What is phenylketonuria?

Phenylketonuria (PKU) is an autosomal recessive genetic disorder. Affected children inherit a disease-causing gene variant from each parent, who are typically asymptomatic carriers. If either parent’s family has a history of PKU—or if the firstborn child is diagnosed with PKU—couples may consult a prenatal diagnostic specialist to undergo genetic testing, thereby minimizing the risk of having an affected child. But what exactly is phenylketonuria? The following section provides a detailed explanation.

What Is Phenylketonuria?

Phenylketonuria is a relatively common inborn error of amino acid metabolism caused by a deficiency in the enzyme responsible for metabolizing phenylalanine. Specifically, defects in the phenylalanine metabolic pathway prevent the conversion of phenylalanine into tyrosine, leading to accumulation of phenylalanine and its corresponding ketoacid, which are then excreted in large amounts in the urine. Clinically, PKU manifests primarily as hypopigmentation of the skin and hair, intellectual disability, and a characteristic musty or “mousy” odor in the urine and sweat. Although infants with PKU appear normal at birth, early symptoms—including vomiting, irritability, and delayed growth and development—typically emerge between 3 and 6 months of age. By age one year, clinical manifestations become more pronounced. Early diagnosis and prompt treatment are essential to prevent complications. Currently, dietary management is the mainstay of therapy: infants are fed a specially formulated low-phenylalanine infant formula, and during the toddler years, complementary foods should emphasize low-protein options such as starches, vegetables, and fruits.

Knowledge Extension: What Causes Phenylketonuria?

1. Phenylalanine Hydroxylase Deficiency

Genetic analyses of PKU patients have identified over 100 distinct pathogenic mutations. These mutations result in deficient or dysfunctional phenylalanine hydroxylase (PAH), the enzyme primarily responsible for converting phenylalanine to tyrosine. In most cases, PKU arises from PAH deficiency in hepatocytes, impairing phenylalanine metabolism and causing progressive elevation of blood phenylalanine levels. Excess phenylalanine is alternatively metabolized via transamination into phenylpyruvic acid, which can cause neurotoxic damage to brain tissue.

2. Deficiencies in Other Enzymes or Cofactors

Phenylalanine metabolism also requires several other enzymes and cofactors. Genetic defects affecting enzymes such as GTP cyclohydrolase I or 6-pyruvoyltetrahydropterin synthase reduce their enzymatic activity, disrupting the biosynthesis of tetrahydrobiopterin (BH4)—a critical cofactor for PAH. BH4 deficiency leads to secondary elevation of blood phenylalanine and consequent neurological impairment.

The above provides an overview of phenylketonuria. We hope this information is helpful to you.