Long-term Follow-up and Outcome of Phenylketonuria Patients on Sapropterin: A Retrospective Study

Author:

Keil Stefanie12,Anjema Karen3,van Spronsen Francjan J.3,Lambruschini Nilo4,Burlina Alberto5,Bélanger-Quintana Amaya6,Couce Maria L.7,Feillet Francois8,Cerone Roberto9,Lotz-Havla Amelie S.10,Muntau Ania C.10,Bosch Annet M.11,Meli Concetta A.P.12,Billette de Villemeur Thierry13,Kern Ilse14,Riva Enrica15,Giovannini Marcello15,Damaj Lena16,Leuzzi Vincenzo17,Blau Nenad11819

Affiliation:

1. University Children’s Hospital Zürich, Zurich, Switzerland;

2. Pediatrics, Children’s Hospital Regensburg, University of Regensburg, Regensburg, Germany;

3. University of Groningen, University Medical Center Groningen, Beatrix Children’s Hospital, Groningen, Netherlands;

4. Hospital Sant Joan de Déu, Barcelona, Spain;

5. Division of Inherited Metabolic Diseases, Department of Pediatrics, University Hospital Padova, Padova, Italy;

6. U Enfermedades Metabólicas, Hospital Ramón y Cajal, Madrid, Spain;

7. Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Department of Pediatrics, Hospital Clinico Universitario de Santiago de Compostela, Santiago de Compostela, Spain;

8. Reference Center for Inborn Errors of Metabolism, Vandoeuvre les Nancy, France;

9. Il Clinica Pediatrica “G. Gaslini,” Dipartimento di Pediatria Errori congeniti del Metabolismo, Universitá degli Studi di Genova, Genoa, Italy;

10. Department of Inborn Errors of Metabolism and Molecular Pediatrics, Dr von Hauner Children’s Hospital, Munich, Germany;

11. Department of Pediatrics, Emma Children’s Hospital, and Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands;

12. University Hospital, Catania, Italy;

13. Service de neuropédiatrie, Pathologie du développement, Hôpital Trousseau, and Université Pierre et Marie Curie, Paris, France;

14. Pediatric Nephrology and Metabolism, Children’s Hospital, University of Geneva, Geneva, Switzerland;

15. Ospedale San Paolo, Milan, Italy;

16. Department of Pediatrics, Teaching Hospital of Rennes, Rennes, France;

17. Department of Pediatrics, Sapienza Università, Rome, Italy;

18. University Children’s Hospital Heidelberg, Heidelberg, Germany; and

19. Research Center for Child, Zurich, Switzerland

Abstract

OBJECTIVE: Sapropterin dihydrochloride, the synthetic form of 6R-tetrahydrobiopterin (BH4), is an approved drug for the treatment of patients with BH4-responsive phenylketonuria (PKU). The purpose of this study was to assess genotypes and data on the long-term effects of BH4/sapropterin on metabolic control and patient-related outcomes in 6 large European countries. METHODS: A questionnaire was developed to assess phenotype, genotype, blood phenylalanine (Phe) levels, Phe tolerance, quality of life, mood changes, and adherence to diet in PKU patients from 16 medical centers. RESULTS: One hundred forty-seven patients, of whom 41.9% had mild hyperphenylalaninemia, 50.7% mild PKU, and 7.4% classic PKU, were followed up over ≤12 years. A total of 85 different genotypes were reported. With the exception of two splice variants, all of the most common mutations were reported to be associated with substantial residual Phe hydroxylase activity. Median Phe tolerance increased 3.9 times with BH4/sapropterin therapy, compared with dietary treatment, and median Phe blood concentrations were within the therapeutic range in all patients. Compared with diet alone, improvement in quality of life was reported in 49.6% of patients, improvement in adherence to diet was reported in 47% of patients, and improvement in adherence to treatment was reported in 63.3% of patients. No severe adverse events were reported. CONCLUSIONS: Our data document a long-term beneficial effect of orally administered BH4/sapropterin in responsive PKU patients by improving the metabolic control, increasing daily tolerance for dietary Phe intake, and for some, by improving dietary adherence and quality of life. Patient genotypes help in predicting BH4 responsiveness.

Publisher

American Academy of Pediatrics (AAP)

Subject

Pediatrics, Perinatology and Child Health

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