This web page was produced as an assignment for Genetics 564, an undergraduate capstone course at UW-Madison.
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What is Maple Syrup Urine Disease?
Maple Syrup Urine Disease (MSUD) is a genetic, metabolic disorder that occurs in infants. It results from the body’s inability to break down three amino acids: valine, leucine, and isoleucine. Since the body cannot break the amino acids down, they build up very quickly. Symptoms show within a few hours to days after a baby is born. The disease has to be treated immediately. [1,2]
Symptoms and DiagnosisThe first and most obvious symptom is the sweet smell of maple syrup in urine, sweat, and ear wax. Infants will also appear lethargic and do not eat well. If these symptoms go unnoticed for several days after birth, it can lead to seizure-like spasms, lung failure, and coma. With no treatment, MSUD can be fatal. Depending on how long it was left untreated, permanent brain damage and developmental delays can occur.
In order to confirm diagnosis, blood plasma testing can be done to check for the levels of the three amino acids. Genetic testing can also be performed. All newborns who receive newborn screening are tested for MSUD regardless of symptoms or genetic background. [1,2] |
What Causes MSUD?
The severe build up of the three amino acids valine, leucine, and isoleucine are the immediate cause of symptoms. These are classified as branched chain amino acids. [3] The build up of branched chain amino acids is caused by defective protein called branched chain alpha-ketoacid dehydrogenase (Figure 1). This protein is responsible for breaking down the branched chain amino acids. This protein has four units that comprise it: E1a, E1b, E2, and E3. When E1a, E1b, and/or E2 are defected, it cannot function properly. Therefore, valine, leucine, and isoleucine are not broken down in the body. [4, 5, 6] Genetic mutations cause the protein defects. A variety of genes and mutations are associated with the disorder. [7]
MSUD and the DBT Gene
There are three genes that lead to MSUD, each affecting different parts of the branched chain alpha-ketoacid dehydrogenase. The DBT gene affects the E2 part of this protein. DBT mutations are autosomal recessive. Patients with a mutation in this gene are considered to have Type II MSUD. [1] It was first identified that the E2 unit itself was mutated and eventually the gene that codes for it was discovered. [4,5,7,8] Many studies have looked at what mutations cause it and there are to date 70 mutations in the DBT gene that all lead to the same symptoms. [9] The mutations lead to various malformations of the E2 subunit and prevent the unit as a whole from functioning. The gene is found on chromosome 1p21.2. [9]
Gap in Knowledge
It is currently unknown what specifically causes poor feeding in infants with DBT mutations. Other symptoms that are a part of MSUD have been well studied because they affect neurological function. Poor feeding usually stops once infants are placed on a special diet, but could still have long term affects.
Patient Resources and Societies
References
1 Strauss, K., Puffenberger, E., Morton, H. (May 2013). Maple Syrup Urine Disease. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK1319/#msud.molgen.TA
2 National Organization for Rare Disorders. (2017). Rare Disease Data Base: Maple Syrup Urine Disease. Retrieved from https://rarediseases.org/rare-diseases/maple-syrup-urine-disease/#supporting-organizations
3 Menkes, J. (February 1959). Maple Syrup Disease Isolation and Identification of Organic Acids in the Urine. Retrieved from http://pediatrics.aappublications.org.ezproxy.library.wisc.edu/content/pediatrics/23/2/348.full.pdf
4 Peinemann, F., Danner, D. (1994). Maple Syrup Urine Disease 1954 to 1993. Retrieved from https://link-springer-com.ezproxy.library.wisc.edu/content/pdf/10.1007%2FBF00735389.pdf
5 Danner, D., Armstrong, S., Heffelfiner, E., et al. (March 1985). Absence of Branched Chain Acyl-Transferase as a Cause of Maple Syrup Urine Disease. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC423615/pdf/jcinvest00120-0092.pdf
6 Danner, D., Doering, CB (June 1998). Human mutations affecting branched chain alpha ketoacid dehydrogenase. Retrieved from https://www.bioscience.org/1998/v3/d/danner/3.htm
7 Nellis, M., Danner, D. (December 2000). Gene Preference in Maple Syrup Urine Disease. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1234918/#RF3
8 Litwer, S., Danner, D. (September 1985). Identification of a cDNA in lgt11 for the transacylase component of branched chain keto acid dehydrogenase. Retrieved from https://www-sciencedirect-com.ezproxy.library.wisc.edu/science/article/pii/0006291X85913336
9 Genetics Home Reference. (July 2017). DBT gene diydrolipoamide branched chain transacylase E2. Retrieved from https://ghr.nlm.nih.gov/gene/DBT#conditions
10 Silao, C., Padilla, C., Matsuo, M. (February 2004). A novel deletion creating a new terminal exon of the dihydrolipoyl transacylase gene is a founder mutation of Filipino maple syrup urine disease. Retrieved from https://www-sciencedirect-com.ezproxy.library.wisc.edu/science/article/pii/S1096719203002439#BIB9
