.gov.
The consensus conference panel was charged with answering a number of important questions related to PKU screening and treatment. Here are summaries of these questions and of the consensus statement.
PKU is defined as a complete absence or profound deficiency of phenylalanine hydroxylase (PAH) activity that typically results in high elevations of blood phenylalanine (greater than 20 mg/dL or 1200 micromol/L)) and accumulation of phenylketones in the urine. Partial deficiency of the enzyme results in hyperphenylalaninemia, characterized by lower elevation of blood phe and no phenylketone accumulation. PKU has a reported incidence in the U.S. of about 1 in 13,500 to 1 in 19,000 live births. For hyperphenylalaninemia, the estimate is approximately 1 in 48,000 newborns. But definitions of PKU and hyperphenyl-alaninemia vary from state to state. The incidence varies according to ethnic background of the child, with a higher incidence in White and Native American populations and lower incidence in African American, Hispanic, and Asian populations.
There is great genetic and clinical variability among persons with PKU, as there is for all genetic diseases. More than 400 different mutations in the phenylalanine hydroxylase gene have now been identified. Since most people with PKU have two distinct mutations (that is, they are "compound heterozygotes"), there are a huge number of possible genetic combinations that contribute to clinical and biochemical variations. Certain mutations are associated with PKU while others are associated with hyperphenylalaninemia.
In some cases, predicting enzyme activity in PKU may be possible if the genetic mutation is known. But the relationship between the mutation and the clinical expression is not always constant or easy to predict. Modifier genes may influence the expression of the mutant PAH gene, but so far such genes have not been identified. Also, there is individual variation in the transport of phe into the brain, which may explain some of the variation in clinical course among treated persons with PKU, as well as severity of the outcome in those off-diet. The physiological mechanisms that account for the mental retardation in PKU are still not well understood, but phenylalanine itself is thought to be the major toxic agent.
In addition to genetic factors that contribute to variability among persons with PKU, environmental and lifestyle factors also contribute to the variations. For example, age when treatment is started and degree of diet control can explain differences in outcome between two people with the same genetic mutations.
There are no data on early treated people with PKU who are beyond early adulthood since few are past 40 years of age. Thus, we have no scientific basis on which to base predictions of clinical outcomes beyond this age for early-treated persons.
Since the early 1960’s newborn infants in the U.S. have been screened for PKU through collection of blood samples within the first days of life. Infants who have elevated levels are referred to PKU treatment centers for diagnostic evaluation and treatment as needed. The three main laboratory methods used in the U.S. are the Guthrie Bacterial Inhibition Assay (BIA), fluorometric analysis, and tandem mass spectrometry. Each of these methods can reliably detect PKU.
U.S. screening programs have been very effective, but PKU is still being missed on rare occasion. There are few recent data to determine the magnitude of missed cases. Home births and early hospital discharge may contribute to missed cases, but errors can occur in any part of the screening process including specimen collection, lab testing and reporting of results.
All states screen for PKU, but there is great variation in the screening protocols from state to state, including different criteria for defining a positive PKU screening test. Follow-up services also vary greatly. Not all newborns and their families have access to the same level of care.
Professionals agree that infants with blood phe levels greater than 10 mg/dL (600 micromol/L) should be started on the diet as soon as possible, ideally by the time the infant is 7 to 10 days old. Newborns with levels between 7 and 10 mg/dL (420-600 micromol/L) that persist more than a few days also typically are started on treatment. Excluding deficiency of 44tetrahydrobiopterin (the cofactor for phe hydroxylase) is an important part of the diagnostic process.
There is no worldwide or U.S. consensus on what are optimal blood phe levels for treating PKU and hyperphenylalaninemia. (See chart, page 4). The British guidelines for PKU treatment developed in 1993 recommend that blood phe levels in infants and young children be kept between 2-6 mg/dL, with some relaxation allowed after childhood. However, the British policy acknowledges that higher limits for older children may be associated with impaired cognitive performance. The 1997 German guidelines recommend that phe levels be kept between 0.7-4 mg/dL (42-240 micromol/L) until age 10; then up to 15 mg/dL (900 micromol/L) between 10 and 15 years; and up to 20 mg/dL (1200 micromol/L) after 15 years (but lifelong follow-up to evaluate for late-onset problems). In the U.S., no guidelines have existed. The most commonly reported blood phe recommendation for U.S. clinics, as reported by the American Academy of Pediatrics (AAP) survey, is 2-6 mg/dL (120-360 micromol/L) for children up to age 12 years and 2-10 mg/dL (120-600 micromol/L) for persons over age 12.
