PEDIATRICS Vol. 108 No. 4 October 2001, pp. 972-982

SPECIAL ARTICLE:
National Institutes of Health Consensus Development Conference Statement: Phenylketonuria: Screening and Management, October 16-18, 2000

National Institutes of Health Consensus Development Panel

From the National Institutes of Health Consensus Development Panel, Bethesda, Maryland.

	ABSTRACT

Top Abstract Conclusion References

Objective.  To provide health care providers, patients, and the general public with a responsible assessment of currently available data regarding screening for and management of phenylketonuria (PKU).

Participants.  A nonfederal, nonadvocate, 14-member panel representing the fields of pediatrics, genetics, human development, public policy, nursing, and molecular physiology and including patient representatives. In addition, 19 experts in pediatrics, medical genetics, psychology, pediatric neurology, biochemical and molecular genetics, and gene therapy presented data to the panel and to a conference audience of 312.

Evidence.  The literature was searched using Medline for January 1980 through July 2000, and an extensive bibliography of 3394 references was provided to the panel. Experts prepared abstracts for their conference presentations with relevant citations from the literature. Scientific evidence was given precedence over clinical anecdotal experience.

Consensus Process.  The panel, answering predefined questions, developed its conclusions based on the scientific evidence presented in open forum and the scientific literature. The panel composed a draft statement, which was read in its entirety and circulated to the experts and the audience for comment. Thereafter, the panel resolved conflicting recommendations and released a revised statement at the end of the conference. The panel finalized the revisions within a few weeks after the conference. The draft statement was made available on the World Wide Web immediately after its release at the conference and was updated with the panel's final revisions. The statement is available at http://consensus.nih.gov.

Conclusions.  Genetic testing for PKU has been in place for almost 40 years and has been very successful in preventing severe mental retardation in thousands of children and adults. Metabolic control is necessary across the lifespan of individuals with PKU. A comprehensive, multidisciplinary, integrated system is needed to delivery of care to individuals with PKU. Greatly needed are consistency and coordination between screening, treatment, data collection, and patient support programs. There should be equal access to culturally sensitive, age-appropriate treatment programs. Ethically sound, specific policies for storage, ownership, and use in future studies of archived samples remaining from PKU testing should be established. Research into the pathophysiology of PKU and relationship to genetic, neural, and behavioral variation is strongly encouraged. Uniform policies must be established to remove financial barriers to the acquisition of medical foods and modified low-protein foods and to provide access to support services needed to maintain metabolic control in individuals with PKU. Research on nondietary alternative treatments for PKU is strongly encouraged. To achieve optimal statistical power and cross-cultural applicability, it will be beneficial to use data acquired via national and international collaboration.phenylketonuria, hyperphenylalanimea, phenylketonuria screening, phenylalanine-restricted diet, maternal phenylketonuria, newborn screening, phenylalanine monitoring, phenylketonuria outcomes.

Classic phenylketonuria (PKU) is a rare metabolic disorder (and orphan disease) that usually results from a deficiency of a liver enzyme known as phenylalanine hydroxylase (PAH). This enzyme deficiency leads to elevated levels of the amino acid phenylalanine (Phe) in the blood and other tissues. The untreated state is characterized by mental retardation, microcephaly, delayed speech, seizures, eczema, behavior abnormalities, and other symptoms. Approximately 1 of every 15 000 infants in the United States is born with PKU.

Because effective treatments exist to prevent symptoms, all states screen infants for PKU. The current treatment for this disorder involves strict metabolic control using a low-Phe diet that includes specialized medical foods. The newborn screening programs for PKU have been remarkably successful: When diagnosed early in the newborn period and treated to achieve good metabolic control, infants have normal health and development and can expect a normal life span.

Metabolic control of PKU can be difficult to achieve, and poor control can result in significant decline of mental and behavioral performance. Women with PKU must also maintain strict metabolic control before and during pregnancy to prevent fetal damage. Scientists are actively exploring nondietary treatments for PKU.

Research on PKU continues to broaden the knowledge base from which informed decisions about screening and treatment can be made. After a day and a half of expert presentations and public discussion of the biology and biochemistry of PKU, epidemiology and genetics, screening strategies, and treatment regimens, an independent, nonfederal panel weighed the scientific evidence and drafted a statement that was presented on the third day. The consensus development panel's statement addressed the following questions:

1. What are the incidence and prevalence of PKU and other forms of hyperphenylalaninemia, and what is known about the genetic and clinical variability?
2. What newborn screening strategies are available for diagnosis, what is the effectiveness of these strategies, and what cost savings are generated by screening and treatment?
3. What treatment regimens are used to prevent the adverse consequences of PKU? What is known about the effectiveness of these treatment and management strategies overall and with respect to variables such as time of initiation of medical nutrition therapy, levels of Phe at various ages, methods for enhancing dietary compliance, duration of dietary management, and dietary regimens for women of childbearing age and other adults?
4. Based on this information, what are the recommended strategies for optimal newborn screening and diagnosis and lifelong management and follow-up of PKU?
5. What research is needed to gather information that will optimize the outcomes for individuals with PKU and their families?

	1. WHAT ARE THE INCIDENCE AND PREVALENCE OF PKU AND OTHER FORMS OF HYPERPHENYLALANINEMIAS, AND WHAT IS KNOWN ABOUT THE GENETIC AND CLINICAL VARIABILITY?

