Phenylketonuria: symptoms, treatment, diagnosis and genetics

Phenylketonuria (PKU) is an inherited, autosomal recessive condition that was first described by a Norwegian physician, Dr. Ivar Asbjorn Folling, in 1934 [1]. Patients with PKU have problems processing phenylalanine, an essential amino acid (protein building block) found in almost all foods. Raised phenylalanine levels can cause severe brain damage and other neurological, behavioral, cognitive, physical and dermatological problems [2, 3].

How common is phenylketonuria?

In the United States, PKU occurs in 1 in 10,000 to 1 in 15,000 newborns [4], with estimates up to 1 in 25,000 [2]; in Europe, it occurs in approximately 1 in 10,000 newborns [5]. The occurrence varies among geographic regions and ethnic groups, and is rare in African Americans and Ashkenazi Jews [6].

Symptoms of phenylketonuria

Symptoms vary depending on the severity of the condition, which depends on the levels of phenylalanine hydroxylase (PAH), the enzyme that normally converts phenylalanine to other forms, in the body. Classic PKU – the most severe form of the condition – results when PAH is missing, and mild or moderate forms of PKU occur when PAH levels are reduced.

Signs and symptoms of PKU include

• Musty odor in breath, skin or urine due to excess amount of phenylalanine
• Microcephaly
• Hyperactivity
• Developmental delay
• Skin rashes

Raised phenylalanine levels cause destruction of myelin, the protective layer of nerves in the brain, resulting in neurological problems like

• Seizures
• Abnormal muscle movements
• Tremors
• Behavioral problems
• Intellectual disability

Mild or moderate forms of PKU are less likely to result in brain damage [3, 6, 7]. As high phenylalanine levels affect melanin production, PKU patients may have pale eyes, skin and hair [6].

Phenylketonuria diet

Treatment of PKU consists of maintaining phenylalanine levels within normal range through a controlled diet of food low in phenylalanine. The patient must follow this diet for life to prevent symptoms appearing. Phenylalanine is found in protein, therefore the PKU diet excludes high‑protein food and contains foods low in protein [2, 4], including most fruits and vegetables and other low-protein food or phenylalanine-free food preparations [2, 6, 8]. Potatoes and grains may also be limited [3].

The following foods are protein-rich and should be avoided [2, 4, 8]

• Dairy products (mild, egg, cheese)
• Fish
• Meat (red meat and poultry)
• Nuts and seeds
• Tofu and soya products
• Beans
• Bread and wheat products (flour, pasta, cake, biscuits)

Phenylalanine intake and levels in the body should be regularly monitored [8]. The amount of phenylalanine that is safe for someone with PKU to consume is highly individual [2].

A highly restrictive diet can cause vitamin deficiencies, and taking supplements can be beneficial [4]; however, this should be done under supervision as vitamins, supplements and other medications may contain phenylalanine, aspartame or even milk powder. A physician can prescribe special PKU nutritional supplements [3].

Keeping a food diary can help people with PKU keep track of their food intake, and make it easier to discuss diet with their healthcare providers [3].  

As long as the PKU diet is followed, people with PKU can have healthy, normal lives.

Phenylketonuria and aspartame

The artificial sweetener aspartame should be avoided as is it converted to phenylalanine in the body and can therefore cause levels of phenylalanine to rise. It is found in [8]

• Sugar substitutes (e.g., in low-calorie diet foods, sweetener for tea or coffee)
• Diet fizzy drinks and other soft drinks
• Chewing gum
• Some alcoholic drinks

Drug treatment for phenylketonuria

A Food and Drug Administration (FDA)-approved drug, sapropterin, is available for the treatment of PKU, but it does not work for everyone [3]. Patients should continue with the PKU diet while on sapropterin, although it may allow for a less restrictive diet for some people [3, 6, 8].  

The FDA has also approved a novel enzyme therapy, pegvaliase-pqpz, for adult patients with uncontrolled concentrations of phenylalanine in the blood despite current treatment [3].

Pregnancy and phenylketonuria

It is important for women with PKU to adhere to the PKU diet before and during pregnancy to reduce the risk of having high phenylalanine levels that can harm the unborn baby. Called maternal PKU, it can cause a baby to have a low birth weight, microcephaly and heart problems, as well as developmental delay, intellectual disability and behavior problems. A woman who adheres to the PKU diet and controls her phenylalanine levels can have a normal pregnancy and a healthy baby [2, 3, 8].  

Diagnosis of phenylketonuria through newborn screening

PKU is usually detected through newborn screening, which is performed in many countries worldwide during the baby’s first days of life. Newborn screening detects certain treatable genetic, endocrine, and metabolic disorders that can affect the long-term health of the baby [9]. The test requires collection of a few drops of blood, usually from the baby’s heel, and if results are positive, meaning phenylalanine levels in the blood are high, further confirmatory tests are performed [3, 4].

Babies born with PKU do not initially show symptoms, and PKU is only noticed when brain damage has already occurred. Early treatment prevents symptoms; therefore, identifying PKU as early as possible is vital for the baby’s development.

