International best practice for the evaluation of responsiveness to sapropterin dihydrochloride in patients with phenylketonuria

Ania C. Muntau, Darius J. Adams, Amaya Bélanger-Quintana, Tatiana V. Bushueva, Roberto Cerone, Yin Hsiu Chien, Ana Chiesa, Turgay Coşkun, Javier de las Heras, François Feillet, Rachel Katz, Florian Lagler, Flavia Piazzon, Fran Rohr, Francjan J. van Spronsen, Paula Vargas, Gisela Wilcox, Kaustuv Bhattacharya

Research output: Contribution to journalReview article

3 Citations (Scopus)

Abstract

Phenylketonuria (PKU) is an inherited metabolic disease caused by phenylalanine hydroxylase (PAH) deficiency. As the resulting high blood phenylalanine (Phe) concentration can have detrimental effects on brain development and function, international guidelines recommend lifelong control of blood Phe concentration with dietary and/or medical therapy. Sapropterin dihydrochloride is a synthetic preparation of tetrahydrobiopterin (6R-BH4), the naturally occurring cofactor of PAH. It acts as a pharmacological chaperone, reducing blood Phe concentration and increasing dietary Phe tolerance in BH4-responsive patients with PAH deficiency. Protocols to establish responsiveness to sapropterin dihydrochloride vary widely. Two meetings were held with an international panel of clinical experts in PKU management to develop recommendations for sapropterin dihydrochloride response testing. At the first meeting, regional differences and similarities in testing practices were discussed based on guidelines, a literature review, outcomes of a global physician survey, and case reports. Statements developed based on the discussions were sent to all participants for consensus (>70% of participants) evaluation using a 7-level rating system, and further discussed during the second meeting. The experts recommend sapropterin dihydrochloride response testing in patients with untreated blood Phe concentrations of 360–2000 μmol/L, except in those with two null mutations. For neonates, a 24-h sapropterin dihydrochloride loading test is recommended; responsiveness is defined as a decrease in blood Phe ≥30%. For older infants, children, adolescents, and adults, a test duration of ≥48 h or a 4-week trial is recommended. The main endpoint for a 48-h to 7-day trial is a decrease in blood Phe, while improved Phe tolerance is the endpoint to be assessed during a longer trial. Longer trials may not be feasible in some locations due to lack of reimbursement for hospitalization, while a 4-week trial may not be possible due to limited access to sapropterin dihydrochloride or public health regulation. A 48-h response test should be considered in pregnant patients who cannot achieve blood Phe ≤360 μmol/L with a Phe-restricted diet. Durability of response and clinical benefits of sapropterin dihydrochloride should be assessed over the long term. Harmonization of protocols is expected to improve identification of responders and comparability of test results worldwide.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalMolecular Genetics and Metabolism
Volume127
Issue number1
DOIs
StatePublished - May 2019

Fingerprint

Phenylketonurias
Phenylalanine
Practice Guidelines
Blood
Phenylalanine Hydroxylase
Testing
sapropterin
Guidelines
Metabolic Diseases
Public health
Nutrition
Brain
Durability
Hospitalization
Public Health
Newborn Infant
Pharmacology
Diet
Physicians
Mutation

