3-hydroxy-3-methylglutaric aciduria (3HMG) is a genetic, metabolic condition. People with 3HMG  cannot properly break down leucine, which is an amino acid (protein building block) that is found in many foods.¹ Their bodies are also unable to make ketones, which are molecules normally produced by the liver when the body breaks down fat for energy. This results in a build-up of toxic metabolites (due to incomplete breakdown of leucine) and not enough energy being produced, especially when the body is under stress conditions such as fasting or illness.^1,2

Symptoms often present early on in life and may include vomiting, dehydration, extreme tiredness and lack of energy (lethargy) and weak muscle tone (hypotonia).^1-4 People with 3HMG are at risk of metabolic crises which, if left untreated, can lead to life-threatening complications including seizures, coma and early death.^1,3-5

In Australia, 3HMG 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, 3HMG is often diagnosed after symptoms develop. Early detection and management of 3HMG is important to prevent life-threatening complications.^1,3,4

Synonyms:^2,5 3-hydroxy-3-methylglutaryl-CoA lyase deficiency; HMG-CoA lyase deficiency; Hydroxymethylglutaric aciduria; HMGCL deficiency; HMGCLD; HL 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.

ORPHA:20 3-hydroxy-3-methylglutaric aciduria

ICD-11: 5C50.E0 Classical organic aciduria

Symptoms of 3HMGa and the age-of-onset (age where the symptoms begin to present) vary between individuals. In most cases, symptoms will present within the first year of life but in rarer cases, it may not present until adulthood.^2-3

Common symptoms in babies may include weak muscle tone (hypotonia), vomiting, dehydration, and extreme tiredness and lack of energy (lethargy). People with 3HMG are at risk of developing low blood sugar (hypoglycaemia),metabolic acidosis (a build-up of too much acid in the blood) and hyperammonemia (elevated ammonia levels in the blood).^1-5 Episodes of metabolic crisis are more likely to occur during times of stress, illness and fasting. Metabolic crisis may result in developmental delay in children, affecting speech and motor development,^2,3 and if left untreated, it can also lead to life-threatening complications such as breathing issues, seizures, coma and early death.^1,3-5

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.

3HMG is a genetic condition. It is caused by disease-causing genetic changes (variants) in the HMGCL gene on Chromosome 1.² The HMGCL gene is responsible for producing the 3-hydroxy-3-methylglutaryl-CoA-lyase enzyme.

All individuals have two copies (alleles) of the HMGCL gene – one copy inherited from each parent. 3HMG is an autosomal recessive condition, which means both copies of the HMGCL 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, 3-hydroxy-3-methylglutaric aciduria (3HMG) 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 3HMG. If the test results suggest that there is a risk of the baby having one of screened conditions, laboratory staff will promptly get in touch with healthcare providers. The healthcare providers will then arrange for the baby to have further testing to confirm if the baby actually has 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 3HMG 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, 3HMG is often diagnosed after symptoms develop.

Diagnosis of 3HMG may be made based on clinical evaluation of symptoms, laboratory tests on blood and urine samples to detect for increased levels of certain plasma acylcarnitines and urinary organic acids, and confirmed by genetic testing.^2,3

As part of the diagnostic process, doctors may do a differential diagnosis, which is to rule out other conditions that have similar symptoms, such as other organic acidemias, Reye’s syndrome, fatty acid oxidation disorders and sepsis.^1,2

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 3HMG; however, early diagnosis and appropriate management can help prevent or reduce the risk of life-threatening complications. Treatment focuses on prompt management of metabolic acidosis, dietary management, and life-long monitoring and on-going specialist care.⁶

Metabolic acidosis is a medical emergency. In the case of metabolic crisis, immediate medical intervention is required to prevent life-threatening complications. Reported management approaches for acute metabolic decompensation in  3HMG include rapid provision of intravenous glucose and supportive treatment,¹ as well as in some cases, use of ketone salts (with hospital drug committee approval and federal government notification).⁶

Dietary management typically involves a controlled protein diet, and in some cases a fat-restricted diet as well, alongside adequate carbohydrate intake to support energy needs.⁶ The tolerated amount of protein and fat in diets may change over time and should be managed by a metabolic specialist team. Fasting should be avoided. Dietary supplementation with L-carnitine is also often used.^1,6 Dietary strategies that have been used to treat 3HMG in Australia have been described in Treatment of HMG-CoA Lyase Deficiency—Longitudinal Data on Clinical and Nutritional Management of 10 Australian Cases.

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 3-hydroxy-3-methylglutaric aciduria may include general practitioners (GP), paediatricians, geneticists, metabolic doctors and other healthcare workers who are trained to look after 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

Treatment of HMG-CoA Lyase Deficiency—Longitudinal Data on Clinical and Nutritional Management of 10 Australian Cases, published in 2023, is a review of Australian treatment that aims to provide detailed description of dietary strategies as guidance on the acute and long-term management of  3HMG.⁶ Table 3 includes their recommended practice guidelines.

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.

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.

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.

3HMG 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 relevant to 3HMG can be found at:

• Genetic and Rare Diseases (GARD) Information Center: 3-hydroxy-3-methylglutaric aciduria
• National Organization for Rare Disorders (NORD): 3-hydroxy-3-methylglutaric aciduria
• MedlinePlus Genetics: 3-hydroxy-3-methylglutaryl-CoA lyase deficiency

Orphanet: 3-hydroxy-3-methylglutaric aciduria

Online Mendelian Inheritance in Man, OMIM^®: #246450 – 3-hydroxy-3-methylglutaryl-CoA lyase deficiency; HMGCLD

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.