Frequent monitoring of blood phe levels is important, especially during the early years of life. Based on the AAP survey, monitoring in the U.S. varies from weekly to monthly during the first year of life, with weekly being the more common. After one year, monitoring ranges from monthly to every three months, most commonly occurring monthly by 18 years of age.
The AAP survey found that most but not all clinics advocate lifelong treatment for control of blood phe. Reinstituting the diet is universally acknowledged to be difficult.
Other treatment possibilities are being explored, including somatic gene therapy.
There is considerable controversy over the extent to which persons early-treated for PKU have subtle problems involving cognitive functions, school achievement, behavior, and quality of life. Questions remain about how early to begin treatment, effects of fluctuations in metabolic control, level of optimal metabolic control, and effects of relaxing metabolic control. Many studies over the past two decades have attempted to address these questions. There are many limitations of the studies, however; these include small numbers of subjects, inconsistent use of comparison groups, and excessive reliance on intelligence tests as the primary measure of outcome.
The panel carefully reviewed the literature and commissioned a statistical "meta-analysis" to synthesize results from appropriate studies and enhance the statistical power of the research data. This analysis clearly showed that age at starting diet and degree of metabolic control significantly influence outcome in PKU, even for early-treated children.
Degree of metabolic control also is related to development of cognitive skills and behavior. Those with higher phe levels show significantly lower scores on measures of attention, intelligence, and "reaction time." Elevated phe levels have a moderate relationship to performance in cognitive functions and behavioral difficulties. Although these studies combine results from children and adults who vary widely in age, the evidence suggests that good metabolic control is associated with better cognitive performance throughout the lifespan.
Stopping the diet before 8 years of age is associated with lower I.Q. scores. The effects of stopping the diet at older ages (12 years and above) is less clear. Adults with PKU who are not on restricted diets appear to show fairly stable I.Q. scores, but have poorer performance on tests of attention and speed of processing information. Thus, the European countries do not recommend completely stopping the diet. Evidence shows that the diet is necessary lifelong, though some relaxation may be tolerable in some cases as the person ages.
Barriers to diet adherence include the nature of the diet, economic resources, psychosocial, social and emotional factors, and health care systems. We need a comprehensive, multidisciplinary approach to PKU treatment. Families need equal access to monitoring and care, education, follow-up by physicians, nutritionists, nurses, social workers and other health care team members, low phe or no phe medical foods, and modified low protein foods.
Metabolic control in women with PKU who are pregnant or planning a pregnancy is crucial because of the serious effects of high phe levels on the fetus. Microcephaly (small head), mental retardation, and congenital heart disease are just a few of the problems of babies born to women who are not well controlled on the diet. Recent data show that phe levels above 6 mg/dL (360 micrromol/L) during pregnancy are associated with significant and increasing decrements in I.Q. of the child as phe levels rise. British and German standards are set at 1-4 mg/dL (60-240 micromol/L) before and during pregnancy, while the Maternal PKU Collaborative Study recommends 2-6 mg/dL (120-360 micromol/L) based on extensive study of over 500 pregnancies.
Recommended Blood Phe Levels
Frequency of Monitoring
Duration of Diet Treatment
A phe-restricted diet, including medical foods and low protein foods, most likely will be necessary for all individuals with PKU throughout life. Although no definitive studies exist on the effects of diet treatment in adults, data suggest that high phenylalanine levels in adolescents and adults adversely affect cognitive function. Individual case reports document a variety of serious problems in adults with PKU after stopping the diet.
Maternal PKU
Previously Untreated PKU
Anyone with mental retardation and severe behavioral disturbances of unknown cause should be screened for PKU regardless of age. Persons with mental retardation due to PKU who have severe behavioral disturbances should be considered for diet treatment lasting at least 6 months. Many reports show that untreated adults can be helped by the diet.
Uniform Standards
States should adopt uniform blood phe levels to establish a diagnosis of PKU or hyperphenylalaninemia, and standardize newborn screening reporting.
Genotyping
Mutation analysis should be done on all persons with PKU for the purpose of initial diagnosis, genetic and management counseling, long-term prognosis, and for research on the frequency of various genetic mutations. (Editor’s note: This test is not yet routinely available in the U.S.)
Newborn Screening
There are many issues related to handling of newborn screening samples that states need to address. These include storage and use of blood samples. New laboratory technologies should be considered carefully. Regionalization of newborn screening also should be considered, especially in states with a low population.
The panel acknowledges that many areas of PKU research are still inadequately explored even more than 35 years after newborn screening began. We need to have more studies on the relationship between genetic mutations and clinical expression, on the effects of aging, and on the factors that enhance metabolic control throughout life. We also need to have research that will look at the effects of varying degrees of metabolic control on cognition and behavior, especially in adolescents and adults. We need to evaluate ways to increase diet adherence in maternal PKU and to do more research on late-treated adults. We need to investigate a wide range of potential new non-diet treatments for PKU. National and international collaboration will help us answer the many questions that still exist about PKU and its treatment.