Hyperphenylalaninemia results from impaired metabolism of Phe caused by deficient activity of the enzyme PAH. People with PKU have a complete absence or profound deficiency of enzyme activity, typically show very high elevations of blood Phe (>20 mg/dL), and accumulate phenylketones. A partial deficiency of PAH results in non-PKU hyperphenylalaninemia and a lower degree of blood Phe elevation without phenylketone accumulation. Both forms of hyperphenylalaninemia, which account for the vast majority of cases, are autosomal recessive disorders caused by mutations in the PAH gene. Rarely, mutations in other genes that are necessary for synthesizing or recycling the tetrahydrobiopterin cofactor of PAH also result in hyperphenylalaninemia but are not addressed in this consensus statement.

Incidence and Prevalence

Newborn screening has been under way for nearly 40 years in the United States. Nevertheless, few useful data are available regarding the incidence and prevalence of PKU and other forms of hyperphenylalaninemia. Data from the 1994 Newborn Screening Report of the Council of Regional Networks for Genetic Services were used to address the incidence of this clinically heterogeneous metabolic disease. The nature of the data allows only an estimate of the PKU and non-PKU hyperphenylalaninemia incidence. For PKU, the reported incidence ranges from 1 per 13 500 to 1 per 19 000 newborns. For non-PKU hyperphenylalaninemia, a wide range of variation in reporting exists between states, resulting in a composite estimate of 1 per 48 000 newborns. The report also identified large variations in the incidence of PKU by ethnic group: a higher incidence in whites and Native Americans and a lower incidence in blacks, Hispanics, and Asians.

The data available in the 1994 Newborn Screening Report are limited, and there is nonuniformity in the blood Phe levels used by individual states to define positive screening tests. Definitions of classic PKU and non-PKU hyperphenylalaninemia vary. Some states failed to report data by sex and ethnicity, and 2 failed to report the total number of newborns screened. Also, some state laboratories were noncompliant with regard to reporting newborn screening data. Instances in which data from first screens were not reported separately from follow-up test results added to the difficulty. Composite data were unavailable on the prevalence of PKU and non-PKU hyperphenylalaninemias.

Genetic and Clinical Variability

Like all genetic disorders, PKU demonstrates extensive genetic and clinical variability. The PAH gene is a single locus with >400 identified mutations, including deletions, insertions, missense mutations, splicing defects, and nonsense mutations. The fact that most individuals with PKU are compound heterozygotes generates the potential for numerous possible genotypic combinations and undoubtedly contributes to the clinical heterogeneity. These mutations also contribute to the biochemical heterogeneity and may be chiefly responsible for the biochemical phenotype. Genetic contributions to the phenotype are complex, consisting of documented allelic heterogeneity within the PAH gene. Certain PAH alleles are associated with non-PKU hyperphenylalaninemia and others with PKU. In addition, genes at other loci may influence Phe transport within the brain and the size and metabolic control of the Phe pool. This molecular heterogeneity for PKU results in wide phenotypic heterogeneity, contributing to biochemical individuality. In some cases, predicting enzymatic activity based on the PAH genotype may be possible. However, the relationship between the clinical phenotype and the genotype is not always constant.

The existence of discordant phenotypes among siblings who share the same genotype at the PAH locus implies the existence of other genetic and environmental factors that influence clinical phenotype. The presence of modifier genes would be consistent with clinical variation, but modifier genes have not yet been identified. Indeed, a small number of individuals with PKU have no mental retardation even without dietary treatment. There is variation in the transport of Phe into the brain, which may explain, in part, different clinical symptoms and severity. The pathophysiologic mechanisms leading to mental retardation undoubtedly are complex. Evidence implicates Phe as the "toxic" agent in PKU. Hyperphenylalaninemia inhibits the transport of large, neutral amino acids (LNAA) into the brain. Reduction of LNAA in the brain is thought to cause inhibition of protein synthesis and neurotransmitter synthesis, leading to deficient dopamine and serotonin levels. Studies are beginning to explore the relationship between specific genotypes and response to supplementation with tetrahydrobiopterin, the cofactor for PAH.

The observed clinical variability between individuals results partly from these genetic factors, but environmental and lifestyle factors undoubtedly contribute to the variation. For example, age at diagnosis, age at commencement of metabolic control, and degree of metabolic control can explain the variation between 2 individuals with genetically identical mutations. Moreover, the variation observed depends on the specific trait examined, whether it is mental retardation in untreated cases, blood Phe level, neurologic and neuropsychiatric deficits, or brain Phe concentration. There are no data yet on the clinical manifestations of PKU as early-treated individuals age because few are past 40 years of age. Consequently, new clinical features of PKU may become evident over time, and there is no scientific basis from which to predict future clinical outcomes.

	2. WHAT NEWBORN SCREENING STRATEGIES ARE AVAILABLE FOR DIAGNOSIS, WHAT IS THE EFFECTIVENESS OF THESE STRATEGIES, AND WHAT COST SAVINGS ARE GENERATED BY SCREENING AND TREATMENT?

Since the early 1960s, newborn infants in the United States have been screened for PKU through the collection of neonatal blood samples on special paper cards within the first days of life. Blood samples are evaluated for the presence of abnormally elevated Phe levels, and infants found to have high levels of Phe are referred for diagnostic evaluation and comprehensive treatment and care.

