Beta-ketothiolase deficiency is a genetic metabolic condition in which the body cannot properly process ketone bodies and isoleucine.^1-3 Ketone bodies are molecules made by the liver when the body breaks down its fat stores,² and they are normally processed further to produce energy.³ Isoleucine is an amino acid (one of the building blocks of protein). It is found in foods that contain protein, and is important for normal body function and maintaining a healthy balance of important metabolic processes in the body (metabolic homeostasis). When ketone bodies and isoleucine are not processed properly, this results in a build up of harmful substances (toxic metabolites) in the body.^1,3

In beta-ketothiolase deficiency, the build-up of the toxic metabolites in the body can lead to episodes of ketoacidosis, a condition where the blood becomes too acidic. These episodes can be set off (triggered) by infections, stress, or periods of not eating (fasting), during which the body will switch to using its fat stores for energy.^1,2 In some rare cases, these episodes can also be triggered by eating large amount of protein-rich food. Ketoacidosis can cause symptoms such as fruity-smelling breath, vomiting, difficulty breathing and extreme tiredness (lethargy).^1,2 In severe cases, ketoacidosis can be life-threatening and may lead to coma and early death if not treated promptly.¹ Children may also have developmental delay resulting from severe ketoacidosis episodes.³

In Australia, beta-ketothiolase deficiency is often detected shortly after birth via newborn bloodspot screening (NBS) programs. Additional testing is required to confirm the diagnosis. For individuals who are not screened at birth, beta-ketothiolase deficiency is often diagnosed after symptoms develop.

Synonyms:^1,3 MAT deficiency; 2-methylacetoacetyl-coenzyme A thiolase deficiency ; mitochondrial methylacetoacetyl-coenzyme A thiolase deficiency; 3-ketothiolase deficiency; 3-oxothiolase deficiency; Alpha methylacetoacetic aciduria; Alpha-methyl-acetoacetyl-CoA thiolase deficiency; Mitochondrial acetoacetyl-coenzyme A thiolase deficiency; T2 deficiency

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.

ORPHA134: Beta-ketothiolase deficiency

ICD-11: 5C50.DY Other specified disorders of branched-chain amino acid metabolism

Symptoms of beta-ketothiolase deficiency are usually not present at birth, but often develop between the ages of 5 months to 2 years old, or later in childhood, if children are not diagnosed and treated early.^1,2  Symptoms present during episodes of ketoacidosis, which occurs when the blood becomes too acidic due to a build‑up of ketones and other acids. These episodes are more likely to occur during times of stress, illness, fasting and in some cases, high protein intake, and the frequency of the episodes may decrease with age.¹

Symptoms of ketoacidosis may include fruity-smelling breath, vomiting, shortness of breath (dyspnoea), rapid breathing (tachypnoea), extreme tiredness (lethargy) and in some cases, seizures.^1,2 If left untreated, ketoacidosis can lead to coma and early death.

Children with beta-ketothiolase deficiency tend not to have symptoms in between episodes of ketoacidosis, but repeated severe episodes may lead to developmental delay.¹

Please speak to your medical team to learn more about the symptoms of this condition.

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.

Beta-ketothiolase deficiency is a genetic condition. It is caused by disease-causing genetic changes (variants) in the ACAT1 gene located on Chromosome 11.^1,4 The ACAT1 gene provides instructions for making a mitochondrial enzyme (protein) called acetyl-CoA acetyltransferase (ACAT).^1,3 This enzyme plays an important role in breaking down ketone bodies (important source of energy during fasting or illness) and the amino acid isoleucine (important for normal growth and maintaining healthy balance of metabolic processes in the body).

All individuals have two copies (alleles) of the ACAT1 gene – one on each chromosome that is inherited from each parent. Beta-ketothiolase deficiency is an autosomal recessive condition, which means both copies of the ACAT1 gene must have the disease-causing genetic variants. 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

Newborn screening

In Australia, beta-ketothiolase deficiency 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 beta-ketothiolase deficiency. 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 beta-ketothiolase deficiency may 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, beta-ketothiolase deficiency is often diagnosed after symptoms develop.

