Maple syrup urine disease wiki

Maple syrup urine disease wiki DEFAULT

Maple syrup urine disease


Maple syrup urine disease is an inherited disorder in which the body is unable to process certain protein building blocks (amino acids) properly. The condition gets its name from the distinctive sweet odor of affected infants' urine. It is also characterized by poor feeding, vomiting, lack of energy (lethargy), abnormal movements, and delayed development. If untreated, maple syrup urine disease can lead to seizures, coma, and death.

Maple syrup urine disease is often classified by its pattern of signs and symptoms. The most common and severe form of the disease is the classic type, which becomes apparent soon after birth. Variant forms of the disorder become apparent later in infancy or childhood and are typically milder, but they still lead to delayed development and other health problems if not treated.


Maple syrup urine disease affects an estimated 1 in 185,000 infants worldwide. The disorder occurs much more frequently in the Old Order Mennonite population, with an estimated incidence of about 1 in 380 newborns.


Mutations in the BCKDHA, BCKDHB, and DBT genes can cause maple syrup urine disease. These three genes provide instructions for making proteins that work together as part of a complex. The protein complex is essential for breaking down the amino acids leucine, isoleucine, and valine, which are present in many kinds of food, particularly protein-rich foods such as milk, meat, and eggs.

Mutations in any of these three genes reduce or eliminate the function of the protein complex, preventing the normal breakdown of leucine, isoleucine, and valine. As a result, these amino acids and their byproducts build up in the body. Because high levels of these substances are toxic to the brain and other organs, their accumulation leads to the serious health problems associated with maple syrup urine disease.

Researchers are studying other genes related to the same protein complex that may also be associated with maple syrup urine disease.


This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Other Names for This Condition

  • BCKD deficiency
  • Branched-chain alpha-keto acid dehydrogenase deficiency
  • Branched-chain ketoaciduria
  • Ketoacidemia
  • MSUD

Additional Information & Resources

Genetic Testing Information

Genetic and Rare Diseases Information Center

Patient Support and Advocacy Resources

Research Studies from

Catalog of Genes and Diseases from OMIM

Scientific Articles on PubMed


  • Burrage LC, Nagamani SC, Campeau PM, Lee BH. Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders. Hum Mol Genet. 2014 Sep 15;23(R1):R1-8. doi: 10.1093/hmg/ddu123. Epub 2014 Mar 20. Review. Citation on PubMed or Free article on PubMed Central
  • Carleton SM, Peck DS, Grasela J, Dietiker KL, Phillips CL. DNA carrier testing and newborn screening for maple syrup urine disease in Old Order Mennonite communities. Genet Test Mol Biomarkers. 2010 Apr;14(2):205-8. doi: 10.1089/gtmb.2009.0107. Citation on PubMed
  • Harris-Haman P, Brown L, Massey S, Ramamoorthy S. Implications of Maple Syrup Urine Disease in Newborns. Nurs Womens Health. 2017 Jun - Jul;21(3):196-206. doi: 10.1016/j.nwh.2017.04.009. Citation on PubMed
  • Oyarzabal A, Martínez-Pardo M, Merinero B, Navarrete R, Desviat LR, Ugarte M, Rodríguez-Pombo P. A novel regulatory defect in the branched-chain α-keto acid dehydrogenase complex due to a mutation in the PPM1K gene causes a mild variant phenotype of maple syrup urine disease. Hum Mutat. 2013 Feb;34(2):355-62. doi: 10.1002/humu.22242. Epub 2012 Dec 12. Citation on PubMed
  • Simon E, Flaschker N, Schadewaldt P, Langenbeck U, Wendel U. Variant maple syrup urine disease (MSUD)--the entire spectrum. J Inherit Metab Dis. 2006 Dec;29(6):716-24. Epub 2006 Oct 25. Citation on PubMed
  • Strauss KA, Puffenberger EG, Carson VJ. Maple Syrup Urine Disease. 2006 Jan 30 [updated 2020 Apr 23]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from Citation on PubMed
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MeSH Review: 

Chuang, al., Liao, al., Mitsubuchi, al., Chuang, al., Chuang, al., et al.