Screening Strategies

The 3 main laboratory methods used for population-based screening of newborns for PKU in the United States are the Guthrie Bacterial Inhibition Assay (BIA), fluorometric analysis, and tandem mass spectrometry. The Guthrie BIA is inexpensive, simple, and reliable. Fluorometric analysis and tandem mass spectrometry are quantitative, can be automated, and produce fewer false positives than BIA. Tandem mass spectrometry can simultaneously obtain tyrosine levels that can be used in interpreting Phe levels and identifying numerous other metabolic disorders on a single sample.

Effectiveness

Effective screening of newborn infants for PKU requires competence in a number of complex, interrelated systems: specimen collection, specimen transport and tracking, laboratory analysis, data collection and analysis, locating and contacting families of infants with abnormal results, diagnosis, treatment, and long-term management, including psychological, nursing, and social services and medical nutritional therapy, genetic counseling, and family counseling. Although the US screening programs have been highly effective, there is concern that infants with PKU could be missed. This could occur at any step in the process: specimen collection, laboratory procedures, or initiation of treatment and clinical follow-up. Although missing an infant with PKU through screening is considered extremely rare, there are few recent data available to accurately determine the magnitude of the problem or define the actual cause of the missed cases. Home births and early hospital discharge may increase the number of missed cases.

All states include PKU testing in their newborn screening programs. Through these programs, the nation has been quite successful in identifying children affected with PKU and in preventing the mental retardation associated with PKU through comprehensive treatment and care. Nonetheless, there is great variation in practice in all areas of newborn screening protocols in the United States. All but 4 states permit parental refusal. Even criteria for defining a positive PKU screen vary between states. Some states have newborn screening advisory boards to guide policy decisions, whereas others rely on state health department staff. Some states fund their programs by charging fees; other programs are supported only by appropriated funds. For states that charge a fee, some bill patients, whereas others bill referring physicians, hospitals, or third-party payers. Funding sources and the services covered vary greatly. The levels of follow-up services also vary immensely. The availability of psychological nursing services, social services, genetic counseling, medical nutrition therapy, parent education about PKU, medical foods and modified low-protein foods, and the resulting economic burden on families also show discrepancies. Many families need these and other ancillary services to address difficulties in school, family problems, and behavioral disorders. Because of this variation in practice, not all newborns and their families have access to the same level of care.

States also differ in policies governing how information about test results is provided to parents and whether parents can decline testing of their children. In addition, there seems to be a lack of explicit policies regarding retention, ownership, and use of blood specimens for purposes other than PKU detection.

Cost Savings

Most economic analyses of PKU screening are >10 years old, and methodological approaches vary widely. However, all published studies find that PKU screening and treatment represent a net direct cost savings to society, although the analyses assume 100% compliance and typically exclude the costs of operating data systems and follow-up components of a newborn screening program.

3. WHAT TREATMENT REGIMENS ARE USED TO PREVENT THE ADVERSE CONSEQUENCES OF PKU? WHAT IS KNOWN ABOUT THE EFFECTIVENESS OF THESE TREATMENT AND MANAGEMENT STRATEGIES OVERALL AND WITH RESPECT TO VARIABLES SUCH AS TIME OF INITIATION OF DIETARY MANAGEMENT, LEVELS OF PHENYLALANINE AT VARIOUS AGES, METHODS FOR ENHANCING DIETARY COMPLIANCE, DURATION OF DIETARY MANAGEMENT, AND DIETARY REGIMENS FOR WOMEN OF CHILDBEARING AGE AND OTHER ADULTS?

Implementing a Phe-restricted diet early in life can significantly reduce mental deficiencies associated with PKU. Professionals agree that infants with PKU who have blood Phe levels >10 mg/dL should be started on treatment to establish metabolic control of Phe levels as soon as possible, ideally by the time the neonate is 7 days old. Most physicians begin medical nutritional therapy in newborns with levels between 7 and 10 mg/dL that persist more than a few days. Before treatment starts, however, tetrahydrobiopterin deficiency must be excluded.

Metabolic control via medical nutrition therapy involves the use of medical foods including medical protein sources and modified low-protein products in addition to the provision of required amounts of Phe through small amounts of natural protein. The response is monitored through periodic measurement of blood Phe levels in conjunction with analysis of nutritional intake and review of nutrition status. However, metabolic control via dietary treatment is only 1 component of a comprehensive treatment program.

There is no consensus concerning optimal levels of blood Phe, either across different countries or among treatment centers in the United States. The British policy for dietary treatment recommends that blood Phe levels in infants and young children be maintained between 2 and 6 mg/dL, with relaxation of Phe levels after childhood. However, the British policy statement acknowledges that these higher limits in older children may be associated with impaired cognitive performance. The German Working Group for Metabolic Diseases recommended that Phe levels be maintained at 0.7 to 4 mg/dL until the age of 10 years, 0.7 to 15 mg/dL between 10 and 15 years, and 0.7 to 20 mg/dL after 15 years, along with a need for lifelong follow-up to evaluate for possible late sequelae. Criteria in France are similar. Formally recommended guidelines for blood Phe levels do not exist in the United States. The most commonly reported blood Phe recommendations in US clinics are 2 to 6 mg/dL for patients 12 years and 2 to 10 mg/dL for those >12 years of age.

