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Classification & external resources
ICD-10 E70.0
ICD-9 270.1
OMIM 261600
DiseasesDB 9987
MedlinePlus 001166
eMedicine ped/1787  derm/712
MeSH D010661

Phenylketonuria (PKU) is an autosomal recessive genetic disorder characterized by a deficiency in the enzyme phenylalanine hydroxylase (PAH). This enzyme is necessary to metabolize the amino acid phenylalanine to the amino acid tyrosine. When PAH is deficient, phenylalanine accumulates and is converted into phenylketones, which are detected in the urine.

Left untreated, this condition can cause problems with brain development, leading to progressive mental retardation and seizures. However, PKU is one of the few genetic diseases that can be controlled by diet. A diet low in phenylalanine and high in tyrosine can bring about a nearly total cure.



Phenylketonuria was discovered by the Norwegian physician Asbjørn Følling in 1934[1] when he noticed that hyperphenylalaninemia (HPA) was associated with mental retardation. In Norway, this disorder is known as Følling's disease, named after its discoverer.[2] Dr. Følling was one of the first physicians to apply detailed chemical analysis to the study of disease. His careful analysis of the urine of two retarded siblings led him to request many physicians near Oslo to test the urine of other retarded patients. This led to the discovery of the same substance that he had found in eight other patients. The substance found was subjected to much more basic and rudimentary chemical analysis. He conducted tests and found reactions that gave rise to benzaldehyde and benzoic acid, which led him to conclude the compound contained a benzene ring. Further testing showed the melting point to be the same as phenylpyruvic acid, which indicated that the substance was in the urine. His careful science inspired many to pursue similar meticulous and painstaking research with other disorders.


The incidence of PKU is about 1 in 15,000 births, but the incidence varies widely in different human populations from 1 in 4,500 births among the population of Ireland[3] to fewer than one in 100,000 births among the population of Finland.[4]

Screening and presentation

  PKU is normally detected using the HPLC test, but some clinics still use the Guthrie test, part of national biochemical screening programs.

If a child is not screened at birth (e.g. in home deliveries), the disease may present clinically with seizures, albinism (excessively fair hair and skin), and a "musty odor" to the baby's sweat and urine (due to phenylacetate, one of the ketones produced).

Untreated children are normal at birth, but fail to attain early developmental milestones, develop microcephaly, and demonstrate progressive impairment of cerebral function. Hyperactivity, EEG abnormalities and seizures, and severe mental retardation are major clinical problems later in life. A "musty" odor of skin, hair, sweat and urine (due to phenylacetate accumulation); and a tendency to hypopigmentation and eczema are also observed.

In contrast, affected children who are detected and treated at birth are less likely to develop neurological problems and have seizures and mental retardation, though such clinical disorders are still possible.


Classical PKU is caused by a defective gene for the enzyme phenylalanine hydroxylase (PAH), which converts the amino acid phenylalanine to other essential compounds in the body. A rarer form of the disease occurs when PAH is normal but there is a defect in the biosynthesis or recycling of the cofactor tetrahydrobiopterin (BH4) by the patient.[5] This cofactor is necessary for proper activity of the enzyme. Other, non-PAH mutations can also cause PKU [6].

The PAH gene is located on chromosome 12 in the bands 12q22-q24.1. More than four hundred disease-causing mutations have been found in the PAH gene.[7]. PAH deficiency causes a spectrum of disorders including classic phenylketonuria (PKU) and hyperphenylalaninemia (a less severe accumulation of phenylalanine).[8]

PKU is an autosomal recessive genetic disorder, meaning that each parent must have at least one defective allele of the gene for PAH, and the child must inherit two defective alleles, one from each parent. As a result, it is possible for a parent with PKU phenotype to have a child without PKU if the other parent possesses at least one functional allele of the PAH gene; but a child of two parents with PKU will always inherit two defective alleles, and therefore the disease.

Phenylketonuria can exist in mice, which have been extensively used in experiments into an effective treatment for PKU[9]. The macaque monkey's genome was recently sequenced, and it was found that the gene encoding phenylalanine hydroxylase has the same sequence which in humans would be considered the PKU mutation.

Metabolic pathways


The enzyme phenylalanine hydroxylase normally converts the amino acid phenylalanine into the amino acid tyrosine. If this reaction does not take place, phenylalanine accumulates and tyrosine is deficient. Excessive phenylalanine can be metabolized into phenylketones though the minor route, a transaminase pathway with glutamate. Metabolites include phenylacetate, phenylpyruvate and phenylethylamine[10]. Detection of phenylketones in the urine is diagnostic.

Phenylalanine is a large, neutral amino acid (LNAA). LNAAs compete for transport across the blood brain barrier (BBB) via the large neutral amino acid transporter (LNAAT). Excessive phenylalanine in the blood saturates the transporter. Thus, excessive levels of phenylalanine significantly decrease the levels of other LNAAs in the brain. But since these amino acids are required for protein and neurotransmitter synthesis, phenylalanine accumulation disrupts brain development in children, leading to mental retardation.[11]


If PKU is diagnosed early enough, an affected newborn can grow up with normal brain development, but only by eating a special diet low in phenylalanine for the rest of his or her life. This requires severely restricting or eliminating foods high in phenylalanine, such as breast milk, meat, chicken, fish, nuts, cheese and other dairy products. Starchy foods such as potatoes, bread, pasta, and corn must be monitored. Many diet foods and diet soft drinks that contain the sweetener aspartame must also be avoided, as aspartame consists of two amino acids: phenylalanine and aspartic acid.

