Phenylketonuria (PKU) is a rare inherited metabolic disorder that causes a dangerous buildup of the amino acid phenylalanine in the body. It results from a deficiency or absence of the enzyme phenylalanine hydroxylase (PAH), which is responsible for breaking down phenylalanine into tyrosine. When not managed, high levels of phenylalanine become toxic to the brain, leading to intellectual disability and other serious symptoms. Common early signs include eczema-like skin rashes, behavioral changes, seizures, and delayed growth.¹ Newborn screening programs routinely test for PKU using a simple heel-prick blood test, allowing for early detection and treatment. Other diagnostic methods include plasma amino acid analysis and genetic testing.

What is Phenylketonuria?

Phenylketonuria results from a disruption in the normal metabolism of phenylalanine. The disorder gets its name from the excessive levels of phenylketones (such as phenylpyruvic acid) that are excreted in the urine. These ketones are byproducts of phenylalanine metabolism when it cannot be adequately broken down. The accumulation of these substances poses a threat to brain development and function, especially in infants and young children.

What Causes Phenylketonuria?

PKU is inherited in an autosomal recessive pattern, meaning both parents must carry a faulty gene for their child to be affected. The condition is caused by mutations in the gene responsible for encoding phenylalanine hydroxylase (PAH), which is located on chromosome 12q24.1. More than 1,000 different mutations have been identified, many of which alter the enzyme’s structure or function.²

This enzyme is essential for converting phenylalanine to tyrosine, a precursor for neurotransmitters such as dopamine and norepinephrine. A deficiency in PAH leads to elevated levels of phenylalanine in the blood and reduced availability of tyrosine, both of which contribute to impaired brain function.

Pathophysiology of Phenylketonuria

Amino acids are the building blocks that form all proteins. They are essential macronutrients found in most foods and are necessary for life. In individuals with phenylketonuria (PKU), the body lacks the enzyme phenylalanine hydroxylase, which is needed to break down the amino acid phenylalanine into another amino acid called tyrosine.³ PAH requires tetrahydrobiopterin (BH4) as a cofactor, along with molecular oxygen and iron, to function. In PKU, a lack of PAH leads to elevated phenylalanine levels in the blood and urine, which can cause neurotoxic effects, including intellectual disability and neurological issues. While tyrosine levels typically remain normal, they may decrease in severe cases due to reduced conversion.

The excess phenylalanine interferes with brain development and neurotransmitter synthesis, which may result in cognitive deficits. It is hypothesized that phenylalanine disrupts brain growth, myelination, and neuronal function. High phenylalanine concentrations may also impair the transport of large neutral amino acids (LNAAs) into the brain, affecting the synthesis of neurotransmitters like dopamine and serotonin. If untreated, these disruptions can lead to significant developmental and cognitive challenges. Phenylalanine is also found in artificial sweeteners like aspartame.⁴

People with phenylketonuria are advised to strictly limit their intake of high-protein foods and foods containing phenylalanine. Specialized diets and medical formulas are used to supply the necessary amino acids while minimizing phenylalanine intake, helping prevent the appearance of symptoms.

Types of Phenylketonuria

Phenylketonuria has various types. The types are decided on the basis of phenylalanine and its products present in the blood.

Hyperphenylalaninemia:

This condition is characterized by slightly elevated levels of phenylalanine, typically ranging from 120 to 600 μmol/L. It is considered a milder form of PKU, and affected individuals generally have a low risk of intellectual disability. Dietary interventions are often not necessary, but monitoring is still important.

Mild PKU:

In this form, blood levels of phenylalanine are moderately elevated, typically between 600 and 1200 μmol/L. These individuals may require dietary management to avoid neurological symptoms, though the risk of significant developmental issues is lower than in classic PKU.

Classic PKU:

This is the most severe form of PKU, where there is a near-complete absence of phenylalanine hydroxylase activity. Blood phenylalanine levels are usually above 1200 μmol/L, and individuals are at high risk for intellectual disability, neurological impairments, and behavioral issues if left untreated. Strict dietary management is essential to prevent severe consequences..

Symptoms of Phenylketonuria

PKU symptoms typically do not appear at birth. Symptoms develop gradually over the first few months of life and can range from mild to severe. Early signs include:⁵

Skin Symptoms:

PKU causes eczema. Eczema involves skin conditions like rashes, dry and itchy patches on the skin, blisters, and skin infections.

Behavioral & Neurological Symptoms:

Tremors — shaking or trembling movements in one or more parts of the body.
Increased activity in the child or other behavioral problems
Epilepsy: Seen in a significant portion of patients, with about 23% affected by adulthood.
Seizure (fits) like features.
Sometimes, paralysis is also present in one or more limbs. Paralysis is the inability to move the limbs freely.

Color Changes in Skin & Hair:

Phenylalanine also produces a substance called melanin. Melanin is important in giving color to body hair and skin. Decreased phenylalanine breakdown results in reduced melanin. So the babies born with PKU are more light-skinned, light-haired, and light-eyed than their other siblings or parents without the disease.