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

Cite this

Muntau, Ania C. ; Adams, Darius J. ; Bélanger-Quintana, Amaya ; Bushueva, Tatiana V. ; Cerone, Roberto ; Chien, Yin Hsiu ; Chiesa, Ana ; Coşkun, Turgay ; de las Heras, Javier ; Feillet, François ; Katz, Rachel ; Lagler, Florian ; Piazzon, Flavia ; Rohr, Fran ; van Spronsen, Francjan J. ; Vargas, Paula ; Wilcox, Gisela ; Bhattacharya, Kaustuv. / International best practice for the evaluation of responsiveness to sapropterin dihydrochloride in patients with phenylketonuria. In: Molecular Genetics and Metabolism. 2019 ; Vol. 127, No. 1. pp. 1-11.
@article{aa655ff4b49f454d90d4153ee2d61576,
title = "International best practice for the evaluation of responsiveness to sapropterin dihydrochloride in patients with phenylketonuria",
abstract = "Phenylketonuria (PKU) is an inherited metabolic disease caused by phenylalanine hydroxylase (PAH) deficiency. As the resulting high blood phenylalanine (Phe) concentration can have detrimental effects on brain development and function, international guidelines recommend lifelong control of blood Phe concentration with dietary and/or medical therapy. Sapropterin dihydrochloride is a synthetic preparation of tetrahydrobiopterin (6R-BH4), the naturally occurring cofactor of PAH. It acts as a pharmacological chaperone, reducing blood Phe concentration and increasing dietary Phe tolerance in BH4-responsive patients with PAH deficiency. Protocols to establish responsiveness to sapropterin dihydrochloride vary widely. Two meetings were held with an international panel of clinical experts in PKU management to develop recommendations for sapropterin dihydrochloride response testing. At the first meeting, regional differences and similarities in testing practices were discussed based on guidelines, a literature review, outcomes of a global physician survey, and case reports. Statements developed based on the discussions were sent to all participants for consensus (>70{\%} of participants) evaluation using a 7-level rating system, and further discussed during the second meeting. The experts recommend sapropterin dihydrochloride response testing in patients with untreated blood Phe concentrations of 360–2000 μmol/L, except in those with two null mutations. For neonates, a 24-h sapropterin dihydrochloride loading test is recommended; responsiveness is defined as a decrease in blood Phe ≥30{\%}. For older infants, children, adolescents, and adults, a test duration of ≥48 h or a 4-week trial is recommended. The main endpoint for a 48-h to 7-day trial is a decrease in blood Phe, while improved Phe tolerance is the endpoint to be assessed during a longer trial. Longer trials may not be feasible in some locations due to lack of reimbursement for hospitalization, while a 4-week trial may not be possible due to limited access to sapropterin dihydrochloride or public health regulation. A 48-h response test should be considered in pregnant patients who cannot achieve blood Phe ≤360 μmol/L with a Phe-restricted diet. Durability of response and clinical benefits of sapropterin dihydrochloride should be assessed over the long term. Harmonization of protocols is expected to improve identification of responders and comparability of test results worldwide.",
author = "Muntau, {Ania C.} and Adams, {Darius J.} and Amaya B{\'e}langer-Quintana and Bushueva, {Tatiana V.} and Roberto Cerone and Chien, {Yin Hsiu} and Ana Chiesa and Turgay Coşkun and {de las Heras}, Javier and Fran{\cc}ois Feillet and Rachel Katz and Florian Lagler and Flavia Piazzon and Fran Rohr and {van Spronsen}, {Francjan J.} and Paula Vargas and Gisela Wilcox and Kaustuv Bhattacharya",
year = "2019",
month = "5",
doi = "10.1016/j.ymgme.2019.04.004",
language = "English (US)",
volume = "127",
pages = "1--11",
journal = "Molecular Genetics and Metabolism",
issn = "1096-7192",
publisher = "Academic Press Inc.",
number = "1",

}

Muntau, AC, Adams, DJ, Bélanger-Quintana, A, Bushueva, TV, Cerone, R, Chien, YH, Chiesa, A, Coşkun, T, de las Heras, J, Feillet, F, Katz, R, Lagler, F, Piazzon, F, Rohr, F, van Spronsen, FJ, Vargas, P, Wilcox, G & Bhattacharya, K 2019, 'International best practice for the evaluation of responsiveness to sapropterin dihydrochloride in patients with phenylketonuria', Molecular Genetics and Metabolism, vol. 127, no. 1, pp. 1-11. https://doi.org/10.1016/j.ymgme.2019.04.004

International best practice for the evaluation of responsiveness to sapropterin dihydrochloride in patients with phenylketonuria. / Muntau, Ania C.; Adams, Darius J.; Bélanger-Quintana, Amaya; Bushueva, Tatiana V.; Cerone, Roberto; Chien, Yin Hsiu; Chiesa, Ana; Coşkun, Turgay; de las Heras, Javier; Feillet, François; Katz, Rachel; Lagler, Florian; Piazzon, Flavia; Rohr, Fran; van Spronsen, Francjan J.; Vargas, Paula; Wilcox, Gisela; Bhattacharya, Kaustuv.

In: Molecular Genetics and Metabolism, Vol. 127, No. 1, 05.2019, p. 1-11.

Research output: Contribution to journalReview article

TY - JOUR

T1 - International best practice for the evaluation of responsiveness to sapropterin dihydrochloride in patients with phenylketonuria

AU - Muntau, Ania C.

AU - Adams, Darius J.

AU - Bélanger-Quintana, Amaya

AU - Bushueva, Tatiana V.

AU - Cerone, Roberto

AU - Chien, Yin Hsiu

AU - Chiesa, Ana

AU - Coşkun, Turgay

AU - de las Heras, Javier

AU - Feillet, François

AU - Katz, Rachel

AU - Lagler, Florian

AU - Piazzon, Flavia

AU - Rohr, Fran

AU - van Spronsen, Francjan J.

