Phenylketonuria (PKU) is a genetic, metabolic condition where there is a build-up of phenylalanine (phe) in the body. Phe is an amino acid and is found in foods containing protein.¹ The body only needs a small amount of phe and will usually convert the remaining phe into another amino acid called tyrosine.² Individuals with PKU cannot convert excess phe into tyrosine, which leads to a build-up of phe in the body. If PKU is not treated, phe can build up to harmful levels in the body and this can affect many body systems including the brain and nervous system.^3,4

PKU can vary between mild to severe forms. If left untreated, the most severe form, known as classic PKU, can lead to permanent intellectual disability This is less likely for the milder forms of PKU.²

In Australia, PKU is often detected shortly after birth via newborn bloodspot screening (NBS) programs. For individuals who are not screened at birth, PKU is often diagnosed after symptoms develop. Early detection and management of PKU (typically through a strict low-protein diet) can prevent long term damage. Treatment of PKU is life-long. Mothers who have PKU and no longer follow a phe-restricted diet have an increased risk of having children with an intellectual disability, because their babies may be exposed to very high levels of phe before birth.⁴

There is also another type of PKU caused by deficiency of a cofactor called BH4 that helps metabolism of phe.¹ This condition will also result in high levels of phe that can be detected by newborn bloodspot screening but further tests will be required to confirm deficiency of the BH4 cofactor. This type of PKU cannot be treated through a restricted diet; however, it is treatable with medication.

Synonyms: PKU, PAH deficiency, phenylalanine hydroxylase deficiency, Oligophrenia Phenylpyruvica, Folling disease, hyperphenylalaninemia.²

Universal rare disease classifications provide a common language for recording, reporting and monitoring diseases. Please visit the Rare Disease Classifications page for more information about these internationally recognised classifications.

ORPHA:716 Phenylketonuria

ICD-11:5C50.0 Phenylketonuria

Early diagnosis and treatment of PKU enables a child with PKU to grow and develop in a similar way to their healthy peers who don’t have PKU. However, if not diagnosed and treated early, high levels of phe in the blood can cause:¹

• developmental delays noticeable in the very first year of life
• neurological conditions such as intellectual disability, hyperactivity and poor coordination
• aggressive behaviour or emotional disturbances including anxiety
• severe brain damage if left untreated

Please speak to your medical team to learn more about the symptoms and complications of PKU.

Rare diseases are often serious and progressive, exhibiting a high degree of symptom complexity, leading to significant disability. Majority of the estimated two million Australians living with a rare disease meet the Australian Government’s definition for disability (in accordance to the Australian Public Service Commission and Australian Bureau of Statistics), and many experience severe and permanent disability impacts. If you or someone you care for is experiencing disability-related impacts from a rare condition, please speak with a health or disability professional for advice. Information about relevant disability support can be found at the RARE Portal’s Disability Support Information page.

PKU is a genetic condition. It is caused by disease-causing genetic changes (variants) in the PAH gene.² The PAH gene encodes for the PAH enzyme that breaks down the amino acid phenylalanine (phe) into tyrosine.¹

Every individual has two copies (alleles) of the PAH gene – one on each chromosome that is inherited from each parent. PKU is an autosomal recessive condition, which means both copies of the PAH gene must have the disease-causing genetic variants.

Individuals with the genetic variant in only one copy are unaffected but will be a carrier and may pass on that variant to their children. If both parents are carriers (each have a copy of the disease-causing variant), there is a 25% chance the child will inherit both disease-causing variants and have PKU. More information on autosomal recessive inheritance pattern can be found at Centre for Genetics Education: Autosomal recessive inheritance.

If you would like to learn more about the inheritance and impact of this condition, please ask your doctor for a referral to a genetic counsellor. Genetic counsellors are qualified allied health professionals who can provide information and support regarding genetic conditions and testing. More information about genetic counselling can be found at:

• Information on Genetic Services
• The National and State Services pages underneath the ‘Genetic Counselling’ sections listed

Screening

In Australia, PKU is usually detected via the newborn bloodspot screening (NBS) programs.  Shortly after birth and with parental consent, a nurse or midwife will collect the baby’s blood via a heel prick blood test. The healthcare provider will then send it to a specific laboratory to test for a range of rare conditions, including PKU. If the results of these tests suggest that the baby is at risk of having one of these conditions, laboratory staff will quickly get in touch with healthcare providers. The healthcare providers will then arrange for the baby to have further testing that will confirm whether the baby does indeed have the condition. The healthcare providers will also organise for the baby to receive urgent care if required. Depending on your state or territory, parents may or may not receive a notification if the test results are clear. You can find out more about NBS in your state or territory at Australian Government Department of Health, Disability and Ageing: Delivering newborn bloodspot screening programs.

Newborn bloodspot screening is a reliable way to check for certain rare conditions early in life. Although it’s extremely rare, cases can sometimes be missed. If you are concerned your baby may have a condition that they have already been screened for, you should contact a medical professional.

Diagnosis

A diagnosis of PKU can be suspected based on an abnormal result from NBS but additional tests or a clinical examination will be required to confirm a diagnosis. For individuals who are not screened at birth, PKU is often diagnosed after symptoms develop.

