Internal medicine

Pediatrics

Adverse effect

Phenylalanine hydroxylase

Epilepsy

Biology

Psychiatry

Etiology

Cognition

Neurocognitive

Tetrahydrobiopterin

Phenylalanine

Newborn screening

Nitric oxide synthase

Intellectual disability

Amino acid

Nitric oxide

Biochemistry

Medicine

Nature Reviews Disease Primers

Phenylketonuria (PKU; also known as phenylalanine hydroxylase (PAH) deficiency) is an autosomal recessive disorder of phenylalanine metabolism, in which especially high phenylalanine concentrations cause brain dysfunction. If untreated, this brain dysfunction results in severe intellectual disability, epilepsy and behavioural problems. The prevalence varies worldwide, with an average of about 1:10,000 newborns. Early diagnosis is based on newborn screening, and if treatment is started early and continued, intelligence is within normal limits with, on average, some suboptimal neurocognitive function. Dietary restriction of phenylalanine has been the mainstay of treatment for over 60 years and has been highly successful, although outcomes are still suboptimal and patients can find the treatment difficult to adhere to. Pharmacological treatments are available, such as tetrahydrobiopterin, which is effective in only a minority of patients (usually those with milder PKU), and pegylated phenylalanine ammonia lyase, which requires daily subcutaneous injections and causes adverse immune responses. Given the drawbacks of these approaches, other treatments are in development, such as mRNA and gene therapy. Even though PAH deficiency is the most common defect of amino acid metabolism in humans, brain dysfunction in individuals with PKU is still not well understood and further research is needed to facilitate development of pathophysiology-driven treatments. Phenylketonuria is an inherited disorder of phenylalanine metabolism that can result in neurological dysfunction. This Primer reviews the epidemiology, aetiology, diagnosis and management of PKU as well as the impact on patients’ quality of life.

Phenylketonuria