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Genetic: Phenylketonuria

Genetic: Phenylketonuria

Causes and Symptoms
The Future
For more information


Phenylketonuria, or PKU, is an inherited disease caused by a mutation in a gene called the PAH gene on chromosome 12. This gene affects the body's ability to use phenylalanine, one of the amino acids that are the building blocks of proteins.


Children with PKU cannot use phenylalanine, an amino acid that occurs in all protein foods and some artificial sweeteners, particularly aspartame. As a result, the amino acid and two closely related substances build up to harmful levels in the child's body, causing mental retardation and other serious health problems.

Not all children with PKU are as severely affected as those with the so-called classic form of the disorder. Children with classic PKU look normal until they are a few months old, although they may appear to have fairer skin and lighter hair than their parents and siblings. They may also suffer from eczema and other skin disorders, or have a musty or mouse-like odor on their breath or in their sweat or urine that results from the high levels of phenylalanine in the body.

The severe symptoms of classic PKU begin several months after birth, when the baby begins to have seizures, its head appears abnormally small in proportion to the rest of the body, and normal mental development slows down. In later life such children may become hyperactive or develop other neurological problems.

Babies who are born to mothers with uncontrolled PKU (mothers who no longer follow the special PKU diet) are at high risk of being born with mental retardation because they are exposed to high levels of phenylalanine in the mother's blood before birth. These infants may also have a low birth weight and grow more slowly than other children. In addition, the mother has an increased risk of miscarriage before the baby is born.


Phenylketonuria is more common in some countries and ethnic groups than in others. In the United States, it affects about one child in every

10,000–15,000; however, in Turkey it affects one child in every 2,600. High rates of PKU also occur in Ireland, certain parts of Yemen, Eastern Europe, Italy, and China. The country with the lowest rate of PKU is Finland, where only one child in 100,000 is diagnosed with PKU.

In the United States, PKU is more common among Caucasians and Asians than in other races and ethnic groups. It affects males and females equally.

Causes and Symptoms

PKU is caused by a mutation in the PAH gene on chromosome 12. As of 2008 more than 400 mutations in this gene have been identified that can cause PKU. A child must inherit defective genes from both parents in order to develop PKU. Children who have not inherited defective genes from both parents, however, can still be carriers of a defective gene from one of their parents. If such a carrier marries another carrier, the couple has one chance in four of having a baby with PKU.

A person with a defective PAH gene from both parents will lack an enzyme that is needed to convert phenylalanine to other compounds that the body can use. As the unconverted phenylalanine builds up in the baby's body, it begins to damage the brain and central nervous system, leading to the characteristic symptoms of PKU.

In addition to mental retardation, seizures, and the characteristic musty odor associated with PKU, children with the disorder may have the following symptoms:

  • Delayed social skills
  • Hyperactivity
  • Jerking movements of the arms and legs
  • Skin rashes
  • Tremor
  • Self-mutilation
  • Tendency to hold the hands in unusual positions


Most children in the United States and other developed countries undergo mandatory screening programs shortly after birth. The test most commonly used to check for PKU in the United States is the Guthrie test, introduced in 1962, which consists of taking a blood sample from a newborn by the heelstick method. The test is sensitive enough to detect high levels of phenylalanine shortly after birth. In a few cases children may have to have a second blood test at two weeks of age to confirm the diagnosis. It is important to detect PKU as quickly as possible so that treatment can be started promptly, as children who are not treated will become mentally retarded by the end of their first year.


The central form of treatment for phenylketonuria is strict adherence to a diet that is low in phenylalanine. PKU is one of a small number of genetic disorders that can be treated by diet alone. The PKU diet severely restricts or eliminates foods high in phenylalanine, including breast milk, meat, chicken, fish, nuts, cheese, legumes and other dairy products. The person's intake of potatoes, bread, pizza, corn, pasta, and other starchy foods must be carefully monitored. Many diet foods and soft drinks that contain aspartame (NutraSweet) must also be avoided. In many cases the PKU diet must be supplemented with iron and other nutrients that are usually found in foods high in phenylalanine. To provide some variety at mealtimes, there are companies that make low-protein pastas, breads, imitation cheese, baking mixes, and other foods for people with PKU. These foods are covered by medical benefits in some states.

The Doctor Who Discovered PKU

Ivar Asbjørn Følling (1888–1973) was a Norwegian physician and biochemist who identified phenylketonuria and determined its cause. His discovery began in January 1934 when a young mother consulted him about her two children, a son and a daughter, who had been normal at birth but were slowly becoming mentally retarded. When the son was about a year old, Mrs. Egeland noticed that his urine had a strange smell. She consulted Følling because she knew he was an expert in nutritional biochemistry.

