- Author: Georgianne L Arnold, MD; Chief Editor: Luis O Rohena, MD more...
Phenylketonuria (PKU), the most common inborn error of amino acid metabolism, results when a deficiency of the enzyme phenylalanine hydroxylase (PAH) impairs the body’s ability to metabolize the essential amino acid phenylalanine. This leads to accumulation of phenylalanine in body fluids.
Elevated phenylalanine levels negatively impact cognitive function, and individuals with classic phenylketonuria almost always have intellectual disability unless levels are controlled through dietary or pharmacologic treatment.
Signs and symptoms
Skin findings in PKU are as follows:
Fair skin and hair: Resulting from impairment of melanin synthesis, this is the most characteristic cutaneous manifestation of PKU (see the image below); it can be striking in black and Japanese patients, although not all untreated patients are fair; treated patients often have typical pigmentation
Eczema (including atopic dermatitis)
Increased incidence of pyogenic infections
Increased incidence of keratosis pilaris
Decreased number of pigmented nevi
Hair loss 
Other manifestations of untreated PKU are as follows:
Intellectual disability (the most common finding overall)
Musty or mousy odor
Epilepsy (50%) 
Extrapyramidal manifestations (eg, parkinsonism)
Eye abnormalities (eg, hypopigmentation)
See Clinical Presentation for more detail.
Screening for PKU involves the following:
Determination of phenylalanine levels: The standard amino acid analysis done by means of ion exchange chromatography or tandem mass spectrometry
The Guthrie test as a bacterial inhibition assay: Formerly used, but now being replaced by tandem mass spectrometry
Cranial magnetic resonance imaging (MRI) studies may be indicated in older individuals who have abandoned the diet used to manage PKU and are experiencing deficits in motor or cognitive function, or in cases in which behavioral, cognitive, or psychiatric concerns exist. Areas of demyelination are common. In terms of volume loss, the most severely affected brain structures are the cerebrum, the corpus callosum, the hippocampus, and the pons.
See Workup for more detail.
Dietary management and/or pharmacologic treatment are essential for patients with PKU.
The mainstay of dietary management for patients with PKU consists of phenylalanine restriction, as well as the use of medical foods to supplement the patient’s intake of other essential amino acids and of vitamins and minerals. Energy and variety are provided by low-protein foods, including fruits, nonstarchy vegetables, and specially ordered low-protein items.
Patients who refuse dietary treatment may benefit to some degree from consuming large neutral amino acids, which may block phenylalanine entry into the brain and may also result in a modest lowering of plasma phenylalanine levels.
Some patients with phenylketonuria experience significant lowering of plasma phenylalanine levels after administration of sapropterin, a form of the tetrahydrobiopterin (BH4) cofactor. Unfortunately, persons with some residual enzyme activity are more likely to respond than are patients with no residual enzyme.
Phenylketonuria (PKU), the most common inborn error of amino acid metabolism, results from an impaired ability to metabolize the essential amino acid phenylalanine. Deficiency of the enzyme phenylalanine hydroxylase (PAH) leads to accumulation of phenylalanine in body fluids.
Classic phenylketonuria is present when plasma phenylalanine levels exceed 20 mg/dL (1200 µmol/L) without treatment. Lesser degrees of elevation of plasma phenylalanine are referred to as hyperphenylalaninemia. Elevated phenylalanine levels negatively impact cognitive function, and individuals with classic phenylketonuria almost always have intellectual disability unless levels are controlled through dietary or pharmacologic treatment.
In the United States and many other countries, phenylketonuria is detected by newborn screening, and individuals who are appropriately treated (eg, with a diet low in phenylalanine and/or tetrahydrobiopterin) can have normal intelligence and lead a normal life.
In most patients, the classic type of PKU involves a deficiency of PAH that leads to increased levels of phenylalanine in the plasma (>1200 µmol/L; reference range, 35-90 µmol/L) and to excretion of phenylpyruvic acid (approximately 1 g/d) and phenylacetic acid in the urine. PAH catalyzes the conversion of L-phenylalanine to L-tyrosine, the rate-limiting step in the oxidative degradation of phenylalanine (see the image below).
The enzyme PAH crystallizes as a tetramer, with each monomer consisting of a catalytic domain and a tetramerization domain. Examination of the mutations causing phenylketonuria reveals that some of the most frequent mutations are located at the interface of the catalytic and tetramerization domains.
PAH requires a nonprotein cofactor termed tetrahydrobiopterin (BH4). A small percentage of cases of PKU are due to defects in the synthesis or recycling of BH4 (and not PAH), including GTP-CH I, 6-pyruvoyl tetrahydropterin (6-PTS), or dihydropteridine reductase (DHPR).
The mechanism by which elevated phenylalanine levels cause intellectual disability is not known, although restriction of dietary phenylalanine ameliorates this effect if initiated within a few weeks of birth. A strong relation between control of blood phenylalanine levels in childhood and intelligence quotient (IQ) is recognized.
