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Phenylketonuria (PKU) – Causes, Symptoms & Treatment

Phenylketonuria (PKU) is a rare inherited metabolic disorder in which the amino acid phenylalanine cannot be properly broken down. Without treatment, it can lead to severe intellectual disabilities.

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Things worth knowing about "Phenylketonuria"

Phenylketonuria (PKU) is a rare inherited metabolic disorder in which the amino acid phenylalanine cannot be properly broken down. Without treatment, it can lead to severe intellectual disabilities.

What is Phenylketonuria?

Phenylketonuria (PKU) is a rare, hereditary metabolic disorder. People affected by PKU either lack the enzyme phenylalanine hydroxylase (PAH) or have a severely reduced version of it. This enzyme is responsible for converting the amino acid phenylalanine into the amino acid tyrosine. Without this conversion, phenylalanine accumulates in the blood and body tissues, causing significant damage especially to the brain.

PKU is inherited in an autosomal recessive pattern, meaning a child must inherit one defective copy of the gene from each parent in order to develop the condition. In many countries, including Germany and the United States, PKU is detected through routine newborn screening within the first days of life.

Causes

PKU is caused by mutations in the PAH gene located on chromosome 12. This gene provides instructions for producing the phenylalanine hydroxylase enzyme. When this gene is mutated, the enzyme cannot function properly.

Classic PKU: severe or complete enzyme deficiency, very high phenylalanine levels in the blood
Mild PKU or hyperphenylalaninemia: partial enzyme deficiency, moderately elevated phenylalanine levels
Tetrahydrobiopterin (BH4) deficiency: a rare variant in which a cofactor required by the enzyme is absent

Symptoms

Newborns with PKU typically appear healthy at birth. However, without treatment, serious symptoms can develop within the first months and years of life:

Intellectual disability and cognitive impairments
Behavioral problems, hyperactivity, and irritability
Seizures
Fair skin, light hair, and blue eyes (due to reduced melanin production)
Eczema (skin rashes)
Musty body or urine odor caused by the excretion of phenyl ketones
Neurological developmental delays

In patients diagnosed and treated early, these symptoms typically do not occur or occur only in a very mild form.

Diagnosis

PKU is diagnosed as part of routine newborn screening, which is performed within the first 48 to 72 hours of life. A small blood sample is taken from the newborn heel and tested for elevated phenylalanine levels.

Tandem mass spectrometry (MS/MS): Standard method for measuring amino acid concentrations in the blood
Genetic testing: To identify the specific PAH mutation
Enzyme activity measurement: Used in special cases to distinguish between PKU variants
BH4 loading test: To determine whether a patient responds to sapropterin (BH4) therapy

Treatment

Treatment for PKU must be lifelong and aims to keep phenylalanine blood levels within a safe range.

Low-Phenylalanine Diet

The most important treatment is a strict phenylalanine-restricted diet. Since phenylalanine is found in almost all protein-containing foods, affected individuals must severely limit or avoid high-protein foods such as meat, fish, dairy products, eggs, legumes, and nuts. Special low-phenylalanine protein substitutes are used to ensure adequate intake of other essential amino acids.

Medical Therapy

Sapropterin (Kuvan): A synthetic BH4 preparation used in patients with BH4-responsive PKU that helps lower phenylalanine levels.
Pegvaliase (Palynziq): An enzyme substitution therapy for adults with uncontrolled PKU that breaks down phenylalanine in the body.

Pregnancy and PKU

Women with PKU who are pregnant must maintain very strict control of their phenylalanine levels, as elevated levels can harm the unborn child (maternal PKU). This can result in heart defects, microcephaly, and intellectual disability in the child, even if the child itself does not have PKU.

Long-Term Prognosis

With early diagnosis and consistent treatment, children with PKU can achieve normal cognitive development and a good quality of life. Regular monitoring of blood phenylalanine levels is necessary throughout life.

References

Blau N. et al. - Phenylketonuria. The Lancet, 2010; 376(9750): 1417-1427.
National Institutes of Health (NIH) - Phenylketonuria (PKU): MedlinePlus Genetics (2023). Available at: https://medlineplus.gov/genetics/condition/phenylketonuria/
van Wegberg A.M.J. et al. - The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet Journal of Rare Diseases, 2017; 12(1): 162.

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