Maple syrup urine disease (MSUD) is a genetic, metabolic condition where the body cannot properly break down certain proteins found in foods. These proteins are three-branched chain amino acids (BCAAs) called leucine, isoleucine and valine, which are typically get broken down in the body to be used for building muscle, making other essential proteins as well as for energy.^1,2 In MSUD, the enzymes that break down BCAAs are unable to properly or fully carry out their function, leading to incomplete breakdown and build-up of BCAAs and their by-products called keto acids.¹ The build-up of leucine and the keto acids is toxic to the body.³ This can cause symptoms such as poor feeding, extreme tiredness (lethargy), vomiting and a sweet odour (smell) like maple syrup in earwax (cerumen) and urine.^3-5 It can also lead to seizures, comas, progressive brain damage, and can be life-threatening. Symptoms and severity of MSUD can vary widely between individuals. ⁶ Early detection and timely management of MSUD is important to prevent life-threatening complications and long-term damage.^2,3,6,7

MSUD is often classified into the following forms:^3-5

• classic MSUD [ORPHA:268145] – most common and most severe type of MSUD due to no or very little enzyme activity present; symptoms usually present soon after birth
• intermediate MSUD [ORPHA:268162] – symptoms tend to begin between the early months and the early years of childhood and usually tend to be less severe than classic MSUD due to there being some enzyme activity present
• intermittent MSUD [ORPHA:268173] – may not have symptoms at birth (asymptomatic); symptoms present when the body is under stress, such as during illness, fasting, dehydration or other physical stress
• thiamine-responsive MSUD [ORPHA:268184] – less severe than classic and is similar to intermediate MSUD; classification of this form of MSUD is based on individuals be able to respond positively to treatment with thiamine

In Australia, MSUD, particularly the classic type, is often detected shortly after birth via newborn bloodspot screening (NBS) programs. Intermediate MSUD and thiamine‑responsive MSUD can also be detected by newborn screening but may be missed if there are no detectable levels of the metabolites at time of screening.³ Intermittent MSUD may not be detected by newborn screening as the levels only rise with illness.^2,4 For individuals who are not screened at birth or if their MSUD was not detected during the NBS screening, MSUD is often diagnosed after symptoms develop.

Synonyms: BCKD deficiency ; BCKDH deficiency; Branched-chain 2-ketoacid dehydrogenase deficiency; Branched-chain ketoaciduria; MSUD

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:511 Maple syrup urine disease

• ORPHA:268145 Classic maple syrup urine disease
• ORPHA:268162 Intermediate maple syrup urine disease
• ORPHA:268173 Intermittent maple syrup urine disease
• ORPHA:268184 Thiamine-responsive maple syrup urine disease

ICD-11: 5C50.D0 Maple-syrup-urine disease

Symptoms of MSUD vary between individuals.

For classic MSUD, the symptoms usually appear within the first few days of life. Symptoms may include a characteristic sweet maple syrup-like odour (smell) in earwax (cerumen) and urine, poor feeding, irritability and lethargy (extreme tiredness and lack of energy). Infants may show abnormal movements (that looks like fencing or cycling motions) and opisthotonos (which is an abnormal posture that involves arching of the neck, back and limbs).^3-6 If left untreated, the condition can also lead to seizures, brain damage, and cerebral edema (swelling of the brain caused by build-up of fluid) and can progress quickly to coma and early death. Individuals may also develop neuropsychiatric features, such as anxiety, depression, and attention deficit hyperactivity disorder (ADHD).^4,6,7

Individuals with intermediate MSUD and thiamine-responsive MSUD may not develop symptoms straight after birth, but symptoms can present in the early months or years of childhood or later.^3-6 This may include the characteristic maple syrup-odour, poor growth, developmental delay, intellectual disability, poor feeding or decreasing appetite and anorexia. Individuals with intermediate MSUD are also at risk of metabolic crisis and life-threatening complications.⁴

Individuals with intermittent MSUD often have normal growth and development but can develop symptoms of MSUD when the body is under stress, such as during illness, fasting, dehydration or other physical stress. In severe cases, this can also lead to coma and death.⁴

Individuals with MSUD may also develop anxiety, depression, panic disorder and ADHD

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

MSUD is a genetic condition. It is caused by disease-causing genetic changes (variants) in the BCKDHA, BCKDHB, or DBT genes.^4,5 These genes are responsible for producing proteins called E1a, E1b, and E2 that are subunits of the branched chain 2-ketoacid dehydrogenase (BCKAD, also known as BCKDH) complex.

All individuals have two copies (alleles) of each of the BCKDHA, BCKDHB, and DBT genes – one copy inherited from each parent. MSUD is an autosomal recessive condition, which means both copies of an affected gene must have the disease-causing genetic variants.^4,5 More information on autosomal recessive inheritance pattern can be found at Centre for Genetics Education: Autosomal recessive inheritance.

There has also been one reported case of the PPM1K gene that was affected in an individual with mild MSUD.⁵ The PPM1K gene is responsible for producing a protein that interacts with, and regulates, activity of the BCKDH complex.

It should be noted that the BCKDH complex has another subunit (E3) produced by the DLD gene. Disease-causing genetic variants in DLD are not associated with MSUD but is associated with another condition, pyruvate dehydrogenase E3 deficiency.⁵

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, MSUD 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 MSUD. 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 MSUD 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, MSUD is often diagnosed after symptoms develop.

