Pathophysiology
When phenylalanine (Phe) cannot be metabolized by the body, a typical diet that would be healthy for people without PKU causes abnormally high levels of Phe to accumulate in the blood, which is toxic to the brain. If left untreated (and often even in treatment), complications of PKU include severe intellectual disability, brain function abnormalities, microcephaly, mood disorders, irregular motor functioning, and behavioral problems such as attention deficit hyperactivity disorder, as well as physical symptoms such as a "musty" odor, eczema, and unusually light skin and hair coloration. Classical PKU
Classical PKU, and its less severe forms "mild PKU" and "mild hyperphenylalaninemia" are caused by a mutated gene for the enzyme phenylalanine hydroxylase (PAH), which converts the amino acid phenylalanine ("Phe") to other essential compounds in the body, in particular tyrosine. Tyrosine is a conditionally essential amino acid for PKU patients because without PAH it cannot be produced in the body through the breakdown of phenylalanine. Tyrosine is necessary for the production of neurotransmitters like epinephrine, norepinephrine, and dopamine.PAH deficiency causes a spectrum of disorders, including classic phenylketonuria (PKU) and mild hyperphenylalaninemia (also known as "hyperphe" or "mild HPA"), a less severe accumulation of phenylalanine. Compared to classic PKU patients, patients with "hyperphe" have greater PAH enzyme activity and are able to tolerate larger amounts of phenylalanine in their diets. Without dietary intervention, mild HPA patients have blood Phe levels higher than those with normal PAH activity.
Males and females are affected equally. The disease was discovered in 1934 by Ivar Asbjørn Følling, with the importance of diet determined in 1935. Gene therapy, while promising, requires a great deal more study as of 2014. Signs and symptoms
Untreated PKU can lead to intellectual disability, seizures, behavioral problems, and mental disorders. It may also result in a musty smell and lighter skin. A baby born to a mother who has poorly treated PKU may have heart problems, a small head, and low birth weight.Because the mothers body is able to break down phenylalanine during pregnancy, infants with PKU are normal at birth. The disease is not detectable by physical examination at that time, because no damage has yet been done. Newborn screening is performed to detect the disease and initiate treatment before any damage is done. The blood sample is usually taken by a heel prick, typically performed 2–7 days after birth. This test can reveal elevated phenylalanine levels after one or two days of normal infant feeding.If a child is not diagnosed during the routine newborn screening test and a phenylalanine-restricted diet is not introduced, then phenylalanine levels in the blood will increase over time. Toxic levels of phenylalanine (and insufficient levels of tyrosine) can interfere with infant development in ways that have permanent effects. The disease may present clinically with seizures,  hypopigmentation (excessively fair hair and skin), and a "musty odor" to the babys sweat and urine (due to phenylacetate, a carboxylic acid produced by the oxidation of phenylacetone).