The term "hyperphenylalaninemia" refers to a wide range of disorders and is used to identify a biochemical phenotype characterized by persistently elevated serum phenylalanine (Phe) concentrations. Phenylketonuria (PKU) refers to a specific type of hyperphenylalaninemia, usually defined clinically with a plasma Phe value exceeding 16.5 mg/dL (1000
mM) and a low tolerance for dietary Phe. PKU is customarily caused by a deficiency of the phenylalanine hydroxylase apoenzyme (PAH), but other causes may include a deficiency of dihydropteridine reductase (DHPR) or reduced production of biopterin (BH
Screening of newborns for PKU has been generally accepted as cost-effective and efficacious, especially when coupled with screening for congenital hypothyroidism (U.S. Congress Office of Technology Assessment, 1986). Effective screening depends on smooth integration and appropriate timing of sample collection, laboratory testing, followup, diagnosis, treatment, and evaluation of outcome (American Academy of Pediatrics, 2000; Therrell, Panny, Davidson, et al., 1992). Universal screening systems are designed to respond to Federal and State mandates to provide all children with special needs, including those in traditionally underserved populations, with access to effective treatment.
Screening is universal across U.S. jurisdictions. Screening systems, however, vary in breadth and depth (CORN, 1996; Pass, Lane, Fernhoff, et al., in press; Therrell, Panny, Davidson, et al., 1992). Procedures for establishing screening policy, providing laboratory services, and determining program rules and regulations vary. This variability particularly affects three aspects of screening systems: (1) the criteria used in screening laboratories to diagnose infants with PKU, (2) followup procedures to confirm and treat infants presumed to have PKU, and (3) financing for screening (including education, testing, and followup) and treatment (including infant formula and food).
All screening and diagnostic laboratory testing must meet the standards of the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), which include requirements for laboratory directors and technical supervisors (Public Law 100-578, 1988). There is no CLIA-approved proficiency testing program for bloodspot screening, however, and the
Centers for Disease Control and Prevention (CDC) is filling this role. States vary in their laboratory testing procedures and in the Phe levels above which newborns are considered at risk for PKU. Currently, 15 of the 60 U.S. laboratories participating in the CDC Newborn Screening Quality Assurance Program hold that followup should begin at levels above 4 mg/dL (250
mM), 43 begin followup at values between 2 mg/dL (125
mM) and 3.5 mg/dL (~220 mM), and 1 begins followup at 6 mg/dL (375 mM) (CDC, no date). Some States suggest taking a repeat filter paper specimen on certain lower elevated levels, and others suggest that all elevations be referred for serum followup because false positives are infrequent and delays in diagnosis and treatment can affect outcome.
Certain serum diagnostic tests have been recommended for confirmatory testing (Pass, Lane, Fernhoff, et al., in press), including plasma Phe and tyrosine concentrations. If Phe is elevated, a test of erythrocyte DHPR activity and a urine pteridine profile are recommended. Confirmatory laboratories should have the capability to perform ion exchange chromatography (or another accepted method for measuring plasma Phe and tyrosine), erythrocyte DHPR analysis, and urinary pteridine testing (California Department of Health Services, 1997). Biopterin studies are also suggested by most screening programs, along with supplemental tests that may help in further diagnosis and nutritional management. These include a complete amino acid profile, urine organic acid analysis, and DNA analysis for specific mutations in PAH. Evaluation of parental PAH genotypes by biochemical or molecular methods may also be useful in diagnosis, prognosis, and genetic counseling. Core and supplemental tests and procedures for the diagnosis of hyperphenylalaninemia and PKU are summarized in Table 1 (California Department of Health Services, 1997).
Further management of PKU depends on the outcome of diagnostic testing and clinical evaluation. Management is urgent because the cognitive ability of children with PKU is related to the age at which blood Phe is reduced to therapeutic levels. Once the diagnosis of PKU is confirmed, metabolic control should be achieved as rapidly as possible, ideally within the first 2 to 3 weeks of life; all screening programs report compliance with this recommendation.
The financing mechanisms of newborn screening programs vary (American Academy of Pediatrics, 2000; CORN, 1996). In 1997, 11 U.S. programs did not charge a fee for newborn screening (Simmank, Therrell, 1997); this number decreased to 9 in 1999 (Therrell, personal communication, 2000). Of the States charging a fee, only 12 reported using the money to cover the costs of treatment, including formula (CORN, 1996). Federal funding allows compensation for supplemental foods and formula as part of the Women, Infants, and Children program, or from Medicaid if the individual qualifies. Those ineligible for Federal funding do not always have access to third-party payers of the costs of food and formula required in all States. State laws mandating third-party coverage vary. In self-employment insurance programs, payment decisions may rest with the employer (California Department of Health Services, 1997).
Fluorometric 1 = Perkin Elmer Wallac KitFluorometric 2 = Astoria Pacific Kit
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