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. The body only needs a small amount of these BCAAs for growth and repair, and will normally convert any excess into energy or other substances. In MSUD, the enzymes that break down BCAAs do not work properly, leading to incomplete breakdown and build up of BCAAs and their by-products called keto acids. These keto acids are toxic to the body and in severe cases, can cause symptoms soon after birth such as poor feeding, extreme tiredness (lethargy), vomiting and a sweet odor (smell) like maple syrup in earwax (cerumen) and urine. If untreated, it can also lead to seizures, comas, progressive brain damage and can be life-threatening.

Symptoms and severity of OTC deficiency can vary widely between individuals, with the following range:

• classic MSUD [ORPHA:268145] – most severe type
• intermediate MSUD [ORPHA:268162] – symptoms tend to begin later (later onset) and are less severe than classic type
• 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; similar to intermediate MSUD but responds well to treatment with thiamine

In Australia, MSUD, in particular the classic type, is often detected shortly after birth via newborn bloodspot screening (NBS) programs. 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. Early detection and management of MSUD is important to prevent long term damage and life-threatening complications.

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

Rare diseases typically display a high level of symptom complexity. There is often a wide range of symptoms and the symptoms may vary between individuals in terms of its presentation, severity, duration and impact.

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.

MSUD is a genetic condition. It is caused by disease-causing genetic changes (variants) in the BCKDHA, BCKDHB, or DBT genes. 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. 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. 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.

If you would like to learn more about the inheritance and impact of MSUD, 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.

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 encephalopahty, 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.

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

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, and other metabolic specialists and care team. 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. 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. Palliative care 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. For 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, 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.

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

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.

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.

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, 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

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

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.