Phenylketonuria

Phenylketonuria is an autosomal recessive metabolic disorder caused by mutations in the PAH gene, resulting in a deficiency of the enzyme phenylalanine hydroxylase.

Phenylketonuria is caused by a mutation in the PAH gene, most commonly a missense mutation, resulting in a deficiency of the hepatic enzyme phenylalanine hydroxylase, which is responsible for converting phenylalanine to tyrosine. This deficiency leads to the accumulation of phenylalanine and its metabolites in the body, causing brain dysfunction if untreated. In classic phenylketonuria, phenylalanine hydroxylase activity is absent or significantly reduced, while in mild phenylketonuria or mild hyperphenylalaninemia, partial enzymatic activity is preserved. The accumulation of phenylalanine and its metabolites triggers several biochemical changes involved in the pathogenesis of brain damage, including reduced activity of pyruvate kinase, HMG-CoA reductase, and monoamine oxidase B, along with impaired glutamatergic neurotransmission and hypomyelination.

The incidence of phenylketonuria is estimated at 1 in 15,000 live births in the US and 1 in 100,000 live births in Europe.

Phenylketonuria is typically detected through newborn screening, enabling early intervention. If left untreated, it can lead to seizures, eczema, intellectual disability, behavioral disturbances with autistic traits, parkinsonism, musty body odor, and reduced skin and hair pigmentation.

The prognosis of phenylketonuria is significantly improved with early detection and strict dietary management, with most patients achieving normal development with adequate disease control.