Phenylketonuria
Phenylketonuria, or PKU, is a rare inherited metabolic disorder in which the body cannot properly break down the amino acid phenylalanine, that is found in many protein-containing foods (such as meat, dairy, eggs, nuts) and in some sweeteners (e.g. aspartame).
In PKU, a deficiency of the enzyme phenylalanine hydroxylase (PAH) leads to accumulation of phenylalanine in the blood and brain. If not treated, high phenylalanine levels are toxic, affecting the brain’s development and causing permanent intellectual disability, along with other neurological problems.
Thanks to newborn screening and early dietary treatment, most children with PKU today can grow and develop without serious complications.
What causes PKU?
PKU is caused by mutations in the PAH gene, which provides instructions for making the enzyme phenylalanine hydroxylase. This enzyme normally converts phenylalanine into another amino acid, tyrosine.
Because PKU is an autosomal recessive disease, a child must inherit two mutated PAH genes (one from each parent) to develop it; and the parents, who each carry one mutated and one normal copy, are usually asymptomatic carriers.
In some countries there are also “variant” or “mild” forms of hyperphenylalaninemia with partial enzyme activity, which may allow a more liberal diet.
Symptoms in infants and children
When Phenylketonuria is not treated, symptoms usually develop gradually within the first months of life. A newborn with PKU often looks completely healthy at birth.
Typical features of untreated or poorly controlled PKU include:
- Developmental delay, where the baby may not reach milestones (sitting, walking, talking) at the expected age.
- Intellectual disability ranging from mild to severe, if high phenylalanine levels persist.
- Seizures and abnormal EEG findings.
- Behavioural problems: irritability, hyperactivity, attention difficulties, autistic-like features.
- “Musty” or “mousy” odour of the breath, skin or urine, due to phenylalanine breakdown products.
- Light pigmentation, fair skin, blond hair, blue/light eyes compared with other family members, due to reduced melanin production.
- Eczema-like skin rash.
With early diagnosis and strict metabolic control, most of these symptoms can be prevented.
How common is PKU?
PKU is a rare disease, but its frequency varies between populations. Roughly:
- In many European countries and North America: around 1 in 8,000–15,000 live births.
- In some regions the disease is more or less frequent, depending on carrier frequency in the population.
Diagnosis
Today, Phenylketonuria is usually diagnosed via newborn screening:
- A few drops of blood are collected from the baby’s heel (dried blood spot) a couple of days after birth.
- The sample is analysed for elevated phenylalanine levels.
- If screening is positive, additional tests confirm the diagnosis:
- repeat plasma phenylalanine measurement,
- phenylalanine/tyrosine ratio,
- sometimes PAH gene testing.
In settings without newborn screening, PKU may be suspected when a child shows:
- developmental delay or intellectual disability,
- seizures, behavioural problems,
- musty body odour and light pigmentation,
and blood tests reveal markedly elevated phenylalanine.
Treatment and prognosis
The cornerstone of Phenylketonuria management is lifelong control of phenylalanine levels.
Main treatment strategies
- Phenylalanine-restricted diet
- A special low-protein diet started as early as possible (ideally in the first weeks of life).
- Strict limitation of natural protein intake (meat, fish, eggs, dairy, nuts, many grains).
- Use of phenylalanine-free amino acid formulas and special medical foods to provide enough protein and nutrients for normal growth.
- Regular monitoring
- Frequent blood tests (especially in infancy and childhood) to monitor phenylalanine levels and adjust the diet accordingly.
- Adjunct therapies (in some patients)
- Certain individuals with specific PAH mutations may respond to sapropterin (BH4), a synthetic cofactor that increases residual enzyme activity and allows a less strict diet.
- Newer treatments (such as enzyme substitution or gene-based approaches) are being studied in some countries.
Prognosis
When Phenylketonuria is diagnosed early (via newborn screening) and treated consistently with good metabolic control, most people with this condition can have normal intellectual development, attend mainstream school and lead independent adult lives.
Poor adherence to dietary treatment or late diagnosis, especially in early childhood, significantly increases the risk of irreversible intellectual disability and neurological problems.
Women with the disease need particularly careful metabolic control before and during pregnancy to protect the developing baby from high maternal phenylalanine levels, known as maternal PKU syndrome.
Sources:
- Andrea M. Zuñiga Vinueza, Recent Advances in Phenylketonuria: A Review (2023)
- Naz Al Hafid & John Christodoulou, Phenylketonuria: a review of current and future treatments (2015)
- European Expert Group, European guidelines on diagnosis and treatment of phenylketonuria: First revision (2025)
- Anita MacDonald et al., Current Insights into Nutritional Management of Phenylketonuria: An Update for Children and Adolescents (2023)
- Eduardo Remor et al., What is known about patients’ quality of life with Phenylketonuria and their caregivers? A scoping review (2024)