Maple Syrup Urine Disease
Brief Summary of Disease
Your body relies on molecules like proteins, carbohydrates, and amino acids for energy, growth, and development. These molecules are consumed through your diet, and your body metabolises them for use in everyday biological processes. Individuals born without some of the enzymes necessary to break down and use these molecules have what are known as inborn errors of metabolism. Maple syrup urine disease (MSUD), so-called because of one of its most characteristic symptoms whereby the urine takes on a sweet aroma, is an example of an inborn error of metabolism. MSUD occurs when an individual lacks the enzyme complex necessary to break down the amino acids leucine, isoleucine, and valine.1 When consumed, these amino acids and related molecules build up in the patient’s system, causing a variety of symptoms.1 Symptoms can be managed through dietary changes and liver transplants but the disease can be fatal.2 MSUD affects one in 185,000 but, due to isolated breeding in founder populations, tends to be more common among American Mennonites and individuals of Ashkenazi Jewish descent.1
Etiology & Pathology
Symptoms of MSUD become evident shortly after birth and follow patients throughout their entire lives.2 The disease is caused by genetic mutations that affect the function of the enzyme complex necessary for breaking down leucine, isoleucine, and valine.3 Different mutations affect the enzyme complex’s function to varying degrees; patient’s with a mutation that results in little to no enzyme function have a severe form of the disease called classical MSUD, while patient’s with mutations that allow them to retain some enzyme function have less severe forms.2 Mutations occur in the genes BCKDHA, BCKDHB, or DBT and are inherited in an autosomal recessive manner; therefore, children must inherit the affected gene from both parents in order to display symptoms (Figure 1).1,3 The amino acids build up in the body, affecting the nervous system, respiratory system, and pancreas.2,4
Patients with classical MSUD experience little to no enzyme function and therefore experience severe symptoms.2 Patients with intermediate or intermittent MSUD have mutations that only partially inactivate the enzyme complex, allowing them to break down limited amounts of the amino acids.2 These patients experience symptoms that are less severe or that fluctuate.2 One characteristic symptom is the sweet odour of urine and earwax, which has been likened to the aroma of maple syrup.3 Additionally, newborns quickly display spastic and abnormal movements, lethargy, irritability, and failure to feed.1,2 If the disease continues without treatment, patients develop neurological defects and encephalopathy.1,2 Neurological defects are typically less severe in individuals with intermediate MSUD and those with intermittent MSUD may display normal development.2 Without proper diagnosis and treatment, newborns with classical MSUD experience fatal respiratory and neurological complications.1
Classical MSUD is diagnosed in infancy, either through newborn screening or the appearance of symptoms.2 The first symptom to arise is usually the maple syrup-like smell of the earwax, which becomes evident within hours of birth.2 Within a few days, irritability and inability to feed may be detected.2 Following the first ten days, newborns may experience respiratory failure and fall into a coma.2
Infants with MSUD may be identified through newborn screening, which uses a modern technique called tandem mass spectrometry to screen blood samples for over 30 different disorders, including MSUD.1 This technique scans the blood for abnormal amino acids levels, significantly improving MSUD diagnosis and preventing the onset of dangerous and fatal symptoms. Newborn screening is not always accurate, and some newborns, especially those with more mild forms of the disease, may not be identified.1 If the disease is particularly mild, patients may not be diagnosed until childhood, when they present with symptoms like anorexia and delayed development.2 There are other limitations to newborn screening. The tests can be subjective, as individual states in America are responsible for defining the cut-off for what “abnormal” amino acid levels are.2 Secondly, infants with a different rare metabolic condition, hydroxyprolinemia, may be incorrectly identified as having MSUD.2 Lastly, newborn screening is not available in all parts of the world, and even when available, results may not be obtained before devastating symptoms develop.2 There is a critical need for the expansion and improvement of newborn screening so that infants with MSUD can receive treatment prior to experiencing neurological defects, respiratory problems, coma, and death.