Frequent monitoring of blood Phe levels is necessary, especially during the early years of life, with less frequent monitoring as age increases. Current practices with regard to the frequency of monitoring during the first year vary from once every week to once a month, with once a week being more common. Frequencies after 1 year of age range from once every month to once every 3 months, with monitoring occurring approximately once a month by 18 years of age in most US clinics.

Surveys of clinical practices suggest that most clinics advocate lifelong dietary treatment for metabolic control of blood Phe levels. Resuming the diet after discontinuation is very difficult, and expertise in issues of adherence is needed. Adherence, cost of treatment, independence, and prepregnancy management become salient issues during adolescence and young adulthood.

Somatic gene therapy for PKU is being explored in animal model studies and holds promise for possible PKU treatment. Other avenues involving enzymes that degrade Phe in the digestive system also hold promise. Dietary supplementation with a variety of additives has not borne fruit but is an active area of research.

Efficacy of Treatments for Early-Treated PKU

Questions remain about the extent to which children treated early for PKU demonstrate subtle problems in cognitive function, school achievement, behavioral adjustment, and quality of life. Related issues concern how early to begin treatment, effects of fluctuations in metabolic control, level of optimal metabolic control, and relaxation of metabolic control. Controversy surrounds these issues.

Many studies of intellectual, cognitive, and behavioral outcomes have attempted to address treatment efficacy. There are limitations to these studies, however, including small samples, inconsistent use of comparison groups, and excessive reliance on intelligence tests as the primary outcome measure. Therefore, the panel carefully reviewed the literature and commissioned an empirical synthesis of these studies by meta-analysis.

Although many individuals with PKU manifest no cognitive and behavioral deficits, many comparisons of individuals with PKU and controls show lower performance on IQ tests, with larger differences in other cognitive domains. Children with PKU score somewhat lower than expected on IQ tests based on parent and sibling IQs, but their performance is still in the average range. Evidence of differences in behavioral adjustment is inconsistent despite anecdotal reports suggesting greater risk for internalizing psychopathology and attention disorders. The mechanism mediating this phenotypic variation is unknown, and current hypotheses are inadequate to account for this variation.

Age at treatment initiation and level of metabolic control clearly influence outcomes. There is an inverse relationship between age at treatment initiation and IQ even in early-treated PKU. Moreover, new evidence suggests that high plasma Phe levels during the first 2 weeks of life can affect the structural development of the visual system. Although the visual deficits are mild, this warrants efforts to initiate treatment earlier.

The degree of metabolic control is related to the development of cognitive skills and behavioral adjustments. Those with poorer metabolic control (ie, elevated Phe levels) show significantly lower scores on measures of IQ, attention, and reaction time. Similarly, Phe levels show moderate relationships with performance on measures of cognitive functions and the presence of behavioral difficulties. These studies combine results from children and adults who vary widely in age, but the evidence suggests that good metabolic control is associated with better cognitive performance across the lifespan.

Dietary discontinuation before 8 years of age is associated with poorer performance on IQ measures. The effects of dietary discontinuation at older ages (12 years) are less clear. Adults with PKU who are not on restricted diets show stable IQ scores but also manifest poorer performance on measures of attention and speed of processing. Therefore, European countries do not recommend complete discontinuation of the restricted diet. Higher levels of Phe are accepted with frequent monitoring. Evidence shows that the patient with PKU must be maintained on a lifelong restricted Phe diet, although some relaxation may be tolerable in some cases as the person ages.

Adherence to Treatment Regimens

PKU treatment is complex, requiring regular collection of blood samples, recording of food intake, maintenance of a highly restrictive diet, and regular and frequent visits to a PKU clinic. Barriers to adherence include factors associated with the treatment regimen itself as well as economic resources, psychosocial issues, social and emotional factors, and health care system issues.

A coordinated approach to PKU treatment is needed, including a comprehensive, multidisciplinary, integrated system for care delivery. Crucial to achieving adherence to treatment is assurance of equal access to routine monitoring and care, including periodic monitoring; initial and ongoing patient and family education; patient follow-up by physicians, dieticians, nurses, social workers, and other members of the health care team; and low- or no-Phe medical foods and modified low-protein foods. Adherence improves if individuals with PKU have a social support system, positive attitudes toward the benefits of treatment, and a belief that PKU is manageable. Creative use of community and regional support mechanisms hold promise for improving adherence to the comprehensive PKU treatment regimen.

Metabolic Control in Women of Childbearing Age

Metabolic control in women planning conception and those whose pregnancies are unplanned is important because of the serious consequences to the fetus exposed to elevated Phe levels in utero. Most observed adverse consequences reflect processes that originate in the first trimester. The fetus is vulnerable to potentially serious sequelae, which include microcephaly, mental deficiency, and congenital heart disease.

There is a strong relationship between increasing Phe levels and abnormalities in the neonate. Reports indicate that fetuses exposed to maternal Phe levels of 3 to 10 mg/dL had a 24% incidence of microcephaly, and those exposed to levels >20 mg/dL had a 73% incidence. Similarly, congenital heart disease was not seen among offspring of women with Phe levels <10 mg/dL and was seen among 12% for levels >20 mg/dL. Recent data indicate that Phe levels >6 mg/dL during pregnancy are associated with significant linear decrements in the child's IQ through 7 years of age.