Subtle neuropsychological deficits in children with treated phenylketonuria are under investigation. Some investigators have attributed these deficits to small residual neurotransmitter abnormalities (eg, reduced production of neurotransmitters as a result of deficient tyrosine transport across the neuronal cell membranes).
A small percentage of children with elevated phenylalanine levels exhibit normal PAH levels but have a deficiency in synthesis or recycling of BH4 (see Tetrahydrobiopterin Deficiency). This condition is termed malignant phenylketonuria. The BH4 cofactor is also required for hydroxylation of tyrosine (a precursor of dopamine) and tryptophan (a precursor of serotonin). Thus, individuals with BH4 cofactor deficiency can have additional neurologic problems that are not fully corrected by dietary phenylalanine reduction alone, but often require additional treatments that may not be fully effective.
PKU is an autosomal recessive disorder caused by mutations in the PAH gene, which expresses PAH. This gene is located on 12q23.2, spans about 171 kb, and contains 13 exons. More than 500 different mutations in the PAH gene have been identified.
The PAH gene shows great allelic variation, and pathogenic mutations have been described in all 13 exons of the PAH gene and its flanking region. The mutations can be of various types, including missense mutations (62% of PAH alleles), small or large deletions (13%), splicing defects (11%), silent polymorphisms (6%), nonsense mutations (5%), and insertions (2%).
For the small percentage of PKU caused by BH4 defects, biopterin synthesis defects are caused by mutated alleles at 3 other loci (11q22.3-23.3, 10q22, and 2p13) or by BH4 recycling defects involving abnormalities localized to 4p15.1-16.1.
PKU displays a marked genotypic heterogeneity, both within populations and between different populations. Genotype and phenotype are broadly related (ie, reproducible mild versus severe mutations), but unrelated individuals with identical mutations have some degree of variability in phenylalanine tolerance.
United States statistics
Disease frequency varies by population. The prevalence in the general US population is approximately 4 cases per 100,000 individuals, and the incidence is 350 cases per million live births. Approximately 0.04-1% of the residents in intellectual disability clinics are affected by PKU. A low incidence is reported in African Americans (1/50,000).
A high incidence is reported in Turkey (approximately 1 case in 2600 births), the Yemenite Jewish population (1/5300), Scotland (1:5300), Estonia (1:8090), Hungary (1/11,000), Denmark (1/12,000), France (1/13,500), the United Kingdom (1/14,300), Norway (1/14,500), China (1/17,000), Italy (1/17,000), Canada (1/20,000), Minas Gerais State in Brazil (1/20,000), and the former Yugoslavia (1/25,042). A low incidence is reported in Finland (< 1/100,000) and Japan (1/125,000).
Age-, sex-, and race-related demographics
Phenylketonuria is most commonly diagnosed in neonates because of newborn screening programs. Consider phenylketonuria at any age in an individual with developmental delay or intellectual disability because infants are missed by newborn screening programs on rare occasions.
No sex predilection is known. Women with phenylketonuria must restrict their phenylalanine levels during pregnancy to avoid birth defects and intellectual disability in their infants. Untreated maternal PKU increases the risk for developmental problems in offspring.
In the United States, phenylketonuria is most common in whites. Worldwide, phenylketonuria is most common in whites and Asians.
The prognosis for normal intelligence is excellent when patients have been put on a diet low in phenylalanine in the first month of life, with careful monitoring. However, school functioning can be mildly impaired in some children, particularly when dietary control is poor.
A quantitative, proportional relation exists between blood phenylalanine levels and IQ for early-treated patients with PKU assessed either during the critical early childhood years (age 0-12 y) or by a lifetime Index of Dietary Control. A 100-μmol/L increase in phenylalanine has resulted in a 1.3- to 4.1-point reduction in IQ.
Patients with PKU who are treated early and continuously can have a normal health-related quality of life and course of life. Well-treated patients should have IQs within approximately 5-8 points of their siblings.
Most untreated individuals with phenylketonuria have profound intellectual disability. After the discovery of phenylketonuria, routine testing of institutionalized patients with intellectual disability identified a 1% incidence of phenylketonuria in this group.
Psychological problems, including agoraphobia and other disorders, have been reported in individuals both on and off dietary treatment. Treated patients with phenylketonuria often experience subtle performance and attention and behavioral changes, especially when phenylalanine levels exceed 360 µmol/L.
Teach parents how to administer the diet at home, and involve all caregivers as well. Children should begin involvement in their dietary planning as soon as they are developmentally ready. Poor dietary control is often associated with increasing noncompliance by older children, but it could also be due to a more relaxed dietary approach by parents and increasing dietary errors.
Women with PKU should be educated about the risks of untreated pregnancy and the benefits of dietary and, in some cases, pharmacologic, treatment. Patients with PKU should avoid aspartame (an artificial sweetener). Aspartame is widely used in medicines, vitamins, beverages, and other substances.
