Phenylketonuria: reduced tyrosine brain influx relates to reduced cerebral protein synthesis

Orphanet Journal of Rare Diseases

Francjan J van Spronsen¹  Pieter JJ Sauer¹  Anne MJ Paans²  Harold W de Valk³  Dirk-Jan Reijngoud¹  Marieke Hoeksma⁴  Martijn J de Groot⁴ 

[1] Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands;Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands;Department of Internal Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands;Laboratory of Metabolic Diseases, Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

关键词: Positron emission tomography;    Cerebral protein synthesis;    Blood–brain barrier;    Tyrosine;    Phenylalanine;    Phenylketonuria;   

Others  :  863575
DOI  :  10.1186/1750-1172-8-133

 received in 2013-05-10, accepted in 2013-08-21,  发布年份 2013

【 摘 要 】

Background

In phenylketonuria (PKU), elevated blood phenylalanine (Phe) concentrations are considered to impair transport of large neutral amino acids (LNAAs) from blood to brain. This impairment is believed to underlie cognitive deficits in PKU via different mechanisms, including reduced cerebral protein synthesis. In this study, we investigated the hypothesis that impaired LNAA influx relates to reduced cerebral protein synthesis.

Methods

Using positron emission tomography, L-[1-¹¹C]-tyrosine (¹¹C-Tyr) brain influx and incorporation into cerebral protein were studied in 16 PKU patients (median age 24, range 16 – 47 years), most of whom were early and continuously treated. Data were analyzed by regression analyses, using either ¹¹C-Tyr brain influx or ¹¹C-Tyr cerebral protein incorporation as outcome variable. Predictor variables were baseline plasma Phe concentration, Phe tolerance, age, and ¹¹C-Tyr brain efflux. For the modelling of cerebral protein incorporation, ¹¹C-Tyr brain influx was added as a predictor variable.

Results

¹¹C-Tyr brain influx was inversely associated with plasma Phe concentrations (median 512, range 233 – 1362 μmol/L; delta adjusted R²=0.571, p=0.013). In addition, ¹¹C-Tyr brain influx was positively associated with ¹¹C-Tyr brain efflux (delta adjusted R²=0.098, p=0.041). Cerebral protein incorporation was positively associated with ¹¹C-Tyr brain influx (adjusted R²=0.567, p<0.001). All additional associations between predictor and outcome variables were statistically nonsignificant.

Conclusions

Our data favour the hypothesis that an elevated concentration of Phe in blood reduces cerebral protein synthesis by impairing LNAA transport from blood to brain. Considering the importance of cerebral protein synthesis for adequate brain development and functioning, our results support the notion that PKU treatment be continued in adulthood. Future studies investigating the effects of impaired LNAA transport on cerebral protein synthesis in more detail are indicated.

【 授权许可】

   
2013 de Groot et al.; licensee BioMed Central Ltd.

【 图 表 】

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