What is PKU?

Definition

Phenylketonuria (PKU) can be defined as a rare metabolic disorder caused by a deficiency in the production of the hepatic (liver) enzyme phenylalanine hydroxylase (PAH). PKU is the most serious form of a class of diseases referred to as "hyperphenylalaninemia," all of which involve above normal (elevated) levels of phenylalanine in the blood. The primary symptom of untreated PKU, mental retardation, is the result of consuming foods that contain the amino acid phenylalanine, which is toxic to brain tissue.

PKU is an inherited, autosomal recessive disorder. It is the most common genetic disease involving "amino acid metabolism." PKU is incurable, but early, effective treatment can prevent the development of serious mental incapacity.

PKU facts provided by March of Dimes

PKU (phenylketonuria) is an inherited disorder of body chemistry that, if untreated, causes mental retardation. Fortunately, through routine newborn screening, almost all affected newborns are now diagnosed and treated early, allowing them to grow up with normal intelligence.

About 1 baby in 14,000 is born with PKU in the United States . The disorder occurs in all ethnic groups, although it is more common in individuals of Northern European and Native American ancestry than in those of African-American, Hispanic and Asian ancestry.

What is PKU?
Due to a missing or deficient enzyme, children with PKU cannot process a part of the protein called phenylalanine, which is present in nearly all foods. Without treatment, phenylalanine builds up in the bloodstream and causes brain damage and mental retardation.

How does PKU affect a child?
Children born with PKU appear normal for the first few months. If untreated, by three to six months they begin to lose interest in their surroundings and, by the time they are a year old, they are obviously developmentally delayed. Children with untreated PKU who have suffered central nervous system damage often are irritable, restless and destructive. They may have a musty odor about them, and may have dry skin, rashes or convulsions. They usually are physically well developed and tend to have blonder hair than their siblings.

Who gets PKU?
PKU is inherited when both parents have the PKU gene and both pass it on to their baby. A parent who has the PKU gene, but not the disease, is called a "carrier." A carrier has a normal gene as well as a PKU gene in each cell. A carrier's health is not affected in any known way.

When both parents are carriers, there is a one-in-four (25 percent) chance that both will pass the PKU gene on to a child, causing the child to be born with the disease. There also is a two in four (50-50) chance that the baby will inherit the PKU gene from one parent and the normal gene from the other, making it a carrier like its parents. There also is a one-in-four chance that both will pass on the normal gene, and the baby will neither have the disease nor be a carrier. These chances are the same in each pregnancy.

Are all babies tested for PKU?
All states and U.S. territories screen for PKU. Babies are tested before they leave the hospital. This was the nation’s first newborn screening test. Developed with the help of the March of Dimes, the test has been routinely administered since the 1960s, sparing thousands of children from mental retardation.

How is the test done?
The baby's heel is pricked and a few drops of blood are taken. (The same blood sample can be used to screen for a number of other inborn errors of body chemistry.) The blood generally is sent to a regional medical laboratory to find out if it has more than a normal amount of phenylalanine, and findings are sent to the health care professional responsible for the baby’s care. If results are abnormal, more tests are done to determine whether the baby has PKU or if there is some other cause of high phenylalanine levels.

The test is highly accurate when performed as recommended, when the baby is more than 24 hours of age but less than seven days. However, early discharge from the hospital is becoming more common, and many babies are tested within the first 24 hours of life. Since some cases of PKU can be missed when the test is performed this early, the American Academy of Pediatrics recommends that infants whose initial test was taken within the first 24 hours of life be tested again at one to two weeks of age.

Can PKU symptoms be prevented?
Yes. Mental retardation can be prevented if the baby is treated with a special diet that is low in phenylalanine begun within the first 7 to 10 days of life.

At first, the baby is fed a special formula that contains protein but no phenylalanine. Breast milk or infant formula is used sparingly to supply only as much phenylalanine as the baby can tolerate. Later, certain vegetables, fruits, some grain products (for example, certain cereals and noodles) and other low-phenylalanine foods are added to the diet, but no regular milk, cheese, eggs, meat, fish and other high protein foods are ever allowed. Since protein is essential for normal growth and development, the child must continue to have one of the special formulas which are high in protein and essential nutrients, but contain little or no phenylalanine. Diet drinks and foods that contain the artificial sweetener aspartame (which contains phenylalanine and is sold as Nutrasweet or Equal) must be strictly avoided.

Children and adults with PKU require follow-up care at a medical center or clinic that specializes in this disorder. The diet for each person must be individualized, depending upon how much phenylalanine can be tolerated, his or her age, weight and other factors. All affected persons need regular blood tests to measure if the levels of phenylalanine are too high or too low. Testing for babies may be as often as once a week for the first year, then once or twice a month throughout childhood. The diet must then be adjusted accordingly.

Individuals with PKU must remain on a restricted diet throughout childhood and adolescence, and generally for life (although some relaxation of the diet may be possible in some cases as the individual ages). Until the 1980s, health care providers believed that children with PKU could safely discontinue their special diet around age 6 when brain growth was completed. However, high blood levels of phenylalanine in children and adolescents can lead to a decrease in IQ, to learning disabilities, and to behavioral disturbances in most—but perhaps not all—children with PKU.