 Schadewaldt,  Bodner-Leidecker,  Hammen,  Wendel,  

Disease relevance of Maple Syrup Urine Disease

High impact information on Maple Syrup Urine Disease

Chemical compound and disease context of Maple Syrup Urine Disease

Biological context of Maple Syrup Urine Disease

  • Complementation of defective leucinedecarboxylation in fibroblasts from a maple syrup urine disease patient by retrovirus-mediated gene transfer [14].
  • Effect of insulin on leucinekinetics in maple syrup urine disease[15].
  • Assessment of whole body L-leucine oxidation by noninvasive L-[1-13C]leucine breath tests: a reappraisal in patients with maple syrup urine disease, obligate heterozygotes, and healthy subjects [16].
  • The maple syrup urine disease metabolites, i.e., L-leucine, L-isoleucine, and L-valine and their corresponding ketoacids caused a prolongation of the G1 and S phases, when administered in combination at concentrations corresponding to approximately the highest recorded plasma levels in patients with the disease (1 x level) [4].
  • Seven infants diagnosed with methylmalonyl-CoA mutase deficiency (n=2), ornithine carbamoyltransferase deficiency (n=1), propionic acidaemia (n=1), isovaleric acidaemia (n=1), maple syrup urine disease (n=1) and glutaric acidemia type I (n=1) were tried with breastfeeding over two years [17].

