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IEM

Maple syrup urine disease

MSUD is caused by faults in genes responsible for breaking down branched-chain amino acids (BCAAs). This leads to a build-up of harmful substances in the body, which can cause severe health problems if not managed. It typically affects infants and young children.

Autosomal recessive IEM Tier B OMIM:248600
1:185,000
Prevalence
Population estimate
25%
Inheritance
Autosomal recessive - chance of passing to each child
3
Associated genes
BCKDHA, BCKDHB, DBT

Available at Jeen Health

Clinical tests that include this

Carrier Screening panel
BCKDHA, BCKDHB, DBT - 3 of 1,008 genes on this panel
Expanded carrier screening for recessive and X-linked conditions
Newborn Genetic Screening panel
BCKDHA, BCKDHB, DBT - 3 of 258 genes on this panel
Genomic newborn screening for actionable paediatric conditions

Overview

Maple syrup urine disease (MSUD) is an inherited metabolic condition where the body cannot properly break down certain protein building blocks called branched-chain amino acids (BCAAs). These BCAAs are leucine, isoleucine, and valine. When they cannot be broken down, they and their by-products build up in the body, becoming toxic [PMID:31613437].

This build-up can damage the brain and other organs. The condition gets its name from the distinctive sweet, maple syrup-like smell of the urine and sometimes the earwax of affected individuals. MSUD is a rare condition, affecting approximately 1 in 185,000 newborns globally, though prevalence can vary between populations.

Symptoms & clinical features

Symptoms of MSUD can vary in severity and typically appear within the first few days of life for the most common and severe form, known as classic MSUD. Initial signs may include poor feeding, lethargy, irritability, and a distinctive maple syrup smell in the urine and sweat [PMID:31613437].

As harmful substances accumulate, infants may experience vomiting, muscle stiffness or floppiness, and seizures. If left untreated, this can progress to coma and life-threatening brain swelling. Milder forms of MSUD exist, where symptoms might be less severe, appear later in childhood, or only during periods of stress or illness. These forms are often referred to as intermediate or intermittent MSUD.

Video: Genetics 101

Affected organs

MSUD primarily affects the central nervous system, including the brain. The accumulation of toxic BCAA by-products can cause severe neurological damage. This can lead to intellectual disability, developmental delay, and movement problems. In severe cases, brain swelling (cerebral oedema) can occur, which is a medical emergency.

The condition can also affect other body systems, with metabolic crises impacting overall health. The liver is involved in metabolism, and while not typically a primary organ of damage in MSUD, its metabolic function is central to the disease process.

Multiple body systems
Multiple body systems
Systemic involvement
Cellular impact
Cellular impact
Mechanism at cellular level

Risks & severity

MSUD exists on a spectrum of severity. Classic MSUD is the most common and severe form, presenting in the first week of life with rapid symptom progression and a high risk of life-threatening complications if not promptly treated. Without early diagnosis and strict dietary management, severe neurological damage and early death are common outcomes.

Intermediate MSUD and intermittent MSUD are milder forms where symptoms may appear later, be less severe, or only manifest during metabolic stress. The long-term prognosis for individuals with MSUD depends heavily on early diagnosis and consistent management throughout their lives. Even with treatment, individuals with MSUD may experience learning difficulties or other neurological challenges [PMID:31613437]. Acute metabolic crises, often triggered by illness or stress, remain a risk for all forms of MSUD and require urgent medical attention.

Genetic causes

Maple syrup urine disease is caused by pathogenic variants in one of several genes that are vital for the breakdown of branched-chain amino acids (BCAAs). These genes are BCKDHA, BCKDHB, and DBT [PMID:31613437]. These genes provide instructions for making different parts of an enzyme complex called branched-chain alpha-keto acid dehydrogenase (BCKD).

The BCKD enzyme complex is like a metabolic machine that helps to dismantle leucine, isoleucine, and valine. When there is a pathogenic variant in BCKDHA, BCKDHB, or DBT, the BCKD enzyme complex does not work correctly, or at all. This means the BCAAs cannot be properly processed, leading to their toxic build-up in the blood and tissues, causing the symptoms of MSUD.

  • BCKDHA
    branched chain keto acid dehydrogenase E1 subunit alpha
    The *BCKDHA* gene provides instructions for a key component of an enzyme complex critical for breaking down specific amino acids, with variants linked to Maple Syrup Urine Disease.
  • BCKDHB
    branched chain keto acid dehydrogenase E1 subunit beta
    The BCKDHB gene provides instructions for a component of an enzyme complex essential for breaking down specific amino acids, with variants linked to Maple Syrup Urine Disease.
  • DBT
    dihydrolipoamide branched chain transacylase E2
    The DBT gene provides instructions for a crucial component of an enzyme complex responsible for breaking down specific branched-chain amino acids, such as leucine, isoleucine, and valine.

Inheritance pattern

MSUD is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of a pathogenic gene variant - one from each parent - to develop the condition. People who have only one copy of a pathogenic variant are called carriers. Carriers typically do not show symptoms of MSUD themselves because their one working copy of the gene is sufficient for normal BCAA metabolism.

If both parents are carriers of the same pathogenic variant, there is a 25% chance with each pregnancy that their child will inherit two copies of the variant and develop MSUD. There is a 50% chance the child will be a carrier like their parents, and a 25% chance the child will inherit two normal copies of the gene and not be affected or a carrier.