Unfortunately, few women who have discontinued dietary treatment achieve metabolic control before conception and maintain it during pregnancy. The acceptable target levels vary between US clinics, with some considering <10 mg/dL acceptable and others considering a more liberal <15 mg/dL acceptable. These levels are higher than the current United States Maternal Phenylketonuria Collaborative Study recommendation of 2 to 6 mg/dL. British and German standards set lower acceptable target ranges (1-4 mg/dL).

Several interventions have been used to increase adherence to diet, including mentoring by well-trained mothers of children with PKU and peer counseling. British guidelines for PKU management strongly recommend strategies to help children take responsibility for their own diets and blood testing by school age, thus preparing them to be more responsible for their own care when they are contemplating conception.

	4. BASED ON THIS INFORMATION, WHAT ARE THE RECOMMENDED STRATEGIES FOR OPTIMAL NEWBORN SCREENING AND DIAGNOSIS AND LIFELONG MANAGEMENT AND FOLLOW-UP OF PKU?

Comprehensive Approach to Lifelong Care

A programmatic, multidisciplinary approach to lifelong care is needed for PKU treatment with sensitivity to the transition from screening to treatment. Continuity of care from infancy through adulthood is considered medically necessary for optimal outcomes. Treatment guidelines should be established that are consistent across US clinical facilities that serve individuals with PKU and their families so they can expect consistent treatment. Equal access to treatment for all individuals with PKU is highly desirable. Current barriers to access include inconsistent policies on the part of third-party payers, Medicaid and Medicare, and other state and federal entities concerning funding of medical foods and low-protein products, follow-up for metabolic control, and psychosocial support and educational programs. Mandated screening for PKU implies a societal responsibility for comprehensive long-term follow-up and treatment. Outcome monitoring should consist of periodic intellectual, neurologic, neuropsychological, and behavioral assessment. Access to medical foods is essential for maintenance of metabolic control throughout life. Specialized medical foods and low-protein products are a medical necessity and should be treated as such. Reimbursement for these medical foods and products should be covered by third-party providers.

Age of Initiation of Treatment for Infants With PKU

Treatment of neonates born with PKU should be initiated as soon as possible but no later than 7 days after birth. Phe levels should be reduced as rapidly as possible. Breastfeeding is encouraged along with Phe-free formula. Because of the need for early initiation of treatment, hospitals should ensure that screening samples are sent for analysis within 24 hours of collection and results are returned to responsible parties within 7 days of an infant's birth.

Recommended Levels of Phe for Classic PKU

Maintenance of Phe levels between 2 and 6 mg/dL for neonates through 12 years of age seems to be medically necessary for ensuring optimal outcome. Furthermore, in light of findings that Phe levels are related to cognitive function in adolescents and adults, it is recommended that Phe levels be maintained between 2 and 15 mg/dL after 12 years of age. Considering the paucity of data on the relationship between Phe level and brain function after 12 years of age and the fact that brain development continues during adolescence, even lower Phe levels (2-10 mg/dL) are strongly encouraged during this period. Treatment decisions must consider factors related to individual differences in inherent metabolic control, gender, age, childbearing status, and behavioral and cognitive functioning.

Frequency of Phe Monitoring

The frequency of Phe monitoring varies according the individual's needs. Suggested guidelines are as follows: once weekly during the first year, twice monthly from 1 to 12 years of age, monthly after 12 years of age, and twice weekly during pregnancy of a woman with PKU. There should be increased emphasis on patient participation in monitoring programs with age and recognition that individual factors, such as inherent metabolic control, age, and childbearing status, influence decisions about frequency of monitoring. Development of a reliable home-testing method and measures to increase adherence is recommended.

Duration of Dietary Treatment

The goal in PKU treatment is to maintain metabolic control of Phe for optimal adaptation and outcome. Treatment varies to some extent depending on each individual's characteristics. To achieve optimal metabolic control and outcome, a restricted-Phe diet, including medical foods and low-protein products, probably is medically necessary for almost all patients with classic PKU throughout the life span. Although no definitive studies on the effects of dietary treatment in adults exist, data suggest that elevated Phe levels in adolescents and adults adversely affect cognitive function, and individual case reports have documented deterioration of adult patients with PKU after diet discontinuation. Patients who have discontinued the diet should contact their clinic or treating physician to evaluate the necessity or advisability of resuming dietary treatment.

Maternal PKU

It is recommended that Phe levels <6 mg/dL be achieved at least 3 months before conception. Therefore, outreach and educational programs for adolescents and women of childbearing age that focus on social support, positive attitudes toward metabolic control of Phe, family planning, conscious reproductive choice, and information about managing maternal PKU are strongly recommended. Participation in such programs should occur before planned pregnancy so that optimal metabolic control of Phe can be achieved before conception. If conception occurs when the woman is not in metabolic control, counseling should be offered. Metabolic control should be achieved as soon as possible, and Phe levels should be monitored twice weekly, or at least once per week. The recommended level is 2 to 6 mg/dL during pregnancy. Focusing on the overall nutritional status of the pregnant mother, including intake of vitamins (folic acid and vitamin B₁₂, in particular) and other nutrients, is essential. Furthermore, a comprehensive approach that provides psychosocial support for the family as a whole and continuity of care for infants should be developed and followed. Parenting classes that focus on infant stimulation and maternal mental health (eg, maternal depression) and adherence to dietary treatment may be indicated for high-risk mothers. Social support systems are especially important in such instances.

