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Phenylketonuria as a model for protein misfolding diseases and for the development of next generation orphan drugs for patients with inborn errors of metabolism

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Journal of Inherited Metabolic Disease

Abstract

The lecture dedicated to Professor Horst Bickel describes the advances, successes, and opportunities concerning the understanding of the biochemical and molecular basis of phenylketonuria and the innovative treatment strategies introduced for these patients during the last 60 years. These concepts were transferred to other inborn errors of metabolism and led to significant reduction in morbidity and to an improvement in quality of life. Important milestones were the successful development of a low-phenylalanine diet for phenylketonuria patients, the recognition of tetrahydrobiopterin as an option to treat these individuals pharmacologically, and finally market approval of this drug. The work related to the discovery of a pharmacological treatment led metabolic researchers and pediatricians to new insights into the molecular processes linked to mutations in the phenylalanine hydroxylase gene at the cellular and structural level. Again, phenylketonuria became a prototype disorder for a previously underestimated but now rapidly expanding group of diseases: protein misfolding disorders with loss of function. Due to potential general biological mechanisms underlying these disorders, the door may soon open to a systematic development of a new class of pharmaceutical products. These pharmacological chaperones are likely to correct misfolding of proteins involved in numerous genetic and nongenetic diseases.

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Abbreviations

PKU:

Phenylketonuria

PAH:

Phenylalanine hydroxylase

BH4 :

Tetrahydrobiopterin

ER:

Endoplasmic reticulum

ERAD:

Endoplasmic reticulum associated degradation

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Acknowledgments

We wish to thank our patients and their families. We are grateful to Anita MacDonald for linguistic revision of the manuscript. We would like to express our gratitude to all our coworkers who contributed to the ongoing research behind this work.

Details of funding

This work was supported by the Bavarian Genome Research Network, BayGene.

Competing interests

Ania C. Muntau is a member of the scientific advisory board of Merck Serono S.A., Geneva, Switzerland, regarding treatment for phenylketonuria.

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Authors and Affiliations

  1. Dr. von Hauner Children’s Hospital, Department of Molecular Pediatrics, Ludwig Maximilians University, Lindwurmstrasse 4, 80337, Munich, Germany

    Ania C. Muntau & Søren W. Gersting

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  1. Ania C. Muntau
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  2. Søren W. Gersting
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Correspondence to Ania C. Muntau.

Additional information

Communicated by: Jerry Vockley

The Bickel Memorial Lecture 2009, held on the occasion of the International SHS Symposium “Homocysteine, Folate and Cobalamin Disorders”, Fulda, Germany, November 11-13, 2009

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Muntau, A.C., Gersting, S.W. Phenylketonuria as a model for protein misfolding diseases and for the development of next generation orphan drugs for patients with inborn errors of metabolism. J Inherit Metab Dis 33, 649–658 (2010). https://doi.org/10.1007/s10545-010-9185-4

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