♀ Carrier parent 1 altered copy ♂ Carrier parent 1 altered copy Affected Carrier Carrier Unaffected Affected Carrier Unaffected Circles = females · Squares = males

When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.

Diagnosis & testing

Diagnosis of MSUD is typically made through newborn screening programmes, which are standard practice in the UK for all babies. This screening, usually performed by a heel prick test shortly after birth, detects elevated levels of BCAAs in the blood [PMID:31613437]. If screening results suggest MSUD, further diagnostic tests are performed, including specialised blood and urine tests to confirm the presence of specific BCAA by-products.

Genetic testing, typically ordered by a clinical geneticist or metabolic specialist, confirms the diagnosis by identifying pathogenic variants in the BCKDHA, BCKDHB, or DBT genes. This is often done as part of an NHS Genomic Medicine Service pathway. The relevant R-codes for genetic testing for metabolic disorders like MSUD would be requested through a local Genomic Laboratory Consortium.

Management & lifestyle

Management of MSUD focuses on preventing the build-up of toxic BCAAs through lifelong strict dietary control. This involves a specialised diet that is very low in protein, particularly foods rich in leucine, isoleucine, and valine. Individuals with MSUD often require special medical formulas that provide essential nutrients without the problematic BCAAs.

Regular monitoring of blood BCAA levels is essential to adjust the diet as needed. During periods of illness or stress, individuals with MSUD are at risk of metabolic crises, which require immediate medical intervention, often in a hospital setting, to prevent serious complications. This typically involves intravenous administration of glucose and amino acid-free fluids. For some individuals, particularly those with severe forms, a liver transplant may be considered as a treatment option, as it can provide the necessary enzyme activity.

UK care pathway

In the UK, individuals suspected of having MSUD are usually identified through the national newborn screening programme. If the screening result is abnormal, the baby will be referred to a metabolic specialist within the NHS for further assessment and confirmation of the diagnosis.

Genetic testing for MSUD forms part of the NHS Genomic Medicine Service pathway, accessible via a referral from a specialist clinician. A clinical geneticist can arrange for relevant genetic tests (R-codes) to identify the specific genetic cause. Genetic counsellors are available to provide information and support to families regarding inheritance patterns, testing for family members, and reproductive options.

Frequently asked questions

What does it mean if my baby's urine smells sweet like maple syrup?

A sweet, maple syrup-like smell in a baby's urine, or sometimes their earwax, can be a key sign of Maple Syrup Urine Disease (MSUD). If you notice this, it's very important to contact your doctor immediately, as early diagnosis and treatment are crucial for this condition.

Is Maple Syrup Urine Disease curable?

Maple Syrup Urine Disease is not currently curable, but it is manageable. Lifelong strict dietary management, including special medical foods, is essential to control the build-up of harmful substances and prevent severe health problems. In some cases, a liver transplant might be considered.

How will my child's diet be managed if they have MSUD?

Managing the diet for a child with MSUD involves a strict low-protein diet, carefully controlled to limit branched-chain amino acids (BCAAs). This typically includes specialised medical formulas and carefully measured solid foods. A metabolic dietitian will work closely with your family to create and adjust the diet plan.

Can carriers of MSUD develop symptoms?

Individuals who are carriers for MSUD typically do not develop symptoms of the condition. They have one working copy of the gene, which is usually enough for their body to process branched-chain amino acids normally. Carriers are generally healthy but can pass the gene variant on to their children.

What happens during a metabolic crisis in MSUD?

A metabolic crisis in MSUD occurs when branched-chain amino acids (BCAAs) build up rapidly, often triggered by illness, stress, or not following the special diet. Symptoms can include vomiting, lethargy, irritability, seizures, and can quickly progress to coma. Urgent medical attention is needed, often involving hospitalisation for intravenous fluids and close monitoring.

References

  1. Blackburn PR, Gass JM, Vairo FPE. Maple syrup urine disease: mechanisms and management. The application of clinical genetics. 2017. PMID: 28919799
  2. Strauss KA, Carson VJ, Soltys K. Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes. Molecular genetics and metabolism. 2020. PMID: 31980395
  3. Deon M, Guerreiro G, Girardi J. Treatment of maple syrup urine disease: Benefits, risks, and challenges of liver transplantation. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience. 2023. PMID: 37340513
  4. Frazier DM, Allgeier C, Homer C. Nutrition management guideline for maple syrup urine disease: an evidence- and consensus-based approach. Molecular genetics and metabolism. 2014. PMID: 24881969
  5. EFRON ML. AMINOACIDURIA. The New England journal of medicine. 1965. PMID: 14281543
  6. Spada M, Angelico R, Dionisi-Vici C. Maple Syrup Urine Disease and Domino Liver Transplantation: When and How? Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2019. PMID: 31038782
  7. Wendel U, Lombeck I, Bremer HJ. Maple-syrup-urine disease. The New England journal of medicine. 1983. PMID: 6835327
  8. Al Shidhani A, Al Hinai A, Al Thihli K. Congenital Hyperinsulinism and Maple Syrup Urine Disease: A Challenging Combination. Journal of clinical research in pediatric endocrinology. 2023. PMID: 34738771
Educational content. This page is not medical or genetic advice, is not individually reviewed by a clinician for each reader, and should not replace a consultation with a qualified healthcare professional or genetic counsellor.