PAH

About PAH

PAH on chromosome 12q23.2 encodes phenylalanine hydroxylase, a liver enzyme that converts phenylalanine to tyrosine using tetrahydrobiopterin, BH4, as a cofactor. Variants on both copies cause phenylketonuria, PKU, an autosomal recessive disorder affecting roughly 1 in 12,000 newborns, with large differences between populations. Without treatment, phenylalanine accumulates and causes irreversible intellectual disability, seizures, behavioral problems, lighter skin and hair due to reduced melanin production, and a musty odor. PKU was described by the Norwegian physician Asbjorn Folling in 1934, and it was the first disorder targeted by population wide newborn screening after Robert Guthrie developed a blood spot test in the early 1960s. Today screening is usually done by tandem mass spectrometry. Early diagnosis and lifelong dietary management restricting phenylalanine allow normal development. Sapropterin, a synthetic form of BH4, helps a subset of patients with responsive variants, and pegvaliase is an enzyme that degrades phenylalanine. Maternal PKU, in which high maternal phenylalanine harms the developing fetus, can cause microcephaly, heart defects, and intellectual disability, which is why metabolic control around pregnancy is an important part of care.