Phenylketonuria

Phenylketonuria (PKU) is a rare, inherited, metabolic disorder that can result in mental retardation and other neurological problems. People with this disease have difficulty breaking down and using (metabolizing) the amino acid phenylalanine. PKU is sometimes called Folling's disease in honor of Dr. Asbjorn Folling who first described it in 1934.

Phenylalanine is an essential amino acid. These substances are called "essential" because the body must get them from food to build the proteins that makeup its tissues and keep them working. Therefore, phenylalanine is required for normal development. Phenylalanine is a common amino acid and is found in all natural foods. However, natural foods contain more phenylalanine than required for normal development. This level is too high for patients with PKU, making a special low-phenylalanine diet a requirement.

The incidence of PKU is approximately one in every 15,000 births (1/15,000).There are areas in the world where the incidence is much higher, particularlyIreland and western Scotland. In Ireland the incidence of PKU is 1/4,500 births. This is the highest incidence in the world and supports a theory that the genetic defect is very old and of Celtic origin. Countries with very littleimmigration from Ireland or western Scotland tend to have low rates of PKU.In Finland, the incidence is less than 1/100,000 births. Caucasians in the United States have a PKU incidence of 1/8,000, whereas Blacks have an incidenceof 1/50,000.

There are a number of specific types of PKU. Maternal phenylketonuria is a condition in which a high level of phenylalanine in a mother's blood causes mental retardation in her child when in the uterus. A woman who has PKU and is not using a special low-phenylalanine diet will have high levels of phenylalanine in her blood. Her high phenylalanine levels will cross the placenta and affect the development of her child. The majority of children born from thesepregnancies are mentally retarded and have physical problems, including smallhead size (microcephaly) and congenital heart disease. Most of these children do not have PKU. There is no treatment for maternal phenylketonuria. Control of maternal phenylalanine levels is thought to limit the effects of maternal phenylketonuria.

Hyperphenylalaninemia is a condition in which patients have high levels of phenylalanine in their blood, but not as high as seen in patients with classical PKU. There are two forms of hyperphenylalaninemia: mild and severe.

Tyrosinemia is characterized by a high levels of two amino acids in the blood, phenylalanine and tyrosine. Patients with this disease have many of the same symptoms as seen in classical PKU, including mental retardation. Treatmentconsists of a special diet similar to the diet for PKU. The main difference between the two diets is that patients with tyrosinemia must eat a diet that is low in both phenylalanine and tyrosine.

The underlying cause of PKU is mutation in the gene that tells the body to make the enzyme phenylalanine hydroxylase. This enzyme allows the body to breakdown phenylalanine and ultimately use it to build proteins. Normally, the first step in phenylalanine metabolism is conversion to tyrosine, another aminoacid. The genetic mutations result in no enzyme or poor quality enzyme beingmade. As a consequence, phenylalanine is not converted and builds up in thebody. The high levels of phenylalanine can be detected in the blood and urine.

PKU is a genetic disease. A child must inherit defective genes from both parents to develop PKU. A person with one defective gene and one good gene will develop normally because the good gene will make sufficient phenylalanine hydroxylase. People with one good gene are called carriers because they do not have the disease, but are capable of passing the defective gene on to their children.

If both parents are carriers of defective phenylalanine hydroxylase genes, then the chances of their child having PKU is one in four or 25%. The chances that their child will be a carrier is two in four, or 50%. These percentages hold for each pregnancy.

Children with PKU appear normal at birth, but develop irreversible mental retardation unless treated early. Treatment consists of a special diet that contains very little phenylalanine. This diet must be used throughout the patient's life. Untreated newborns develop disease symptoms at age three to five months. At first they appear to be less attentive and may have problems eating.By one year of age, they are mentally retarded.

Patients with PKU tend to have lighter colored skin, hair, and eyes than other family members. They are also likely to have eczema and seizures. PKU patients have a variety of neurologic symptoms. Approximately 75-90% of PKU patients have abnormal electrocardiograms (ECGs), which measure the activity of their heart. Their sweat and urine may have a "mousy" smell that is caused by phenylacetic acid, a byproduct of phenylalanine metabolism. Untreated PKU children tend to be hyperactive and demonstrate loss of contact with reality (psychosis).

PKU must be detected shortly after birth. Although children with PKU appear normal at birth, they already have high phenylalanine levels. Screening is theonly way to detect PKU before symptoms start to develop. In many areas of the world, screening newborns for PKU is performed routinely. The test is typically performed between one and seven days after birth. Blood is obtained by pricking the heel of the newborn and analyzing it for phenylalanine concentration.

The only treatment for persons with PKU is to limit the amount of phenylalanine in their diet. PKU patients should eat a special diet that is low in phenylalanine. The diet has small amounts of phenylalanine because it is essentialfor normal growth and development. The diet should be started before the fourth week of life to prevent mental retardation. If started early enough, thediet is 75% effective in preventing severe mental retardation. Many natural foods, including breast milk, must be avoided because they contain more phenylalanine than PKU patients can tolerate. However, low protein, natural foods,including fruits, vegetables, and some cereals, are acceptable on the diet. Monitoring of blood phenylalanine levels must be done to ensure that normal levels are maintained.

Patients who make a small amount of phenylalanine hydroxylase can eat a limited amount of regular food if their phenylalanine levels remain within an acceptable range. Low-phenylalanine and phenylalanine-free foods are available commercially. The special diet must be used throughout the patient's life.

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