Summary
In recent years, an increasing number of national guidelines on the treatment of phenylketonuria (PKU) have emerged. Most of these guidelines are dedicated to the care of children, while less attention is paid to the care of adults, although all guidelines underline the importance of diet for life. This review aims to summarize issues that need to be addressed within a guideline on the treatment of PKU, especially when care for patients beyond childhood is concerned. In this respect, it is of importance that adult patients, both willing and unwilling to be treated, need a guideline for care and follow-up. In PKU there is certainly a need for an improved unified guideline, especially after childhood, although many of the considerations in this article also apply to recommendations for treatment of children. Such a guideline will be a tool to improve treatment in PKU patients but should also include recommendations for collecting data for clinical and research purposes. Guideline development should also focus on nutritional, neuropsychological and psychosocial issues and not only on target plasma phenylalanine concentrations. In addition, guidelines must address not only what has to be done but also how it can be done, thereby improving concordance with the recommendations for treatment and management.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abadie V, Berthelot J, Feillet F, et al (2005) Consensus national sur la prise en charge des enfants dépistés avec une hyperphénylalaninémie. Arch Pediatr 12: 594–601. doi:10.1016/j.arcped.2005.02.004
Bekhof J, van Spronsen FJ, Crone MR, van Rijn M, Oudshoorn CG, Verkerk PH (2003) Influence of knowledge of the disease on metabolic control in phenylketonuria. Eur J Pediatr 162: 440–442
Bekhof J, van Rijn M, Sauer PJ, Ten Vergert EM, Reijngoud DJ, van Spronsen FJ (2005) Plasma phenylalanine in patients with phenylketonuria self-managing the diet. Arch Dis Child 90: 163–164. doi:10.1136/adc.2003.040451
Bosch AM, Tybout W, van Spronsen FJ, de Valk HW, Wijburg FA, Grootenhuis MA (2007) The course of life and quality of life of early and continuously treated Dutch patients with phenylketonuria. J Inherit Metab Dis 30: 29–34. doi:10.1007/s10545-006-0433-6
Brown AS, Fernhoff PM, Waisbren SE, et al (2002) Barriers to successful dietary control among pregnant women with phenylketonuria. Genet Med 4: 84–89. doi:10.1097/00125817-200203000-00006
Brumm VL, Azen C, Moats A, Stern AM, Broomand C, Nelson MD (2004) Neuropsychological outcome of subjects participating in the PKU Adult Collaborative Study: A preliminary review. J Inherit Metab Dis 27: 549–566. doi:10.1023/B:BOLI.0000042985.02049.ff
Burgard P, Schmidt E, Rupp A, Schneider W, Bremer HJ (1996) Intellectual development of the patients of the German collaborative study of children treated for phenylketonuria. Eur J Pediatr 155(Supplement 1): S33–S38. doi:10.1007/PL00014245
Burgard P, Bremer HJ, Bührdel P, et al (1999) Rationale for the German recommendations for phenylalanine level control in phenylketonuria. Eur J Pediat 158: 46–54. doi:10.1007/s004310051008
Cabana MD, Rand CS, Powe NR, et al (1999) Why don’t physicians follow clinical practice guidelines? A framework for improvement. JAMA 282: 1458–1465. doi:10.1001/jama.282.15.1458
Cerone R, Schiaffino MC, Di Stefano S, Veneselli E (1999) Phenylketonuria: diet for life or not? Acta Paediatr 88: 664–666. doi:10.1080/08035259950169350
