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By Michele A. Lloyd-Puryear, M.D., Ph.D., and Bradford L. Therrell, Ph.D.
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 4).
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).
Table 1. State laboratory fees and methods
Fluorometric 1 = Perkin Elmer Wallac Kit
Fluorometric 2 = Astoria Pacific Kit
|State/Jurisdiction||PKU Laboratory||PKU Method||Abnormal (mg/dL)||Comprehensive NBS Fee|
|1. Alabama||State||BIA||>=2.0 if < 24 hr old
>=4.0 if < 48 hr old
>=6.0 if > 48 hr old
|3. Arizona||State (Contract)||Fluorometric 1||>=2.1||$20 (1st ) $15 (2nd)|
|5. California||8 Contract Labs||Fluorometric 2||Phe/Tyr > 1.5||$42|
|6. Colorado||State||Fluorometric 1||>=2.1||$33.50 (2 samples)|
|9. District of Columbia||Neo Gen (Contract)||MS/MS||>=2.0||$14.52|
|13. Idaho||Oregon||BIA||>=4.0||No fee|
|14. Illinois||State||Fluorometric 2||>=4.0||$32|
|15. Indiana||Indiana Univ. (Contract)||Fluorometric 1||>=2.3||$28.50|
|16. Iowa||State||Fluorometric 1||>=3.1||$31|
|17. Kansas||State||BIA||>=4.0||No fee|
|20. Maine||U. Mass. (Contract)||MS/MS||>=2.3||$26.75|
|21. Maryland||State||BIA||>=2.0||$15.75 (2nd free)|
|22. Massachusetts||U. Mass. (Contract)||MS/MS||>=2.3||$49|
|23. Michigan||State||Fluorometric 1||>=2.0||$39|
|24. Minnesota||State||BIA||>=2.0 if <24 hrs old
>=4.0 if >24 hrs old
|25. Mississippi||Tennessee (Contract)||Fluorometric 2||>=4.0||$25|
|26. Missouri||State||Fluorometric 1||>=3.0||$13|
|27. Montana||State||Fluorometric 1||>=3.0||$10.19|
|28. Nebraska||2 Contract||Fluorometric 1||>=3.4||$53 / $54.60 (2 labs)|
|29. Nevada||Oregon (Contract)||BIA||>=4.0||$32|
|30. New Hampshire||U. Mass (Contract)||MS/MS||>=2.3||$18|
|31. New Jersey||State||Fluorometric 1||>=2.1||$34|
|32. New Mexico||State||Fluorometric 1||>=3.0||$20|
|33. New York||State||BIA||>=3.0||No fee|
|34. North Carolina||State||MS/MS||>=2.5; Phe/Tyr >=3|
|35. North Dakota||Iowa (Contract)||1||>=3.1||$16|
|37. Oklahoma||State||Enzyme (Accuwell)||>3.5||$10.50|
|39. Pennsylvania||Neo Gen (Contract)||MS/MS||>=2.0||No fee|
|40. Rhode Island||U. Mass. (Contract)||MS/MS||>=2.3||$59|
|41. South Carolina||State||Fluorometric||>=4.0||$21|
|42. South Dakota||Clin. Labs of Midwest (Contract)||Quantase||>=4.0||$12.28|
|43. Tennessee||State||Fluorometric 2||>=4.0||$10|
|44. Texas||State||BIA||>=4.0||$13.75 each sample|
|45. Utah||State||Fluorometric 1||>=2.1||$27.00 (2nd at no chrge.)|
|46. Vermont||U. Mass (Contract)||MS/MS||>=2.3||$27|
|48. Washington||State||BIA||>=3.0; phe/tyr >=2 if <24 hrs old
>=4.0 if >24 hrs old
|49. West Virginia||State||Fluorometric 2||>=4.0||No fee|
|50. Wisconsin||State||Fluorometric 1||>=2.1||$55.50|
|51. Wyoming||Colorado (Contract)||Fluorometric 1||>=2.1||No fee|
- American Academy of Pediatrics. A report from the Newborn Screening Task Force. Serving the family from birth to the medical home. Pediatrics 2000;106(Suppl.):1-39.
- California Department of Health Services. Cost and availability of dietary treatment of phenylketonuria (PKU). Berkeley (CA): Pacific Southwest Regional Genetics Network; 1997.
- Council of Regional Networks for Genetic Services (CORN). Newborn screening: an overview of newborn screening programs in the United States, Canada, Puerto Rico, and the Virgin Islands. Springfield (IL): Council of Regional Networks for Genetic Services (CORN) and Great Lakes Regional Genetics Group (GlaRGG); Illinois Department of Public Health; 1996.
- Hannon, H. Personal communication, Mar. 2000.
- Pass KA, Lane PA, Fernhoff PM, et al. U.S. newborn screening system guidelines II: follow-up of children, diagnosis, management, and evaluation. J Pediatrics. In press.
- Public Law 100-578: Clinical Laboratory Improvement Amendments of 1988.
- Simmank J, Therrell BL. A national survey of fee structures in U.S. newborn screening systems. In: Levy HL, Hermos RJ, Grady GF, editors. Proceedings III International Society for Neonatal Screening, Boston. 20-23 Oct 1996. Watertown (MA): IKON/MAP; 1997:339-41.
- Therrell BL, Panny SR, Davidson J, Eckman J, Hannon WH, Henson MA, et al. U.S. newborn screening system guidelines: statement of the Council of Regional Networks for Genetic Services. Screening 1992;1:135-47.
- Therrell BL. Personal communication, June 2000.
- U.S. Congress Office of Technology Assessment. Newborn screening for congenital disorders. In:Healthy Children: Investing in the Future.OTA-H-345. Washington (DC): U.S. Government Printing Office; Feb 1986.