Phenylketonuria (PKU) is a monogenic disease in which mutations in the gene located on chromosome 12q22-24, which encodes phenylalanine hydroxylase (PAH), cause deficite liver enzyme activity, leading to increased phenylalanine (Phe) in the blood and tissues. Accumulation of Phe at plasma and tissue levels with decreased tyrosine biosynthesis is implicated in the pathogenesis of PKU. Williams (2011) classifies PKU into a classical form in which Phe levels are above 1,200 μmol/l and a medium form in which Phe concentration is between 600-1,200 μmol/l. In newborns with PKU the serum Phe concentration at birth is within normal limits but increases in the first days of life. Some authors believe that elevated Phe and lower tyrosine values cause brain damage leading to mental retardation and seizures. In the absence of treatment the delay in cognitive development becomes evident after 6 months of age and is progressive.

The pathogenesis of cognitive dysfunction is not yet well understood. Increased blood levels of Phe allow the accumulation of a large number of metabolites in the central nervous system (CNS), with toxic effects, which cause diffuse brain damage localized mainly in the dopaminergic pathways of the dorsolateral region of the prefrontal cortex and in the white matter (4). Literature data support that excess Phe interferes with the synthesis of brain proteins involved in myelin and neurotransmitter formation. Surtees and Blau (2005) believe that impaired transport of long-chain neutral amino acids (LNAA) across the blood-brain barrier is essential in the pathogenesis of mental dysfunction in PKU patients (Fig. 1). Phenylalanine enters the brain using the long-chain amino acid transporter LAT1, in com petition with 8 other amino acids (tyrosine, tryptophan, valine, isoleucine, leucine, threonine, methionine, his ti dine). The affinity of the LAT1 transporter for Phe is high, leading to a transport rate even at only moderately elevated concentrations. Phenylalanine is preferentially transported across the blood-brain barrier in de triment of other LNAAs, resulting in increased brain concentrations of Phe and decreased brain concentrations of other LNAAs (8,9).

In patients with moderate PAH deficiency with a moderately increased Phe concentration, low neurotransmitter concentrations have been found and it has been suggested that dopamine deficiency results from being cited in the prefrontal cortex. Compared to dopamine deficiency, serotonin deficiency has a greater influence, leading to psychosocial dysfunction and impaired cognitive function. Neurobiologically, synthesis of brain proteins, especially myelin, is essential for normal brain development and function. Low concentrations of any LNAA result not only in low levels of myelin, but also of other proteins, including the brain enzymes tyrosine hydroxylase, tryptophan hydroxylase and pyruvate kinase (11).

Cognitive dysfunction in PKU patients can be explained by two hypotheses. 

• The prefrontal cortex is affected by low dopamine concentrations, a consequence of decreased availability of tyrosine, which is the precursor of the dopaminergic pathway.
• Increased Phe concentrations are due to decreased myelin biosynthesis, napsin formation and dendritic arborization. Pérez-Dueñas (2006) observed in PKU patients in whom dietary treatment was initiated early a correlation between white matter volume and serum Phe. Likewise, Vilaseca (2010) observed in 27 of the treated PKU patients changes in white and grey brain matter volume depending on strict adherence to the diet.

Mental development depends on the time of diagnosis, the early start of treatment and its continuity. Late diagnosis or lack of compliance with treatment leads to the appearance of symptoms characteristic of the disease: specific odour of skin, hair and urine, trunk hypotonia, hypertonia of the extremities, irritability, skin lesions, photosensitivity, autistic behaviour, recurrent seizures.

Inadequate metabolic control has severe consequences for neuropsychomotor development, which vary according to age. Infants with PKU exhibit mental retardation, microcephaly, seizures, behavioural disorders, growth disorders and eczemalike skin lesions. The clinical picture in children includes mental dysfunction, memory impairment, attention deficit, behavioural disorders, eczema-like skin lesions.

Adolescents with PKU have neuropsychological disorders, depression, anxiety, eczema-like skin lesions. Karimzadeh (2012) followed 105 patients diagnosed with PKU and observed the presence of hyperkinetic syndrome with attention deficit in 85.7% of patients, autistic behaviour in 57.1%, oppositional disorders in 84.2% and anxiety disorders in 74.2%. The author found a causal link between the presence of these behavioural problems and serum Phe levels.

In a 2010 study of 20 children diagnosed with the classic form of PKU and treated early, da Silva tracked their intellectual performance. The author concluded that early diagnosis combined with rigorous control of diet and Phe levels can prevent the onset of the cognitive deterioration characteristic of PKU, with the cognitive development of these children generally being within normal limits, allowing them to integrate well into society. In cases where low Phe levels are not maintained, it is noted that executive function impairments occur with repercussions on learning and social adaptation.

Gassio (2005) cognitively assessed 37 patients with PKU, noting that they all showed varying degrees of delay in mental development, problems with visual and spatial orientation, impaired executive function and attention compared to the control group, and that all these cognitive problems were directly related to the increased Phe values recorded in the first 6 years of life.

Vilaseca (2010) considers that in PKU patients the degree of intelligence is in direct correlation with dietary compliance both in the first 6 years of life and later, recommending strict continuation of dietary treatment regardless of age