After the meeting was over, a number of families wondered what controversial issues had arisen. While the conference statement attempted to consider all of the scientific evidence and appears to have converged on the majority opinion of those in attendance, there were many points of discussion that generated controversy, including these:
There is still no agreement on how (and even whether) PKU should be categorized according to blood phe levels. The consensus statement broadly defines "PKU" and "hyperphenylalaninemia." In Europe, three categories are generally used: Type 1 is hyperphenylalaninemia (blood phe levels under 10 mg/dL or 600 micromol/L on a normal diet), Type 2 is Moderate PKU (levels 10-20 mg/dL or 600-1200 micromol/L) on a normal diet) and Type 3 is Classical PKU (levels above 20 mg/dL or 1200 micromol/L). Everyone acknowledges that hyperphenylalaninemia is really a continuum of blood phe elevations and classification is only sometimes helpful.
A number of professionals from other countries were invited to the meeting. Their expertise was invaluable in expanding our perspectives on PKU treatment. At times they also sparked controversy and debate.
For example, the French have had a liberal attitude toward diet treatment compared to the rest of the world. The current policy is to relax the diet at age 10 for children with classical PKU, allowing phe levels up to "20-22 mg/dL (1200-1320 micromol?L)," but not stopping the medical food. For children with Type 2 (Moderate PKU), they allow complete diet discontinuation. This policy likely reflects both their limited experience with the diet (national screening only since 1979) and the view in France that food and mealtime have a significance that outweighs the risk of relaxing diet. They admit the long-term effects of high phe levels are unknown.
The Germans, while allowing relaxation of the diet after age 10 (to 15 mg/dL or 900 micromol/L) and again after age 15 (to 20 mg/dL or 1200 micromol/L), have an even stricter policy for blood control in the early years than either the English or the new U.S. guidelines (see above chart). They recommend levels between 0.7 and 4 mg/dL (42 and 240 micromol/L) or the first 10 years of life. This reflects their belief that the first years of life are most critical for brain development and only phe levels that low provide protection for the developing brain and nervous system. After age 10 they find I.Q. to be fairly stable, independent of the level. However, they recognize that behavior and performance may be influenced by changes in phe levels, even in adults. Dr. Peter Burgard from Germany emphasized that so-called "recommended" diet relaxation levels are really the "maximum allowed" and says, "We never encourage the upper limits." The upper limit for older children and adults was based primarily on the difficulty of maintaining lower blood phe levels. This is true of the new U.S. "15 mg/dL (900 micromol/L) upper limit" for those above 12 years of age.
The new U.S. guidelines represent a consensus of what U.S. PKU programs have been recommending, in conjunction with a detailed analysis of the medical literature on the relationship between phe levels and outcome on a variety of measures. From the special statistical analysis commissioned by the consensus panel on a large number of PKU studies, it is clear that for ensuring optimal outcome in a wide range of areas, the lower the blood phe level the better (without going too low). This is certainly true for young children and is likely true for adolescents and adults as well. In your editor’s opinion, maintaining lower blood phe levels at all ages is the only true assurance that children, adolescents and adults with PKU will function optimally, protecting them from a plethora of both subtle and significant problems that can result from high phe levels.
The U.S. consensus statement does not offer different recommendations related to "type" of PKU, but there appears to be general agreement that for "classical PKU," diet control is especially critical and a lifelong necessity. Dr. Richard Koch reported on preliminary results of a follow-up study of 70 of the original participants in the National Collaborative Study of Children Treated for PKU, now adults in their early 30’s. Only seven of this group were on the diet. Among those off the diet, there was a very high incidence of neurological problems, eczema, various phobias, depression, and mental illness. Many fewer graduated from college than those who were on the diet. This confirms the importance of diet for optimal functioning in adulthood.
While unanimous consensus was not reached on some issues, this is mainly due to the absence of definitive scientific data. As well-known genetics researcher Dr. Savio Woo so aptly stated at the meeting: "As imperfect as science is in telling us exactly when to treat PKU/hyperphenylalaninemia and how long to continue, it is crucial to adopt standards. While those standards may be as imperfect as the science, we can always adjust them based on our experience." Hopefully, the new standards will provide a basis for decision-making regarding PKU treatment, will serve as an impetus for improving services and programs for PKU nationwide, and will promote further research. Future newsletters will summarize some of the presentations that provided background material for the panel’s recommendations.