11 Ali, E., Ngu, L. (September 2018). Fourteen new mutations of BCKDHA, BCKDHB and DBT genes associated with maple syrup urine disease (MSUD) in Malaysian population. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140420/#bb0155
12 Imtiaz, F., Al-Mostafa, A., Allam, R., et al. (June 2017). Twenty novel mutations in BCKDHA, BCKDHB and DBT genes in a cohort of 52 Saudi Arabian patients with maple syrup urine disease. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388912/
13 Evarsson, A., Chuang, J., Wynn, R., et al. (March 2000). Crystal structure of human branched-chain α-ketoacid dehydrogenase and the molecular basis of multienzyme complex deficiency in maple syrup urine disease. Retrieved from https://www.sciencedirect.com/science/article/pii/S0969212600001052
Menkes, J., Hurst, P., Craig, J. (1954). A New Syndrome: Progressive Infantile Cerebral Dysfunction Associated with an Unusual Urinary Substance. Retrieved from http://pediatrics.aappublications.org.ezproxy.library.wisc.edu/content/pediatrics/14/5/462.full.pdf
MSUD Family Support Group. (2019). Retrieved from http://www.msud-support.org
2 National Organization for Rare Disorders. (2017). Rare Disease Data Base: Maple Syrup Urine Disease. Retrieved from https://rarediseases.org/rare-diseases/maple-syrup-urine-disease/#supporting-organizations
3 Menkes, J. (February 1959). Maple Syrup Disease Isolation and Identification of Organic Acids in the Urine. Retrieved from http://pediatrics.aappublications.org.ezproxy.library.wisc.edu/content/pediatrics/23/2/348.full.pdf
4 Peinemann, F., Danner, D. (1994). Maple Syrup Urine Disease 1954 to 1993. Retrieved from https://link-springer-com.ezproxy.library.wisc.edu/content/pdf/10.1007%2FBF00735389.pdf
5 Danner, D., Armstrong, S., Heffelfiner, E., et al. (March 1985). Absence of Branched Chain Acyl-Transferase as a Cause of Maple Syrup Urine Disease. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC423615/pdf/jcinvest00120-0092.pdf
6 Danner, D., Doering, CB (June 1998). Human mutations affecting branched chain alpha ketoacid dehydrogenase. Retrieved from https://www.bioscience.org/1998/v3/d/danner/3.htm
7 Nellis, M., Danner, D. (December 2000). Gene Preference in Maple Syrup Urine Disease. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1234918/#RF3
8 Litwer, S., Danner, D. (September 1985). Identification of a cDNA in lgt11 for the transacylase component of branched chain keto acid dehydrogenase. Retrieved from https://www-sciencedirect-com.ezproxy.library.wisc.edu/science/article/pii/0006291X85913336
9 Genetics Home Reference. (July 2017). DBT gene diydrolipoamide branched chain transacylase E2. Retrieved from https://ghr.nlm.nih.gov/gene/DBT#conditions
10 Silao, C., Padilla, C., Matsuo, M. (February 2004). A novel deletion creating a new terminal exon of the dihydrolipoyl transacylase gene is a founder mutation of Filipino maple syrup urine disease. Retrieved from https://www-sciencedirect-com.ezproxy.library.wisc.edu/science/article/pii/S1096719203002439#BIB9
11 Ali, E., Ngu, L. (September 2018). Fourteen new mutations of BCKDHA, BCKDHB and DBT genes associated with maple syrup urine disease (MSUD) in Malaysian population. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140420/#bb0155
12 Imtiaz, F., Al-Mostafa, A., Allam, R., et al. (June 2017). Twenty novel mutations in BCKDHA, BCKDHB and DBT genes in a cohort of 52 Saudi Arabian patients with maple syrup urine disease. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388912/
13 Evarsson, A., Chuang, J., Wynn, R., et al. (March 2000). Crystal structure of human branched-chain α-ketoacid dehydrogenase and the molecular basis of multienzyme complex deficiency in maple syrup urine disease. Retrieved from https://www.sciencedirect.com/science/article/pii/S0969212600001052
Menkes, J., Hurst, P., Craig, J. (1954). A New Syndrome: Progressive Infantile Cerebral Dysfunction Associated with an Unusual Urinary Substance. Retrieved from http://pediatrics.aappublications.org.ezproxy.library.wisc.edu/content/pediatrics/14/5/462.full.pdf
MSUD Family Support Group. (2019). Retrieved from http://www.msud-support.org
Images
Header: https://cbmaplefarm.com/shop/category/vermont-maple-syrup/
Image 1: https://www.express.co.uk/life-style/health/841566/urine-smell-wee-maple-syrup-disease-symptoms-cause-treatment-liver-transplant-seizures
Image 2: https://globalgenes.org/raredaily/rhode-island-adds-immune-deficiency-newborn-screening-test/
Image3: https://www.walmart.com/ip/BCAD-2-MSUD-Oral-Supplement-Vanilla-1-lb-Can-Powder-Case-of-6/996069142
Figure 1: https://www.sciencedirect.com/science/article/pii/S0969212600001052
Chromosome Image: https://ghr.nlm.nih.gov/gene/DBT#conditions
Image 1: https://www.express.co.uk/life-style/health/841566/urine-smell-wee-maple-syrup-disease-symptoms-cause-treatment-liver-transplant-seizures
Image 2: https://globalgenes.org/raredaily/rhode-island-adds-immune-deficiency-newborn-screening-test/
Image3: https://www.walmart.com/ip/BCAD-2-MSUD-Oral-Supplement-Vanilla-1-lb-Can-Powder-Case-of-6/996069142
Figure 1: https://www.sciencedirect.com/science/article/pii/S0969212600001052
Chromosome Image: https://ghr.nlm.nih.gov/gene/DBT#conditions