Phenylketonuria: Genetic Disorder

Updated October 3, 2019

This article was scientifically reviewed by Aishwarya Arjunan

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A list of references is also included at the bottom of this article.

Phenylketonuria, often referred to as PKU, is a genetic condition that increases the levels of phenylalanine in the blood.

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This is due to a deficiency of the phenylalanine hydroxylase (PAH) enzyme. If too much phenylalanine accumulates in the blood and the condition is left untreated, it can lead to intellectual disability and other serious health problems.

The signs and symptoms associated with PKU can range from asymptomatic to severe depending on the type an individual has. If this condition is identified and treated early, individuals with PKU can lead healthy lives.

Phenylketonuria is part of a group of disorders known as inborn errors of metabolism.

What Is Phenylketonuria?

Phenylketonuria is a genetic condition that results in increased levels of the amino acid phenylalanine in the blood.

PKU is caused by mutations in the PAH gene which is responsible for the creation of the enzyme, phenylalanine hydroxylase (PAH) 1 2.

The PAH enzyme is necessary to help break down the amino acid phenylalanine to a different amino acid called tyrosine.

Without this enzyme, toxic levels of phenylalanine build up in the bloodstream and can cause irreversible damage.

Amino acids are building blocks of protein and phenylalanine is one that is obtained through our diets (all proteins and artificial sweeteners such as aspartame).

There can be two forms of PKU: classic PKU and a milder form called either variant PKU or non-PKU hyperphenylalaninemia 3 4.

Classic PKU 5 6 is the most common and most severe form of the condition. Individuals with this type produce very little to no PAH enzyme which can result in high levels of phenylalanine in the blood.

If individuals with Classic PKU are not diagnosed and treated with dietary modification early, then they are at risk for intellectual disability in addition to other issues such as seizures, small head size, eczema, low bone density, behavioral and gait issues, along with a musty odor.

All of these symptoms can be avoided if dietary modifications are made shortly after birth/diagnosis and maintained throughout one’s life.

Variant PKU or non-PKU hyperphenylalaninemia 7 is the less common and less severe form of the condition.

This type occurs when an individual has higher amounts of PAH enzyme activity but are still at risk of developing symptoms associated with the classic form mentioned above.

It is still important to monitor one’s level of phenylalanine intake. Some individuals with the milder form may not need a modified diet or treatment but this is not the case for every individual with the milder form.

It is important to treat the condition based on the guidance of a medical profession and the levels of phenylalanine in the blood.

How Common Is PKU?

Phenylketonuria is a rare genetic disorder that can be seen in individuals of all ethnic backgrounds, male and female.

In the United States, one in every 10,000 to 15,000 newborns is affected by phenylketonuria and 1 in 50 people may be a carrier of PKU 8.

It is more common in individuals of Turkish (1 in 2,600 births), Irish (1 in 4,500 births), East Asian (1 in 10,000 births) and Northern European (1 in 10,000 births) descent 9.

Typically, the condition is diagnosed shortly after birth as all newborns in the United States are screened for this condition along with a number of others within a few days of birth.

What are the symptoms associated with Phenylketonuria?

While babies with PKU don’t typically show any symptoms at birth, it’s important to identify and diagnose newborns early so the onset of symptoms can be prevented as they can be irreversible if left untreated.

Symptoms associated with this condition when untreated include 10 11 12:

  • Irritability
  • Seizures (epilepsy)
  • Developmental delay
  • Intellectual disability (average IQ of untreated children is ~50)
  • Skin rashes such as eczema
  • Musty body odor
  • pale skin, eyes and hair color — high levels of phenylalanine interferes with the production of melanin which is responsible for pigmentation
  • Gait problems
  • Low bone density (osteopenia)
  • Behavioral, emotional, and social problems
  • Psychiatric disorders such as depression

These symptoms can be either mild or severe depending on the amount of phenylalanine in one’s blood.

As with other conditions, the symptoms seen vary from person to person.

Maternal PKU 13 - Females with untreated PKU (uncontrolled phenylalanine levels) who become pregnant are at high risk for having problems during pregnancy such as increased risk for miscarriage or intrauterine growth restriction.

Children born to women with untreated PKU are at risk of having microcephaly (small head size), congenital heart disease, and other developmental or facial abnormalities.