Screening and Treatment of Previously Untreated Patients

Individuals with mental retardation or severe behavioral disturbances of undetermined cause, such as hyperactivity, aggression, self-injurious behavior, and pica, should be screened for PKU regardless of age. Individuals with mental retardation caused by PKU who are experiencing severe behavioral disturbances should be considered for dietary treatment lasting for at least 6 months because metabolic control has been reported to improve behavior in such patients.

Uniform Standards

States should adopt a uniform definition of the Phe level for establishing the diagnosis of PKU and non-PKU hyperphenylalaninemia. Standardized data reporting must include the number of individuals with PKU and non-PKU hyperphenylalaninemia, the number of individuals tested, and reports by sex and self-reported ethnicity.

Genotyping

Mutation analysis and genotype determination should be performed on all persons with PKU for initial diagnosis, genetic and management counseling, follow-up, and long-term prognosis. Additional laboratories capable of performing genotype analysis must be developed. Optimal therapeutic management might entail mutation analysis. Information about mutation frequency can be useful for calculating allele frequency and incidence of PKU.

Storage and Use of Samples

States and other institutions that store samples should develop a policy to address the following issues surrounding the storage and use of blood samples remaining after newborn screening:

• Length of time for which all samples will be stored.
• Ownership of samples.
• Uses, other than the follow-up of newborn screening, that will be allowed and under what conditions.
• Informed consent procedures.

Development of a System-Oriented Screening Program

Newborn screening strategies should take a total system approach. This system must include the following:

• A method for sending samples to the laboratory for analysis within 24 hours of collection.
• A standard approach nationwide of reporting abnormal results that leads to the referral of the newborn into appropriate care for diagnostic evaluation and management.
• Assurance that infants and families have access to the full complement of services necessary to treat the disorder (ie, physicians, geneticists, dietitians, and other health care professionals with expertise in treatment of metabolic disorders, genetic counseling, nursing, psychological and social services, medical food protein sources, and age-appropriate low-protein modified products).
• Clinical services that meet the needs of the adolescent and adult with PKU.

New Laboratory Technologies

Adoption of new laboratory technologies should be based on benefits to the screened population, improvements in sensitivity and specificity of testing, and cost effectiveness. Instrumentation that quantitatively measures Phe and tyrosine concentrations is beneficial in the early positive identification of PKU and reduces the incidence of false-positive results. Any new laboratory technology must be evaluated thoroughly and implemented carefully to avoid temporary or long-term negative effects on established PKU screening programs.

Regionalization

Often, especially for states with smaller populations, regional associations for PKU screening and therapeutic oversight provide greater laboratory and patient care efficiencies and promote common standards.

	5. WHAT RESEARCH IS NEEDED TO GATHER INFORMATION THAT WILL OPTIMIZE THE OUTCOMES FOR INDIVIDUALS WITH PKU AND THEIR FAMILIES?

• Studies are needed to determine the relationship between variations in the behavioral and neural phenotypes associated with blood Phe concentrations. These phenotypes should be based on quantitative assessment of brain structure and function and contemporary neuropsychological assessment. Research on basic pathophysiology is essential.
• What is the relationship between genetic mutation and phenotypic variation in PKU?
• What aspects of treatment programs are associated with optimal long-term outcomes? Potential factors, including genetic variation, sociodemographic predictors, age, duration of treatment, and Phe levels, should be studied.
• Evaluation and analysis are necessary to measure the clinical utility, validation, and cost effectiveness of the use of tandem mass spectrometry for PKU screening. This evaluation should include awareness of broader issues of its application to neonatal screening for a variety of genetic disorders.
• Longitudinal studies to study the effects of aging on treated individuals with PKU should be performed.
• Evaluation of various modalities to increase dietary adherence in preconception and maternal PKU is indicated.
• Studies are needed to identify the factors that enhance maintenance of metabolic control throughout life, which could be used for program development. It is important to evaluate the effects of variations in metabolic control on cognitive functions and behavioral adjustment, especially in adolescents and adults.
• Investigations should examine a wide range of potential new treatments other than medical nutritional therapy for PKU, including enzymes that might degrade Phe in the intestine, the role of LNAA, tetrahydrobiopterin supplementation, and the potential role of somatic gene therapy. PKU animal models will be valuable in these studies.
• Research studies on individuals who did not receive early treatment for PKU, including those in institutions, would be valuable.

	CONCLUSIONS

Top Abstract Conclusion References

• Genetic testing for PKU has been in place for almost 40 years and has been very successful in preventing severe mental retardation in thousands of children and adults. However, many questions remain unanswered.
• Metabolic control is necessary across the life span of individuals with PKU.
• A comprehensive, multidisciplinary, integrated system is needed to deliver care to individuals with PKU.
• Greatly needed are consistency and coordination between screening, treatment, data collection, and patient support programs.
• There should be equal access to culturally sensitive, age-appropriate treatment programs.
• Ethically sound, specific policies for storage, ownership, and use in future studies of archived samples remaining from PKU testing should be established.
• Research into the pathophysiology of PKU and relationship to genetic, neural, and behavioral variation is strongly encouraged.
• Uniform policies must be established to remove financial barriers to the acquisition of medical foods and modified low-protein foods and to provide access to support services needed to maintain metabolic control in individuals with PKU.
• Research on nondietary alternatives to treatment of PKU is strongly encouraged.
• To achieve optimal statistical power and cross-cultural applicability, it will be beneficial to use data acquired via national and international collaboration.

