PKU is a disease caused by the liver's inability to produce a particular type of PAH enzyme. This enzyme converts (metabolizes) the amino acid called phenylalanine into another amino acid, tyrosine. This is the only role of PAH in the body. A lack of PAH results in the buildup of abnormally high phenylalanine concentrations (or levels) in the blood and brain. Above normal levels of phenylalanine are toxic to the cells that make up the nervous system and causes irreversible abnormalities in brain structure and function in PKU patients. Phenylalanine is a type of teratogen. Teratogens are any substance or organism that can cause birth defects in a developing fetus.

The liver is the body's chief protein processing center. Proteins are one of the major food nutrients. They are generally very large molecules composed of strings of smaller building blocks or molecules called amino acids. About twenty amino acids exist in nature. The body breaks down proteins from food into individual amino acids and then reassembles them into "human" proteins. Proteins are needed for growth and repair of cells and tissues, and are the key components of enzymes, antibodies, and other essential substances.

The extensive network of nerves in the brain and the rest of the nervous system are made up of nerve cells. Nerve cells have specialized extensions called dendrites and axons. Stimulating a nerve cell triggers nerve impulses, or signals, that speed down the axon. These nerve impulses then stimulate the end of an axon to release chemicals called "neurotransmitters" that spread out and communicate with the dendrites of neighboring nerve cells.

Many nerve cells have long, wire-like axons that are covered by an insulating layer called the myelin sheath. This covering helps speed nerve impulses along the axon. In untreated PKU patients, abnormally high phenylalanine levels in the blood and brain can produce nerve cells with "deformed" axons and dendrites, and cause imperfections in the myelin sheath referred to as hypomyelination and demylenation. This loss of myelin can "short circuit" nerve impulses (messages) and interrupt cell communication. A number of brain scan studies also indicate a degeneration of the "white matter" in the brains of older patients who have not maintained adequate dietary control.

PKU can also affect the production of one of the major neurotransmitters in the brain, called dopamine. The brain makes dopamine from the amino acid tyrosine. PKU patients who do not consume enough tyrosine in their diet cannot produce sufficient amounts of dopamine. Low dopamine levels in the brain disrupt normal communication between nerve cells, which results in impaired cognitive (mental) function.

Some preliminary research suggests that nerve cells of PKU patients also have difficulty absorbing tyrosine. This abnormality may explain why many PKU patients who receive sufficient dietary tyrosine still experience some form of learning disability.

IQ (intelligence quotient) tests provide a measure of cognitive function. The IQ of PKU patients is generally lower than the IQ of their healthy peers. Students with PKU often find academic tasks difficult and must struggle harder to succeed than their non-PKU peers. They may require special tutoring and need to repeat some of their courses. Even patients undergoing treatment programs may experience problems with typical academic tasks as math, reading, and spelling. Visual perception, visual-motor skills, and critical thinking skills can also be affected. Ten years of age seems to be an important milestone for PKU patients. After age 10, variations in a patient's diet seems to have less influence on their IQ development.

People with PKU tend to avoid contact with others, appear anxious and show signs of depression. However, some patients may be much more expressive and tend to have hyperactive, talkative, and impulsive personalities. It is also interesting to note that people with PKU are less likely to display such "antisocial" habits as lying, teasing, and active disobedience. It should be emphasized that current research findings are still quite preliminary and more extensive research is needed to clearly show how abnormal phenylalanine levels in the blood and brain might affect behavior and academic performance.

One in fifty individuals in the United States have inherited a gene for PKU. About five million Americans are PKU carriers. About one in 15,000 babies test positive for PKU in the United States. Studies indicate that the incidence of this disease in Caucasian and Native American populations is higher than in African-American, Hispanic, and Asian populations.

PKU symptoms are caused by alterations or "mutations" in the genetic code for the PAH enzyme. Mutations in the PAH gene prevent the liver from producing adequate levels of the PAH enzyme needed to break down phenylalanine. The PAH gene and its PKU mutations are found on chromosome 12 in the human genome. In more detail, PKU mutations can involve many different types of changes, such as deletions and insertions, in the DNA of the gene that codes for the PAH enzyme.

PKU is described as an inherited, autosomal recessive disorder. The term autosomal means that the gene for PKU is not located on either the X or Y sex chromosome. The normal PAH gene is dominant to recessive PKU mutations. A recessive genetic trait, such as PKU, is one that is expressed—or shows up—only when two copies are inherited (one from each parent).

A person with one normal and one PKU gene is called a carrier. A carrier does not display any symptoms of the disease because their liver produces normal quantities of the PAH enzyme. However, PKU carriers can pass the PKU genetic mutation onto their children. Two carrier parents have a 25% chance of producing a baby with PKU symptoms, and a 50% chance having a baby that is a carrier for the disease. Although PKU conforms to these basic genetic patterns of inheritance, the actual expression, or phenotype, of the disease is not strictly an "either/or" situation. This is because there are at least 400 different types of PKU mutations. Although some PKU mutations cause rather mild forms of the disease, others can initiate much more severe symptoms in untreated individuals. The more severe the PKU mutation, the greater the effect on cognitive development and performance (mental ability).

Untreated PKU patients develop a broad range of symptoms related to severely impaired cognitive function, sometimes referred to as mental retardation. Other symptoms can include extreme patterns of behavior, delayed speech development, seizures, a characteristic body odor, and light body pigmentation. The light pigmentation is due to a lack of melanin, which normally colors the hair, skin and eyes. Melanin is made from the amino acid tyrosine, which is lacking in untreated cases of PKU. Physiologically, PKU patients show high levels of phenylalanine and low levels of tyrosine in the blood. Babies do not show any visible symptoms of the disease for the first few months of life. However, typical PKU symptoms usually do show up by a baby's first birthday.

