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Metabolic phenotypes of phenylketonuria. Kinetic and molecular evaluation of the Blaskovics protein loading test

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Summary

Background: As part of the German Collaborative Study of Children Treated for Phenylketonuria (PKU), a three-day protein loading test was applied to children at 6 months of age. This load elicits three principal types of blood phenylalanine (Phe) response, with types I and III clinically corresponding to classic PKU and mild hyperphenylalaninaemia not requiring diet (MHP), respectively. An intermediate type II, clinically corresponding to mild PKU, is characterized by early decline of blood Phe from above 1200 μmol/L down to levels between 600 and 1200 μmol/L at 72 h. Aims: Unbiased classification and kinetic and molecular characterization of the intermediate Phe response; estimation of phenotypic variability of Phe disposal.Method: A kinetic model with zero-order protein synthesis and first-order rate of metabolic disposal of Phe is applied to 157 tests. Results: A model of exponentially saturated activation describes the acceleration of Phe disposal from day 1 to 3 in the intermediate type of response. Eleven of 14 p.Y414C functional hemizygotes and two of three p.R261Q homozygotes manifested this kinetic type. The rate estimates of Phe metabolic disposal differ widely in patients with identical PAH genotype, yet are highly correlated with the Phe level at 72 h.

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Abbreviations

AV:

assigned phenotypic value according to Guldberg et al (1998)

HPA:

hyperphenylalaninaemia

K out :

first-order kinetic constant of metabolic loss/disposal

MHP:

mild hyperphenylalaninaemia

PAH:

phenylalanine hydroxylase

Phe:

phenylalanine

Phe72:

blood level of phenylalanine 72 h after start of loading (morning of day 4)

PKU:

phenylketonuria

PRA:

predicted residual activity (mean of in vitro activities, per cent of normal)

t 1/2 :

phenylalanine half-life (50% elimination time)

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Acknowledgement

The German 1978 to 1995 Collaborative Study of Children Treated for Phenylketonuria (headed until 1989 by the late Professor Horst Bickel, thereafter by Professor Hans Joachim Bremer) received financial support from Stiftung Volkswagenwerk and Bundesministerium für Forschung und Technologie (BMBF). Eight paediatric centres participated in the study: Berlin (E. Mönch), Düsseldorf (Hildegard Przyrembel, U. Wendel), Göttingen (A.W. Behbehani, W. Voss), Hamburg (P. Koepp, P. Clemens), Heidelberg (Hildgund Schmidt, P. Lutz, K. Bartholomé, F.K. Trefz), München (J. Schaub, W. Endres), Münster (H. Gröbe, K. Ullrich), and Ulm (Dorothea Leupold). Additional acknowledgements appeared 1990 in Eur J Pediatr 149(Supplement 1): S3–S4.

Thanks are due to Sylvia Koerner for excellent administrative work and data handling, and to Elfriede Quak, Rainer Bielen and Verena Wahl for expert technical assistance with genotype analysis.

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Authors and Affiliations

  1. Institute of Human Genetics, Frankfurt University Hospital, Theodor-Stern-Kai 7, D-60590, Frankfurt/Main, Germany

    U. Langenbeck

  2. Centre for Paediatric and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany

    P. Burgard & M. Lindner

  3. Children’s Hospital, University of Düsseldorf, Düsseldorf, Germany

    U. Wendel

  4. Divisions of Human Genetics and Clinical Genetics, Innsbruck Medical University, Innsbruck, Austria

    J. Zschocke

Authors
  1. U. Langenbeck
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  2. P. Burgard
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  3. U. Wendel
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  4. M. Lindner
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  5. J. Zschocke
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Consortia

German Collaborative Study on Phenylketonuria (PKU) / Hyperphenylalaninemia (HPA)

Corresponding author

Correspondence to U. Langenbeck.

Additional information

Communicating editor: Michael Gibson

Competing interests: None declared

References to electronic databases: Phenylketonuria: OMIM +261600. Phenylalanine hydroxylase: EC 1.14.16.1.

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Langenbeck, U., Burgard, P., Wendel, U. et al. Metabolic phenotypes of phenylketonuria. Kinetic and molecular evaluation of the Blaskovics protein loading test. J Inherit Metab Dis 32, 506–513 (2009). https://doi.org/10.1007/s10545-009-1152-6

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  • DOI: https://doi.org/10.1007/s10545-009-1152-6

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