Anatomical context of Maple Syrup Urine Disease

Gene context of Maple Syrup Urine Disease


  1. The need of essential amino acids in children. An evaluation based on the intake of phenylalanine, tyrosine, leucine, isoleucine, and valine in children with phenylketonuria, tyrosine amino transferase defect, and maple syrup urine disease. Kindt, E., Halvorsen, S. Am. J. Clin. Nutr. (1980) [Pubmed]
  2. Glutamate and gamma-aminobutyric acid neurotransmitter systems in the acute phase of maple syrup urine disease and citrullinemia encephalopathies in newborn calves. Dodd, P.R., Williams, S.H., Gundlach, A.L., Harper, P.A., Healy, P.J., Dennis, J.A., Johnston, G.A. J. Neurochem. (1992) [Pubmed]
  3. Whole-body L-leucine oxidation in patients with variant form of maple syrup urine disease. Schadewaldt, P., Bodner-Leidecker, A., Hammen, H.W., Wendel, U. Pediatr. Res. (2001) [Pubmed]
  4. Prolongation of G1 and S phase in C-6 glioma cells treated with maple syrup urine disease metabolits. Morphologic and cell cycle studies. Liao, C.L., Herman, M.M., Bensch, K.G. Lab. Invest. (1978) [Pubmed]
  5. Monoamine oxidase and catechol-o-methyltransferase activity in cultured fibroblasts from patients with maple syrup urine disease, Lesch-Nyhan syndrome and healthy controls. Singh, S., Willers, I., Kluss, E.M., Goedde, H.W. Clin. Genet. (1979) [Pubmed]
  6. Branched-chain amino acid-free parenteral nutrition in the treatment of acute metabolic decompensation in patients with maple syrup urine disease. Berry, G.T., Heidenreich, R., Kaplan, P., Levine, F., Mazur, A., Palmieri, M.J., Yudkoff, M., Segal, S. N. Engl. J. Med. (1991) [Pubmed]
  7. E2 transacylase-deficient (type II) maple syrup urine disease. Aberrant splicing of E2 mRNA caused by internal intronic deletions and association with thiamine-responsive phenotype. Chuang, J.L., Cox, R.P., Chuang, D.T. J. Clin. Invest. (1997) [Pubmed]
  8. Molecular and biochemical basis of intermediate maple syrup urine disease. Occurrence of homozygous G245R and F364C mutations at the E1 alpha locus of Hispanic-Mexican patients. Chuang, J.L., Davie, J.R., Chinsky, J.M., Wynn, R.M., Cox, R.P., Chuang, D.T. J. Clin. Invest. (1995) [Pubmed]
  9. Maple syrup urine disease caused by a partial deletion in the inner E2 core domain of the branched chain alpha-keto acid dehydrogenase complex due to aberrant splicing. A single base deletion at a 5'-splice donor site of an intron of the E2 gene disrupts the consensus sequence in this region. Mitsubuchi, H., Nobukuni, Y., Akaboshi, I., Indo, Y., Endo, F., Matsuda, I. J. Clin. Invest. (1991) [Pubmed]
  10. Metabolism of [1-(14)C] and [2-(14)C] leucine in cultured skin fibroblasts from patients with isovaleric acidemia. Characterization of metabolic defects. Tanaka, K., Mandell, R., Shih, V.E. J. Clin. Invest. (1976) [Pubmed]
  11. Glucose and alanine metabolism in children with maple syrup urine disease. Haymond, M.W., Ben-Galim, E., Strobel, K.E. J. Clin. Invest. (1978) [Pubmed]
  12. Thiamin-responsive maple-syrup-urine disease: decreased affinity of the mutant branched-chain alpha-keto acid dehydrogenase for alpha-ketoisovalerate and thiamin pyrophosphate. Chuang, D.T., Ku, L.S., Cox, R.P. Proc. Natl. Acad. Sci. U.S.A. (1982) [Pubmed]
  13. On the mechanisms of the formation of L-alloisoleucine and the 2-hydroxy-3-methylvaleric acid stereoisomers from L-isoleucine in maple syrup urine disease patients and in normal humans. Mamer, O.A., Reimer, M.L. J. Biol. Chem. (1992) [Pubmed]
  14. Complementation of defective leucine decarboxylation in fibroblasts from a maple syrup urine disease patient by retrovirus-mediated gene transfer. Mueller, G.M., McKenzie, L.R., Homanics, G.E., Watkins, S.C., Robbins, P.D., Paul, H.S. Gene Ther. (1995) [Pubmed]
  15. Effect of insulin on leucine kinetics in maple syrup urine disease. Collins, J.E., Umpleby, A.M., Boroujerdi, M.A., Leonard, J.V., Sonksen, P.H. Pediatr. Res. (1987) [Pubmed]
  16. Assessment of whole body L-leucine oxidation by noninvasive L-[1-13C]leucine breath tests: a reappraisal in patients with maple syrup urine disease, obligate heterozygotes, and healthy subjects. Schadewaldt, P., Bodner, A., Brösicke, H., Hammen, H.W., Wendel, U. Pediatr. Res. (1998) [Pubmed]
  17. Breastfeeding experience in inborn errors of metabolism other than phenylketonuria. Huner, G., Baykal, T., Demir, F., Demirkol, M. J. Inherit. Metab. Dis. (2005) [Pubmed]
  18. Control of pyruvate and beta-hydroxybutyrate utilization in rat brain mitochondria and its relevance to phenylketonuria and maple syrup urine disease. Land, J.M., Mowbray, J., Clark, J.B. J. Neurochem. (1976) [Pubmed]
  19. Inhibition, by 2-oxo acids that accumulate in maple-syrup-urine disease, of lactate, pyruvate, and 3-hydroxybutyrate transport across the blood-brain barrier. Cremer, J.E., Teal, H.M., Cunningham, V.J. J. Neurochem. (1982) [Pubmed]
  20. Maple syrup urine disease: analysis of branched chain ketoacid decarboxylation in cultured fibroblasts. Wendel, U., Wentrup, H., Rüdiger, H.W. Pediatr. Res. (1975) [Pubmed]
  21. Reduction of glutamate uptake into cerebral cortex of developing rats by the branched-chain alpha-keto acids accumulating in maple syrup urine disease. Funchal, C., Rosa, A.M., Wajner, M., Wofchuk, S., Pureur, R.P. Neurochem. Res. (2004) [Pubmed]
  22. Molecular basis of maple syrup urine disease: novel mutations at the E1 alpha locus that impair E1(alpha 2 beta 2) assembly or decrease steady-state E1 alpha mRNA levels of branched-chain alpha-keto acid dehydrogenase complex. Chuang, J.L., Fisher, C.R., Cox, R.P., Chuang, D.T. Am. J. Hum. Genet. (1994) [Pubmed]
  23. Molecular basis of intermittent maple syrup urine disease: novel mutations in the E2 gene of the branched-chain alpha-keto acid dehydrogenase complex. Tsuruta, M., Mitsubuchi, H., Mardy, S., Miura, Y., Hayashida, Y., Kinugasa, A., Ishitsu, T., Matsuda, I., Indo, Y. J. Hum. Genet. (1998) [Pubmed]
  24. Maple syrup urine disease: domain structure, mutations and exon skipping in the dihydrolipoyl transacylase (E2) component of the branched-chain alpha-keto acid dehydrogenase complex. Chuang, D.T., Fisher, C.W., Lau, K.S., Griffin, T.A., Wynn, R.M., Cox, R.P. Mol. Biol. Med. (1991) [Pubmed]
  25. Molecular phenotypes in cultured maple syrup urine disease cells. Complete E1 alpha cDNA sequence and mRNA and subunit contents of the human branched chain alpha-keto acid dehydrogenase complex. Fisher, C.W., Chuang, J.L., Griffin, T.A., Lau, K.S., Cox, R.P., Chuang, D.T. J. Biol. Chem. (1989) [Pubmed]
  26. Enzymatic method for branched chain alpha-ketoacid determination: application to rapid analysis of urine and plasma samples from maple syrup urine disease patients. Burgos, C., Civallero, G.E., de Kremer, R.D., Gerez de Burgos, N.M., Blanco, A. Acta physiologica, pharmacologica et therapeutica latinoamericana : órgano de la Asociación Latinoamericana de Ciencias Fisiológicas y [de] la Asociación Latinoamericana de Farmacología. (1999) [Pubmed]
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Medical condition

