Journal of Inherited Metabolic Disease

, Volume 33, Issue 6, pp 649–658 | Cite as

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

Review

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.

Abbreviations

PKU

Phenylketonuria

PAH

Phenylalanine hydroxylase

BH4

Tetrahydrobiopterin

ER

Endoplasmic reticulum

ERAD

Endoplasmic reticulum associated degradation

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Copyright information

© SSIEM and Springer 2010

Authors and Affiliations

  1. 1.Dr. von Hauner Children’s Hospital, Department of Molecular PediatricsLudwig Maximilians UniversityMunichGermany

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