Created page with "'''Other Names: ''' PKU; Phenylalanine hydroxylase deficiency; Oligophrenia phenylpyruvica; Folling disease Phenylketonuria (PKU) is a genetic metabolic disorder that increa..."
Phenylketonuria (PKU) is a genetic metabolic disorder that increases the body's levels of [[phenylalanine]]. Phenylalanine is one of the building blocks ([[amino acids]]) of [[protein]]s. Humans cannot make phenyalanine, but it is a natural part of the foods we eat. However, people do not need all the phenyalanine they eat, so the body converts extra phenylalanine to another harmless amino acid, [[tyrosine]]. People with PKU cannot properly break down the extra phenylalanine to convert it to tyrosine. This means phenylalanine builds up in the person's blood, urine, and body. If PKU is not treated, phenylalanine can build up to harmful levels in the body.
| image = [[File:L-Phenylalanin_-_L-Phenylalanine.svg|thumb|alt=Chemical structure of phenylalanine]]
PKU varies from mild to severe. The most severe form is known as '''classic PKU'''. Without treatment, children with classic PKU develop permanent intellectual disability. Light skin and hair, seizures, developmental delays, behavioral problems, and psychiatric disorders are also common. Less severe forms, sometimes called "'''mild PKU'''", "variant PKU" and "non-PKU hyperphenylalaninemia", have a smaller risk of brain damage. Mothers who have PKU and no longer follow a phenylalanine-restricted diet have an increased risk of having children with an intellectual disability, because their children may be exposed to very high levels of phenylalanine before birth.
| prognosis = Good with treatment
| frequency = 1 in 12,000 births
== '''Cause''' ==
| deaths = Rare with treatment
[[File:Inborn errors of metabolism of phenylalanine and tyrosine.svg|thumb]]
}}
Mutations in the '''PAH gene''' cause phenylketonuria. The PAH gene provides instructions for making an enzyme called [[phenylalanine hydroxylase]]. This enzyme converts the amino acid [[phenylalanine]] to other important compounds in the body. If gene mutations reduce the activity of phenylalanine hydroxylase, phenylalanine from the diet is not processed effectively. As a result, this amino acid can build up to toxic levels in the blood and other tissues. Because nerve cells in the brain are particularly sensitive to phenylalanine levels, excessive amounts of this substance can cause brain damage.
[[File:Inborn_errors_of_metabolism_of_phenylalanine_and_tyrosine.svg|thumb|Metabolic pathway of phenylalanine and tyrosine]]
'''Phenylketonuria''' ('''PKU''') is a rare [[genetic disorder]] characterized by the inability to metabolize the amino acid [[phenylalanine]]. This condition is caused by a deficiency in the enzyme [[phenylalanine hydroxylase]], which is necessary for converting phenylalanine to [[tyrosine]].
Classic PKU, the most severe form of the disorder, occurs when phenylalanine hydroxylase activity is severely reduced or absent. People with untreated classic PKU have levels of phenylalanine high enough to cause severe brain damage and other serious health problems. Mutations in the PAH gene that allow the enzyme to retain some activity result in milder versions of this condition, such as variant PKU or non-PKU hyperphenylalaninemia.
== Genetics ==
PKU is inherited in an [[autosomal recessive]] pattern, meaning that an individual must inherit two copies of the defective gene, one from each parent, to be affected by the disorder. The gene responsible for PKU is located on chromosome 12.
Changes in other genes may influence the severity of PKU, but little is known about these additional genetic factors.
== Pathophysiology ==
In individuals with PKU, the accumulation of phenylalanine in the body can lead to a variety of health problems. High levels of phenylalanine can cause damage to the [[brain]] and [[nervous system]], leading to intellectual disability and other neurological issues.
== '''Inheritance''' ==
== Clinical Features ==
[[File:Autorecessive.svg|thumb|right|Autosomal recessive inheritance, a 25% chance]]
[[File:NIH_microcephaly.jpg|left|thumb|Microcephaly is a possible feature of untreated PKU]]
This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
Symptoms of PKU can vary but often include intellectual disability, [[microcephaly]], [[seizures]], and behavioral problems. If untreated, PKU can lead to severe developmental delays and neurological complications.
== Diagnosis ==
== '''Symptoms''' ==
[[File:Phenylketonuria_testing.jpg|left|thumb|Newborn screening for PKU]]
Phenylalanine plays a role in the body's production of melanin. The pigment is responsible for skin and hair color. Therefore, infants with the condition often have lighter skin, hair, and eyes than brothers or sisters without the disease.
PKU is typically diagnosed through [[newborn screening]] programs, which test for elevated levels of phenylalanine in the blood. Early detection is crucial for preventing the adverse effects of the disorder.
== Treatment ==
Other symptoms may include:
The primary treatment for PKU is a [[phenylalanine-restricted diet]], which involves limiting the intake of foods high in phenylalanine, such as meat, dairy, and nuts. Special medical formulas and foods are often used to ensure adequate nutrition while maintaining low phenylalanine levels.
* Delayed mental and social skills
== Complications ==
* Head size much smaller than normal
If PKU is not managed properly, individuals may experience severe intellectual disability, behavioral problems, and other neurological issues. Pregnant women with PKU must maintain strict control of their phenylalanine levels to prevent [[maternal PKU syndrome]], which can affect the developing fetus.
* Hyperactivity
== Prevention ==
* Jerking movements of the arms or legs
[[File:Phenylalanine_warning_for_phenylketonurics.jpg|left|thumb|Warning label for phenylketonurics]]
* Mental disability
Genetic counseling is recommended for families with a history of PKU. Prenatal testing and carrier screening can help identify at-risk pregnancies and individuals.
