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

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• 作者：Martijn J de Groot (1) (2)
  Marieke Hoeksma (1) (2)
  Dirk-Jan Reijngoud (2) (3)
  Harold W de Valk (4)
  Anne MJ Paans (5)
  Pieter JJ Sauer (1) (3)
  Francjan J van Spronsen (1) (3)
  
• 关键词：Phenylketonuria ; Phenylalanine ; Tyrosine ; Blood–brain barrier ; Cerebral protein synthesis ; Positron emission tomography
• 刊名：Orphanet Journal of Rare Diseases
• 出版年：2013
• 出版时间：December 2013
• 年：2013
• 卷：8
• 期：1
• 全文大小：283KB
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• 作者单位：Martijn J de Groot (1) (2)
  Marieke Hoeksma (1) (2)
  Dirk-Jan Reijngoud (2) (3)
  Harold W de Valk (4)
  Anne MJ Paans (5)
  Pieter JJ Sauer (1) (3)
  Francjan J van Spronsen (1) (3)
  
  1. Department of Metabolic Diseases, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
  2. Laboratory of Metabolic Diseases, Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
  3. Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
  4. Department of Internal Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
  5. Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
  

文摘

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.