Consensus Development Panel

R. Rodney Howell, MD

Panel and Conference Chairperson
Professor and Chairman
Department of Pediatrics
University of Miami School of Medicine
Miami, Florida

Aravinda Chakravarti, PhD

Henry J. Knott Professor and Director
McKusick-Nathans Institute of Genetic Medicine
Johns Hopkins University School of Medicine
Baltimore, Maryland

Geraldine Dawson, PhD

Professor of Psychology
Center on Human Development and Disability
University of Washington
Seattle, Washington

Claibourne I. Dungy, MD, MPH

Professor and Director
Division of General Pediatrics and Adolescent Medicine
Department of Pediatrics
Children's Hospital of Iowa
University of Iowa Health Care
Iowa City, Iowa

Jack M. Fletcher, PhD

Professor
Department of Pediatrics
University of Texas-Houston Medical School
Houston, Texas

Desirée Jackson, PhD

Assistant Professor
Department of Biology
Texas Southern University
Houston, Texas

Mark S. Kamlet, PhD

Provost and Professor of Economics
  and Public Policy
Carnegie Mellon University
Pittsburgh, Pennsylvania

Felissa R. Lashley, PhD, RN

Dean and Professor
School of Nursing
Southern Illinois University Edwardsville
Edwardsville, Illinois

Bonnie S. LeRoy, MS

Director, Graduate Program
  in Genetic Counseling
Institute of Human Genetics
University of Minnesota
Minneapolis, Minnesota

Mary Courtney Moore, PhD, RN, RD

Research Assistant Professor
Department of Molecular Physiology
  and Biophysics
Vanderbilt University School of Medicine
Nashville, Tennessee

Patti J. Patterson, MD, MPH

Vice President for Rural and Community Health
Texas Tech University Health Sciences Center
Lubbock, Texas

William B. Rizzo, MD

Professor of Pediatrics and Human Genetics
Medical College of Virginia
Richmond, Virginia

M. Anne Spence, PhD

Professor
Department of Pediatrics
University of California, Irvine
Orange, California

Stephanie Stremer

Student
University of Wisconsin-Madison
Madison, Wisconsin

Speakers

Véronique Abadie, MD

Service de Pédiatrie Générale
Hôpital Necker-Enfants Malades
Paris, France

Colleen Azen, MS

Coordinator, Biostatistics
Maternal PKU Collaborative Study
Division of Medical Genetics
Children's Hospital Los Angeles
Los Angeles, California

Peter Burgard, PhD

Department of General Pediatrics
University of Heidelberg
Pediatric and Developmental Psychology
University Children's Hospital
Heidelberg, Germany

Forrester Cockburn, MD

Emeritus Professor of Child Health
University of Glasgow
Royal Hospital for Sick Children
Glasgow, Scotland

Flemming Güttler, MD, PhD

Head, Department of Inherited Metabolic Disease and Molecular Genetics
Associate Professor
University of Copenhagen
John F. Kennedy Institute
Glostrup, Denmark

Richard Koch, MD

Principal Investigator
Maternal PKU Collaborative Study
Division of Medical Genetics
Children's Hospital Los Angeles
Los Angeles, California

Harvey L. Levy, MD

Senior Associate in Medicine and Genetics
Children's Hospital, Boston
Associate Professor of Pediatrics
Harvard Medical School
Boston, Massachusetts

Michele A. Lloyd-Puryear, MD, PhD

Chief, Genetic Services Branch
Maternal and Child Health Bureau
Health Resources and Services Administration
Rockville, Maryland

Reuben Matalon, MD, PhD

Director
Biochemical/Molecular Genetics
University of Texas Medical Branch at Galveston
Galveston, Texas

Kimberlee Michals, PhD, RD, LD

Associate Professor of Nutrition
Department of Human Development and   Consumer Sciences
College of Technology
Department of Pediatrics
University of Texas Medical Branch
University of Houston
Houston, Texas

  Mary Kay Z. Pelias, PhD, JD

   Professor of Genetics
Department of Biometry and Genetics
Louisiana State University Medical Center
New Orleans, Louisiana

  Joachim Pietz, MD

   Department of Pediatric Neurology
University of Heidelberg
Heidelberg, Germany

  Charles R. Scriver, MD

   Alva Professor of Human Genetics
McGill University-Montreal Children's Hospital   Research Institute
Montreal, Quebec, Canada

  Margretta R. Seashore, MD, FAAP, FACMG

   Director, Genetics Consultative Services
Professor of Genetics and Pediatrics
Yale University School of Medicine
New Haven, Connecticut

  Friedrich K. Trefz, MD

   Head, Children's Hospital Reutlingen
University of Tubingen School of Medicine
Reutlingen, Germany

