Dictionary Definition

phenylketonuria n : a genetic disorder of metabolism; lack of the enzyme needed to turn phenylalanine into tyrosine results in an accumulation of phenylalanine in the body fluids which causes various degrees of mental deficiency [syn: PKU]

User Contributed Dictionary



phenylketonuria (abbreviated as PKU)
  1. a metabolic disorder in which individuals lack the liver enzyme phenylalanine hydroxylase (PAH) which is needed to metabolize the amino acid phenylalanine

Extensive Definition

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 phenylpyruvate (also known as phenylketone), which is detected in the urine. PKU is found on chromosome number 12.
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 be a very effective treatment. There is no cure. Damage done is irreversible so early detection is crucial.


Phenylketonuria was discovered by the Norwegian physician Asbjørn Følling in 1934 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. 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 affected siblings led him to request many physicians near Oslo to test the urine of other affected 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 (taste). 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.

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. Most babies in developed countries are screened for PKU soon after birth.
If a child is not screened during the routine Newborn Screening test (typically performed at least 12 hours and generally 24-28 hours after birth), 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). In most cases a repeat test should be done at approximately 2 weeks of age to verify the initial test and uncover any Phenylketonuria that was initially missed.
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 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. This cofactor is necessary for proper activity of the enzyme. Other, non-PAH mutations can also cause PKU. 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. PAH deficiency causes a spectrum of disorders including classic phenylketonuria (PKU) and hyperphenylalaninemia (a less severe accumulation of phenylalanine).
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. 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 through the minor route, a transaminase pathway with glutamate. Metabolites include phenylacetate, phenylpyruvate and phenylethylamine. 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.


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, legumes 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.)
The oral administration of tetrahydrobiopterin (a cofactor in the oxidation of phenylalanine) can reduce blood levels of the amino acid in certain patients. The company BioMarin Pharmaceutical has produced a tablet preparation of the compound (Kuvan), the first drug that can actually treat PKU, though concern has been expressed over its safety, cost, and the potential for PKU sufferers to override the benefits of the drug by increasing their intake of phenylalanine to dangerous levels.
There are a number of other therapies currently under investigation, including gene therapy, and an injectable form of PAL. 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. 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. 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. 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.


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 to fewer than one in 100,000 births among the population of Finland.



  • Frank L. Lyman. (1963) Phenylketonuria Springfield: Thomas. 318 p.
  • Bickel, H.; F. P. Hudson & L. I. Woolf. (1971) Phenylketonuria and some other inborn errors of amino acid metabolism: biochemistry, genetics, diagnosis, therapy Stuttgart, G. Thieme Verlag. 336 p. ISBN 3134669013.

External links

phenylketonuria in Arabic: فينايلكيتونوريا
phenylketonuria in Czech: Fenylketonurie
phenylketonuria in Danish: Fenylketonuri
phenylketonuria in German: Phenylketonurie
phenylketonuria in Modern Greek (1453-): Φαινυλκετονουρία
phenylketonuria in Spanish: Fenilcetonuria
phenylketonuria in French: Phénylcétonurie
phenylketonuria in Korean: 페닐케톤 요증
phenylketonuria in Croatian: Fenilketonurija
phenylketonuria in Indonesian: Fenilketonuria
phenylketonuria in Italian: Fenilchetonuria
phenylketonuria in Hebrew: פנילקטונוריה
phenylketonuria in Hungarian: Fenilketonúria
phenylketonuria in Dutch: Fenylketonurie
phenylketonuria in Japanese: フェニルケトン尿症
phenylketonuria in Norwegian: Fenylketonuri
phenylketonuria in Norwegian Nynorsk: Fenylketonuri
phenylketonuria in Polish: Fenyloketonuria
phenylketonuria in Portuguese: Fenilcetonúria
phenylketonuria in Russian: Фенилкетонурия
phenylketonuria in Simple English: Phenylketonuria
phenylketonuria in Slovak: Fenylketonúria
phenylketonuria in Serbian: Фенилкетонурија
phenylketonuria in Finnish: Fenyyliketonuria
phenylketonuria in Swedish: Fenylketonuri
phenylketonuria in Thai: ฟีนิลคีโตนูเรีย
phenylketonuria in Turkish: Fenilketonüri
phenylketonuria in Chinese: 苯丙酮尿症
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