What is PKU?

PKU (phenylketonuria), in its “classic” form, is a rare, inherited metabolic disease that results in mental retardation and other neurological problems when treatment is not started within the first few weeks of life. When treatment is begun early and well-maintained, affected children can expect normal development and a normal life span. (Not all elevations of blood phenylalanine require treatment; any child with a level less than 6 mg/dl does not need to be on a special diet and is not risk for mental retardation.) Until recently, the only treatment was a very strict diet that limits the amino acid, phenylalanine. Now, however, there is a drug called Kuvan that can help in some cases.

The Enzyme Deficiency

The disease arises from the absence of a single enzyme called phenylalanine hydroxylase. This enzyme normally converts the essential amino acid, phenylalanine, to another amino acid, tyrosine. Failure of the conversion to take place results in a buildup of phenylalanine. Through a mechanism that is not well understood, the excess phenylalanine is toxic to the central nervous system and causes the severe problems normally associated with PKU. Not every child has the same degree of enzyme deficiency and thus the treatment for each child has to be individualized. The nature of the treatment for an individual child must be determined by an experienced PKU treatment program.

Genetics

PKU is carried through an "autosomal recessive" gene. This means that two people who conceive a child must both be "silent carriers" of the gene in order for there to be a chance that the baby will have PKU. When two carriers conceive a child, there is a one in four (or 25%) chance for each pregnancy that the baby will have PKU. The incidence of carriers in the general population is approximately one in fifty people, but the chance that two carriers will mate is only one in 2500. Carrier tests are available only through PKU treatment programs.

Over 500 different genetic mutations have been identified that result in defective functioning of the phenylalanine hydroxylase enzyme, resulting in elevated phenylalanine levels. Each different mutation or combination of mutations results in more or less enzyme activity in the effected person.

Screening

Because of the very positive outcome when children are treated early and well, newborn screening for PKU is carried out in every state in the US and in many other countries. Such screening started in the mid-1960's. Although PKU affects only one out of every approximately 10,000 babies born in the US, there are several hundred babies diagnosed and put on the diet each year. Children with the severe form of PKU once were destined to become mentally retarded and spend their lives in institutions. Children with the disease are now growing up normally. They are attending college and becoming productive adults as doctors, lawyers, teachers and engineers because of early diagnosis and strict treatment.

Treatment Options

The diet for PKU was developed in the 1960’s, and until December 2007 when the new drug Kuvan was approved by FDA, it has been the ONLY treatment shown to be effective.

Diet. The diet for the most severe form of PKU, called “classic PKU,” eliminates all of the very high protein foods since all protein contains phenylalanine. This means that all concentrated sources of protein must be eliminated from the diet in order to limit the amount of phenylalanine. Except in rare circumstances, the diet does not allow consumption of meat, fish, poultry, milk, eggs, cheese, ice cream, legumes, nuts, or many products containing regular flour.

A synthetic formula is used as a nutritional substitute for the eliminated foods. This formula is very expensive. Fortunately, a number of states have mandated insurance coverage for the cost, or in some instances the state health department may provide the formula to families of affected children. There are many different formula options available now, from powders that mix with liquid (the traditional form) to pills and various flavored bars.

The diet is supplemented with special low protein foods and weighed or measured amounts of fruits, vegetables and some grain products. These foods are allowed in quantities that suit the individual child's tolerance for phenylalanine; some can have fairly liberal diets and still maintain good control of blood phe, while others must have a very strict diet. Some states now have laws mandating insurance coverage of the expensive special low protein foods.

Kuvan. Kuvan, produced by Biomarin Pharmaceutical Inc., is a drug that, in some people with PKU, can enhance enzyme activity and lower blood phe levels. Kuvan is a form of the cofactor for the phenylalanine hydroxylase enzyme, called tetrahydrobiopterin or BH4. When given in sufficiently large doses, it can cause whatever residual enzyme activity exists to work harder and thereby reduce blood phe levels. It is most likely to be effective in those with significant residual enzyme activity, such as those with “variant” PKU or mild hyperphenylalaninemia. It is not possible to know in advance whether an individual with PKU will be responsive to the drug, so it must be tried for a length of time to determine if it will be effective. If it is effective, then a dosage requirement needs to be determined by the doctor. In rare cases, someone on the diet has been able to discontinue the diet entirely; but more typically, use of Kuvan has resulted in greater tolerance for dietary phenylalanine while the diet is still maintained.

Unlike for diet treatment, where we have nearly 50 years of experience, there is no long term experience with Kuvan. FDA approval was based on short term trials which showed the side effects were not significant and demonstrated that it helped some individuals to lower blood phe levels and/or improve dietary tolerance for phenylalanine.

(Please see the Research section of this website, Should I try the New Drug? Weighing Risks versus Benefits, from the Fall 2007 issue of National PKU News, for concerns about this drug).

Diet Maintenance

In the early days of treating PKU, clinicians believed that treatment could be stopped at an early age (6-10 years). However, it is now known that stopping treatment can result in a variety of serious problems, especially for those with “classic” PKU, the most serious type. These include drops in IQ, learning disabilities, behavior problems such as hyperactivity and irritability, neurological problems such as tremors, eczema (a skin disorder) and personality disorders (including schizophrenia, panic attacks and agoraphobia).

As a result of the problems that have developed in young people who have discontinued treatment, it is believed that treatment should be maintained for a lifetime. It is also now generally believed that keeping blood phenylalanine levels in the range of 2-6 mg/dl is the safest, especially in infancy and early childhood. Frequent blood monitoring to achieve this goal is critical. All individuals, male or female, who have stopped treatment would be wise to return to treatment under the supervision of a PKU treatment program.

Maternal PKU

Continuing the diet or returning to the diet for women who have stopped it is especially important for young women with PKU who want to become pregnant. Kuvan is not suitable for women who are pregnant, as it has not been tested for this group of women, so diet treatment is mandatory. Women with PKU who have high levels of phenylalanine in their blood have a very large probability of harming their unborn baby. "Maternal PKU" has become a significant concern as young women who were once taken off the diet are now reaching childbearing ages in ever-increasing numbers. A large collaborative study has shown that returning the woman to diet before conception and keeping blood phenylalanine levels below 6 mg/dl results in the best outcome for the baby. Many children born to mothers with PKU are developing normally because of early and strict treatment.

PKU Treatment Programs

There is at least one specialized PKU treatment program in most US states. In some less-populated states, families may need to travel to another nearby state, or the treatment may be coordinated through a state health department. All children with PKU ideally should be followed by a specialized PKU program with adequate monitoring facilities. Information about the nearest PKU treatment program can be obtained through the state newborn screening program.