Infants with Tyrosinemia Type 1: Should phenylalanine be supplemented?

Abstract

Tyrosinemia type 1 (HT1) is an inborn error of tyrosine catabolism caused by fumarylacetoacetase deficiency. Biochemically, this results in accumulation of toxic metabolites including succinylacetone. Clinically, HT1 is characterized by severe liver, kidney, and neurological problems. Treatment with NTBC and dietary restriction of tyrosine and phenylalanine have strongly improved outcome, but impaired neurocognitive development has been reported. Whether impaired neurocognitive outcome results from high blood tyrosine or low blood phenylalanine concentrations is currently unknown. In this report, two HT1 newborns, diagnosed by neonatal screening, are presented. The first patient showed low phenylalanine concentrations, growth retardation, neurological impairments, and skin problems, clearly improving after institution of phenylalanine supplementation (~30 mg/kg/day) at age 6 months, while both blood phenylalanine and tyrosine concentrations increased. In the second patient, phenylalanine supplementation (~20 mg/kg/day) was initiated as soon as low phenylalanine concentrations were observed at age 19 days. On this regimen, blood phenylalanine concentrations increased, and hypophenylalaninemia was less frequently observed than in the first patient, whereas blood tyrosine concentrations tended to increase. Clinically, no growth, neurological, or skin problems have been observed. The combination of knowledge obtained from these cases suggests that hypophenylalaninemia rather than hypertyrosinemia during the first months of life may impair neurocognitive development in young HT1 infants. Phenylalanine supplementation should really be considered in HT1 patients with consistently low blood phenylalanine concentrations during the first months of life. However, the minimal phenylalanine concentrations acceptable and the optimal phenylalanine supplementation regimen require further investigation.

Competing interests: None declared

Appendices

Take-Home Message

Phenylalanine supplementation should really be considered in HT1 patients with consistently low blood phenylalanine concentrations during the first months of life.

Compliance with Ethical Guidelines

Conflicts of Interest

Esther van Dam has received advisory board fees from Merck Serono.

Margreet van Rijn has received research grants, consultancy fees, and advisory board fees from Merck Serono and Nutricia Research; speaker’s honoraria from Merck Serono, Nutricia Research, and Orphan Europe; and expert testimony fees from Merck Serono.

Terry G.J. Derks has received research grants from Sigma Tau and Vitaflo and speaker’s honoraria form Nutricia and Vitaflo.

Francjan J. van Spronsen has received research grants, advisory board fees, and/or speaker’s honoraria from Merck Serono, Merck (the Netherlands), Nutricia Research, and Vitaflo.

Danique van Vliet, Gineke Liefaard-Venema, Marrit M. Hitzert, Roelineke J. Lunsing, and M. Rebecca Heiner-Fokkema declare that they have no conflicts of interest.

Informed Consent

All procedures followed were in accordance with the Helsinki Declaration of 1975, as revised in 2000. This study was waived from approval from the responsible committee on human experimentation. Informed consent was obtained from all patients for which identifying information is included in this article.

Details of the Contributions of the Authors

Danique van Vliet drafted the initial manuscript, revised the manuscript, and approved the final manuscript as submitted.

Esther van Dam performed the dietary follow-up of the second patient, drafted the initial manuscript, and approved the final manuscript as submitted.

Margreet van Rijn performed the dietary follow-up of both patients, critically reviewed the manuscript, and approved the final manuscript as submitted.

Terry G.J. Derks performed the treatment and monitoring of both patients, cowrote the manuscript, and approved the final manuscript as submitted.

Gineke Venema-Liefaard performed the dietary follow-up of the first patient, critically reviewed the manuscript, and approved the final manuscript as submitted.

Marrit M. Hitzert performed assessment of spontaneous motor repertoire in patient 2, critically reviewed the manuscript, and approved the final manuscript as submitted. Roelineke J. Lunsing performed was responsible for neurological follow-up of both patients, critically reviewed the manuscript, and approved the final manuscript as submitted.

M. Rebecca Heiner-Fokkema was responsible for the biochemical analyses, critically reviewed the manuscript, and approved the final manuscript as submitted.

Francjan J. van Spronsen was responsible for the diagnosis of HT1, performed the treatment and monitoring of both patients, cowrote the manuscript, and approved the final manuscript as submitted.