Introduction 

Metabolism refers to the way in which food is turned into fuel to maintain our bodies. To function normally, building blocks called amino acids are converted to proteins that play vast roles in growth, maintenance and hormone signalling. 

Issues can arise when we get random mutations, or inherit faulty genes that disrupt this process – these are called inborn errors of metabolism.  

Phenylketonuria (PKU) is a metabolic disorder that stems from mutations in the gene coding for phenylalanine hydroxylase (PAH). PAH is involved in amino acid conversion.

Those with phenylketonuria usually follow a low-protein diet to avoid a buildup of phenylalanine.¹ This article will explain about the things individuals with PKU should avoid to prevent negative health impacts. 

Pathophysiology of PKU 

PKU is an autosomal recessive disorder. To inherit the disease, you must have a faulty copy of the PAH gene from both parents. The parents are known as ‘carriers’ of the mutation since they can pass it down to their child, but do not exhibit the disease themselves.² 

The PAH gene is responsible for making an enzyme that turns one amino acid into another. Specifically, it converts phenylalanine into tyrosine, which is further processed into catecholamine neurotransmitters.  

Mutations in the PAH gene cause changes in the shape of the enzyme, which means that these neurotransmitters cannot be made. Instead of being broken down, phenylalanine builds up in the blood and brain.  

This excess of phenylalanine in the blood plasma is known as hyperphenylalaninemia, causing these symptoms in untreated individuals: 

• Behavioural disorders 
• Developmental disorders 
• Cognitive impairments³ 
• Acquired microcephaly, unusually small head
• Eczema
• Irritability
• Hypertonicity (muscle stiffness)
• Agitated behaviour
• Hyperactivity
• Occasional seizures
• Hypopigmentation – blond hair and blue eyes can result from a lack of melanin, or less pigmented skin
• A ‘mousy’ scent due to the secretion of phenylacetic acid

This arises as low levels of neurotransmitters impair cognitive development, and lead to the onset of symptoms such as anxiety and depression.⁴ 

The newborn blood spot test, known as the heel prick, is used to measure blood phenylalanine levels at birth. It is usually done when the baby is 5 days old.

Dietary restrictions for PKU

Low-Phenylalanine Diet

A diet low in phenylalanine is crucial for positive cognitive development of people affected by PKU.⁵

Phenylalanine is an amino acid that is found in most protein rich foods. It is also present in artificial sweeteners like aspartame when broken down. 

Restricted Foods

Avoid foods that are high in protein, for example:

• Meat
• Fish
• Eggs
• Dairy products like milk, cheese and yogurt
• Nuts (Including foods with processed nuts like peanut butter)
• Legumes (Beans and lentils)
• Foods containing aspartame, such as sweets made with gelatin, ice cream and diet drinks⁶

Allowed Foods 

It is recommended to consume foods with low protein content:⁷

• Fruits
• Vegetables
• Starches like bread, cereals and pasta
• For babies, there are special phenylalanine-free infant formulas⁸

Trace amounts of protein are present in fruits and vegetables, which is safe for PKU individuals to consume. A diet with completely no protein is impossible to maintain as your body still requires them to function normally. Phenylalanine is still essential to growth, and children’s tolerance may vary.

Monitoring and management 

Phenylalanine levels can be monitored through the use of a few tools:⁹

• Frequent blood testing, to measure phenylalanine levels
• Food records which can be compared with blood test results to adjust diet and provide additional planning
• PKU clinic visits with paediatric exams for children, offering support

These actions will support those with PKU and ensure they receive the help they need.

Challenges and considerations

There can be multiple difficulties that accompany life with PKU, so it is important to know how to support someone who has this condition. 

Adherence to Dietary Restrictions

A strict diet is hard to manage, especially at social events or settings. Finding food that caters to PKU restrictions might be tricky in some establishments, like a steakhouse. 