If a female with PKU is planning a pregnancy, it is important to be managed by a metabolic geneticist and dietician to ensure that there aren’t any complications with the pregnancy and development.

How is Phenylketonuria diagnosed?

In the United States, diagnosis of PKU will come via newborn screening from a physician, generally a pediatrician or medical geneticist.

A diagnosis of PKU is made when an individual has 14:

  • A plasma phenylalanine concentration persistently above 120 µmol/L (2 mg/dL) and altered ratio of phenylalanine to tyrosine in the untreated state with normal BH4 cofactor metabolism; and/or
  • Two pathogenic variants in PAH identified by molecular genetic testing.

If phenylketonuria isn’t identified via newborn screening, your child may develop symptoms associated with the conditions such as irritability, vomiting and delays in development and the doctor may order additional testing.

How is Phenylketonuria treated?

While there is no cure for PKU, treatment and modified diets can help ensure that individuals avoid experiencing any of the symptoms associated with the condition.

The amount of PAH enzyme deficiency varies among individuals so treatment is individualized based on the levels of phenylalanine in one’s blood.

Typically, individuals with phenylketonuria will follow a diet that limits the amount of phenylalanine consumed.

This diet must be followed for life. This means avoiding or strictly limiting 15:

  • Milk and all other dairy products, including yogurt, cheese, and ice cream
  • Meat and poultry
  • Fish
  • Eggs
  • Nuts and peanut butter
  • Dried beans
  • Regular flour
  • Regular infant formula (special formula is available for infants with PKU)
  • All foods and drinks made with the artificial sweetener aspartame
  • In addition to following a strict diet, children with PKU will also need to drink a special PKU formula to ensure that their body is receiving all of the essential amino acids it needs except for phenylalanine.

Individuals will also need to monitor the phenylalanine levels in their blood.

Medication 16: In 2007, the United States Food and Drug Administration (FDA) approved sapropterin (Kuvan) for the treatment of PKU.

Sapropterin (also known as BH4) helps lower phenylalanine levels in the blood. This medication must be used in conjunction with a PKU diet.

This medication is most effective in children with milder cases of PKU.

In 2018, Palynziq was approved by the FDA for adults with PKU.

It is an injectable enzyme therapy for individuals who have uncontrolled phenylalanine levels in the blood on current treatment.

What is the life expectancy of an individual with Phenylketonuria?

An individual with this disorder will have a normal life span.

The life expectancy of an individual with untreated PKU is not thought to be different from an individual without PKU.

However, the quality of life can be vastly different as untreated PKU causes severe and irreversible brain damage.

Individuals who are treated early and follow their modified diet can lead normal lives with normal intelligence and lifespan.

Individuals with milder forms of PKU may lead a normal life without treatment as well.

How is Phenylketonuria inherited?

We have 46 chromosomes in each cell of our bodies. These chromosomes can be organized into 23 pairs.

One of each pair of chromosomes is inherited from each parent. Our genetic information, or our genes, is carried on the chromosomes.

Genes are instructions telling our bodies how to grow and develop.

While each person has two working copies of each gene, parents of children with PKU will have one copy that has a mutation and one copy that is working without any problems.

Because they have one working copy of the gene, they do not have any signs or symptoms of PKU.

This is called “autosomal recessive inheritance”. Parents who have one copy with a gene mutation are called “carriers”.


Credit: U.S. National Library of Medicine

PKU occurs when an individual inherits two mutations in the PAH gene.

When two carrier parents have a child who inherits both copies with a gene mutation, one from each parent, the child will have PKU.

What are the chances that I will pass Phenylketonuria to my child?

If neither parent has a disease causing gene mutation; that is, neither parent is a carrier, then it is highly unlikely that phenylketonuria will be passed down.

If only one parent has a mutation, is a carrier for PKU, and the other parent has two normal working copies of the PAH gene, the children of that couple will each have a 50 percent chance (1/2) of being an unaffected carrier of PKU.

If both parents are carriers of PKU, then there is a 1 in 4 or 25% chance in each pregnancy to have a child with PKU. This also means that there is a 3 in 4 or 75% chance in each pregnancy to not have a child with PKU.

Is prenatal testing available?