In the case of PKU, it is often detected by measuring phe levels, which begin to rise immediately after birth in affected babies. If phe levels are found to be high, doctors will request more tests to confirm a diagnosis of PKU. Immediately after diagnosis, the baby is referred to a metabolic clinical service where they are prescribed a special formula to maintain safe levels of phe in the blood.¹ It is critical that PKU is detected early and managed immediately after diagnosis to prevent long term damage.¹

There is currently no curative treatment for PKU. In Australia, treatment for most people with PKU involves a life-long strict low-protein diet and a special nutritional supplement, together with regular blood tests to measure the phe level and regular attendance at a metabolic clinic.¹ The recommended amount of protein from food and supplement varies between individuals – this depends on an individual’s phe tolerance, which may also change over time. Strict compliance with diet and maintaining phe concentrations within the recommended reference ranges can help to ensure normal development and life expectancy. When PKU is diagnosed early and treated with diet and supplementation, children can reach their full potential.^1,3

Some people with PKU may benefit from a medication containing sapropterin (BH4), which is an enzyme cofactor. For more information, please refer to The PKU Handbook.²

Please speak to your medical team to learn more about the possible treatment or management options for your condition. Treatment will depend on an individual’s specific condition and symptoms. It is also important to stay connected to your medical team so that you can be made aware of any upcoming clinical trial opportunities.

Clinical care for rare diseases often involves a multidisciplinary team of medical, care and support professionals. Please note that the information provided here is as a guide and that RVA does not necessarily monitor or endorse specific clinics or health experts.

Healthcare professionals involved in the treatment of PKU may include metabolic doctors, nurses, dieticians, psychologists and social workers who are trained to look after people with metabolic disorders.³ The need for different healthcare professionals may change over a person’s lifetime and extend beyond those listed here.

Metabolic Dietary Disorders Association (MDDA): Metabolic Clinics include a list of metabolic clinics in Australia that provide comprehensive diagnostic and management services for children and adults with inborn errors of metabolism, including PKU.

• Australasian Consensus Guidelines for the Management of Phenylketonuria (PKU) Throughout the Lifespan
• Australasian Consensus Guidelines for the Management of Maternal Phenylketonuria (PKU)
• PKU Fruit Veg and Protein Counting Lists
• Australasian BH4 Clinical Guideline
• The PKU Handbook

Individuals living with rare diseases may have complex medical issues and disabilities, which are not always visible. It is often useful to refer to their medical history as well as personal information such as a medical card, doctor’s letter, or if available, a rare disease passport, for relevant information.

Metabolic Dietary Disorders Association (MDDA): Latest Research Updates has information about key areas of ongoing research for various inborn errors of metabolism conditions, including PKU.

There are specific considerations around participating in rare disease research, including clinical trials. It is important to be mindful of issues such as data privacy, research ethics, consent and differences in research regulations between Australia and other countries.

If you are interested in finding clinical trials for your condition, please visit the following websites; however, there may not be any clinical trials available:

• Australian Clinical Trials
• ClinicalTrials.gov

It is best to discuss your interest in any clinical trials with your medical team to determine suitability and eligibility.

Please note that RVA does not necessarily monitor or endorse each group/organisation’s operational governance and activities.

Australian Organisation:

Metabolic Dietary Disorders Association (MDDA)
Website: https://mdda.org.au/

Metabolic Dietary Disorders Association Inc (MDDA) is the national peak consumer body dedicated to supporting, educating, connecting, and representing all individuals their families and carers living with Inborn Errors of protein Metabolism (IEpM).

Please note that RVA does not monitor or endorse each group/organisation’s operational governance and activities. When engaging with a group, please consider the information on the RARE Portal’s Finding Helpful Peer and Community Supports page.

PKU vary between individuals, and each person’s experience is unique.

If you would like to share your personal story with RVA, please visit the Rare Voices Australia: Share Your Story page. RVA will consider your story for publishing on our website and inclusion on the RARE Portal.

• Metabolic Dietary Disorders Association (MDDA): Patient Pathways Telehealth Nurse
• Services Australia Carer Allowance is a supplementary payment if you care for someone who needs daily support
• Australian Government Department of Health, Disability and Aging: Inborn Errors of Metabolism program helps people with protein metabolic disorders pay for their specialised food
• MDDA: School Starters Resource is a guide for planning and discussing your child’s PKU/IEM management with the preschool or school

For information on available government and social services that provide support for individuals with a rare disease, please visit the National and State Services pages.

People living with a rare disease, including families and carers, often face unique challenges such as diagnostic delays, misdiagnoses, limited treatment options, and limited access to rare disease specialists and support. These challenges may impact people’s emotional wellbeing and quality of life. Many people find it helpful to seek mental health and wellbeing support to cope with ongoing stress and uncertainty. Connecting with people who have shared experiences through a support group may also be helpful. Information about relevant mental health and wellbeing support can be found at:

• Mental Health and Wellbeing Support for Australians Living with a Rare Disease
• The National and State Services pages underneath the ‘Mental Health’ sections listed

For more resources on diet and nutrition, exercise, education, preparing for school or childcare, financial support, dental care, and obstetric care please see The PKU Handbook.

• GeneReviews^® : Phenylalanine Hydroxylase Deficiency
• Online Mendelian Inheritance in Man, OMIM^®: #261600 Phenylketonuria; PKU
• Orphanet: Phenylketonuria
• Human Phenotype Ontology (HPO): Phenylketonuria
• Inborn Errors of Metabolism Knowledgebase: Phenylalanine hydroxylase deficiency

This page has been co-developed by Rare Voices Australia (RVA)’s RARE Portal team in consultation with Metabolic Dietary Disorders Association and the Australian Society for Inborn Errors of Metabolism.

If you are aware of any additional information that may benefit stakeholders with an interest in this page, or if you notice any broken links or inaccurate information, please let us know via the Contribute page.