Abstract
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.
Highlights
First described in 1934 by Abjörn Fölling, phenylketonuria (PKU; OMIM # 261600) is an autosomal recessive inborn error of L-phenylalanine (Phe) metabolism
Phenylketonuric patients present with high Phe concentrations in their tissues and hyperphenylalaninemia (HPA) due to total or partial deficiency of phenylalanine hydroxylase (PAH; EC # 1.14.16.1) activity, as well as low tyrosine (Tyr) concentrations [1]
It has been demonstrated that the brain tissue is vulnerable to oxidative stress due to high O2 consumption, high tissue concentrations of iron, low level of antioxidant defenses, the presence of excitatory amino acids and dopamine metabolism, which generate hydrogen peroxide [22]
Summary
The main findings presented by phenylketonuric patients are severe neurological damage, including corpus callosum, striatum, and cortical alterations and hypomyelination, that result in intellectual deficit and neurodegeneration [18,19,20,21]. The pathophysiology underlying the brain damage is not well understood yet. The main hypothesis is that Phe and its metabolites act as neurotoxins in the brain. Some pathomechanisms involving metabolic alterations are proposed and will be discussed below
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