Phenylketonuria is a disorder of amino acid metabolism that causes a clinical syndrome of intellectual disability with cognitive and behavioral abnormalities caused by elevated serum phenylalanine. The primary cause is deficient phenylalanine hydroxylase activity. Diagnosis is by detecting high phenylalanine levels and normal or low tyrosine levels. Treatment is lifelong dietary phenylalanine restriction. Prognosis is excellent with treatment.
Phenylketonuria (PKU) may occur in all ethnic groups, but prevalence varies widely among different geographic regions. Inheritance is autosomal recessive; incidence is approximately 1/10,000 births among White people and East Asian populations (1).
For information on other related amino acid disorders, see table Phenylalanine and Tyrosine Metabolism Disorders. See also Approach to the Patient With a Suspected Inherited Disorder of Metabolism.
General reference
1. van Spronsen FJ, Blau N, Harding C, Burlina A, Longo N, Bosch AM. Phenylketonuria. Nat Rev Dis Primers. 2021;7(1):36. Published 2021 May 20. doi:10.1038/s41572-021-00267-0
Pathophysiology of PKU
Excess dietary phenylalanine (ie, that not used for protein synthesis) is normally converted to tyrosine by phenylalanine hydroxylase; tetrahydrobiopterin (BH4) is an essential cofactor for this reaction. When one of several gene mutations results in deficiency or absence of phenylalanine hydroxylase, dietary phenylalanine accumulates; the brain is the main organ affected, possibly due to disturbance of myelination.
Some of the excess phenylalanine is metabolized to phenylketones, which are excreted in the urine, giving rise to the term phenylketonuria. The degree of enzyme deficiency, and hence severity of hyperphenylalaninemia, varies among patients depending on the specific mutation.
Variant forms
Although nearly all cases (98 to 99%) of PKU result from phenylalanine hydroxylase deficiency, phenylalanine can also accumulate if BH4 is not synthesized because of deficiencies of dihydrobiopterin synthase or not regenerated because of deficiencies of dihydropteridine reductase. Additionally, because BH4 is also a cofactor for tyrosine hydroxylase, which is involved in the synthesis of dopamine and serotonin, BH4 deficiency alters synthesis of neurotransmitters, causing neurologic symptoms independently of phenylalanine accumulation.
Symptoms and Signs of PKU
Most children with phenylketonuria are normal at birth but develop symptoms and signs slowly over several months as phenylalanine accumulates. The hallmark of untreated PKU is severe intellectual disability.
Children also manifest extreme hyperactivity, gait disturbance, and psychoses and often exhibit an unpleasant, mousy body odor caused by phenylacetic acid (a breakdown product of phenylalanine) in urine and sweat. Children also tend to have a lighter skin, hair, and eye color than unaffected family members, and some may develop a rash similar to infantile eczema. If treatment is not begun early, children may develop extreme hyperactivity and intractable seizures.
Diagnosis of PKU
Routine neonatal screening
Phenylalanine levels
(See also the American College of Medical Genetics and Genomics Therapeutic Committee's 2013 diagnosis and management guidelines for phenylalanine hydroxylase deficiency.)
In the United States and many other countries, all neonates are screened for phenylketonuria 24 to 48 hours after birth with one of several blood tests; abnormal results are confirmed by directly measuring phenylalanine levels. In classic PKU, neonates often have phenylalanine levels > 20 mg/dL (1.2 mM/L). Those with partial deficiencies typically have levels < 8 to 10 mg/dL while on a normal diet (levels > 6 mg/dL require treatment); distinction from classic PKU requires a mutation analysis identifying mild mutations in the gene or, less often, liver phenylalanine hydroxylase activity assay showing activity between 5% and 15% of normal.
BH4 deficiency is distinguished from other forms of PKU by elevated concentrations of biopterin or neopterin in urine, blood, cerebrospinal fluid, or all 3; genetic testing also can be used. Recognition is important, and the urine biopterin profile should be determined routinely at initial diagnosis because standard PKU treatment does not prevent neurologic damage.
Children in families with a positive family history can be diagnosed prenatally by using direct mutation studies after chorionic villus sampling or amniocentesis.
Treatment of PKU
Dietary phenylalanine restriction
Treatment of phenylketonuria is lifelong dietary phenylalanine restriction. All natural protein contains about 4% phenylalanine. Therefore dietary staples include
Low-protein natural foods (eg, fruits, vegetables, certain cereals)
Protein hydrolysates treated to remove phenylalanine
Phenylalanine-free elemental amino acid mixtures
There are many commercially available phenylalanine-free products. Some phenylalanine is required for growth and metabolism; this requirement is met by measured quantities of natural protein from milk or low-protein foods.
Prognosis for PKU
Adequate treatment begun in the first days of life prevents the severe manifestations of the disease. However, mild cognitive deficits and mental health issues may still occur even with good dietary control. Treatment begun after 2 to 3 years may be effective only in controlling the extreme hyperactivity and intractable seizures.
Children born to mothers with poorly controlled PKU (ie, they have high phenylalanine levels) during pregnancy are at high risk of microcephaly and developmental deficit.
Key Points
PKU is caused by one of several gene mutations that result in deficiency or absence of phenylalanine hydroxylase so that dietary phenylalanine accumulates; the brain is the main organ affected, possibly because of disturbance of myelination.
PKU causes a clinical syndrome of intellectual disability with cognitive and behavioral abnormalities; if untreated, the intellectual disability is severe.
In the United States and many other countries, all neonates are screened for phenylketonuria 24 to 48 hours after birth with one of several blood tests; abnormal results are confirmed by directly measuring phenylalanine levels.
Treatment is lifelong dietary phenylalanine restriction; adequate treatment begun in the first days of life prevents many manifestations of the disease.
Although prognosis is excellent with treatment, frequent monitoring of plasma phenylalanine levels is required; recommended targets are between 2 mg/dL and 6 mg/dL (120 to 360 micromol/L) for all children.
More Information
The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
American College of Medical Genetics and Genomics Therapeutic Committee: Diagnosis and management guidelines for phenylalanine hydroxylase deficiency (2013)
Online Mendelian Inheritance in Man (OMIM) database: Complete gene, molecular, and chromosomal location information