Diagnosis of MSUD may involve clinical evaluation of symptoms, laboratory tests on blood samples to test for amino acids as well as on urine samples to test for organic acids, and measurement of BCKAD enzyme activity on white blood cells or skin fibroblasts, and confirmed by genetic testing.^3,4

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 propionic acidemia, methylmalonic acidemia (MMA), glycine encephalopathy, and urea cycle disorders such as carbamoyl-phosphate synthetase 1 deficiency, ornithine transcarbamylase deficiency, citrullinemia type I,  argininosuccinic aciduria (ASA), arginase deficiency and N-acetylglutamate synthetase (NAGS) deficiency.³

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

Treatment of MSUD involves life-long dietary management focused on controlling intake of the branched-chain amino acids (BCAAs), regular metabolic monitoring and immediate management of metabolic crisis.^3,4,6 Early detection and timely management of MSUD is important to prevent life-threatening complications and long-term damage.^2,3,6,7

The life-long dietary management of MSUD involves a strict low-protein diet (to restrict intake of the BCAAs from food) accompanied by specialised nutritional supplements to provide necessary nutrients,² including isoleucine and valine which are important for growth and essential body processes.³ The recommended amount of protein from food and supplement varies between individuals – this depends on an individual’s tolerance, which may also change over time and during illness, and needs to be monitored regularly and adjusted accordingly.^2,3

For some individuals, thiamine supplements may be trialled in addition to the diet – individuals that respond well to the thiamine supplementary are referred to as being thiamine-responsive. It should be noted that thiamine therapy is used as a supplementation and not a replacement for dietary restriction.³

As individuals with MSUD are at risk of metabolic crisis, regular metabolic monitoring is recommended to ensure the levels of BCAAs in the body are kept within a recommended range to prevent metabolic crisis.³ In the case of metabolic crisis, immediate medical intervention is required to prevent life-threatening complications.^3,4

As pregnancy can place strain on the body, individuals with MSUD should be carefully monitored throughout pregnancy and at delivery to help ensure safe and successful outcomes.^3,4,6

Liver transplantation may be an option for individuals with severe classic MSUD that cannot be managed with dietary restrictions; whilst this option can help manage the condition, it cannot reverse symptoms such as brain damage and intellectual disability.^4,6

Management of symptoms such as developmental delay and neuropsychiatric features may involve physiotherapy, occupational therapy, speech therapy, and management of anxiety and depression.^4,6

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.

Healthcare professionals involved in the clinical care of individuals with MSUD may include general practitioners (GP), paediatricians, geneticists, metabolic physicians, genetic counsellors, metabolic dieticians, neurologists, physiotherapists, occupational therapists, speech therapists, psychiatrists, psychologists and others.⁴ 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.

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.

For many rare diseases, 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

The ASIEM Low Protein Handbook for MSUD has been prepared by members of the
Australasian Society for Inborn Errors of Metabolism (ASIEM), a special interest
group of the Human Genetics Society of Australasia (HGSA), and was published in 2007.

The following guidance is available from international experts outside Australia; however, there may be information that is not relevant or applicable to the Australian context, and may not be up to date:

• Comprehensive Iranian guidelines for the diagnosis and management of maple syrup urine disease: an evidence- and consensus- based approach was developed based on a consensus of physicians of different centers in Iran who are experts in the diagnosis and management of this disease; published in 2025.
• Nutrition management guideline for maple syrup urine disease: An evidence- and consensus-based approach was developed by the Genetic Metabolic Dietitians International (GMDI) and Southeast Regional Newborn Screening and Genetics Collaborative (SERC), United States of America; published in 2014.

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 may be special considerations for the emergency management of individuals living with MSUD:

• Individuals with MSUD are at risk of metabolic crisis, which can be life-threatening and requires immediate medical intervention
• any trauma care or surgical procedures should involve consultation with a metabolic specialist⁴
• Orphananesthesia: Anaesthesia recommendations for patients suffering from Maple syrup urine disease includes considerations for emergency management and surgery when treating individuals with MSUD; please note that this was last modified in 2015 and may not be up to date.

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

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.

MSUD varies between individuals, and each person’s experience is unique.

Personal story shared with RVA : Ava’s Story

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.

The ASIEM Low Protein Handbook for MSUD

MSUD – Fruit and Veg Counting Lists

MSUD – General Protein Counting Lists

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 MSUD can be found at:

• The ASIEM Low Protein Handbook for MSUD
• Metabolic Dietary Disorders Association (MDDA): Maple syrup urine disease (MSUD)
• Genetic and Rare Diseases (GARD) Information Center: Maple syrup urine disease
• National Organization for Rare Disorders (NORD): Maple Syrup Urine Disease

Orphanet: Maple syrup urine disease

GeneReviews®: Maple Syrup Urine Disease

Online Mendelian Inheritance in Man, OMIM^®: #248600 Maple syrup urine disease; Type IA; MSUD1A

Online Mendelian Inheritance in Man, OMIM^®: #620698 Maple syrup urine disease; Type IB; MSUD1B

Online Mendelian Inheritance in Man, OMIM^®: #620699 Maple syrup urine disease; Type II; MSUD2

Online Mendelian Inheritance in Man, OMIM^®: #615135 Maple syrup urine disease; mild variant; MSUDMV

This page has been developed by Rare Voices Australia (RVA)’s RARE Portal team. If you would like to see more information added to this page, please reach out via the Contact form. If you would like to share relevant resources for this condition, please visit the Contribute page.

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.