Diagnosis of beta-ketothiolase deficiency may be made based on clinical examination, biochemical tests on blood and urine samples to detect increased levels of certain organic acids, and confirmed by genetic testing. In some cases, a skin biopsy may also be performed to get samples for enzyme activity tests to detect if the beta-ketothiolase enzyme is working properly.¹

As part of the diagnostic process for beta-ketothiolase deficiency, doctors may do a differential diagnosis, which is to rule out other conditions that have similar symptoms, such as sepsis, other organic acidurias, HSD10 disease, succinyl-CoA:3-ketoacid CoA transferase deficiency, and other conditions that can cause ketoacidosis in childhood.¹

Please speak to your medical team to learn more about the available pathways for diagnosis of this condition.

There is currently no curative treatment for beta-ketothiolase deficiency; however, early diagnosis and appropriate management can help prevent or reduce the risk of life-threatening complications. Treatment focuses on prompt management of ketoacidosis, long-term dietary management (including avoidance of fasting), and regular monitoring of metabolic stability.^1,5

Ketoacidosis is a medical emergency that requires urgent treatment to prevent serious complications. With early diagnosis and careful management, the risk of ketoacidosis episodes may be reduced, although they may still occur, particularly during illness or other physical stress. During periods of illness, such as fever or vomiting, intravenous glucose may be administered to reduce the risk of developing ketoacidosis.¹

Long-term dietary management typically involves a low-protein diet with mild restriction of protein, avoidance of high-fat foods and ketogenic diets, and avoidance of fasting.^1,3,5 In some cases, dietary supplementation such as L-carnitine may be recommended.

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. For many rare diseases, treatment options may be limited. Participation in a clinical trial may provide access to new or emerging therapies.

Healthcare professionals involved in the clinical care of individuals with beta-ketothiolase deficiency may include general practitioners (GPs), paediatricians,  metabolic physicians, geneticists, neurologists, and other metabolic specialists and healthcare workers who are trained to look after people with metabolic disorders. The need for different healthcare professionals may change over a person’s lifetime and extend beyond those listed here.

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.

This may not be applicable to all rare diseases but for many, palliative care services may be relevant and useful. Palliative care services are available for people (adults, children and their families) living with a life-limiting illness and is not only for end-of-life care. It can also help at any stage of illness from diagnosis onwards, and will look different for different people. Palliative care services provide assistance, support, resources and tools to help people manage their illness and the symptoms, ease pain, and improve comfort and quality of life. If this is relevant to you and you wish to find out more information about palliative care and how it can help you, please visit:

• Australian Institute of Health and Welfare: Palliative care Overview
• Australian Government Department of Health, Disability and Ageing: Palliative care
• Palliative Care Australia

If you know of any relevant clinical care guidelines for beta-ketothiolase deficiency, please let us know via the  Contribute page.

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.

In addition, individuals, their parents, families and carers often develop extensive expertise on their specific rare disease. It is important to recognise that they can contribute valuable knowledge about their rare condition. Rare diseases often impact individuals differently, so it’s important to consider a person’s lived experience.

If you know of any relevant emergency management guidelines or information relevant to emergency care, please let us know via the  Contribute page.

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. For more information, please visit the RARE Portal’s Considerations for Participating in Health and Medical Research page.

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 research, including clinical trials,  with your medical team to determine suitability and eligibility.

We are not aware of any rare disease organisations specifically for beta-ketothiolase deficiency in Australia. If you are aware of any relevant Australian organisations, please let us know via the Contribute page.

Genetics Alliance Australia (GAA) may be able to provide some support for families and individuals affected by an undiagnosed or rare genetic condition for which there is no disease specific organisation in Australia.

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.

Beta-ketothiolase deficiency varies 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.

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 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 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

Further information on beta-ketothiolase deficiency can be found at:

• Genetic and Rare Diseases (GARD) Information Center: Beta-ketothiolase deficiency
• MedlinePlus Genetics: Beta-ketothiolase deficiency

Orphanet: Beta-ketothiolase deficiency

Online Mendelian Inheritance in Man, OMIM^®: # 203750 Alpha-methylacetoacetic aciduria

This page has been developed by Rare Voices Australia (RVA)’s RARE Portal team.

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.