Variations Among Programs in Time of Initiation of Diet Treatment, Level of Control, & Diet Relaxation/Discontinuation

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By Margretta R. Seashore, M.D., FAAP, FACMG

A survey was sent to the directors of 111 clinics in the United States that treat patients with phenylketonuria (PKU), and we received 87 responses. These 87 clinics were treating a total of 4,669 patients. Approximately one-half of the patients were younger than 12 years of age, and 93 percent of these were on a phenylalanine (Phe)-restricted diet. Of those patients 12 years of age and older, 54 percent were on a Phe-restricted diet. The survey instrument included questions about diagnosis, initiation of treatment, assessment of biochemical control, and continuation of dietary restriction.

Blood Phe Concentrations That Initiate Treatment

The clinic directors were asked what concentration of Phe caused them to make a presumptive diagnosis of PKU and begin dietary restriction of Phe. For 70 of the 87 clinics (80 percent), a Phe concentration of 10 mg/dL or less (600 µM) was considered the appropriate level to begin dietary restrictions. At 10 of the 87 (11 percent), treatment began at a concentration of between 10 and 15 mg/dL (600 to 900 µM). Five clinics (6 percent) considered a concentration of more than 15 mg/dL (900 µM) the appropriate level to initiate treatment.

Current Practice Regarding Diet Maintenance

The clinic directors were asked about their approach to long-term treatment of PKU. Some 99 percent of the clinics prescribed a restricted diet for life for males; 85 percent prescribed a restricted diet for life for females. These practices had been in place for more than 7 years at 54 of the 87 clinics (62 percent), and for more than 3 years at 10 of the 87 (11 percent).

Blood Phe Levels During Treatment

The most commonly advocated levels were 2 to 6 mg/dL (120-360 µM) for patients up to 12 years of age, and 2 to 10 mg/dL (120-600 µM) for patients older than 12 years of age.

Monitoring Intervals After Instituting a Phe-Restricted Diet

Monitoring consisted of measurement of Phe concentration in a blood sample, collected at most centers from patients after they had fasted overnight. Monitoring intervals varied according to the age of patients. At less than 1 year of age, the mean frequency was 3.6 times per month (the range was 1 to 8 times per month). Between the ages of 1 and 3 years, the mean frequency was 1.9 times per month (the range was 0.33 to 4 times per month). The frequency of monitoring decreased with increasing age. By 18 years of age, the mean frequency was 1.0 times per month (the range was 0 to 4 times per month).

Laboratory Technique Used

The laboratory technique used for measuring serum or plasma Phe varied from the semiquantitative Guthrie method used in 19 of the 87 clinics (22 percent) to highly quantitative plasma amino acid column chromatography used by 19 (22 percent) and HPLC by 4 (5 percent). A majority of the clinics (41 of the 87, or 47 percent) used the McCaman-Robins fluorometric method.

Time Between Testing and Notification

The amount of time between obtaining blood from patients and reporting the results to the family varied from 1 to 10 days. Most clinics reported the results within 1 to 3 days (52 of the 87, or 60 percent). Five clinics (6 percent) needed 8 to 10 days.

Need for Further Research

Deficiencies in our knowledge still affect our ability to treat patients with PKU optimally. Some involve the pathophysiology of central nervous system injury in PKU, such as the relationship of brain Phe concentration to outcome, the existence of modifying genetic factors, and genotype-phenotype correlation between phenylalanine hydroxylase (PAH) mutations and the clinical phenotype. Other deficiencies involve factors related to compliance with a restricted diet, such as how to design a more palatable diet. We also need a better definition of who should resume the diet. Ideally, a diet treatment that addressed abnormal PAH protein or the gene mutation in PAH may have the best chance of producing a normal outcome.


  • American Academy of Pediatrics Committee on Genetics. Newborn screening fact sheets. Pediatrics 1989; 83:449-64.
  • Azen CG, Koch R, Friedman EG, Berlow S, Coldwell J, Krause W, et al. Intellectual development in 12-year-old children treated for phenylketonuria. Am J Dis Child 1991;145:35-9.
  • Beasley MG, Costello PM, Smith I. Outcome of treatment in young adults with phenylketonuria detected by routine neonatal screening between 1964 and 1971. Q J Med 1994;87:155-60.
  • Cockburn F, Barwell B, Brenton D. Report of Medical Research Council Working Party on Phenylketonuria. Recommendations on the dietary management of phenylketonuria. Arch Dis Child 1993;68:426-27.
  • Fisch RO, Matalon R, Weisberg S, Michals K. Phenylketonuria: current dietary treatment practices in the United States and Canada. J Am Coll Nutr 1997;16:147-51.
  • Levy HL, Waisbren SE. PKU in adolescents: rationale and psychosocial factors in diet continuation. Acta Paediatr Suppl 1994;407:92-7.
  • Möller HE, Vermathen P, Ullrich K, Weglage J, Koch HG, Peters PE. In-vivo NMR spectroscopy in patients with phenylketonuria: changes of cerebral phenylalanine levels under dietary treatment. Neuropediatrics 1995;26:199-202.
  • Naughten ER, Kiely B, Saul I, Murphy D. Phenylketonuria: outcome and problems in a "diet-for-life" clinic. Eur J Pediatr 1987;146:A23-4.
  • Pietz J, Dunckelmann R, Rupp A, Rating D, Meinck HM, Schmidt H. Neurological outcome in adult patients with early-treated phenylketonuria. Eur J Pediatr 1998:157:824-30.
  • Potocnik U, Widhalm K. Long-term follow-up of children with classical phenylketonuria after diet discontinuation: a review. J Am Coll Nutr 1994;13:232-6.
  • Rey F, Abadie V, Plainguet F, Rey J. Long-term followup of patients with classical phenylketonuria after diet relaxation at 5 years of age. The Paris Study. Eur J Pediatr 1996;155:S39-44.
  • Scriver C, Kaufman S, Eisensmith R, Woo S. The hyperphenylalaninemias. In: Scriver R, Beaudet A, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill; 1995; p. 1015-75.
  • Seashore MR, Wappner R, Cho S, de la Cruz F. Development of guidelines for treatment of children with phenylketonuria: report of a meeting at the National Institute of Child Health and Human Developmentheld August 15, 1995, National Institutes of Health, Bethesda, Maryland. Pediatrics 1999;104:e67.
  • Smith I, Beasley MG, Ades AE. Effect on intelligence of relaxing the low phenylalanine diet in phenylketonuria. Arch Dis Child 1991;66:311-6.
  • Smith I. Treatment of phenylalanine hydroxylase deficiency. Acta Paediatr Suppl 1994;407:60-5.
  • Walter JH, Tyfield LA, Holton JB, Johnson C. Biochemical control, genetic analysis and magnetic resonance imaging in patients with phenylketonuria. Eur J Pediatr 1993;152:822-7.
  • Wappner R, Cho S, Kronmal RA, Schuett V, Seashore MR. Management of phenylketonuria for optimal outcome: a review of guidelines for phenylketonuria management and a report of surveys of parents, patients, and clinic directors. Pediatrics 1999;104:e68.

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