What happens when phenylalanine hydroxylase is missing in phenylketonuria?

In phenylketonuria (PKU), the absence or inactivity of the enzyme phenylalanine hydroxylase prevents the body from converting the amino acid phenylalanine into tyrosine.1

This metabolic block causes phenylalanine and its abnormal breakdown products, such as ketone compounds, to accumulate to toxic levels in the blood, urine, and cerebrospinal fluid. These high levels interfere with central nervous system processes, reducing the production of essential neurotransmitters like dopamine. Over time, this leads to nerve cell damage, demyelination, and severe cognitive dysfunction, including seizures and developmental delays.1

Additionally, because tyrosine is a precursor to melanin, the inability to produce it often results in reduced pigmentation, typically manifesting as fair skin, blue eyes, and blond hair. Managing this condition requires a strict, lifelong diet low in phenylalanine to prevent these systemic complications.1