Diagnosis of phenylketonuria in pregnancy

Non-invasive prenatal tests (NIPT) can detect PKU during pregnancy, and invasive procedures, like amniocentesis or chorionic villus sampling (CVS) can confirm the finding. As it is an autosomal recessive condition, parents may be carriers without their knowledge, so early testing and detection can be beneficial for prospective parents, allowing them to be informed and prepared.

Is phenylketonuria genetic?

PKU is a genetic disorder that is caused by variants in the PAH gene. These variants cause an absence or deficiency of the enzyme phenylalanine hydroxylase that is responsible for processing phenylalanine. Without phenylalanine hydroxylase, phenylalanine levels build up causing the symptoms of PKU [2].

One of the reactions catalyzed by phenylalanine hydroxylase is the conversion of phenylalanine to tyrosine. Tyrosine in turn, is required for melanin production, and melanin is involved in hair and eye color. Therefore, people with PKU may have pale skin, hair and eyes [2, 6, 10]. You can read more about melanin and hair color in our article Red hair it’s in your genes.

The amount of phenylalanine hydroxylase activity (absent or decreased) influences the disease severity and is determined by the genetic variant; more than 300 variants have been identified [6]. Genetic testing can be used to identify the causative variant [3, 4].

Inheritance of phenylketonuria

The genetic changes (variants) that cause PKU are passed down from parent to child. In other words, children inherit the variants from their parents.

Genes are inherited in pairs: one from the mother and one from the father. PKU is inherited in an autosomal recessive pattern, which means that both genes need to have the genetic variant for it to cause the disease. A person who has one healthy gene and one with the variant is called a carrier; they do not have symptoms and can pass either the variant or the healthy gene to their offspring. There is a 1 in 4 chance (25%) that the child of two carriers will inherit variants from both parents and have PKU and a 1 in 2 chance (50%) that they will inherit one variant and be a carrier [6, 8].

Carrier screening is a genetic test that can determine whether asymptomatic people are carriers of genetic diseases, including PKU, and this can be beneficial for people during family planning.

Raising awareness of phenylketonuria

Started in 2013, International PKU day is celebrated every year on June 28. The date was chosen, as it is the birthday of Horst Bickel who helped create the PKU diet, and Robert Guthrie who developed the Guthrie test in 1960 [11]. The Guthrie test was the first form of newborn screening that was developed specifically for PKU. It became a state-mandated test in the US and slowly spread throughout the world. Over time, more disorders were added. With technological and scientific advancements, the Guthrie test developed into the foundation for the newborn screening tests that are offered today. PKU, the first condition detected by newborn screening, is a great example of how early detection and management have an integral role in helping patients take informed decisions and live healthy lives.

This article is for informational purposes only and cannot replace professional medical advice or counseling. Always visit your healthcare provider if you have concerns about a medical condition or your well-being.

References

[1] Woolf, Louis I, and John Adams. “The Early History of PKU.” International journal of neonatal screening vol. 6,3 59. 29 July 2020, doi:10.3390/ijns6030059
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570064/

[2] MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine (US); [updated 24 Jun 2020]. Phenylketonuria. [updated 25 April 2023]. Retrieved 26 June 2023 from: https://medlineplus.gov/genetics/condition/phenylketonuria/

[3] Mayo Clinic. Phenylketonuria (PKU). 13 May 2022. Retrieved 26 June 2023 from https://www.mayoclinic.org/diseases-conditions/phenylketonuria/symptoms-causes/syc-20376302

[4] Cleveland Clinic. Phenylketonuria (PKU). Retrieved 26 June 2023 from https://my.clevelandclinic.org/health/diseases/17816-phenylketonuria

[5] van Wegberg, A M J et al. “The complete European guidelines on phenylketonuria: diagnosis and treatment.” Orphanet journal of rare diseases vol. 12,1 162. 12 Oct. 2017, doi:10.1186/s13023-017-0685-2 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5639803/pdf/13023_2017_Article_685.pdf

[6] National Organization for Rare Disorders. Phenylketonuria. Last updated 24 July 2019. Retrieved 26 June 2023 from https://rarediseases.org/rare-diseases/phenylketonuria/

[7] OMIM #261600 PHENYLKETONURIA; PKU. Last updated 09 December 2022. Retrieved 26 June 2023 from https://www.omim.org/entry/261600

[8] NHS. Phenylketonuria. Retrieved 26 June 2023 from https://www.nhs.uk/conditions/phenylketonuria/

[9] CDC Centers for Disease Control and Prevention. Newborn Screening Portal. Retrieved 26 June 2023 from https://www.cdc.gov/newbornscreening/

[10] MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine (US); [updated 24 Jun 2020]. PAH gene phenylalanine hydroxylase. Retrieved 27 June 2023 from: https://medlineplus.gov/genetics/gene/pah/#conditions

[11] International PKU day. Retrieved 26 June from https://www.pkuday.org/