  Susan E. Waisbren, PhD

   Senior Psychologist
Inborn Errors of Metabolism Service
Associate Professor of Psychology
Department of Psychiatry
Harvard Medical School
Boston, Massachusetts

  Marilyn C. Welsh, PhD

   Professor
Department of Psychology
University of Northern Colorado
Greeley, Colorado

  Keith F. Widaman, PhD

   Professor
Department of Psychology University of   California, Davis
Davis, California

  Savio L. C. Woo, PhD

   Professor and Director
Institute for Gene Therapy and Molecular Medicine
Mount Sinai School of Medicine
New York, New York

PLANNING COMMITTEE

  Duane Alexander, MD

   Planning Committee Chairperson
Director
National Institute of Child Health and Human   Development
National Institutes of Health
Bethesda, Maryland

  John A. Bowersox

   Communications Specialist
Office of Medical Applications of Research
Office of the Director
National Institutes of Health
Bethesda, Maryland

  Marie Bristol-Power, PhD

   Health Scientist Administrator
Mental Retardation and Developmental   Disabilities Branch
National Institute of Child Health and Human Development
National Institutes of Health
Bethesda, Maryland

  Felix de la Cruz, MD, MPH

   Chief
Mental Retardation and Developmental   Disabilities Branch
National Institute of Child Health
  and Human Development
National Institutes of Health
Bethesda, Maryland

  Franklin Desposito, MD

   Director
Center for Human and Molecular Genetics
UMDNJ-New Jersey Medical School
Newark, New Jersey

  Jerry M. Elliott

   Program Analysis and Management Officer
Office of Medical Applications of Research
Office of the Director
National Institutes of Health
Bethesda, Maryland

  John H. Ferguson, MD

   Director (Retired)
Office of Medical Applications of Research
Potomac, Maryland

  Karin F. Helmers, PhD

   Program Director
Division of Extramural Activities
National Institute of Nursing Research
National Institutes of Health
Bethesda, Maryland

  Richard Koch, MD

   Principal Investigator
Maternal PKU Collaborative Study
Division of Medical Genetics
Children's Hospital Los Angeles
Los Angeles, California

  Cara J. Krulewitch, PhD, CNM

   Program Director
National Institute of Nursing Research
National Institutes of Health
Bethesda, Maryland

  Harvey L. Levy, MD

   Senior Associate in Medicine and Genetics
Children's Hospital, Boston
Associate Professor of Pediatrics
Harvard Medical School
Boston, Massachusetts

  Edward R. B. McCabe, MD, PhD

   Professor and Executive Chair
Department of Pediatrics
Physician-in-Chief
Mattel Children's Hospital at UCLA
UCLA School of Medicine
Los Angeles, California

  Catherine McKeon, PhD

   Senior Advisor for Genetic Research
Division of Diabetes, Endocrinology,
  and Metabolic Diseases
National Institute of Diabetes and Digestive
  and Kidney Diseases
National Institutes of Health
Bethesda, Maryland

  Kathryn D. Moseley, MS, RD

   Metabolic Dietitian
Children's Hospital Los Angeles
Los Angeles, California

  Margretta R. Seashore, MD, FAAP, FACMG

   Director, Genetics Consultative Services
Professor of Genetics and Pediatrics
Yale University School of Medicine
New Haven, Connecticut

  Philip H. Sheridan, MD

   Program Director, Neurodevelopment
  and Pediatric Neurology
National Institute of Neurologic Disorders
  and Stroke
National Institutes of Health
Bethesda, Maryland

  Elizabeth J. Thomson, RN, MS, CGC

   Program Director
Ethical, Legal, and Social Implications (ELSI   Research)
National Human Genome Research Institute
National Institutes of Health
Bethesda, Maryland

  Judith M. Whalen, MPA

   Associate Director for Science Policy, Analysis, and   Communication
National Institute of Child Health and
  Human Development
National Institutes of Health
Bethesda, Maryland

Conference Sponsors

National Institute of Child Health and Human Development
Duane Alexander, MD
Director

Office of Medical Applications of Research
Barnett S. Kramer, MD, MPH
Director

Conference Cosponsors

National Human Genome Research Institute
Francis S. Collins, MD, PhD
Director

National Institute of Diabetes and Digestive and   Kidney Diseases
Allen M. Spiegel, MD
Director

National Institute of Neurologic Disorders and Stroke
Gerald D. Fischbach, MD
Director

National Institute of Nursing Research
Patricia A. Grady, PhD, RN, FAAN
Director

NIH Office of Rare Diseases
   Stephen C. Groft, PharmD
Director

Maternal and Child Health Bureau of the Health   Resources and Services Administration
Peter C. van Dyck, MD, MPH
Associate Administrator

The following references were selected by the panel chair from references submitted with abstracts prepared by conference speakers.

	FOOTNOTES

Received for publication Feb 13, 2001; accepted Feb 13, 2001.

Address correspondence to John Bowersox, Communications Specialist, Office of Disease Prevention, National Institutes of Health, Bethesda, MD 20892. E-mail: bowersoj{at}od.nih.gov

	ABBREVIATIONS

PKU, phenylketonuria; PAH, phenylalanine hydroxylase; Phe, phenylalanine; LNAA, large, neutral amino acids; BIA, Bacterial Inhibition Assay.

	REFERENCES

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