Channon S, German E, Cassina C, Lee P (2004) Executive functioning, memory, and learning in phenylketonuria. Neuropsychology 18: 613–20. doi:10.1037/0894-4105.18.4.613
Channon S, Mockler C, Lee P (2005) Executive functioning and speed of processing in phenylketonuria. Neuropsychology 19: 679–686. doi:10.1037/0894-4105.19.5.679
Channon S, Goodman G, Zlotowitz S, Mockler C, Lee PJ (2007) Effects of dietary management of phenylketonuria on long-term cognitive outcome. Arch Dis Child 92: 213–218. doi:10.1136/adc.2006.104786
Clarke JTR, Gates RD, Hogan SE, Barrett M, MacDonald GW (1987) Neuropsychological studies on adolescents with phenylketonuria returned to phenylalanine-restricted diets. Am J Ment Retard 92: 255–262
Cleary M, Walter JH (2001) Assessment of adult phenylketonuria. Ann Clin Biochem 38: 450–458. doi:10.1258/0004563011901217
Crone MR, van Spronsen FJ, Oudshoorn K, Bekhof J, van Rijn G, Verkerk PH (2005) Behavioural factors related to metabolic control in patients with phenylketonuria. J Inherit Metab Dis 28: 627–637. doi:10.1007/s10545-005-0014-0
Feldmann R, Denecke J, Grenzebach M, Weglage J (2005) Frontal lobe-dependent functions in treated phenylketonuria: blood phenylalanine concentrations and long-term deficits in adolescents and young adults. J Inherit Metab Dis 28: 445–455. doi:10.1007/s10545-005-0445-7
Finkelson L, Bailey I, Waisbren SE (2001) PKU adults and their return to diet: predicting diet continuation and maintenance. J Inherit Metab Dis 24: 515–516. doi:10.1023/A:1010546000617
Fisch RO, Matalon R, Weisberg S, Michals K (1997) Phenylketonuria: current dietary treatment practices in the United States and Canada. J Am Coll Nutr 16: 147–151
Gassió R, Campistol J, Vilaseca MA, Lambruschini N, Cambra FJ, Fusté E (2003) Do adult patients with phenylketonuria improve their quality of life after introduction/resumption of a phenylalanine-restricted diet? Acta Paediatr 92: 1474–1478. doi:10.1080/08035250310006683
Gleason LA, Michals K, Matalon R, Langenberg P, Kamath S (1992) A treatment program for adolescents with phenylketonuria. Clin Pediatr (Phila) 31: 331–335. doi:10.1177/000992289203100603
Guthrie R, Susi A (1963) A simple phenylalanine method for detecting Phenylketonuria in large populations of newborn infants. Pediatrics 32: 338–343
Hanley WB, Feigenbaum A, Clarke JT, Schoonheyt W, Austin V (1993) Vitamin B12 deficiency in adolescents and young adults with phenylketonuria. Lancet 342: 997. doi:10.1016/0140-6736(93)92047-W
Hvas AM, Nexo E, Nielsen JB (2006) Vitamin B12 and vitamin B6 supplementation is needed among adults with phenylketonuria (PKU). J Inherit Metab Dis 29: 47–53. doi:10.1007/s10545-006-0108-3
Huijbregts SC, de Sonneville LM, Licht R, van Spronsen FJ, Sergeant JA (2002a) A Short-term dietary interventions in children and adolescents with treated phenylketonuria: effects on neuropsychological outcome of a well-controlled population. J Inherit Metab Dis 25: 419–430. doi:10.1023/A:1021205713674
Huijbregts S, de Sonneville L, Licht R, Sergeant J, van Spronsen F (2002b) Inhibition of prepotent responding and attentional flexibility in treated phenylketonuria. Dev Neuropsychol 22: 481–499. doi:10.1207/S15326942DN2202_4
Huijbregts SC, de Sonneville L, Licht R, van Spronsen FJ, Verkerk PH, Sergeant JA (2002c) Sustained attention and inhibition of cognitive interference in treated phenylketonuria: associations with concurrent and lifetime phenylalanine concentrations. Neuropsychologica 40: 7–15. doi:10.1016/S0028-3932(01)00078-1
