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Aging and disease    2015, Vol. 6 Issue (5) : 390-399     DOI: 10.14336/AD.2015.0827
Review Article |
Phenylketonuria Pathophysiology: on the Role of Metabolic Alterations
Patrícia Fernanda Schuck1,*(), Fernanda Malgarin1, José Henrique Cararo1, Fabiola Cardoso2, Emilio Luiz Streck3, Gustavo Costa Ferreira2
1 Laboratório de Erros Inatos do Metabolismo, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
2 Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
3 Laboratório de Bioenergética, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil.
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Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism caused by the deficiency of phenylalanine hydroxylase. This deficiency leads to the accumulation of Phe and its metabolites in tissues and body fluids of PKU patients. The main signs and symptoms are found in the brain but the pathophysiology of this disease is not well understood. In this context, metabolic alterations such as oxidative stress, mitochondrial dysfunction, and impaired protein and neurotransmitters synthesis have been described both in animal models and patients. This review aims to discuss the main metabolic disturbances reported in PKU and relate them with the pathophysiology of this disease. The elucidation of the pathophysiology of brain damage found in PKU patients will help to develop better therapeutic strategies to improve quality of life of patients affected by this condition.

Keywords brain      hyperphenylalaninemia      metabolic alterations      phenylalanine      phenylketonuria     
Corresponding Authors: Patrícia Fernanda Schuck     E-mail:
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present address: Kunming Biomed International, Kunming, Yunnan, 650500, China

Issue Date: 01 October 2015
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Patrícia Fernanda Schuck
Fernanda Malgarin
José Henrique Cararo
Fabiola Cardoso
Emilio Luiz Streck
Gustavo Costa Ferreira
Cite this article:   
Patrícia Fernanda Schuck,Fernanda Malgarin,José Henrique Cararo, et al. Phenylketonuria Pathophysiology: on the Role of Metabolic Alterations[J]. Aging and disease, 2015, 6(5): 390-399.
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Figure 1.  Phenylalanine metabolism. Most of phenylalanine obtained from diet or endogenous proteolysis is hydroxylated producing tyrosine by phenylalanine hydroxylase, which is deficient in PKU. Additional routes include transamination to phenylpyruvate and decarboxylation in order to synthesize phenylethylamine.
Schulpis et al., 2005PKU Patients Blood↓ TAS
↑ 8-OH-DG
Sitta et al., 2009PKU patients leucocytes; normal Individuals leukocytes↑ DNA damage index in vivo
↑ DNA damage index in vitro
Sirtori et al., 2005PKU patients plasma and erythrocytes↓ TAR, GPx
Sitta et al., 2009PKU Patients Blood↓ TAR
Sitta et al., 2009PKU patients plasma and erythrocytes↓ GSH, GPx, TAR, SH
↑ TBA-RS, protein carbonyl
Sanayama et al., 2011PKU patients plasma and erythrocytes↓ TAR, GPx, beta-carotene, Q10
↑ TBA-RS, MDA-modified LDL, CAT, SOD
Ercal et al., 2002Mice brain and red blood cells↑ MDA, G6PD, CAT
Kienzle Hagen et al., 2002Rat brain↑ chemiluminescence
Martinez-Cruz et al., 2002Rat brain and cerebellum↑ Ehrlich adducts, MDA, GSSG, HO-1
↓ GPx, GR, MAPK 1/2
Fernandes et al., 2010Rat brain↑ TBA-RS
Moraes et al., 2010Rat brain↓ CAT, SOD, GPx, G6PD, GSH, TRAP
Moraes et al., 2013Rat brain↑ TBA-RS, protein carbonyl, SOD, ROS
Deon et al., 2015Normal individuals plasma; PKU patients plasma and urine↑ DNA damage index
↑ 8-OH-DG
Simon et al., 2013Rat brain and blood↑ DNA damage index in vivo
↑ DNA damage index in vitro
Rosa et al., 2012Rat brain↓ G6PD
Table 1  Landmark studies showing oxidative stress in phenylketonuria.
Güttler and Lou, 1986PKU patients urine and CSF↓ dopamine, serotonine, HVA, 5-HIAA
Yano et al., 2013PKU patients urine and serum↓ melatonin, 6-sulfatoxymelatonin, dopamine
Pascucci et al., 2002Mouse brain↓ serotonin, Trp, 5-HT
Landvogt et al., 2007PKU patients↓ fluoro-L-dopamine uptake
Sawin et al., 2014Mouse brain↓ catecholamines, serotonin
Harding et al., 2014Mouse brain↓ TH
Justice and Hsia, 1965Mouse brain↓ 5THD
Table 2  Landmarks studies showing impaired neurotransmitter metabolism in phenylketonuria.
Figure 2.  Metabolic alterations involved in the pathophysiology of the brain damage found in phenylketonuric patients. Phenylalanine and its metabolites elicit oxidation of lipids, proteins, and DNA by increasing ROS production and decreasing antioxidant defenses. Bioenergetics is also impaired due to decreased glucose oxidation and alterations of activities of enzymes such as respiratory chain complexes, Krebs cycle enzymes, and creatine kinase. Toxic metabolites also decrease protein, neurotransmitter, and cholesterol synthesis and alter Ca2+ metabolism. ATP, adenosine triphosphate; CAT, catalase; cyt-CK, cytosolic creatine kinase; DNA, desoxiribonucleic acid; G6PD, glucose-6-phosphate dehydrogenase; GPx, glutathione peroxidase; GR, glutathione reductase; GSH, reduced glutathione; MDA, malondialdehyde, mit-CK, mitochondrial creatine kinase; PUFAS, polyunsaturated fatty acid; ROS, reactive oxygen species; SOD, superoxide dismutase.
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