CONDITION: PHENYLKETONURIA (PKU)

CLINICAL SYMPTOMS: Children born with PKU may appear to be normal for the first few months. Untreated, at three to five months they begin to lose interest in their surroundings, and by the time they are one year old, they are mentally retarded. Children with PKU often are irritable, restless and destructive. They may have a musty odor about them, and they often have dry skin or rashes. Some have seizures. However, they are physically well developed. They may have lighter coloring than their relatives.

PATHOLOGY: Phenylalanine hydroxylase (PAH) is reduced or absent, leading to the presence of excess phenylalanine, which interferes with the normal development of the brain, and, in particular, with the development of myelin, a protective covering for nerves. In about 1-3% of cases, a coenzyme vital to the normal function of PAH is deficient. PROGNOSIS: Without treatment, PKU generally leads to severe mental retardation. Children whose blood phenylalanine levels are under strict control from the first few months of life develop normally with no symptoms of PKU. Children whose blood phenylalanine levels are less strictly controlled develop intellectual deficits.

INHERITANCE: autosomal recessive

PREVALENCE: 1:10,000 to 1:15,000

RELEVANT TESTING: Newborn babies can be tested for PKU when only two days old. The baby's heel is pricked and a few drops of blood are taken. The blood is sent to a state or regional screening laboratory to find out if it has an increased amount of phenylalanine. If so, more tests are done to learn whether the baby has PKU or some other cause of high phenylalanine. The gene for PAH is located near the end of the long arm of chromosome 12 (12q24.1). DNA testing is available for prenatal diagnosis and for carrier testing. Because there are so many mutations and the DNA test is expensive ($500-$1,000), DNA testing is not suitable for population screening. In couples in which one member has PKU or is a sibling of a person with PKU and the other has the population risk for being a carrier, the couple may prefer to use biochemical studies for preliminary testing before incurring the expense of DNA studies.

TREATMENT: The baby is put on a low phenylalanine diet. No regular cow's milk formula or meat are allowed because these protein foods have too much phenylalanine in them. At first, the baby is fed a protein formula milk that contains only the amount of phenylalanine required for normal development. Later, certain vegetables and other foods that are low in phenylalanine are added. The affected family incurs a cost of about $10,000 per child per year for formula and low protein food. In many states, the cost of formula is covered by health insurance. In addition, some states have mandated insurance coverage for special low protein foods.

As the child grows, blood samples are tested regularly because the diet has to be changed if the amount of phenylalanine becomes either too high or too low. Children should stay on a low phenylalanine diet as long as possible. In school-age children, a slightly higher blood phenylalanine level than in infancy is probably acceptable.

Researchers have identified a number of different mutations that result in PKU. It may someday be possible to replace the mutant PAH gene in cells in the liver, where the gene is active, using retroviruses to insert the normal gene.

When a woman who has untreated PKU becomes pregnant, her baby is likely to be born mentally retarded and may have congenital heart disease. This situation, known as maternal PKU, has become a great problem because many girls who were treated for PKU and grew up normally are now having babies. Their infants rarely inherit PKU but are likely to be brain-damaged as a result of having been exposed in the womb to their mothers' altered phenylalanine metabolism. There is hope that the fetal damage may be prevented by treatment of the mother during pregnancy with the special low phenylalanine diet. It seems that the best results are obtained when the woman with PKU attains strict control of her blood phenylalanine level before she becomes pregnant, and maintains it throughout the pregnancy. It has been estimated that the cost of special formula to sustain a woman throughout a pregnancy is about $11,000.

An alternative approach to prevent maternal PKU would be in vitro fertilization using egg and sperm from the parents, followed by implantation in a surrogate mother who does not have PKU.