Other Symptoms:

Slow growth — small head size (Microcephaly), low height for weight.
A musty urine, body, or breath smell — due to too much phenylalanine in the body.
Patients are advised to have a diet low in protein, which can lead to B12 deficiency⁶

Diagnosis of PKU: The Role of Metabolic Screening

In healthcare settings, especially in the USA, phenylketonuria is diagnosed by metabolic screening. All 50 states of the USA and many other countries opt for screening tests on the newborn.

Phenylketonuria Screening in Newborns:

Ideally, healthcare providers should perform the PKU screening test 24 hours after a child’s birth, allowing a day for protein intake. The most widely used method for screening PKU in newborns is tandem mass spectrometry, which detects elevated phenylalanine levels and helps differentiate PKU from other metabolic disorders. Blood phenylalanine levels greater than 20 mg/dL (1200 μmol/L) indicate a diagnosis of PKU, which is then confirmed with additional testing.

Diagnostic Tests for PKU:

After a positive screening result, further blood and urine tests are typically performed. Genetic testing may be used, but as you correctly note, it is not required to confirm the diagnosis. Genetic testing is useful for identifying mutations in the PAH gene (which causes PKU) and may help in family planning or understanding a patient’s genotype.

Phenylketonuria Screening in Adults:

In most cases, healthcare providers identify PKU at birth. However, on occasion, healthcare providers might miss a diagnosis in a newborn due to faulty technique or inaccurate sampling.
Consequently, when a person of any age develops intellectual disability or developmental delays, healthcare professionals must conduct PKU metabolic screening and diagnostic tests.

Pregnancy in a PKU patient — Is it Safe?

Pregnancy in PKU patients is safe, but care must be taken. Women with PKU should strictly control their phenylalanine levels during pregnancy to avoid harm to the developing fetus. Elevated phenylalanine levels during pregnancy can lead to maternal PKU syndrome, which can cause low birth weight, small head circumference, heart defects, and developmental delays in the baby. Even if the mother’s PKU is well-controlled, the baby can still experience problems, so managing phenylalanine levels is crucial.⁷ Therefore, even if the mother has mild PKU, she still must be extra careful about her diet during pregnancy.

The newborn of a mother with phenylketonuria does not have the disease, but they might have serious problems.⁸

Low birth weight
Small head circumference
Heart problems
Delayed development
Intellectual disability

Treatment of Phenylketonuria

There is no definite cure for PKU. The focus of treatment is on managing the symptoms and enhancing the quality of life.⁹

Phenylketonuria Diet:

The main way to treat PKU is by taking a diet that has minimal amounts of phenylalanine. Newborns are fed breast milk and a special formula for PKU patients called Lofenalac. When the child can eat solid foods, it is crucial to avoid the following high-protein foods at all costs:

Eggs
Cheese
Nuts
Milk
Beans
Chicken
Beef
Pork
Fish

Proteins and amino acids are an essential part of a diet. Thus, to ensure that the child receives an adequate supply of essential amino acids while excluding phenylalanine, they receive a PKU formula. Dietary restrictions and the continued use of PKU formula are necessary throughout life because this is the only method to control symptoms.

Dietary control improves behavioral and mental dysfunction.¹⁰

The meal plans for PKU patients is not standardised. The plan varies from person to person. A physician, nutritionist/dietician work in close collaboration with patients to make the best possible phenylketonuria diet plan for the patient to cater all of his or her needs. Regular monitoring of phenylalanine levels is also necessary to make any substantial changes in the diet.

Medications for Phenylketonuria:

In some cases, dietary control alone may not be sufficient. The FDA-approved medication sapropterin dihydrochloride (Kuvan) is a synthetic form of tetrahydrobiopterin (BH4), a cofactor that enhances residual activity of phenylalanine hydroxylase in certain patients. Sapropterin can help lower phenylalanine levels and increase dietary protein tolerance, but is more effective in individuals with mild to moderate PKU who retain some enzyme activity.

Other emerging treatments, including enzyme substitution therapy (e.g., pegvaliase) and gene therapy, are under study or have been recently approved for certain adults with PKU. However, their use requires careful selection and monitoring by specialists.

Phenylketonuria and Alkaptonuria

Both phenylketonuria (PKU) and alkaptonuria are inherited metabolic disorders involving amino acid breakdown. PKU is caused by a deficiency of phenylalanine hydroxylase, leading to a buildup of phenylalanine that can damage the brain if untreated. Alkaptonuria results from a deficiency of homogentisate dioxygenase, causing homogentisic acid to accumulate, which darkens urine and leads to joint problems and tissue pigmentation over time. While PKU mainly affects neurological development, alkaptonuria causes physical complications later in life.

Conclusion

Early diagnosis of PKU through newborn screening, followed by lifelong dietary management and medical supervision, remains the most effective strategy to prevent intellectual disability and improve quality of life. Advances in pharmacologic therapies offer additional support for patients with partial enzyme activity or difficulty adhering to dietary restrictions. Pregnancy in women with PKU requires careful phenylalanine control to avoid serious fetal complications. With appropriate management, individuals with PKU can lead healthy, productive lives.

Refrences

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Elhawary, N. A., et al. (2022). Genetic etiology and clinical challenges of phenylketonuria. Human Genomics, 16(1), 22. https://doi.org/10.1186/s40246-022-00398-9
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Understanding Phenylketonuria (PKU)

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