Dr. Følling studied the child's urine in the laboratory and discovered that it contained a chemical related to the amino acid phenylalanine that had never before been identified in human urine. Følling then found that Mrs. Egeland's children lacked the ability to make use of phenylalanine in the diet. He then studied children in a nearby institution for the mentally retarded and found that a significant number of them had the same condition as the Egeland children. Although it took some years afterward for Følling to work out a diet that would protect children with PKU from retardation, his work has saved thousands of children since the 1930s.

Dr. Følling has been termed the most important medical scientist who failed to receive a Nobel Prize for his work. His identification of PKU was a watershed in medicine because it was the first time that a medical researcher demonstrated that a mental disorder like retardation can have a completely biochemical cause.

There is a special infant formula called Lofenalac for babies with PKU. Lofenalac can be used throughout life as a protein source that is

low in phenylalanine and balanced for the remaining essential amino acids.

At one time it was thought that teenagers over the age of eighteen and adults with PKU could stop using the special diet. As of 2008, however, doctors recommended remaining on the PKU diet for life. One reason is maintaining children's normal mental development; children who go off the special diet may lose ten points in IQ or even more. Another reason is lowering the risk of severe PKU in children born to mothers with the disease. Pregnant women with PKU who go off the special diet risk having children who are severely mentally retarded.

In 2007 the Food and Drug Administration (FDA) approved the use of Kuvan, a medication taken by mouth, which supplements the body's production of the enzyme that is needed to digest phenylalanine. The drug was considered an orphan drug until 2004, when the FDA encouraged its further development to treat PKU. Kuvan does not work for all children, however, and some doctors are concerned that children who do benefit from it (about 50 percent of children with classic PKU) may become careless about eating foods containing phenylalanine.

Some children with PKU require psychotherapy in later childhood or adolescence because of problems with self-esteem or frustration with having to follow a restricted diet.


The prognosis of children (and adults) with phenylketonuria depends largely on their willingness to adhere to the PKU diet. Some children and adolescents “cheat” on the diet by eating such foods as French fries, pizza with cheese, potato chips, and bread. Vomiting, severe behavioral disorders, and loss of memory or the ability to concentrate have all been found in people with PKU who go off the special diet. Children and adults who are careful about what they eat and see a nutritionist regularly (once a month is recommended) usually do very well.


Women diagnosed with PKU can help their unborn children by careful adherence to the special diet. People who do not have PKU themselves but have relatives with the disorder may be carriers of the disease. They can have a genetic test before having children to determine whether they are at risk of having a child with PKU.

The Future

The FDA is conducting ongoing tests of Kuvan to see whether it could be modified to benefit more children with PKU. It is possible that other drugs will be developed to treat children with PKU who are not presently helped by Kuvan.

SEE ALSO Developmental disability; Eczema


Amino acids: A group of twenty compounds that are the building blocks of proteins in humans and other animals.

Heelstick: A method for taking a sample of blood from a newborn by pricking the baby's heel with a needle and collecting a drop or two of blood on special filter paper.

Orphan drug: A drug defined by the Food and Drug Administration (FDA) as intended to treat a disease or condition that affects less than 200,000 people in the United States, or a disease of condition that affects more than 200,000 people and there is no reasonable expectation that the company can recover the costs of developing the drug.

Phenylalanine: The amino acid that cannot be used by the bodies of people with phenylketonuria.

For more information


Chiu, Lisa Seachrist. When a Gene Makes You Smell Like a Fish—and Other Tales about the Genes in Your Body. New York: Oxford University Press, 2007.

Kaufman, Seymour. Overcoming a Bad Gene: The Story of the Discovery and Successful Treatment of Phenylketonuria, a Genetic Disease That Causes Mental Retardation. Bloominton, IN: AuthorHouse, 2004.


“FDA Approves Kuvan for Treatment of Phenylketonuria (PKU).” FDA News, December 13, 2007. Available online at (accessed May 17, 2008).


Dolan DNA Learning Center. Phenylketonuria (PKU). Available online at (accessed May 17, 2008). This is an interactive tutorial about PKU.

Genetics Home Reference. Phenylketonuria. Available online at (update January 2008; accessed May 17, 2008).

National Human Genome Research Institute (NHGRI). Learning about Phenylketonuria (PKU). Available online at (updated November 27, 2007; accessed May 17, 2008).

National Institute of Child Health and Human Development (NICHD). Phenylketonuria (PKU). Available online at (updated August 25, 2006; accessed May 17, 2008).

PKU Clinic, University of Washington, Seattle. What Is the Diet for PKU? Available online at (accessed May 17, 2008). Contains a brightly colored graphic illustrating good food choices as well as written information about the diet.

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