There are additional methods that can be used to test for MSUD in cases where newborn screening is unavailable or does not accurately detect the disease. Urine can be tested for the presence of particular molecules associated with MSUD.2 Additionally, cells from the bone marrow or liver tissue can be examined to determine if the enzyme responsible for breaking down the amino acids is functional.2 The disease can also be detected through genetic testing by identifying mutations to the BCKDHA, BCKHDB, or DBT genes.2
Early and accurate detection of MSUD plays an important role in patient prognosis. In order to improve prognosis, patients are put on a low-protein diet immediately following diagnosis to limit the number of amino acids they consume. Amino acids are an essential part of the human diet, and are necessary for normal growth and development, so small amounts must be administered to the patients daily.1 The amount of leucine, isoleucine, and valine an individual with MSUD can tolerate varies, and this must be determined prior to administering the amino acids to prevent triggering symptoms.1 In some rare cases, MSUD is considered to be thiamine-responsive and can be partially treated by taking thiamine (vitamin B1).1 Despite strict adherence to the necessary diet, patients with MSUD may experience what is known as a metabolic crisis, where the levels of leucine in the body become too high.1 These crises can be treated through immediate medical attention but if prolonged can lead to symptoms like brain damage.1 Without treatment, life expectancy for classical MSUD is less than a few weeks. Life expectancy is extended for those with less severe forms of the disease and for patients receiving treatment.
Since MSUD is a recessive genetic disorder, it can be passed from parents to children. If both parents carry a mutated gene, there is a 25% chance that their child will inherit both copies and develop the disease and a 50% chance they will inherit only one copy and become an unaffected carrier. Individuals related to MSUD patients can receive genetic testing to determine if they are a carrier and therefore able to pass it on to their children.1 MSUD can also be detected through prenatal testing during pregnancy by examining amniotic fluid to determine if the enzyme complex responsible for breaking down the amino acids is functional.5 This is typically carried out when the parents are carriers or related to an individual with the disease.2 Prenatal testing provides parents with information about their child’s condition and allows treatment to begin immediately after birth in an attempt to prevent the onset of symptoms. Due to its severe and potentially fatal symptoms, at-risk newborns who have not undergone prenatal testing should be tested for MSUD shortly after birth. MSUD also leads to complications during pregnancy. When women with MSUD become pregnant, they need to be monitored closely, as their body’s protein and amino acid needs increase, potentially resulting in postpartum fatalities.6,7
Preliminary research in Australia is focused on developing a treatment plan for pregnant women with MSUD in an attempt to reduce fatalities of both the fetus and mother.6 The plan features regular monitoring throughout the pregnancy and a suggestion for food, glucose, and amino acid supplements given during and shortly after labour.6 This research represents an important step forward in improving the lives of patients with MSUD, allowing women to have children without fear of how their disease will affect the pregnancy, themselves, and their infant.
MSUD Family Support Group
1. Maple Syrup Urine Disease. NORD Natl Organ Rare Disord. 2010;376:1417-1427. https://rarediseases.org/rare-diseases/maple-syrup-urine-disease/
2. Strauss KA, Puffenberger EG, Morton DH. Maple Syrup Urine Disease. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993. http://www.ncbi.nlm.nih.gov/books/NBK1319/
3. Ekvall SW, Ekvall VK. Pediatric Nutrition in Chronic Diseases and Developmental Disorders: Prevention, Assessment, and Treatment. Oxford University Press; 2005.
4. Maple syrup urine disease. Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. https://rarediseases.info.nih.gov/diseases/3228/maple-syrup-urine-disease
5. Wendel U, Rüdiger HW, Passarge E, Mikkelsen M. Maple syrup urine disease: Rapid prenatal diagnosis by enzyme assay. Humangenetik. 1973;19(1):127-128. doi:10.1007/BF00295241
6. Brown J, Tchan M, Nayyar R. Maple syrup urine disease: tailoring a plan for pregnancy. J Matern Fetal Neonatal Med. 2018;31(12):1663-1666. doi:10.1080/14767058.2017.1323328
7. Yoshida S, Tanaka T. Postpartum death with maple syrup urine disease. Int J Gynecol Obstet, 2010;376:1417-1427. 2003;81(1):57-58. doi:10.1016/S0020-7292(02)00446-0
Cite This Article:
Coles V., Chan G., Lewis K., Ho J. Maple Syrup Urine Disease. Illustrated by W. Y. Wu. Rare Disease Review. November 2019.