What is phenylketonuria (PKU)?

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A genetic disorder caused by a deficiency of the liver enzyme phenylalanine hydroxylase.
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Causes and Symptoms

Phenylketonuria (PKU) is a genetic disorder, occurring in about one in 10,000 births, that disrupts the metabolism of the amino acid phenylalanine. The disorder is caused by a deficiency of phenylalanine hydroxylase, a liver enzyme that catalyzes the conversion of phenylalanine to tyrosine. Since normal phenylalanine metabolism is blocked, the amino acid accumulates in blood and tissues, resulting in progressive, irreversible mental retardation and neurological abnormalities. Most forms of PKU are caused by a mutation—more than two hundred mutations are now characterized—in the gene for phenylalanine hydroxylase. A small percentage of infants with PKU have a variant form of the condition, known as malignant PKU. This disorder is caused by a defect in the synthesis or metabolism of tetrahydrobiopterin, a cofactor for the conversion of phenylalanine to tyrosine, or in other enzymes along the pathway. Without treatment, malignant PKU causes a progressive, lethal deterioration of the central nervous system.

Infants with classic and malignant PKU appear normal; however, if untreated, the condition severely impairs normal brain development and growth after a few months of age, causing mental retardation, seizures, eczema, and neurological and behavioral problems. Affected infants have plasma phenylalanine levels ten to sixty times above normal, along with normal or reduced tyrosine levels and high concentrations of the metabolite phenylpyruvic acid in their urine.

Newborns are screened routinely for PKU within the first three weeks of life, usually by using whole blood obtained from a heel prick. Elevated phenylpyruvic acid levels also can be detected in urine of infants with PKU after adding a few drops of 10 percent ferric chloride, resulting in a deep green color. Newborns often have transient PKU—elevated phenylalanine and phenylpyruvic acid levels in the first few weeks of life that normalizes—so classic PKU should be distinguished from transient conditions. Elevated phenylalanine levels that persist beyond a few weeks of life, accompanied by normal or low tyrosine levels, usually indicate an inborn error of metabolism. Malignant PKU is usually diagnosed by detecting biopterin metabolites in urine or showing that tetrahydrobiopterin supplementation restores normal phenylalanine and tyrosine levels.

Babies of mothers with PKU are at high risk of brain damage, impaired growth, and malformations of the heart and other organs. Managing maternal phenylalanine levels at near normal concentrations appears to be crucial to preventing these cognitive and neurological defects.

The clinical basis for the damaging effects of PKU on the brain is unclear. Elevated phenylalanine levels may interfere with brain myelination or neuronal migration during development. In addition, PKU decreases the levels of the neurotransmitters dopamine and serotonin, which may be the basis for its neurological effects.

Treatment and Therapy

The detrimental effects of PKU can largely be controlled by maintaining phenylalanine levels in the normal range through a strict low-phenylalanine diet. This complex diet, often supplemented with tyrosine, prevents the buildup of phenylalanine and its metabolites in body tissues. Children whose phenylalanine levels are regularly monitored and managed can achieve normal intelligence and development. In infants with malignant PKU, tetrahydrobiopterin or cofactor supplements are required to control phenylalanine levels successfully.

Treatment for PKU must begin at a very early age, before the first three months of life, and usually continue through adulthood, or else some degree of mental retardation or neurological abnormalities is expected. Screening newborns for PKU before three weeks of age is mandated in all fifty US states. Strict control of phenylalanine levels also is indicated for pregnant women with PKU because their babies are at high risk for severe brain damage.

The successful treatment of PKU depends on managing phenylalanine levels. However, the diet is complex and challenging to sustain over many years. Since phenylalanine is an essential amino acid, found in virtually all proteins, maintaining adequate nutrition is nearly impossible on a low-phenylalanine diet. The treatment requires rigorous protein restriction and the substitution of most natural proteins in meat, fish, eggs, and dairy products. Phenylalanine intake must not be too restricted, however, or else phenylalanine deficiency can occur.

In some cases, dietary treatment for PKU can be discontinued or made less restrictive as children age, without causing severe effects. In many cases, however, the ill effects of the disorder carry into adulthood unless dietary management is continued over the long term. Untreated adolescents and adults may exhibit behavioral or neurological problems, difficulty concentrating, poor visual-motor coordination, and a low intelligence quotient (IQ).

Perspective and Prospects

Phenylketonuria was the first inborn error of metabolism shown to affect the brain. This genetic disorder was discovered in the 1930s by Ivar Asbjørn Følling. Since its discovery, PKU has been controlled successfully by rigorous newborn screening programs and careful dietary management of phenylalanine levels in pregnant women and in children with the disease. Newer research has focused on improving medical formulations for low-phenylalanine diets and amino acid supplementation for children and adults.

In the 1980s, clinical trials examined the use of dialysis-like procedures that allowed the rapid breakdown of phenylalanine in the blood. The treatment applies to pregnant women with PKU or those with severely elevated phenylalanine levels resulting from stress or illness. In the late twentieth century, PKU became the focus of gene therapy research. Animal models of PKU have been successfully treated by introducing normal phenylalanine hydroxylase deoxyribonucleic acid (DNA) into the liver cells of mice. Since the underlying genetic defects are known in most cases of PKU, gene therapy appears a likely research focus for long-term treatment.


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