Strategies can be implemented in order to follow a low-protein diet, such as meal planning and support systems. It can be helpful to let friends and family know what can and can’t be eaten, and let them make adjustments to food and drink ahead of time.

When eating out for dinner or lunch, you can check menus to see if they have low-protein options. Usually this may just equate to choosing vegetarian dishes. 

Psychosocial Impact 

PKU can be described as a hidden disability, meaning that its effects aren’t immediately noticed by those with it. This is especially true in PKU individuals who were treated early on or well. They may find difficulty in the following:¹⁰

• Formation of interpersonal relationships
• Achievement of autonomy
• Educational attainment
• Healthy emotional development

It is no surprise that quality of life can be negatively impacted by PKU, as cognitive impairment can occur with improper metabolic control.

Lifelong Management 

To ensure the best outcomes, dietary restrictions should be maintained throughout life. With the help of a dietician, PKU individuals can receive advice on how to follow a low-protein diet. 

Throughout different life stages, this is necessary as adjustments need to be made for both children, adults and during pregnancy as our metabolic requirements change.¹¹

Advances and alternatives

Research and New Therapies 

Gene therapy

There is ongoing research that focuses on gene treatments for fixing the faulty PAH gene, by using viruses. Viruses have to inject their DNA into our cells to survive, and some lay dormant in our genome, fusing into our own DNA. 

We can harness this technology to deliver a genetic sequence that codes for the correct PAH enzyme, instead of viral DNA. This has been achieved in animals but it is difficult to replicate in humans as it may pose unknown risks. It still demonstrates that PAH function can potentially be restored by the presence of a healthy gene, preventing phenylalanine buildup.¹²

CRISPR therapy has been attempted on primates and some patients with PKU. This utilises gene editing technology to directly fix the PAH enzyme. However, some PAH mutations are rarer than others and there are challenges in replicating these in order to trial CRISPR gene editing.¹³ 

Drugs

Other treatments that are currently being used included sapropterin, which is a drug that helps faulty PAH to work. Unfortunately, it isn’t effective against one of the most common mutant forms of the PAH enzyme.

The only other approved medication is pegvaliase, a drug that can break down phenylalanine. Administration of pegvaliase needs to be highly controlled, and it has a large risk of anaphylaxis.¹⁴

Supplementary Treatments 

One strategy has been conceived, in which phenylalanine absorption has been blocked with large neutral amino acids.¹⁵ It has been tested in mice with PKU, showing that it can reduce levels of PKU build-up. More studies must be done before this is trialled in humans.¹⁶

Recommendations for individuals with PKU 

Education and Awareness

It is helpful for people who are involved with someone that has PKU to learn more about the condition in order to help where they can. These charities offer links to information suited to anyone who wants to educate themselves about PKU:

• The National Society for Phenylketonuria (NSPKU) is the oldest charity dedicated to PKU, offering a wealth of resources to help families and individuals
• Metabolic Support UK can answer queries about PKU from their helplines 0845 241 2173 or 0800 652 3181. They can also be contacted by email if preferred
• The British Inherited Metabolic Diseases Group (BIMDG) has a booklet about PKU aimed at teaching children, their families, teachers and social workers about the condition

Healthcare Team Involvement 

A multidisciplinary team may improve the life of someone with PKU. Regularly consulting healthcare providers, and having a specialised dietician may improve management of PKU. Some people may wish to undergo genetic screening in order to identify whether there is risk of their child suffering from PKU.

Summary

Dietary management for people with PKU is essential to their lives, as untreated PKU can have severe impacts on mental and behavioural development. This can hinder quality of life and prevent them from experiencing normal work, interpersonal and educational ventures. It is difficult, but possible to stick to a low-protein diet and cut out foods that include aspartame.

We encourage PKU individuals to remain informed and use resources available to them to adhere to dietary recommendations. Research is ongoing to make the lives of those with PKU easier through the use of drug treatments. Though none are currently in use in the UK, new advances are being made each day and there is endless support for those with this metabolic condition.