Phenylketonuria (NORD)

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.