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Meta-Analysis
. 2021 Mar 23;13(3):1040.
doi: 10.3390/nu13031040.

Protein Substitute Requirements of Patients with Phenylketonuria on BH4 Treatment: A Systematic Review and Meta-Analysis

Fatma Ilgaz  1 , Cyril Marsaux  2 , Alex Pinto  3 , Rani Singh  4 , Carmen Rohde  5 , Erdem Karabulut  6 , Hülya Gökmen-Özel  1 , Mirjam Kuhn  2 , Anita MacDonald  3
Affiliations
Meta-Analysis

Protein Substitute Requirements of Patients with Phenylketonuria on BH4 Treatment: A Systematic Review and Meta-Analysis

Fatma Ilgaz et al. Nutrients. .

Abstract

The traditional treatment for phenylketonuria (PKU) is a phenylalanine (Phe)-restricted diet, supplemented with a Phe-free/low-Phe protein substitute. Pharmaceutical treatment with synthetic tetrahydrobiopterin (BH4), an enzyme cofactor, allows a patient subgroup to relax their diet. However, dietary protocols guiding the adjustments of protein equivalent intake from protein substitute with BH4 treatment are lacking. We systematically reviewed protein substitute usage with long-term BH4 therapy. Electronic databases were searched for articles published between January 2000 and March 2020. Eighteen studies (306 PKU patients) were eligible. Meta-analyses demonstrated a significant increase in Phe and natural protein intakes and a significant decrease in protein equivalent intake from protein substitute with cofactor therapy. Protein substitute could be discontinued in 51% of responsive patients, but was still required in 49%, despite improvement in Phe tolerance. Normal growth was maintained, but micronutrient deficiency was observed with BH4 treatment. A systematic protocol to increase natural protein intake while reducing protein substitute dose should be followed to ensure protein and micronutrient requirements are met and sustained. We propose recommendations to guide healthcare professionals when adjusting dietary prescriptions of PKU patients on BH4. Studies investigating new therapeutic options in PKU should systematically collect data on protein substitute and natural protein intakes, as well as other nutritional factors.

Keywords: BH4; PKU; amino acid mixture; hyperphenylalaninemia; medical formula; phenylalanine hydroxylase deficiency; protein substitute; sapropterin; tetrahydrobiopterin.

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Conflict of interest statement

F.I. and E.K. declare no conflict of interest. A.P. has received an educational grant from Cambrooke Therapeutics and grants from Vitaflo, Danone Nutricia, Merck Serono, Biomarin, and Mevalia to attend scientific meetings. C.R. has received honoraria from Danone Nutricia, MetaX, Schär, Biomarin, and Vitaflo. H.G.-Ö. is a member of the European nutrition expert panel (Biomarin) and she is on the scientific advisory board of Danone Nutricia Metabolics Turkey. R.S. has served on the global medical advisory board for Danone Nutricia and Biomarin. A.M. has received research funding and honoraria from Danone Nutricia, Vitaflo International, Biomarin, MetaX, Applied Pharma Research, and Merck Serono; she is a member of the advisory board for Danone Nutricia, Arla, and Applied Pharma Research. C.M. and M.K. are Danone Nutricia Research employees.

Figures

Figure 1
Figure 1
Study selection process according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flow chart.
Figure 2
Figure 2
Standardized change in phenylalanine intake of long-term responders on BH4 treatment. Means and SDs before/after BH4 are milligram phenylalanine per kilogram bodyweight per day for Belanger-Quintana (2005), Singh (2010), and Aldámiz-Echevarría (2015), and milligram per day for all other studies. Abbreviations: BH4, tetrahydrobiopterin; CI: confidence interval; n: sample size; SD: standard deviation; SMD, standardized mean difference.
Figure 3
Figure 3
Standardized change in natural protein intake of long-term responders on BH4 treatment. Means and SDs before/after BH4 are gram natural protein per day for Demirdas (2013), and gram per kilogram bodyweight per day for all other studies. Abbreviations: BH4, tetrahydrobiopterin; CI: confidence interval; n: sample size; SD: standard deviation; SMD, standardized mean difference.
Figure 4
Figure 4
Standardized change in protein equivalent intake from protein substitute of long-term responders on BH4 treatment. Means and SDs before/after BH4 are gram protein equivalent per day for Lambruschini (2005) and Singh (2011), and gram per kilogram bodyweight per day for all other studies. Abbreviations: BH4, tetrahydrobiopterin; CI: confidence interval; n: sample size; SD: standard deviation; SMD, standardized mean difference.
Figure 5
Figure 5
Standardized change in total protein intake of long-term responders on BH4 treatment. Means and SDs before/after BH4 are gram total protein per day for Feldmann (2017), and gram per kilogram per day for all other studies. Abbreviations: BH4, tetrahydrobiopterin; CI: confidence interval; n: sample size; SD: standard deviation; SMD, standardized mean difference.
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