Phenylketonuria

The National Institutes of Health (NIH) has released a consensus statement on the screening and management of phenylketonuria (PKU). The statement, which was prepared by a nonadvocate group of experts who work in the field, is not an official document of the NIH or the federal government, but rather an independent panel report. The panel met in October 2000 to develop the consensus statement.

This conference was presented by the National Institute of Child Health and Human Development and the NIH Office of Medical Applications of Research. The complete text of the consensus statement may be found on the NIH Web site at http://consensus.nih.gov.

The panel heard expert presentations and public discussion on the biology and biochemistry of PKU, epidemiology and genetics, screening strategies and treatment regimens. On the basis of this information, the panel drafted a consensus statement that addressed, among others, the following questions:

* What are the incidence and prevalence of PKU and other forms of hyperphenylalaninemia?

* What newborn screening strategies are available for diagnosis, and how effective are they?

* What treatment regimens are used to prevent the adverse consequences of PKU?

* What are the recommended strategies for optimal newborn screening and diagnosis, lifelong management and follow-up of PKU?

Introduction

PKU, a form of hyperphenylalaninemia, is a rare metabolic disorder that is caused by a deficiency of the liver enzyme phenylalanine hydroxylase. This deficiency leads to elevated levels of the amino acid phenylalanine (Phe) in the blood and other tissues. Persons with PKU have a complete absence or profound deficiency of enzyme activity, typically show very high elevations of blood Phe (more than 20 mg per dL [1,210 [micro]mol per L]) and accumulate phenylketones. PKU is usually the result of autosomal recessive disorders caused by mutations in the phenylalanine hydroxylase gene. If untreated, the disorder results in mental retardation, microcephaly, delayed speech, seizures, eczema and behavior abnormalities. Approximately one in every 15,000 infants in the United States is born with PKU.

If PKU is detected early, it can be effectively treated with a special diet. The current treatment for PKU is strict metabolic control with a low-Phe diet that includes specialized foods. Newborn screening programs for PKU, which are administered in every state and have been in place for 40 years, have been extremely successful. When diagnosed as newborns and appropriately treated, infants should have normal health and development and can expect a normal life span. Gene therapy and treatments not related to diet are currently being explored. There are currently no data on the clinical manifestations of PKU as patients grow older; few patients are older than 40 years of age.

Incidence and Prevalence

According to data supplied by the states, the reported incidence of PKU ranges from one per 13,500 to one per 19,000 newborns. For non-PKU hyperphenylalaninemia, the composite estimate is one per 48,000 newborns. There are large variations in the incidence of PKU by ethnic group. A higher incidence is seen in whites and Native Americans, while a lower incidence is seen in blacks, Hispanics and Asians.

PKU, like all other genetic disorders, demonstrates genetic and clinical variability. These mutations also contribute to the biochemical heterogeneity and may be responsible for the biochemical phenotype. Genetic contributions to the phenotype are complex, consisting of documented allelic heterogeneity within the phenylalanine hydroxylase gene. Molecular heterogeneity for PKU results in wide phenotypic heterogeneity, which contributes to biochemical individuality. The existence of discordant phenotypes among siblings who share the same genotype at the phenylalanine hydroxylase locus implies that genetic and environmental factors may influence the clinical phenotype.

Screening Strategies

Screening newborns for PKU in the United States began in the early 1960s and has resulted in the prevention of severe mental retardation in thousands of children and adults. Neonatal blood samples are taken during the first days of life and are evaluated for abnormally elevated levels of Phe. The three main laboratory methods used to screen newborns for PKU are the Guthrie bacterial inhibition assay, fluorometric analysis and tandem mass spectrometry.

Effective screening of newborn infants for PKU requires 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 psychologic, nursing and social services, medical nutritional therapy, and genetic and family counseling.

Problems with state-based screening for PKU exist. Great variation in practice occurs in all areas of newborn screening protocols in the United States. All but four states permit parental refusal. Criteria for defining a positive PKU screen varies. Some states have newborn screening advisory boards to guide policy decisions, whereas others rely on state health department staff. States vary in the way their programs are funded, although not all of them charge fees for the testing. Some states bill patients; 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.

Treatment Regimens

Persons with PKU require a Phe-restricted diet, which must begin as early as possible. Most clinics advocate lifelong dietary treatment for metabolic control of blood Phe levels. Infants with PKU who have blood Phe levels higher than 10 mg per dL (605 [micro]mol per L) should begin treatment to establish metabolic control of Phe levels by the time the neonate is seven to 10 days old. Before treatment begins, however, tetrahydrobiopterin deficiency must be excluded. Infants with PKU may be breast-fed, and formula that is free of Phe may be provided.

Metabolic control through diet involves the use of special foods, such as medical protein sources and modified low-protein products, in addition to the required Phe that is provided in small amounts of natural protein. Periodic measurement of blood Phe levels, in conjunction with analysis of nutritional intake and review of nutrition status, is used to monitor the patient's response. Monitoring during the first year of life ranges from once a week to once a month, with once a week being more common. After the infant is one year of age, monitoring varies from once a month to once every three months, occurring approximately once a month by 18 years of age in most U.S. clinics.

The NIH consensus panel recommends the following schedule for monitoring patients with PKU, keeping in mind that treatment may vary depending on the patient: once per week during the first year; twice per month from one to 12 years of age; once per month after 12 years of age; and twice per week during pregnancy of a woman with PKU.

