Phenylketonuria (PKU) is a rare disease of newborn babies when an amino acid called phenylalanine cannot be broken down. This causes the accumulation of phenylalanine. When phenylalanine levels get too high, it can cause brain damage. This can lead to mental and developmental disabilities. You can find more information below.

What is phenylketonuria?

Phenylketonuria (PKU) is an inborn error of metabolism that can be detected through routine newborn screening in the first days of life. PKU is characterized by the absence or deficiency of an enzyme called phenylalanine hydroxylase (PAH) , which is responsible for processing the amino acid phenylalanine.

Amino acids are the chemical building blocks of proteins, essential for proper growth and development. With normal PAH activity, phenylalanine is converted to another amino acid, tyrosine. However, when PAH is absent or deficient, phenylalanine accumulates and is toxic (harmful) to the brain.

Without treatment, most people with PKU develop severe mental disabilities. Treatment to prevent intellectual disability consists of a carefully controlled, phenylalanine-restricted diet beginning in the first days or weeks of life.

What causes phenylketonuria?

PKU is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual inherits one normal gene copy and one abnormal gene copy, they will be a carrier for the condition but will not have symptoms. The risk that two carrier parents will have an affected child is 25% with each pregnancy. The risk is the same for men and women.

More than 300 different changes (mutations) have been identified in the PKU gene. Each child’s diet needs to be adjusted to the individual’s specific phenylalanine tolerance, as different mutations cause varying degrees of PAH enzyme activity and therefore varying degrees of elevation of phenylalanine in the blood.

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What are the symptoms of phenylketonuria?

Babies with PKU often appear normal at birth. With early screening and dietary treatment, affected individuals may never show signs of PKU. However, babies who are not diagnosed and treated in the first days of life may be weak and malnourished. Other symptoms may include vomiting, irritability, and a small pimple-like red skin rash.

Developmental delay may be evident at the age of several months. The average IQ of untreated children is usually less than 50. Intellectual disability in PKU is a direct result of high phenylalanine levels in the brain that cause the destruction of the fatty covering (myelin) of individual nerve fibers. It can also cause depression by reducing brain dopamine and serotonin (neurotransmitter) levels .

Untreated babies with PKU tend to have unusually different eye, skin, and hair color due to high levels of phenylalanine, which interferes with the production of melanin, a pigmentation-causing substance. They may also have a musty or mouse-like body odor caused by phenyl acetic acid in their urine or sweat .

Some untreated PKU patients have neurological symptoms , including seizures, abnormal muscle movements, tight muscles, increased reflexes, involuntary movements, or tremors .

Untreated pregnant women with PKU are at increased risk for miscarriage or fetal growth ( intrauterine growth retardation ) problems. Children of women with untreated PKU may have an abnormally small head (microcephaly), congenital heart disease, developmental abnormalities, or facial abnormalities.

There is a strong correlation between the severity of these symptoms and high maternal phenylalanine levels. As a result, all women with PKU who discontinue treatment should continue treatment and have regular doctor check-ups before becoming pregnant.

How is phenylketonuria diagnosed?

In many developed countries, all newborn babies are routinely tested for a range of diseases and conditions. One of the tests is a blood test that looks for the presence of phenylalanine hydroxylase . If this enzyme is missing or there is too much phenylalanine in the blood, more blood and urine tests will be done. These can confirm the diagnosis of PKU. Almost all cases of PKU are diagnosed with this newborn blood test.

PKU may rarely be missed during the screening process. For this reason, people of any age with developmental delays or intellectual disabilities are often tested for PKU.

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PKU can also be diagnosed before the baby is born. During pregnancy, a woman may request genetic testing to find out if her unborn baby will have the disease. This is done by amniocentesis or chorionic villus sampling .

How is phenylketonuria treated?

The goal of PKU treatment is to maintain plasma phenylalanine levels within 120-360 umol/L (2-6 mg/dL). This is usually achieved with a carefully planned and monitored diet. Limiting a child’s intake of phenylalanine should be done with caution, as it is an essential amino acid. A carefully maintained diet can prevent neurological, behavioral and dermatological problems as well as intellectual disability.

Treatment should be started at a very young age, otherwise there may be some degree of intellectual disability. However, even some children who are treated late do quite well. Studies have repeatedly shown that children with PKU who are treated with a low phenylalanine diet before three months of age perform well with an IQ in the normal range.

If people with PKU stop controlling their dietary intake of phenylalanine, neurological changes often occur. IQs may drop. Other problems that may occur and worsen after dietary regulation is stopped include difficulties with school, behavior problems, mood changes, poor visual-motor coordination, poor memory, poor problem-solving skills, fatigue, tremors, poor concentration, and depression .

After years of debate, there is now almost universal agreement among clinicians that the diet should continue indefinitely and that those who discontinue the diet should immediately return to the diet. Many young adults restarted the diet and found improved mental clarity as a result of lower blood phenylalanine levels.

Since phenylalanine occurs in almost all natural proteins, it is impossible to adequately restrict the diet using only natural foods without compromising health. Therefore, special food preparations that do not contain phenylalanine are useful.

Protein-rich foods such as meat, dairy, fish, and cheese are generally not allowed in the diet. Naturally low-protein foods such as fruits, vegetables, and some grains are allowed in limited quantities.

Medication

In 2007, Kuvan (sapropterin hydrochloride) was approved by the U.S. Food and Drug Administration (FDA) to treat PKU. Kuvan is an oral pharmaceutical formulation that stimulates the activity of BH4, the natural cofactor for the PAH enzyme, to metabolize phenylalanine to tyrosine. Kuvan will be used in conjunction with a phenylalanine-restricted diet. Kuvan, BioMarin Pharmaceutical Inc. is produced by

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In 2018 , Palynziq (pegvaliase-pqpz) was approved by the FDA for adults with PKU. Palynziq is an injectable enzyme therapy for patients with uncontrolled blood phenylalanine concentrations on current therapy. Palynziq, BioMarin Pharmaceutical Inc. is produced by

Remember, your doctor will decide which medicine to take and how.

Long-term outlook for disease

With appropriate treatment, phenylketonuria (PKU) has a good course. By starting and continuing a low phenylalanine diet on time, children with this congenital metabolic disorder have a favorable prognosis and develop completely normally. They can get a job and have children, their life expectancy is not limited.

It should be noted that patients with phenylketonuria always pass on the inheritance characteristic responsible for the metabolic disorder to the next generation. Therefore, chromosome analysis is recommended for people with a family history of phenylketonuria.

How to prevent phenylketonuria?

This problem is an inherited condition, so it cannot be prevented. However, an enzyme test can be done for people who want to have children.

An enzyme assay is a blood test that can determine if a person carries the defective gene that causes this disease. This test can also be done during pregnancy to screen babies in the womb and detect disease if any.

If you have phenylketonuria, you can prevent symptoms by paying attention to what you eat throughout your life.

What to know

PKU is treatable when found early. Doctors will closely monitor children who have this disease. People with PKU must strictly adhere to the right diet for the rest of their lives. This can prevent problems caused by too much phenylalanine.

If your child has phenylketonuria, you should work with their healthcare team to help keep phenylalanine levels within an acceptable range. Your doctor will regularly check the level of phenylalanine in your child’s blood.

Because PKU is a genetic condition, you may want to talk to a genetic counselor about testing other family members and how PKU runs in families. More information and support can be found online at:

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