Phenylketonuria (PKU) is an autosomal recessive disorder resulting from defects in the metabolism of phenylalanine. PKU is a hyperphenylalaninemia with mutlifactorial causes. There are several hyperphenylalaninemias that are not PKU and are called non-PKU hyperphenylalaninemias (HPAs). Hyperphenylalaninemia is defined as a plasma phenylalanine concentration >120μM. PKU is characterized by plasma phenylalanine >1000μM and non-PKU hyperphenylalaninemias have plasma phenylalanine amounts that are <1000μM. PKU is caused by mutation in the phenylalanine hydroxylase gene (gene symbol: PAH). The HPAs are disorders of phenylalanine hydroxylation. Because the reaction catalyzed by PAH involves tetrahydrobiopterin (BH4) as a co-factor, the HPAs can result from defects in any of the several genes required for synthesis and recycling of BH4. Removal of excess phenylalanine normally proceeds via the tyrosine biosynthesis reaction and then via tyrosine catabolism. The first reaction in this process is the PAH catalyzed hydroxylation of phenylalanine.
The PAH gene spans 170 kb located on chromosome 12q23.2 and is composed of 13 exons that encode a 452 amino acid protein. The 5'-untranslated region contains numerous cis-acting and trans-acting regulatory elements. There are many RFLPs and SNPs associated with the PAH gene (for an explanation of RFLPs and SNPs see the Molecular Medicine page). Several hundred disease-causing mutations have been identified in the PAH gene, a complete list can be found at the PAHdb web site.
The non-PKU HPAs can result from any defect in phenylalanine hydroxylation. Many are the result of defects in the metabolism of the BH4 co-factor of PAH. During the PAH catalyzed reaction BH4 is converted to 4α-hydroxytetrahydrobiopterin. The regeneration of BH4 is catalyzed by reactions that involve 4α-carbinolamine dehydratase and dihydropteridine reductase (DHPR). In addition to these latter two enzymes, BH4 can be synthesized in a pathway that requires guanosine triphosphate cyclohydrolase, 6-pyruvoyltetrahydrobiopterin synthase, and sepiapterin reductase. A deficiency in any of the five enzymes will lead to defects in phenylalanine hydroxylation and consequently hyperphenylalaninemia. Because BH4 is involved in additional hydroxylation reactions, notably tryptophan and tyrosine in the brain in the formation of serotonin and the catecholamines, respectively, it is important to correctly diagnose any HPA as being the result of abnormal BH4 homeostasis or defects in PAH.
The major clinical manifestation associated with PKU and many HPAs is impaired cognitive development and function. The precise mechanism for the mental retardation associated with PKU has not been worked out but is thought to be the result of the accumulation of phenylalanine in the brain, which becomes a major donor of amino groups in aminotransferase activity and depletes neural tissue of 2-oxoglutarate (α-ketoglutarate). The absence of 2-oxoglutarate in the brain shuts down the TCA cycle and the associated production of aerobic energy, which is essential to normal brain development. Another hypothesis proposed to explain the severe mental retardation that can result in untreated PKU patients is that the accumulating phenylalanine impairs the transport of tyrosine into the brain. The reduction in brain tyrosine levels would then negatively impact the synthesis of the neurotransmitters, dopamine and norepinephrine.
The product of phenylalanine transamination, phenylpyruvic acid, is reduced to phenylacetate and phenyllactate, and all three compounds appear in the urine. The presence of phenylacetate in the urine imparts a "mousy" odor.
Currently in this country (and many others as well), newborns are routinely screened for PKU by measurement of serum phenylalanine levels. All HPAs, including PKU, occur with a frequency of 5 to 350 cases/million live births. In order to classify the phenotype of PKU into severe and less severe forms, as well as to exclude BH4-deficient HPAs, it is necessary to measure the plasma, urine, and cerebrospinal fluid levels of phenylalanine, pterins and the derivatives of the neurotransmitters derived from tryptophan and tyrosine. The mainstay in treatment of PKU is the low-phenylalanine diet. Optimal treatment requires both early onset (hence the utility of the post-natal assessments in this country) and continuous treatment throughout adolescence and possibly for life. Because of the necessity for phenylalanine in protein synthesis and neurotransmitter synthesis (via conversion to tyrosine) it is important to carefully control the intake of the amino acid. Too little and developmental impairment will occur, too much and severe neurological dysfunction will result.