Parents of children with PKU and affected adults should discuss their diet and treatment questions with health care professionals at one of the special clinics for PKU.

What is maternal PKU?
There are an estimated 3,000 healthy young women of childbearing age with successfully treated PKU in the United States . Most discontinued their special diet in childhood because, at that time, most doctors believed it was safe to do so.

If these young women are eating a normal diet, their blood phenylalanine levels are very high when they become pregnant. During pregnancy, high blood levels of phenylalanine in the mother are devastating to the fetus. In up to 90 percent of such cases, the babies will have mental retardation and/or a small head size (microcephaly). Many also will have heart defects, low birthweight and characteristic facial features. Because most of these babies do not inherit PKU, but are suffering from brain damage entirely caused by their mothers’ high phenylalanine levels during pregnancy, they cannot be helped by the PKU diet.

Fortunately, there is a way to help prevent mental retardation and other problems in babies of women with PKU. It is now clear that these young women need to resume their special diets at least three months prior to pregnancy and continue the diet throughout pregnancy. This controls the blood phenylalanine levels so they can have a healthy baby. They will need at least weekly blood tests throughout pregnancy to make sure blood phenylalanine levels are not too high.

The March of Dimes urges all young women who know or suspect that they were treated for PKU as children to contact their health care provider or clinic before they attempt to conceive, so that their blood phenylalanine levels can be measured and the special diet begun, if necessary.

Occasionally, a woman has undiagnosed PKU that can pose a risk to her baby. These women, who generally were not screened as newborns, usually are mildly affected, and may be diagnosed only following the birth of a baby with PKU-related birth defects. In order to help prevent these birth defects, some doctors recommend screening women who may be at risk of PKU, such as those with a family history of the disorder, so affected women can start the PKU diet prior to pregnancy.

What is new in PKU research?
Researchers are studying the long-term outcome for children who were born from treated maternal PKU pregnancies. While these children usually do not have birth defects, researchers want to see if these children reach their full cognitive potential.

Others are developing a genetically engineered version of the missing enzyme, which eventually may allow affected individuals to eat a more normal diet. March of Dimes and other researchers also are exploring the possibility of treating PKU using gene therapy.

Resources:

Brust, John C. M. The Practice Of Neural Science: From Synapses To Symptoms. New York: McGraw-Hill, 2000.
Gilroy, John. Basic Neurology. 3rd ed. New York: McGraw-Hill, 2000.
Koch, Jean Holt. Robert Guthrie-The PKU Story: Crusade Against Mental Retardation. Pasadena, Calif.: Hope Pub. House, 1997.
Ratey, John J. A User's Guide To The Brain: Perception, Attention, And The Four Theaters Of The Brain. 1st ed. New York: Pantheon Books, 2001.
Schuett, Virginia E. Low Protein Cookery For Phenylketonuria. 3rd ed. Madison: University of Wisconsin Press, 1997.
Walker, John M. Genetics and You. Totowa, N.J.: Humana Press, 1996.
Weiner, William J., Christopher G. Goetz, eds. Neurology For The Non-Neurologist. 4th ed. Philadelphia: Lippincott, Williams & Wilkins, 1999.

Periodicals

Burgard, P. "Development of intelligence in early treated phenylketonuria." European Journal of Pediatrics 159, Suppl. 2 (October 2000): S74-9.
Chang, Pi-Nian, Robert M. Gray, and Lisa Lehn O'Brien. "Review: Patterns of academic achievement among patients treated early with phenylketonuria." European Journal of Pediatrics 159, no.14 (2000): S96-9.
Eastman, J.W., J.E. Sherwin, R. Wong, C.L. Liao, R.J. Currier, F. Lorey, and G. Cunningham. "Use of the phenylalanine:tyrosine ratio to test newborns for phenylketonuria in a large public health screening programme." Journal of Medical Screening 7, no. 3 (2000): 131-5.
MacDonald, A. "Diet and compliance in phenylketonuria." European Journal of Pediatrics 159, Suppl. 2 (Oct. 2000): S136-41.
Smith, Isabel, and Julie Knowles. "Behaviour in early treated phenylketonuria: a systematic review." European Journal of Pediatrics 159, no. 14 (2000): S89-93.
Stemerdink, B.A., A.F. Kalverboer, J.J. van der Meere, M.W. van der Molen, J. Huisman, L.W. de Jong, F.M. Slijper, P.H. Verkerk, and F.J. van Spronsen. "Behaviour and school achievement in patients with early and continuously treated phenylketonuria." Journal of Inherited Metabolic Disorders 23, no. 6 (2000): 548-62.
van Spronsen, F.J.F., M.M. van Rijn, J. Bekhof, R. Koch, and P.G. Smit. "Phenylketonuria: tyrosine supplementation in phenylalanine-restricted diets." American Journal of Clinical Nutrition 73, no. 2 (2001): 153-7.

Wappner, Rebecca, Sechin Cho, Richard A. Kronmal, Virginia Schuett, and Margretta Reed Seashore. "Management of Phenylketonuria for Optimal Outcome: A Review of Guidelines for Phenylketonuria Management and a Report of Surveys of Parents, Patients, and Clinic Directors." Pediatrics 104, no. 6 (December 1999): e68.

What is PKU (Phenylketonuria)?