PKU and Pterin Defects - Description

Other Names

Classic PKU
Phenylalanine Hydroxylase Deficiency


270.1, phenylketonuria


Phenylketonuria (PKU) is a recessive disorder caused by deficiency in phenylalanine hydroxylase, the enzyme that converts the amino acid phenylalanine to tyrosine, leading to an accumulation of phenylalanine in the body. This accumulation is toxic for the development and functioning of the central nervous system and leads to intellectual disability. Phenylalanine is present in almost all foods containing proteins and treatment of PKU involves a restrictive diet with the reduction of phenylalanine and the addition of vitamins and minerals that are necessary for body metabolism. This requires special foods (medical formulas) that contain all amino acids except phenylalanine in addition to special low-protein foods. Most children with PKU are identified by newborn screening. With treatment and early introduction and maintenance of the special diet, normal IQ and development can be expected. Without treatment, symptoms in classic PKU begin by about 6 months of age.

Initial symptoms may include:
  • a musty or "mousy" odor of the body and urine
  • developmental delays in sitting, crawling, and standing
  • microcephaly
If patients remain untreated they may develop:
  • decreased skin and hair pigmentation (due to lack of tyrosine)
  • eczema
  • seizures
  • profound mental retardation

There are different forms of PKU defined by the highest levels of phenylalanine measured in blood. In benign hyperphenylalaninemia, the increase in phenylalanine levels are minimal (phenylalanine 120-360 micromolar, normal 30-90 micromolar) and require no treatment. In mild PKU, there is a mild increase in phenylalanine levels (360-1,200 micromolar, normal 30-90 micromolar) that is more easily controlled by diet or pharmacological therapy. In classic PKU, there is substantial elevation of phenylalanine levels (>1,200 micromolar, normal 30-90 micromolar) that requires strict dietary therapy and is less likely to respond to pharmacological therapy. Some patients, particularly those with mild PKU, respond to therapy with sapropterin, a synthetic form of tetrahydrobiopterin, the cofactor of phenylalanine hydroxylase. Patients with mild phenylketonuria are more likely to respond to this therapy.

Elevated phenylalanine levels can also be caused by defects in the synthesis or recycling of tetrahydrobiopterin, an essential cofactor of phenylalanine hydroxylase and other enzymes involved in neurotransmitter synthesis. These patients, in addition to elevated phenylalanine levels, can have neurotransmitter deficiencies and their treatment differs from that of phenylketonuria. As part of the initial evaluation of a child with high phenylalanine level in newborn screening, metabolic geneticists will exclude a defect in the tetrahydrobiopterin pathway by obtaining additional specialized tests. These consist of the measurement of pterin profile in urine spotted on filter paper and evaluation of the activity of an enzyme, di hydro pteridin reductase (DHPR), in red blood said spotted on filter paper. Therapy in these conditions include the administration of a synthetic form of tetrahydrobiopterin that can normalize plasma phenylalanine level. These patients also require the administration of neurotransmiter precursors.

Diet restriction needs to be continued for life in patients with PKU and repeated monitoring of plasma phenylalanine and tyrosine levels are needed to make sure that they remain within the therapeutic range (phenylalanine 45-360 micromolar, Tyrosine 30-120 micromolar).


Inheritance is autosomal recessive. The only gene associated with PKU is phenylalanine hydroxylase (PAH) which is located on chromosome 12. More than 600 different mutations have been identified in patients with phenylketonuria. There is a correlation between the type of mutations, residual enzyme activity, and highest phenylalanine level. DNA testing can fully confirm a diagnosis of phenylketonuria and, with biochemical testing, help to exclude defects in biopterin synthesis.


Prognosis is good for individuals with PKU who remain on the diet. Relaxation of diet is associated with executive function deficits and an increased risk of attention deficit disorder and problems in school. Patients with defects in tetrahydrobiopterin synthesis or recycling might develop movement disorders and all have developmental delays. These can be improved by therapy, but in the most severe forms this is not completely effective.


PKU occurs in about 1/10,000 live births in the US. [Schulze: 2003] The incidence varies greatly in other populations: Turks - 1/2,600; Irish - 1/4,500; African - 1/100,000; Japanese - 1/143,000; Finnish and Ashkenazi Jewish - 1/200,000. [Günther: 2008]

Helpful Articles

PubMed search for PKU and newborn screening, last 2 years.

Blau N, van Spronsen FJ, Levy HL.
Lancet. 2010;376(9750):1417-27. PubMed abstract

Viau KS, Wengreen HJ, Ernst SL, Cantor NL, Furtado LV, Longo N.
Correlation of age-specific phenylalanine levels with intellectual outcome in patients with phenylketonuria.
J Inherit Metab Dis. 2011. PubMed abstract

PKU and Pterin Defects Module Authors

Author: Nicola Longo, MD, Ph.D. - 8/2011
Compiled and edited by: Lynne M. Kerr, MD, PhD - 7/2011
Content Last Updated: 11/2011

The authors listed above are responsible for the overall PKU and Pterin Defects Module. Authors contributing to individual pages in the module are listed on those pages.

Page Bibliography

Günther T, Schreiber C, Noebauer C, Eicken A, Lange R.
Treatment strategies for pediatric patients with primary cardiac and pericardial tumors: a 30-year review.
Pediatr Cardiol. 2008;29(6):1071-6. PubMed abstract

Schulze A, Lindner M, Kohlmuller D, Olgemoller K, Mayatepek E, Hoffmann GF.
Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications.
Pediatrics. 2003;111(6 Pt 1):1399-406. PubMed abstract