Phenylketonuria (PKU) Disease

Study Notes

PKU is a rare metabolic disease caused by the accumulation of phenylalanine (Phe) to toxic levels in the blood and brain, leading to severe brain disorders.
Phe is an essential amino acid, necessary for life, but it cannot be produced by the body and must be acquired through protein-rich foods.

In normal individuals, the enzyme phenylalanine hydroxylase converts Phe to tyrosine, which is then used to produce neurotransmitters essential for brain development and function.

PKU is caused by a genetic mutation affecting the phenylalanine hydroxylase enzyme, located on chromosome 12.
Over 600 mutations have been described, leading to varying degrees of enzyme function.

Elevated Phe levels and reduced tyrosine levels can alter brain function by:
- Occupying transporters, making it difficult for tyrosine and tryptophan to cross the blood-brain barrier
- Reducing dopamine, norepinephrine, and serotonin levels, leading to abnormal brain development and intellectual disability

Newborn screening is typically done 24 hours after birth, measuring blood Phe levels through a simple laboratory test.
If the screening test shows high Phe levels and low blood tyrosine, a different method is used to confirm the diagnosis.

First-line therapy for PKU is a low Phe diet, including:
- Medical foods such as low or no Phe medical formulas and modified foods
- Elimination of high protein foods like meat, fish, eggs, and dairy
- Customized Phe intake with medical professionals according to individual needs
Two FDA-approved pharmaceutical treatments are available:
- Kuvan, a cofactor for phenylalanine hydroxylase, which helps improve the patient's innate PAH enzyme activity and increase Phe tolerance
- Palynziq, an enzyme that metabolizes Phe, substituting for the defective phenylalanine hydroxylase enzyme, and can be used in adults with PKU