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Phenylketonuria is a hereditary metabolic disorder characterized by the absence or low levels of an enzyme known as phenylalanine hydroxylase, or PAH.

Phenylketonuria is a hereditary metabolic disorder characterized by the absence or low levels of an enzyme known as phenylalanine hydroxylase, or PAH, which is necessary to convert phenylalanine into other substances required by the body. Phenylalanine is an amino acid, one of the units that make up proteins, and is therefore present in most food. Individuals who suffer from this disease are not able to transform phenylalanine into tyrosine, which is an essential amino acid for neurotransmitter synthesis. Phenylalanine accumulation is toxic for the nervous system; therefore, if the disease is not treated in a timely fashion, it can lead to brain damage and mental retardation.

The severity of phenylketonuria symptoms is variable. The most severe type of phenylketonuria is known as classic phenylketonuria. In this case, children appear healthy at birth, but their intellectual development will be impaired unless they receive appropriate treatment. They may also show other symptoms, such as seizures, behavior issues, or psychiatric disorders. Children with this disorder usually have lighter skin and hair than their relatives, as well as skin conditions, such as eczema. Other milder forms of this disorder have a lower risk of brain damage.

On the other hand, children born to mothers with phenylketonuria who do not adequately control their diet are at a significant risk of mental retardation; moreover, they usually have a low weight at birth and their growth is slower than normal. This situation may also lead to cardiac conditions, microcephaly (head smaller than normal), and behavior issues.

Although phenylketonuria does not have a cure, it is possible to fully prevent mental retardation, as well as other associated symptoms, if the newborn is treated with a special phenylalanine-restricted diet within the first 7 to 0 days of life. To do this, it is necessary to test the newborn for phenylketonuria around the first 5 days of life. This test is known as the heel-prick blood test because a few drops of blood are obtained from the newborn’s heel. Pregnant women that do not undergo appropriate follow-up are at higher risk of abortion during pregnancy.

Diet must be customized depending on the amount of phenylalanine that each patient can tolerate, along with the patient’s age, weight, and other factors. It is necessary to regularly perform blood tests to monitor the levels and adjust the diet accordingly. Individuals suffering from this disease must follow a restricted diet during childhood and adolescence, likely during their whole life, although diet may be more flexible at older ages. There currently is a drug (containing the active principle sapropterin) that helps decrease blood phenylalanine levels, in combination with diet interventions, in patients who maintain low levels of PAH activity.

This disease is caused by mutations in the PAH gene. This gene provides the instructions to synthesize an enzyme known as phenylalanine hydroxylase, which is in charge of converting phenylalanine into tyrosine, a necessary substance for the development of the central nervous system. As a consequence of the absence or low levels of this enzyme, phenylalanine accumulates in the body, leading to the characteristic symptoms of the disease. Different mutations lead to different phenylalanine levels and, therefore, to greater or lower severity of symptoms. Changes in other genes may also affect the degree of severity of this disorder.

Approximately one in every 10,000 to 15,000 children is born with phenylketonuria. Most cases are detected early; for this reason, the most severe symptoms of the disease are not often observed.

The inheritance pattern of phenylketonuria is autosomal recessive, i.e. the two copies of the gene must be affected for the disease to develop. Therefore, the two parents must be carriers, which means that each of them must have one copy of the mutated gene and transmit it to their offspring, but they do not suffer from the disease themselves. When both parents are carriers, there is a one in four probability of both of them transmitting the affected gene to a child.

In women diagnosed with phenylketonuria, it is essential to follow a phenylalanine-restricted diet, both before and during pregnancy, to prevent accumulation of this substance to cause damage to the fetus, even if the defective gene has not been inherited.

On the other hand, a genetic counseling consultation is recommended to future parents who suffer from the disease or are aware of cases in the family; in this way, they can know the risk of transmitting the disease to their offspring, perform the genetic tests that are deemed necessary, and take the appropriate prevention measures.

SEEIM – Spanish Society for Inborn Errors of Metabolism

Fenilcetonuria.es – Website that provides information about phenylketonuria

E.S. PKU – European Society for Phenylketonuria