Efficacy of Treatment

Cognitive functioning, school achievement, behavioral adjustment and quality of life are concerns that must be addressed when determining the efficacy of treatment. Many persons with PKU do not manifest cognitive and behavioral deficits. However, when compared with control patients, persons with PKU show lower performance on IQ tests, with larger differences demonstrated in other cognitive domains. Children with PKU score somewhat lower on IQ tests than expected, based on parent and sibling IQs, but their performance is still in the average range. Evidence for differences in behavioral adjustment is inconsistent; anecdotal reports suggest greater risk for internalizing psychopathology and attention disorders.

Assessment of children and adults with PKU indicates that poor metabolic control (i.e., high Phe levels) is associated with lower scores on measures of IQ, attention and reaction time. Similarly, levels of Phe show moderate relationships with performance on measures of cognitive functions and the presence of behavioral difficulties. Age at the initiation of treatment and IQ level are inversely related, even in PKU that is treated early. Evidence suggests that having high levels of plasma Phe during the first two weeks of life can affect the structural development of the visual system, although visual deficits are usually mild.

While in some cases it is possible to relax the strict diet, the NIH consensus panel does not recommend this. Dietary discontinuance before eight years of age is associated with poorer performance on IQ measures. The effects of dietary discontinuance in patients 12 years and older are less clear. Adults with PKU who are not on restricted diets have stable IQ scores, but they perform worse on measures of attention and speed of mental processing. Case reports have documented deterioration of adult patients with PKU after discontinuation of diet.

The treatment of PKU is complex. It requires collecting blood samples, recording food intake, maintaining a highly restrictive diet and visiting a PKU clinic regularly. Adherence to this strict regimen improves if patients with PKU have a social support system, a positive attitude regarding the benefits of treatment and a belief that PKU is manageable in their daily lives.

Appropriate Levels of Phe

No consensus exists regarding the optimal levels of blood Phe. The most commonly reported blood Phe recommendations in U.S. clinics are 2 to 6 mg per dL (120 to 365 [micro]mol per L) for children younger than 12 years and 2 to 10 mg per dL for persons older than 12 years. However, the NIH consensus panel recommends that Phe levels be maintained between 2 and 15 mg per dL (120 to 910 [micro]mol per L) after 12 years of age. Maintenance of Phe levels between 2 and 6 mg per dL for children up to 12 years of age appears to be necessary for ensuring optimal outcome.

Pregnancy and PKU

Women with PKU can conceive and bear children. However, the NIH consensus panel stresses that control of PKU through diet is even more important during pregnancy. Women who are not compliant with a treatment regimen who become pregnant are rarely able to maintain their treatment during pregnancy. Unplanned pregnancies may be particularly troublesome. Exposing a fetus to elevated Phe levels in utero can have serious consequences. The fetus is more likely to experience microcephaly, mental deficiency and congenital heart disease.

Planning pregnancies ensures that the levels of Phe are controlled before conception. The NIH consensus panel recommends that Phe levels of less than 6 mg per dL be achieved at least three months before conception. The recommended level is 2 to 6 mg per dL during pregnancy. Focusing on the overall nutritional status of the pregnant woman is essential. Psychosocial support for the family as a whole and continuity of care for infants should be developed and followed.

Recommended Strategies

The NIH consensus panel believes that state-mandated screening for PKU implies a societal responsibility for comprehensive long-term follow-up and treatment. Experts consider continuity of care from infancy through adulthood medically necessary for optimal outcomes in persons with PKU. To ensure this, treatment guidelines and clinical facilities should be established that are consistent across the United States. Equal access to treatment for all people with PKU is highly desirable. Outcome monitoring should consist of periodic intellectual, neurologic, neuropsychologic and behavioral assessment. Because access to special foods is essential for maintenance of metabolic control, specialized medical foods and low-protein products are medically necessary and should be treated as such.

States should adopt a uniform definition of the Phe level for establishing the diagnosis of PKU and non-PKU hyperphenylalaninemia. Standardized reporting of data must include the number of children born with PKU and with non-PKU hyperphenylalaninemia, the number of children tested, and reports by sex and self-reported ethnicity. In addition, all people with PKU should undergo mutation analysis and genotype determination to aid the initial diagnosis, to enable genetic and management counseling, and to determine follow-up and long-term prognosis.

Newborn screening strategies need to take a total systems approach. This system should include the following: a method for sending samples to the laboratory for analysis within 24 hours of collection; a standard, nationwide approach for 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; and clinical services that meet the needs of adolescents and adults with PKU.

Conclusions

The NIH consensus panel drew the following conclusions:

* Metabolic control via diet is necessary throughout the lifetime of persons with PKU.

* Blood Phe levels in children up to 12 years old should be 2 to 6 mg per dL.

* Blood Phe levels in children older than 12 years should be between 2 and 15 mg per dL.

* Monitoring of persons with PKU should occur once weekly during the first year; twice monthly from one to 12 years of age; monthly after 12 years of age; and twice weekly during pregnancy of a woman with PKU.

* Women with PKU who wish to conceive should achieve Phe levels of less than 6 mg per dL at least three months before conception. The recommended level is 2 to 6 mg per dL during pregnancy.

* A comprehensive, multidisciplinary, integrated system is required for the delivery of care to persons with PKU.

* Greatly needed are consistency and coordination among screening, treatment, data collection and patient support programs.

* Uniform policies need to be established to remove financial barriers to the acquisition of medical foods and modified low-protein foods, as well as to provide access to support services required to maintain metabolic control in persons with PKU.

COPYRIGHT 2001 American Academy of Family Physicians
COPYRIGHT 2001 Gale Group