AU - Vargas, Paula

AU - Wilcox, Gisela

AU - Bhattacharya, Kaustuv

PY - 2019/5

Y1 - 2019/5

N2 - Phenylketonuria (PKU) is an inherited metabolic disease caused by phenylalanine hydroxylase (PAH) deficiency. As the resulting high blood phenylalanine (Phe) concentration can have detrimental effects on brain development and function, international guidelines recommend lifelong control of blood Phe concentration with dietary and/or medical therapy. Sapropterin dihydrochloride is a synthetic preparation of tetrahydrobiopterin (6R-BH4), the naturally occurring cofactor of PAH. It acts as a pharmacological chaperone, reducing blood Phe concentration and increasing dietary Phe tolerance in BH4-responsive patients with PAH deficiency. Protocols to establish responsiveness to sapropterin dihydrochloride vary widely. Two meetings were held with an international panel of clinical experts in PKU management to develop recommendations for sapropterin dihydrochloride response testing. At the first meeting, regional differences and similarities in testing practices were discussed based on guidelines, a literature review, outcomes of a global physician survey, and case reports. Statements developed based on the discussions were sent to all participants for consensus (>70% of participants) evaluation using a 7-level rating system, and further discussed during the second meeting. The experts recommend sapropterin dihydrochloride response testing in patients with untreated blood Phe concentrations of 360–2000 μmol/L, except in those with two null mutations. For neonates, a 24-h sapropterin dihydrochloride loading test is recommended; responsiveness is defined as a decrease in blood Phe ≥30%. For older infants, children, adolescents, and adults, a test duration of ≥48 h or a 4-week trial is recommended. The main endpoint for a 48-h to 7-day trial is a decrease in blood Phe, while improved Phe tolerance is the endpoint to be assessed during a longer trial. Longer trials may not be feasible in some locations due to lack of reimbursement for hospitalization, while a 4-week trial may not be possible due to limited access to sapropterin dihydrochloride or public health regulation. A 48-h response test should be considered in pregnant patients who cannot achieve blood Phe ≤360 μmol/L with a Phe-restricted diet. Durability of response and clinical benefits of sapropterin dihydrochloride should be assessed over the long term. Harmonization of protocols is expected to improve identification of responders and comparability of test results worldwide.

AB - Phenylketonuria (PKU) is an inherited metabolic disease caused by phenylalanine hydroxylase (PAH) deficiency. As the resulting high blood phenylalanine (Phe) concentration can have detrimental effects on brain development and function, international guidelines recommend lifelong control of blood Phe concentration with dietary and/or medical therapy. Sapropterin dihydrochloride is a synthetic preparation of tetrahydrobiopterin (6R-BH4), the naturally occurring cofactor of PAH. It acts as a pharmacological chaperone, reducing blood Phe concentration and increasing dietary Phe tolerance in BH4-responsive patients with PAH deficiency. Protocols to establish responsiveness to sapropterin dihydrochloride vary widely. Two meetings were held with an international panel of clinical experts in PKU management to develop recommendations for sapropterin dihydrochloride response testing. At the first meeting, regional differences and similarities in testing practices were discussed based on guidelines, a literature review, outcomes of a global physician survey, and case reports. Statements developed based on the discussions were sent to all participants for consensus (>70% of participants) evaluation using a 7-level rating system, and further discussed during the second meeting. The experts recommend sapropterin dihydrochloride response testing in patients with untreated blood Phe concentrations of 360–2000 μmol/L, except in those with two null mutations. For neonates, a 24-h sapropterin dihydrochloride loading test is recommended; responsiveness is defined as a decrease in blood Phe ≥30%. For older infants, children, adolescents, and adults, a test duration of ≥48 h or a 4-week trial is recommended. The main endpoint for a 48-h to 7-day trial is a decrease in blood Phe, while improved Phe tolerance is the endpoint to be assessed during a longer trial. Longer trials may not be feasible in some locations due to lack of reimbursement for hospitalization, while a 4-week trial may not be possible due to limited access to sapropterin dihydrochloride or public health regulation. A 48-h response test should be considered in pregnant patients who cannot achieve blood Phe ≤360 μmol/L with a Phe-restricted diet. Durability of response and clinical benefits of sapropterin dihydrochloride should be assessed over the long term. Harmonization of protocols is expected to improve identification of responders and comparability of test results worldwide.

UR - http://www.scopus.com/inward/record.url?scp=85065585702&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065585702&partnerID=8YFLogxK

U2 - 10.1016/j.ymgme.2019.04.004

DO - 10.1016/j.ymgme.2019.04.004

M3 - Review article

C2 - 31103398

AN - SCOPUS:85065585702

VL - 127

SP - 1

EP - 11

JO - Molecular Genetics and Metabolism

JF - Molecular Genetics and Metabolism

SN - 1096-7192

IS - 1

ER -