Kölker S, Christensen E, Leonard JV, et al (2007) Guideline for the diagnosis and management of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I). J Inherit Metab Dis 30: 5–22. doi:10.1007/s10545-006-0451-4
Koch R, Burton B, Hoganson G, et al (2002) Phenylketonuria in adulthood: a collaborative study. J Inherit Metab Dis 25: 333–346. doi:10.1023/A:1020158631102
Lee PJ, McKitterick K, Channon S, Leach A (2007) Improvements in neuropsychometric outcome when re-introducing diet in adulthood in phenylketonuria (PKU). J Inherit Metab Dis 30(Supplement 1): 14 (Abstr.) doi:10.1007/s10545-006-0452-3
Leuzzi V, Rinalduzzi S, Chiarotti F, Garzia P, Trasimeni G, Accornero N (1998) Subclinical visual impairment in phenylketonuria. A neurophysiological study (VEP-P) with clinical, biochemical, and neuroradiological (MRI) correlations. J Inherit Metab Dis 21: 351–364. doi:10.1023/A:1005346422918
Leuzzi V, Tosetti M, Montanaro D, et al (2007) The pathogenesis of the white matter abnormalities in phenylketonuria. A multimodal 3.0 tesla MRI and magnetic resonance spectroscopy (1H MRS) study. J Inherit Metab Dis 30: 209–216. doi:10.1007/s10545-006-0399-4
Levy HL, Waisbren SE (1994) PKU in adolescents: rationale and psychosocial factors in diet continuation. Acta Paediatr Suppl 407: 92–97. doi:10.1111/j.1651-2227.1994.tb13463.x
Levy HL, Burton B, Cederbaum S, Scriver C (2007) Recommendations for evaluation of responsiveness to tetrahydrobiopterin (BH(4)) in phenylketonuria and its use in treatment. Mol Genet Metab 92: 287–291. doi:10.1016/j.ymgme.2007.09.017
Ludolph AC, Ullrich K, Nedjat S, Masur H, Bick U (1992) Neurological outcome in 22 treated adolescents with hyperphenylalaninemia. A clinical and electro-physiological study. Acta Neurol Scand 85: 243–248
MacDonald A, Rylance G, Hall SK, Asplin D, Booth IW (1996) Factors affecting the variation in plasma phenylalanine in patients with phenylketonuria on diet. Arch Dis Child 74: 412–417
McDonnell GV, Esmonde TF, Hadden DR, Morrow JI (1998) A Neurological evaluation of adult phenylketonuria in Northern Ireland. Eur Neurol 39: 38–43. doi:10.1159/000007895
Medical Research Council Working Party on Phenylketonuria (1993a) Phenylketonuria due to phenylalanine hydroxylase deficiency: un unfolding story. BMJ 306: 115–119
Medical Research Council Working Party on Phenylketonuria (1993b) Recommendations on the dietary management of phenylketonuria. Arch Dis Child 68: 426–427
Meyer G, Köpke S, Lenz M, Kasper J, Mühlhauser I (2007) Evidence-based medicine for diabetes educators: a pilot study. Diabet Med 24: 901–905. doi:10.1111/j.1464-5491.2007.02185.x
Michaud PA, Suris J-C, Viner R (2004) The adolescent with a chronic condition. Part II: healthcare provision. Arch Dis Child 89: 943–949. doi:10.1136/adc.2003.045377
Mullen PD (1997) Compliance becomes concordance. BMJ 314: 691–692
National Institutes of Health Consensus Development Panel (2001) National Institutes of Health Consensus Development Conference Statement: Phenylketonuria: screening and management, October 16–18, 2000. Pediatrics 108: 972–982. doi:10.1542/peds.108.4.972
Panis B, van Kroonenburgh MJ, Rubio-Gozalbo ME (2007) Proposal for the prevention of osteoporosis in paediatric patients with classical galactosaemia. J Inherit Metab Dis 30: 982. doi:10.1007/s10545-007-0676-x
Pardridge WM (1998) Blood–brain barrier carrier-mediated transport and brain metabolism of amino acids. Neurochem Res 23: 635–644. doi:10.1023/A:1022482604276
