Phenylketonuria (NORD)

Definitions & Key takeaways

Phenylketonuria (PKU) is an autosomal recessive amino acid metabolism disorder involving impaired metabolism of the amino acid phenylalanine, caused by the absence or reduced activity of phenylalanine hydroxylase. In PKU toxic levels of phenylalanine and phenylketone build up in the body and tyrosine levels drop.

Symptoms include a musty odor of sweat and urine, intellectual disability, seizures, behavioral problems, and other neurological symptoms. In pregnant females, PKU can affect the fetus - causing heart disease, growth problems, intellectual disability, and microcephaly. Treatment is based on a diet with low levels of phenylalanine and supplementing with tyrosine and tetrahydrobiopterin.

Watch video only
Phenylketonuria or PKU is a rare metabolic disease that can lead to severe brain disorders caused by the accumulation of the amino acid phenylalanine to toxic levels in the blood and brain.
Amino acids are the basic building blocks that make up proteins. Phenylalanine, or Phe, is one of the essential amino acids.
It is necessary for life, but our bodies can't make it; therefore, Phe must be acquired through foods that contain protein.
Normally, once Phe enters the body, most of it is converted to tyrosine by the enzyme phenylalanine hydroxylase. Tyrosine is then turned into neurotransmitters important for normal brain development and function.PKU is an autosomal recessive genetic disorder that affects function of the phenylalanine hydroxylase enzyme.
The phenylalanine hydroxylase gene is located on chromosome 12 and over 600 mutations have been described. The degree of enzyme function can vary.
When untreated, people with PKU develop symptoms such as severe intellectual disability, psychiatric disorders, and seizures.
A pregnant woman with PKU must pay special attention to her Phe levels to reduce the risk of Maternal PKU Syndrome that can result in heart defects, microcephaly, and developmental disability in her baby.In PKU, elevated Phe levels and reduced tyrosine levels can change the way the brain functions.
This is because Phe uses the same transporters to get across the blood-brain barrier as other amino acids including- tyrosine and tryptophan.
Tyrosine is needed to synthesize dopamine and norepinephrine, and tryptophan is needed to synthesize the neurotransmitter serotonin.
As Phe levels rise, it occupies all the transporters, making it hard for tyrosine and tryptophan to get across the blood-brain barrier.
As a result, dopamine, norepinephrine, and serotonin levels in the brain begin to fall, leading to abnormal brain development and intellectual disability.Testing for PKU is typically done as part of routine newborn screening approximately 24 hours after birth.
Screening is done by taking a small blood sample from a heel stick and measuring blood Phe levels by a simple laboratory test.
If the screening test shows high levels of Phe and low blood tyrosine, a different method is used to repeat the measurement of the blood amino acids and to confirm the diagnosis.First line therapy for PKU is the low Phe diet.
This includes medical foods such as low or no Phe medical formulas that are a synthetic form of protein and foods modified to be low in protein.
All high protein foods such as meat, fish, eggs, and dairy are eliminated from the diet. Measured amounts of some grains, vegetables and fruit are allowed depending upon the individual patient’s tolerance of small amounts of Phe.
Each patient will need to customize the amount of Phe dietary intake with medical professionals according to their individual needs.In addition to the low Phe diet, two FDA approved pharmaceutical treatments are now available.
Kuvan is a cofactor for phenylalanine hydroxylase which helps improve the PKU patient’s innate PAH enzyme activity and increase their Phe tolerance.
Kuvan must be used in conjunction with the low Phe diet. Palynziq can be used in adults with PKU.
Palynziq is an enzyme, injected under the skin every day by the patient that circulates in the blood, metabolizing Phe, and substitutes for the defective phenylalanine hydroxylase enzyme.
Palynziq works well for many adult PKU patients, but can have serious side effects in some patients.All right, as a quick recap – in PKU, Phe levels build up and tyrosine levels drop.
Symptoms in untreated individuals include seizures and severe developmental delay. In the US and much of the developed world, newborns are routinely screened for PKU.
Treatment initiated soon after birth is based on a diet low in Phe that requires the use of an amino acid-based medical food (formula), severe restriction of dietary natural protein intake, and the ingestion of modified foods that are lower in protein.
Two FDA approved drugs are also available for