If parents want to know their risk of having a child with PKU then they can consider getting carrier screening prior to or in the early stages of pregnancy.

Carrier screening will help identify whether an individual or couple are both carriers for PKU and thus at risk of having a child with the condition.

If a couple is identified to both be carriers for PKU, then prenatal diagnosis via chorionic villus sampling (CVS) or amniocentesis can help determine whether the fetus is affected.

Speaking with a genetic counselor can help determine if this testing is right for you.

Genetic Testing for Phenylketonuria

While blood testing and observing levels of phenylalanine can help establish a diagnosis of phenylketonuria, genetic testing is also available to identify the specific disease causing mutations in the PAH gene.

Speak with your health care provider if you wish to learn more about genetic testing for phenylketonuria.

A referral to a genetic counselor can be helpful to discuss the various testing options for you and your family.

Where can I go to get genetic testing?

Genetic testing is generally ordered by a genetic counselor or medical geneticist.

Speak with your healthcare provider to learn how you can schedule an appointment with your local genetics team.

Sometimes your OBGYN can order prenatal carrier screening for you if you are interested in learning about your PKU carrier status.

DNA testing for Phenylketonuria: Benefits and Limitations

Genetic testing can a mix of benefits and limitations. There is no possibility of physical harm or any biological risk in getting tested aside from the general risk of a blood draw if a blood draw is completed.

Although deciding on testing is entirely voluntary, it can prove to be a complex decision that may raise new health concerns or anxieties.

For this reason, it’s best to seek genetic counseling to help discuss the emotional and social aspects of genetic testing, as well as get an educated interpretation of the results.

With that in mind, here is a short list of the strengths and limitations:

Benefits of Genetic Testing:

  1. Relief from any uncertainty about whether or not PKU is the appropriate diagnosis.
  2. In-depth understanding about the disease and how it impacts you and your health.
  3. You will be in a position to educate your family about the potential risk of passing down the condition or help diagnose other family members who may also have PKU.
  4. Knowing you are a carrier can help you make future family-planning decisions.

Limitations of DNA Testing:

  1. Your new knowledge will not lead to a cure, but will help empower you to make decisions about your health and future
  2. You may not be able to get a conclusive answer after genetic testing which may then lead to a feeling of uncertainty about the diagnosis and family planning.

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Referenced Sources

  1. Phenylketonuria. Genetics Home Reference, U.S. National Library of Medicine. Retrieved Online August 2019.
  2. Regier DS, Greene CL. Phenylalanine Hydroxylase Deficiency. 2000 Jan 10 [Updated 2017 Jan 5]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
  3. Phenylketonuria. Genetics Home Reference, U.S. National Library of Medicine. Retrieved Online August 2019.
  4. Phenylketonuria;PKU.Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 261600: {11/01/2017}.
  5. Regier DS, Greene CL. Phenylalanine Hydroxylase Deficiency. 2000 Jan 10 [Updated 2017 Jan 5]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
  6. Phenylketonuria;PKU.Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 261600: {11/01/2017}.
  7. Regier DS, Greene CL. Phenylalanine Hydroxylase Deficiency. 2000 Jan 10 [Updated 2017 Jan 5]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
  8. Phenylketonuria. National Organization for Rare Disorders (NORD). Retrieved Online August 2019.
  9. Regier DS, Greene CL. Phenylalanine Hydroxylase Deficiency. 2000 Jan 10 [Updated 2017 Jan 5]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
  10. Phenylketonuria. Genetics Home Reference, U.S. National Library of Medicine. Retrieved Online August 2019.
  11. Regier DS, Greene CL. Phenylalanine Hydroxylase Deficiency. 2000 Jan 10 [Updated 2017 Jan 5]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
  12. Phenylketonuria. National Organization for Rare Disorders (NORD). Retrieved Online August 2019.
  13. Phenylketonuria. National Organization for Rare Disorders (NORD). Retrieved Online August 2019.
  14. Regier DS, Greene CL. Phenylalanine Hydroxylase Deficiency. 2000 Jan 10 [Updated 2017 Jan 5]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
  15. National PKU Alliance. Retrieved Online August 2019.
  16. Phenylketonuria. National Organization for Rare Disorders (NORD). Retrieved Online August 2019.