* [[Seizures]]
== See also ==
* Skin rashes
* [[Inborn errors of metabolism]]
* [[Tremors]]
* [[Amino acid metabolism]]
If PKU is untreated, or if foods containing [[phenylalanine]] are eaten, the breath, skin, ear wax, and urine may have a "mousy" or "musty" odor. This odor is due to a buildup of phenylalanine substances in the body.
* [[Genetic disorders]]]]
== See Also ==
== '''Diagnosis''' ==
* [[Tyrosinemia]]
PKU can be easily detected with a simple blood test. All states in the United States require a PKU screening test for all newborns as part of the newborn screening panel. The test is generally done by taking a few drops of blood from the baby before the baby leaves the hospital.
* [[Alkaptonuria]]
* [[Maple syrup urine disease]]
If the screening test is positive, further blood and urine tests are required to confirm the diagnosis. Genetic testing is also done.
[[Category:Genetic disorders]]
Screening for PKU is done with bacterial inhibition assay ([[Guthrie test]]), [[immunoassays]] using [[fluorometric]] or [[photometric]] detection, or amino acid measurement using [[tandem mass spectrometry]] (MS/MS). Measurements done using MS/MS determine the concentration of Phe and the ratio of Phe to tyrosine, the ratio will be elevated in PKU.
[[Category:Metabolic disorders]]
== '''Treatment''' ==
PKU is a treatable disease. Treatment involves a diet that is very low in [[phenylalanine]], particularly when the child is growing. The diet must be strictly followed. This requires close supervision by a registered dietitian or doctor, and cooperation of the parent and child. Those who continue the diet into adulthood have better physical and mental health than those who don't stay on it. "Diet for life" has become the standard most experts recommend. Women who have PKU need to follow the diet before conception and throughout pregnancy.
There are large amounts of phenylalanine in milk, eggs, and other common foods. The artificial sweetener NutraSweet ([[aspartame]]) also contains phenylalanine. Any products containing aspartame should be avoided.
There are several special formulas made for infants with PKU. These can be used as a protein source that is extremely low in phenylalanine and balanced for the remaining essential amino acids. Older children and adults use a different formula that provides protein in the amounts they need. People with PKU need to take formula every day for their entire life.
The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.
* '''[[Sapropterin]]''' (Brand name: Kuvan) approved to reduce blood phenylalanine (Phe) levels in patients with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4-) responsive Phenylketonuria (PKU). Kuvan is to be used in conjunction with a Phe-restricted diet.
* '''[[Pegvaliase]] '''(Brand name: Palynziq) approved to reduce blood phenylalanine concentrations in adult patients with phenylketonuria (PKU) who have uncontrolled blood phenylalanine concentrations greater than 600 micromol/L on existing management.
In 2018, the FDA approved an enzyme substitute called pegvaliase which metabolizes [[phenylalanine]].It is for adults who are poorly managed on other treatments.
'''[[Tetrahydrobiopterin]]''' (BH4) (a cofactor for the oxidation of phenylalanine) when taken by mouth can reduce blood levels of this amino acid in some people. Most people, however, with the "classical" sequence of mutations, will have little or no benefit.
== '''Prognosis''' ==
The outcome is expected to be very good if the diet is closely followed, starting shortly after the child's birth. If treatment is delayed or the condition remains untreated, brain damage will occur. School functioning may be mildly impaired.
If proteins containing phenylalanine are not avoided, PKU can lead to mental disability by the end of the first year of life.
== '''Epidemiology''' ==
The occurrence of PKU varies among ethnic groups and geographic regions worldwide. In the United States, PKU occurs in 1 in 10,000 to 15,000 newborns. Most cases of PKU are detected shortly after birth by newborn screening, and treatment is started promptly. As a result, the severe signs and symptoms of classic PKU are rarely seen.
{{Amino acid metabolic pathology}}
[[Category:Intellectual disability]]
[[Category:Autosomal recessive disorders]]
[[Category:Autosomal recessive disorders]]
[[Category:Amino acid metabolism disorders]]
[[Category:Skin conditions resulting from errors in metabolism]]
[[Category:Disorders causing seizures]]
[[Category:Biology of attention deficit hyperactivity disorder]]
Phenylketonuria (PKU) is a rare genetic disorder characterized by the inability to metabolize the amino acid phenylalanine. This condition is caused by a deficiency in the enzyme phenylalanine hydroxylase, which is necessary for converting phenylalanine to tyrosine.
PKU is inherited in an autosomal recessive pattern, meaning that an individual must inherit two copies of the defective gene, one from each parent, to be affected by the disorder. The gene responsible for PKU is located on chromosome 12.
In individuals with PKU, the accumulation of phenylalanine in the body can lead to a variety of health problems. High levels of phenylalanine can cause damage to the brain and nervous system, leading to intellectual disability and other neurological issues.
Symptoms of PKU can vary but often include intellectual disability, microcephaly, seizures, and behavioral problems. If untreated, PKU can lead to severe developmental delays and neurological complications.
PKU is typically diagnosed through newborn screening programs, which test for elevated levels of phenylalanine in the blood. Early detection is crucial for preventing the adverse effects of the disorder.
The primary treatment for PKU is a phenylalanine-restricted diet, which involves limiting the intake of foods high in phenylalanine, such as meat, dairy, and nuts. Special medical formulas and foods are often used to ensure adequate nutrition while maintaining low phenylalanine levels.
If PKU is not managed properly, individuals may experience severe intellectual disability, behavioral problems, and other neurological issues. Pregnant women with PKU must maintain strict control of their phenylalanine levels to prevent maternal PKU syndrome, which can affect the developing fetus.
Genetic counseling is recommended for families with a history of PKU. Prenatal testing and carrier screening can help identify at-risk pregnancies and individuals.
