Protein substitute needs for patients with Phenylketonuria on BH4 treatment

For around fifty of the known inherited metabolic disorders, the management of these conditions is done through a lifelong commitment to a restricted diet1. In the example of the amino acid disorder Phenylketonuria (PKU), individuals cannot break down the amino acid phenylalanine. If left untreated, this may lead to irreversible brain damage2-4.

For certain patients with PKU, pharmaceutical treatment with synthetic tetrahydrobiopterin (BH4) may help them to relax their restricted diet5-8. While BH4 treatment can support normal growth, a decreased intake of protein substitute may cause deficiency of certain micronutrients9,10.

"Protein substitutes play an essential role in the dietary management of PKU. They provide safe protein, key nutrients, and have an important role to play in metabolic control. With all new pharmaceutical adjunct therapies for PKU, the long-term impact of lowering protein substitute dosage on dietary intake and overall nutritional status should be carefully monitored."

Professor Anita MacDonald, Birmingham Children’s Hospital

recent systematic review and meta-analysis on the protein requirements of patients with PKU on BH4 treatment shows that even when BH4 therapy works, almost half of this subset of PKU patients still needs a protein substitute to meet their protein requirements and achieve good metabolic control11. In any situations where protein requirements are increased (e.g., rapid growth, illness, or pregnancy), it is particularly important to evaluate whether an increase in prescription or re-introduction of protein substitute is necessary.


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  1. White, F.J. Inherited Metabolic Disorders. In Clinical Paediatric Dietetics2020, 502–512.
  2. Blau, N.; van Spronsen, F.J.; Levy, H.L. Phenylketonuria. Lancet 2010, 376, 1417–1427.
  3. Mitchell, J.J.; Trakadis, Y.J.; Scriver, C.R. Phenylalanine hydroxylase deficiency. Genet Med 2011, 13, 697–707.
  4. van Wegberg, A.M.J.; MacDonald, A.; Ahring, K.; Belanger-Quintana, A.; Blau, N.; Bosch, A.M.; Burlina, A.; Campistol, J.; Feillet, F.; Gizewska, M., et al. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis 201712, 162.
  5. Burton, B.K.; Grange, D.K.; Milanowski, A.; Vockley, G.; Feillet, F.; Crombez, E.A.; Abadie, V.; Harding, C.O.; Cederbaum, S.; Dobbelaere, D.; et al. The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin): A phase II, multicentre, open-label, screening study. J. Inherit. Metab. Dis. 2007, 30, 700–707.
  6. Feldmann, R.; Wolfgart, E.; Weglage, J.; Rutsch, F. Sapropterin treatment does not enhance the health-related quality of life of patients with phenylketonuria and their parents. Acta Paediatr. 2017, 106, 953–959.
  7. Hennermann, J.B.; Roloff, S.; Gebauer, C.; Vetter, B.; Von Arnim-Baas, A.; Mönch, E. Long-term treatment with tetrahydrobiopterin in phenylketonuria: Treatment strategies and prediction of long-term responders. Mol. Genet. Metab. 2012, 107, 294–301.
  8. Trefz, F.K.; Burton, B.K.; Longo, N.; Casanova, M.M.-P.; Gruskin, D.J.; Dorenbaum, A.; Kakkis, E.D.; Crombez, E.A.; Grange, D.K.; Harmatz, P.; et al. Efficacy of Sapropterin Dihydrochloride in Increasing Phenylalanine Tolerance in Children with Phenylketonuria: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study. J. Pediatr. 2009, 154, 700–707.e1.
  9. Thiele, A.G.; Rohde, C.; Mütze, U.; Arelin, M.; Ceglarek, U.; Thiery, J.; Baerwald, C.; Kiess,W.; Beblo, S. The challenge of long-term tetrahydrobiopterin (BH4) therapy in phenylketonuria: Effects on metabolic control, nutritional habits and nutrient supply. Mol. Genet. Metab. Rep. 2015, 4, 62–67.
  10. Thiele, A.G.; Weigel, J.F.; Ziesch, B.; Rohde, C.; Mütze, U.; Ceglarek, U.; Thiery, J.; Müller, A.S.; Kiess,W.; Beblo, S. Nutritional Changes and Micronutrient Supply in Patients with Phenylketonuria Under Therapy with Tetrahydrobiopterin (BH4). JIMD Rep. 2012, 9, 31–40.
  11. Ilgaz, F.; Marsaux, C.; Pinto, A.; Singh, R.; Rohde, C.; Karabulut, E.; Gökmen‐Özel, H.; Kuhn, M.; Macdonald, A. Protein substitute requirements of patients with phenylketonuria on bh4 treatment: A systematic review and meta‐analysis. Nutrients 2021, 13.

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