Pietz J, Schmidt E, Matthias P, Kobialka B, Kutscha A, de Sonneville L (1993) EEGs in phenylketonuria. I: follow-up to adulthood; II: short-term diet-related changes in EEGs and cognitive function. Dev Med Child Neurol 35: 54–64
Pietz J, Landwehr R, Kutscha A, Schmidt H, de Sonneville L, Trefz FK (1995) Effect of high-dose tyrosine supplementation on brain function in adults with phenylketonuria. J Pediatr 127: 936–943. doi:10.1016/S0022-3476(95)70031-5
Pietz J, Fätkenheuer B, Burgard P, Armbruster M, Esser G, Schmidt H (1997) Psychiatric disorders in adult patients with early-treated phenylketonuria. Pediatrics 99: 345–350. doi:10.1542/peds.99.3.345
Pietz J, Dunckelmann R, Rupp A, et al (1998) Neurological outcome in adult patients with early-treated phenylketonuria. Eur J Pediatr 157: 824–830. doi:10.1007/s004310050945
Pietz J, Kreis R, Rupp A, et al (1999) Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. J Clin Invest 103: 1169–1178. doi:10.1172/JCI5017
Przyrembel H (1996) Recommendations for protein and amino acid intake in phenylketonuria patients. Eur J Pediatr 155: Suppl 1 S130–S131. doi:10.1007/PL00014229
Rake JP, Visser G, Huismans D, et al (2003) Bone mineral density in children, adolescents and adults with glycogen storage disease type Ia: a cross-sectional and longitudinal study. J Inherit Metab Dis 26: 371–384. doi:10.1023/A:1025111220095
Ris MD, Williams SE, Hunt MM, Berry HK, Leslie N (1994) Early-treatedphenylketonuria: adult neuropsychological outcome. J Pediatr 124: 388–392. doi:10.1016/S0022-3476(94)70360-4
Ris MD, Weber AM, Hunt MM, Berry HK, Williams SE, Leslie N (1997) Adult psychosocial outcome in early-treated phenylketonuria. J Inherit Metab Dis 20: 499–508. doi:10.1023/A:1005389110739
Robinson M, White FJ, Cleary MA, Wraith E, Lam WK, Walter JH (2000) Increased risk of vitamin B12 deficiency in patients with phenylketonuria on an unrestricted or relaxed diet. J Pediatr 136: 545–547. doi:10.1016/S0022-3476(00)90022-2
Rohr F, Munier A, Sullivan D, et al (2004) The resource mothers study. J Inherit Metab Dis 27: 145–155. doi:10.1023/B:BOLI.0000028785.20901.d9
Scriver CR (2007) The PAH gene, phenylketonuria, and a paradigm shift. Hum Mutation 28(9): 831–845
Schmidt H (1996) Intelligence and professional career in young adults treated early for phenylketonuria. Eur J Pediatr 155(Supplement 1): S97–S100. doi:10.1007/PL00014262
Schmidt E, Burgard P, Rupp A (1996) Effects of concurrent phenylalanine levels on sustained attention and calculation speed in patients treated early for phenylketonuria. Eur J Pediatr 155(Supplement 1): S82–S86. doi:10.1007/PL00014258
Schulpis KH, Karikas GA, Papakonstantinou E (2002) Homocysteine and other vascular risk factors in patients with phenylketonuria on a diet. Acta Paediatr 91: 905–909. doi:10.1080/080352502760148612
Schweitzer-Krantz S, Burgard P (2000) Survey of national guidelines for the treatment of phenylketonuria. Eur J Pediatr 159(Supplement 2): S70–73. doi:10.1007/PL00014385
Simon E, Schwarz M, Roos J, Dragano N, Geraedts M, Siegrist J, et al (2008) Evaluation of the quality of life and description of the sociodemographic state of adolescent and young adult patients with phenylketonuria (PKU). Health Qual Life Outcomes 6: 25–31. doi:10.1186/1477-7525-6-25
Smith I, Beasley MG, Ades AE (1990) Intelligence and quality of dietary treatment in phenylketonuria. Arch Dis Childh 65: 472–478
