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Hyperphenylalaninemias are enzymopathies (enzyme inactivity) and aminoacidopathies (inappropriate amino acid processing) that lead to an increase in phenylalanine blood levels due to improper pheylalanine catabolism.

They are all autosomal recessive and exemplified by phenylketonuria and phenylalanine hydroxylase deficiency. All hyperphenylalaninemias stem from loss of function in phenylalanine hydroxylase (PAH or PheH, a liver enzyme which catabolizes phenylalanine to tryosine) and/or genes required to synthesize its cofactor, tetrahydrobiopterin (BH4).

Classic phenylketonuria (PKU) stems from an autosomal recessive PAH mutation that renders it inactive.

Unable to degrade phenylalanine, PKU patients accumulate phenylalanine in their body fluids and the ensuing hyperphenylalaninemia damages the developing nervous system and mature brain. It is treated by complete diet restriction of phenylalanine; if no phenylalanine is ingested, then it cannot accumulate in the body. Phenylalanine hydroxylase variants are frequently benign, with many people being heterozygous at the gene encoding PAH.

The few clinically significant PAH alleles can lead to near-complete loss of PAH activity (classic PKU) or variant PKU (aka non-PKU hyperphenylalaninemia). Variant PKU occurs when PAH carries enough residual activity to lessen the disease phenotype, or prevent the disease despite elevated phenylalanine blood levels.

Rarely, a patient with hyperphenylalaninemia will have normal PAH but be unable to properly synthesize or recycle its cofactor, tetrahydrobiopterin (BH4).

Since BH4 is necessary for the activity of other enzymes, phenylalanine restriction alone will not fully treat the patient. Fortunately, normal BH4 can be administered in large oral doses that allow normal development and even unrestricted consumption of phenylalanine. In addition, BH4 administration can help lower phenylalanine blood levels in patients whose PAH has a weak BH4 affinity.

Hyperphenylalaninemias lead to mental retardation due to an imbalance of amino acids crossing the blood brain barrier.

With too much phenylalanine in the bloodstream, other amino acids are outcompeted and their levels in the brain significantly decrease. This decrease in brain levels of other amino acids leads to disruption of brain development and, to a lesser extent, mature brain function. Patients with PKU are allowed slight flexibility in their diet during adulthood, as elevated phenylalanine blood levels will not have as detrimental an effect after development.

However, elevated phenylalanine levels are detrimental for fetal life. Thus, females with hyperphenylalaninemia expecting to conceive must vigorously restrict their phenylalanine consumption to avoid severe developmental retardation in their offspring.