Abstract
Genotyping of the phenylalanine hydroxylase (PAH) gene offers a new tool for characterizing patients with phenylketonuria (PKU), refining the diagnosis and aiding in the prediction of the clinical outcome and in the implementation of a more adequate treatment. The primary goal of this work was the detailed study of the different allele combinations and the metabolic phenotypes in Spanish PKU patients in order to understand better the clinical heterogeneity of PAH deficiency in our population. The results show that the disease phenotype is a consequence of a combination of mutations at the PAH locus and this observation is valid throughout the spectrum of clinical and biochemical varieties found in Spanish PKU patients. A stronger correlation was found between the predicted residual activity, when known from previous in vitro studies of the mutant proteins, and the Phe tolerance than between the predicted residual activity and the inverse of Phe levels at diagnosis. The observed genotype-phenotype correlations and the available data on the in vitro residual activity of the mutant proteins has enabled the estimation of the severity of most of the mutations found in Spain. This study includes relevant data for clinicians and pediatricians adding to the present knowledge which relates allelic PAH genotypes to biological phenotypes.
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Acknowledgements
The authors wish to thank A. Sánchez for her excellent technical assistance and L. Pérez for her help with the statistical analysis. This work was supported by a grant from the Comunidad Autonoma de Madrid (Acción Coordinada 010). The institutional grant of ‘Fundación Ramón Areces’ to the Centro de Biología Molecular ‘Severo Ochoa’ is gratefully acknowledged.
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Desviat, L.R., Pérez, B., García, M.J. et al. Relationship between Mutation Genotype and Biochemical Phenotype in a Heterogeneous Spanish Phenylketonuria Population. Eur J Hum Genet 5, 196–202 (1997). https://doi.org/10.1007/BF03405917
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DOI: https://doi.org/10.1007/BF03405917