Supplementary infant formulas are used in these patients to provide the amino acids and other necessary nutrients that would otherwise be lacking in a protein free diet. These can continue in other forms as the child grows up. (Since phenylalanine is necessary for the synthesis of many proteins, it is required but levels must be strictly controlled. In addition, tyrosine, which is normally derived from phenylalanine, must be supplemented.)

In those patients with a deficit in BH4 production, or with a PAH PAH mutation resulting in a low affinity of PAH for BH4, treatment consists of giving BH4 as a supplement; this is referred to as BH4 responsive PKU.

There are a number of other therapies currently under investigation, including gene therapy, and an injectable form of PAH. In 2007, a new treatment, a drug named Kuvan, was approved by the FDA. The generic name is sapropterin dihydrochloride,and is a form of BH4. However, the expected cost of $57,000/year for children and up to $200,000/year for adults means that this treatment will likely be out for those who are uninsured. [12]

Treatment of PKU includes the elimination of phenylalanine from the diet, and supplementation of the diet with tyrosine and other amino acids, vitamins and minerals that are otherwise missing from the diet. Phenylalanine is commonly found in protein-containing foods such as meat, dairy products, fish, grains and legumes. Babies who are diagnosed with PKU must immediately be put on a special milk/formula substitute. Later in life, the diet continues to exclude phenylalanine-containing foods.

Previously, PKU-affected people were allowed to go off diet after approximately 8, then 18 years of age. However, physicians now recommend that this special diet should be followed throughout life.

Maternal phenylketonuria

  For women affected with PKU, it is essential for the health of their child to maintain low phenylalanine levels before and during pregnancy.[13] Though the developing fetus may only be a carrier of the PKU gene, the intrauterine environment can have very high levels of phenylalanine, which can cross the placenta. The result is that the child may develop congenital heart disease, growth retardation, microcephaly and mental retardation.[14] PKU-affected women themselves are not at risk from additional complications during pregnancy.

In most countries, women with PKU who wish to have children are advised to lower their blood phenylalanine levels before they become pregnant and carefully control their phenylalanine levels throughout the pregnancy. This is achieved by performing regular blood tests and adhering very strictly to a diet, generally monitored on a day-to-day basis by a specialist metabolic dietitian. When low phenylalanine levels are maintained for the duration of pregnancy there are no elevated levels of risk of birth defects compared with a baby born to a non-PKU mother.[15] Babies with PKU may drink breast milk, while also taking their special metabolic formula. Some research has indicated that an exclusive diet of breast milk for PKU babies may alter the effects of the deficiency, though during breastfeeding the mother must maintain a strict diet to keep their phenylalanine levels low. More research is needed.

See also


  1. ^ a b Folling, A. (1934). "Ueber Ausscheidung von Phenylbrenztraubensaeure in den Harn als Stoffwechselanomalie in Verbindung mit Imbezillitaet". Ztschr. Physiol. Chem. 227: 169-176.
  2. ^ Centerwall, S. A. & Centerwall, W. R. (2000). "The discovery of phenylketonuria: the story of a young couple, two retarded children, and a scientist.". Pediatrics 105 (1 Pt 1): 89-103. PMID 10617710.
  3. ^ DiLella, A. G., Kwok, S. C. M., Ledley, F. D., Marvit, J., Woo, S. L. C. (1986). "Molecular structure and polymorphic map of the human phenylalanine hydroxylase gene". Biochemistry 25: 743-749. PMID 3008810.
  4. ^ Guldberg, P., Henriksen, K. F., Sipila, I., Guttler, F., de la Chapelle, A. (1995). "Phenylketonuria in a low incidence population: molecular characterization of mutations in Finland". J. Med. Genet 32: 976-978. PMID 8825928.
  5. ^ Surtees, R., Blau, N. (2000). "The neurochemistry of phenylketonuria". European Journal of Pediatrics 169: S109-13. PMID 11043156.
  6. ^ PKU 2007 Genetics of Phenylketonuria - A Comprehensive Review
  7. ^ PKU 2007 Genetics of Phenylketonuria - A Comprehensive Review
  8. ^ Phenylalanine hydroxylase (PAH) gene summary, retrieved September 8, 2006
  9. ^ Oh, H. J., Park, E. S., Kang, S., Jo, I., Jung, S. C. (2004). "Long-Term Enzymatic and Phenotypic Correction in the Phenylketonuria Mouse Model by Adeno-Associated Virus Vector-Mediated Gene Transfer". Pediatric Research 56: 278-284. PMID 15181195.
  10. ^ Michals, K., Matalon, R. (1985). "Phenylalanine metabolites, attention span and hyperactivity". American Journal of Clinical Nutrition 42(2): 361-365. PMID 4025205.
  11. ^ Pietz, J., Kreis, R., Rupp, A., Mayatepek, E., Rating, D., Boesch, C., Bremer, H. J. (1999). "Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria". Journal of Clinical Investigation 103: 1169–1178. PMID 10207169.
  12. ^
  13. ^ Lee, P.J., Ridout, D., Walker, J.H., Cockburn, F., (2005). "Maternal phenylketonuria: report from the United Kingdom Registry 1978–97". Archives of Disease in Childhood 90: 143-146. PMID 15665165..
  14. ^ Rouse, B., Azen, B., Koch, R., Matalon, R., Hanley, W., de la Cruz, F., Trefz, F., Friedman, E., Shifrin, H. (1997). "Maternal phenylketonuria collaborative study (MPKUCS) offspring: Facial anomalies, malformations, and early neurological sequelae.". American Journal of Medical Genetics 69 (1): 89–95. PMID 9066890.
  15. ^ Genetics and Louisiana Families
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Phenylketonuria". A list of authors is available in Wikipedia.
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