The phenylalanine-restricted diet with semisynthetic supplementation is not without risk. PKU patients under dietary treatment can have low concentrations of trace elements and cholesterol and can have some disturbance to folate metabolism and distortion of their fatty acid profile. In addition, overtreatment resulting in insufficient phenylalanine intake can cause intellectual disability
The organization National PKU News is a nonprofit entity dedicated to providing up-to-date, accurate news and information to families and professionals dealing with PKU. This site contains excellent articles and links to other information sources. Information on how to subscribe to a PKU newsletter and on how to contact support groups is available. Numerous other PKU Web sites are available to assist families in search of additional information.
Martynyuk AE, Ucar DA, Yang DD, et al. Epilepsy in phenylketonuria: a complex dependence on serum phenylalanine levels. Epilepsia. 2007 Jun. 48(6):1143-50. [Medline].
Cleary MA, Walter JH, Wraith JE, et al. Magnetic resonance imaging of the brain in phenylketonuria. Lancet. 1994 Jul 9. 344(8915):87-90. [Medline].
Sarkissian CN, Gámez A, Scriver CR. What we know that could influence future treatment of phenylketonuria. J Inherit Metab Dis. 2009 Feb. 32(1):3-9. [Medline].
Yannicelli S, Ryan A. Improvements in behaviour and physical manifestations in previously untreated adults with phenylketonuria using a phenylalanine-restricted diet: a national survey. J Inherit Metab Dis. 1995. 18(2):131-4. [Medline].
Burton BK, Grange DK, Milanowski A, et al. The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin): a phase II, multicentre, open-label, screening study. J Inherit Metab Dis. 2007 Oct. 30(5):700-7. [Medline].
Donati A, Vincenzi C, Tosti A. Acute hair loss in phenylketonuria. J Eur Acad Dermatol Venereol. 2009 May. 23(5):613-5. [Medline].
Santos LL, Castro-Magalhaes M, Fonseca CG, et al. PKU in Minas Gerais State, Brazil: mutation analysis. Ann Hum Genet. 2008 Nov. 72:774-9. [Medline].
Stojiljkovic M, Jovanovic J, Djordjevic M, et al. Molecular and phenotypic characteristics of patients with phenylketonuria in Serbia and Montenegro. Clin Genet. 2006 Aug. 70(2):151-5. [Medline].
Guldberg P, Henriksen KF, Sipila I, Guttler F, de la Chapelle A. Phenylketonuria in a low incidence population: molecular characterisation of mutations in Finland. J Med Genet. 1995 Dec. 32(12):976-8. [Medline]. [Full Text].
Bosch AM, Tybout W, van Spronsen FJ, de Valk HW, Wijburg FA, Grootenhuis MA. The course of life and quality of life of early and continuously treated Dutch patients with phenylketonuria. J Inherit Metab Dis. 2007 Feb. 30(1):29-34. [Medline].
Macdonald A, Davies P, Daly A, et al. Does maternal knowledge and parent education affect blood phenylalanine control in phenylketonuria?. J Hum Nutr Diet. 2008 Aug. 21(4):351-8. [Medline].
Vernon HJ, Koerner CB, Johnson MR, Bergner A, Hamosh A. Introduction of sapropterin dihydrochloride as standard of care in patients with phenylketonuria. Mol Genet Metab. 2010 Jul. 100(3):229-33. [Medline]. [Full Text].
Bekhof J, van Rijn M, Sauer PJ, Ten Vergert EM, Reijngoud DJ, van Spronsen FJ. Plasma phenylalanine in patients with phenylketonuria self-managing their diet. Arch Dis Child. 2005 Feb. 90(2):163-4. [Medline]. [Full Text].
Sarkissian CN, Gamez A, Wang L, et al. Preclinical evaluation of multiple species of PEGylated recombinant phenylalanine ammonia lyase for the treatment of phenylketonuria. Proc Natl Acad Sci U S A. 2008 Dec 30. 105(52):20894-9. [Medline]. [Full Text].
Ounap K, Lillevali H, Metspalu A, Lipping-Sitska M. Development of the phenylketonuria screening programme in Estonia. J Med Screen. 1998. 5(1):22-3. [Medline].
Pietz J, Kreis R, Rupp A, et al. Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. J Clin Invest. 1999 Apr. 103(8):1169-78. [Medline]. [Full Text].
Maillot F, Lilburn M, Baudin J, Morley DW, Lee PJ. Factors influencing outcomes in the offspring of mothers with phenylketonuria during pregnancy: the importance of variation in maternal blood phenylalanine. Am J Clin Nutr. 2008 Sep. 88(3):700-5. [Medline].
Waisbren SE, Noel K, Fahrbach K, et al. Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis. Mol Genet Metab. 2007 Sep-Oct. 92(1-2):63-70. [Medline].
Brooks M. Sapropterin Can Be Effective Long-Term in PKU. Medscape. May 24 2013. Available at http://www.medscape.com/viewarticle/804730. Accessed: June 12, 2013.
Keil S, Anjema K, van Spronsen FJ, Lambruschini N, Burlina A, Bélanger-Quintana A, et al. Long-term Follow-up and Outcome of Phenylketonuria Patients on Sapropterin: A Retrospective Study. Pediatrics. 2013 Jun. 131(6):e1881-8. [Medline].