The primary diagnostic test for PKU is the measurement of phenylalanine levels in a drop of blood taken from the heel of a newborn baby's foot. This screening procedure is referred to as the Guthrie test (Guthrie bacterial inhibition assay). In this test, PKU is confirmed by the appearance of bacteria growing around high concentrations of phenylalanine in the blood spot. PKU testing was introduced in the early 1960s and is the largest genetic screening program in the United States. It is required by law in all 50 states. Early diagnosis is critical. It ensures early the treatment PKU babies need to develop normally and avoid the ravages of PKU.

The American Academy of Pediatrics recommends that this test should be performed on infants between 24 hours and seven days after birth. The preferred time for testing is after the baby's first feeding. If the initial PKU test produces a positive result, then follow-up tests are performed to confirm the diagnosis and to determine if the elevated phenylalanine levels may be caused by some medical condition other than PKU. Treatment for PKU is recommended for babies that show a blood phenylalanine level of 7–10 mg/dL or higher for more than a few consecutive days. Another, more accurate test procedure for PKU measures the ratio (comparison) of the amount of phenylalanine to the amount of tyrosine in the blood.

Newer diagnostic procedures (called mutation analysis and genotype determination) can actually identify the specific types of PAH gene mutations inherited by PKU infants. Large-scale studies have helped to clarify how various mutations affect the ability of patients to process phenylalanine. This information can help doctors develop more effective customized treatment plans for each of their PKU patients.

The severity of the PKU symptoms experienced by people with this disease is determined by both lifestyle as well as genetic factors. In the early 1950s, researchers first demonstrated that phenylalanine-restricted diets could eliminate most of the typical PKU symptoms—except for mental retardation. Today, dietary therapy (also called nutrition therapy) is the most common form of treatment for PKU patients. PKU patients who receive early and consistent dietary therapy can develop fairly normal mental capacity to within about five IQ points of their healthy peers. By comparison, untreated PKU patients generally have IQ scores below 50.

Infants with PKU should be put on a specialized diet as soon as they are diagnosed to avoid progressive brain damage and other problems caused by an accumulation of phenylalanine in the body. A PKU diet helps patients maintain very low blood levels of phenylalanine by restricting the intake of natural foods that contain this amino acid. Even breast milk is a problem for PKU babies. Special PKU dietary mixtures or formulas are usually obtained from medical clinics or pharmacies.

Phenylalanine is actually an essential amino acid. This means that it has to be obtained from food because the body cannot produce this substance on its own. Typical diets prescribed for PKU patients provide very small amounts of phenylalanine and higher quantities of other amino acids, including tyrosine. The amount of allowable phenylalanine can be increased slightly as a child becomes older.

In addition, PKU diets include all the nutrients normally required for good health and normal growth, such as carbohydrates, fats, vitamins, and minerals. High protein foods like meat, fish, chicken, eggs, nuts, beans, milk, and other dairy products are banned from PKU diets. Small amounts of moderate protein foods (such as grains and potatoes) and low protein foods (some fruits and vegetables, low protein breads and pastas) are allowed. Sugar-free foods, such as diet soda, which contain the artificial sweetener aspartame, are also prohibited foods for PKU patients. That is because aspartame contains the amino acid phenylalanine.

Ideally, school-age children with PKU should be taught to assume responsibility for managing their diet, recording food intake, and for performing simple blood tests to monitor their phenylalanine levels. Blood tests should be done in the early morning when phenylalanine levels are highest. Infants and young children require more frequent blood tests than older children and adults. The amount of natural foods allowed in a diet could be adjusted to ensure that the level of phenylalanine in the blood is kept within a safe range—two to 6 mg/dL before 12 years of age and 2–15 mg/dL for PKU patients over 12 years old.

A specialized PKU diet can cause abnormal fluctuations in tyrosine levels throughout the day. Thus, some health professionals recommend adding time released tyrosine that can provide a more constant supply of this amino acid to the body. It should be noted that some PKU patients show signs of learning disabilities even with a special diet containing extra tyrosine. Research studies suggests that these PKU patients may not be able to process tyrosine normally.

For PKU caregivers, providing a diet that is appealing as well as healthy and nutritious is a constant challenge. Many PKU patients, especially teenagers, find it difficult to stick to the relatively bland PKU diet for extended periods of time. Some older patients decide to go off their diet plan simply because they feel healthy. However, many patients who abandon careful nutritional management develop cognitive problems, such as difficulties remembering, maintaining focus, and paying attention. Many PKU health professionals contend that all PKU patients should adhere to a strictly controlled diet for life.

One promising line of PKU research involves the synthesis (manufacturing) of a new type of enzyme that can break down phenylalanine in food consumed by the patient. This medication would be taken orally and could prevent the absorption of digested phenylalanine into the patient's bloodstream.

In general, medical researchers express concern about the great variation in treatment programs currently available to PKU patients around the world. They have highlighted the urgent need for new, consistent international standards for proper management of PKU patients, which should emphasize comprehensive psychological as well as physiological monitoring and assessment.

Women with PKU must be especially careful with their diets if they want to have children. They should ensure that phenylalanine blood levels are under control before conception and throughout her pregnancy. Mothers with elevated (higher than normal) phenylalanine levels are high risk for having babies with significant birth defects, such as microencephaly (smaller than normal head size), and congenital heart disease (abnormal heart structure and function), stunted growth, mental retardation, and psychomotor (coordination) difficulties. This condition is referred to as maternal PKU and can even affect babies who do not have the PKU disease.

Early newborn screening, careful monitoring, and a life-long strict dietary management can help PKU patients to live normal, healthy, and long lives.