Thompson AJ, Smith I, Brenton D, et al (1990) Neurological deterioration in young adults with phenylketonuria. Lancet 336: 602–605. doi:10.1016/0140-6736(90)93401-A
Van Rijn M, Hoeksma M, Sauer P, et al (2007) Protein metabolism in adult patients with phenylketonuria. Nutrition 23: 445–453. doi:10.1016/j.nut.2007.03.009
van Spronsen FJ, van Rijn M, van Dijk T, et al (1993) Plasma phenylalanine and tyrosine responses to prolonged overnight fasting breakfast and lunch in phenylketonuria: consequences of sample timing for dietary control. Pediatrics 92: 570–573
van Spronsen FJ, van Rijn M, van Dijk T, et al (1996) Phenylketonuria: plasma phenylalanine responses to different distributions over the day of the daily phenylalanine allowance. Pediatrics 97: 839–844
Villasana D, Butler IJ, Williams JC, Roongta SM (1989) Neurological deterioration in adult phenylketonuria. J Inherit Metab Dis 12: 451–457. doi:10.1007/BF01802042
Waisbren SE, Levy HL (1991) Agoraphobia in phenylketonuria. J Inherit Metab Dis 14: 755–764. doi:10.1007/BF01799946
Waisbren SE, Zaff J (1994) Personality disorder in young women with treated phenylketonuria. J Inherit Metab Dis 17: 584–592. doi:10.1007/BF00711596
Waisbren SE, Rokni H, Bailey I, Rohr F, Brown T, Warner-Rogers J (1997) Social factors and the meaning of food in adherence to medical diets: results of a maternal phenylketonuria summer camp. J Inherit Metab Dis 20: 21–27. doi:10.1023/A:1005349204797
Walter JH, White FJ, Hall SK, et al (2002) How practical are recommendations for dietary control in phenylketonuria? Lancet 360: 55–57. doi:10.1016/S0140-6736(02)09334-0
Weglage J, Fünders B, Wilken B, et al (1992) Psychological and social findings in adolescents with phenylketonuria. Eur J Pediatr 151: 522–525. doi:10.1007/BF01957759
Weglage J, Funders B, Von Teeffelen-Heithoff A, Ullrich K (1993) Phenylketonuria: illness experience and coping mechanisms. Z Kinder Jugendpsychiatr 21: 156–162
Weglage J, Grenzebach M, Pietsch M, et al (2000) Behavioural and emotional problems in early-treated adolescents with phenylketonuria in comparison with diabetic patients and healthy controls. J Inherit Metab Dis 23: 487–496. doi:10.1023/A:1005664231017
White DA, Nortz MJ, Mandernach T, Huntington K, Steiner RD (2001) Deficits in memory strategy use related to prefrontal dysfunction during early development: evidence from children with phenylketonuria. Neuropsychology 15: 221–229. doi:10.1037/0894-4105.15.2.221
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicating editor: Michael Gibson
Competing interests: F. J. van Spronsen is chair of the Scientific Advisory Committee of the Dutch PKU Society, chair of the Scientific Advisory Committee of the European Society of PKU and Allied Disorders, member of the European Advisory Committee on Tetrahydrobiopterin of Merck-Serono, chair of the International Working Group on Large Neutral Amino Acids supported by SHS/Milupa, and chair of the International Working Group on diet for life supported by SHS/Milupa.
References to electronic databases: Phenylketonuria: OMIM 261600.
Rights and permissions
About this article
Cite this article
van Spronsen, F.J., Burgard, P. The truth of treating patients with phenylketonuria after childhood: The need for a new guideline. J Inherit Metab Dis 31, 673–679 (2008). https://doi.org/10.1007/s10545-008-0918-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10545-008-0918-6