Hypervalinemia, is a rare autosomalrecessivemetabolic disorder in which urinary and serum levels of the branched-chain amino acidvaline are elevated, without related elevation of the branched-chain amino acidsleucine and isoleucine.[2][3] It is caused by a deficiency of the enzyme valine transaminase.[4]


Presenting in infancy, symptoms include lack of appetite, vomiting, dehydration, hypotonia and failure to thrive.[5]


Hypervalinemia has an autosomal recessive pattern of inheritance.

Hypervalinemia is inherited in an autosomal recessive manner.[1] This means the defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.[citation needed]



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See also[edit]


  1. ^ abOnline Mendelian Inheritance in Man (OMIM): 277100
  2. ^Tada K, Wada Y, Arakawa T (1967). "Hypervalinemia. Its metabolic lesion and therapeutic approach". Am. J. Dis. Child. 113 (1): 64–67. doi:10.1001/archpedi.1967.02090160114013. PMID 6066688.
  3. ^Wada Y, Tada K, Minagawa A, Yoshida T, Morikawa T, Okamura T (1963). "Idiopathic hypervalinemia: probably a new entity of inborn error of valine metabolism". Tohoku J. Exp. Med. 81: 46–55. doi:10.1620/tjem.81.46. PMID 14077060.
  4. ^Dancis J, Hutzler J, Tada K, Wada Y, Morikawa T, Arakawa T (1967). "Hypervalinemia. A defect in valine transamination". Pediatrics. 39 (6): 813–817. PMID 6067402.
  5. ^"Valinemia | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". Retrieved 2018-04-17.

External links[edit]

Maple Syrup Urine Disease!

Maple syrup urine disease

Autosomal recessive metabolic disorder

Medical condition

Maple syrup urine disease (MSUD) is an autosomalrecessive[1]metabolic disorder affecting branched-chain amino acids. It is one type of organic acidemia.[2] The condition gets its name from the distinctive sweet odor of affected infants' urine, particularly prior to diagnosis and during times of acute illness.[3]

Signs and symptoms[edit]

The disease is named for the presence of sweet-smelling urine, similar to maple syrup, when the person goes into metabolic crisis. Along with the smell being present in ear wax of an affected individual during metabolic crisis. In populations to whom maple syrup is unfamiliar, the aroma can be likened to fenugreek, and fenugreek ingestion may impart the aroma to urine.[4] Symptoms of MSUD varies between patients and is greatly related to the amount of residual enzyme activity.[citation needed]

Classic MSUD[edit]

Infants with classic MSUD will display subtle symptoms within the first 24–48 hours. Subtle symptoms include poor feeding, either bottle or breast, lethargy, and irritability. The infant will then experience increased focal neurologic signs. These neurologic signs include athetoid, hypertonia, spasticity, and opisthotonus that lead to convulsions and coma. If MSUD is left untreated, central neurologic function and respiratory failure will occur and lead to death. Although MSUD can be stabilized, there are still threats of metabolic decompensation and loss of bone mass that can lead to osteoporosis, pancreatitis, and intracranial hypertension. Additional signs and symptoms that can be associated with classic MSUD include intellectual limitation and behavioral issues.[5]

Intermediate MSUD[edit]

Intermediate MSUD has greater levels of residual enzyme activity than classic MSUD. The majority of children with intermediate MSUD are diagnosed between the ages of 5 months and 7 years. Symptoms associated with classic MSUD also appear in intermediate MSUD.[5]

Intermittent MSUD[edit]

Contrary to classic and intermediate MSUD, intermittent MSUD individuals will have normal growth and intellectual development. Symptoms of lethargy and characterized odor of maple syrup will occur when the individual experiences stress, does not eat, or develops an infection. Metabolic crisis leading to seizures, coma, and brain damage is still a possibility.[5]

Thiamine-response MSUD[edit]

Symptoms associated with thiamine-response MSUD are similar to intermediate MSUD. Newborns rarely present with symptoms.[5]

Later onset[edit]

The symptoms of MSUD may also present later depending on the severity of the disease.[4] Untreated in older individuals, and during times of metabolic crisis, symptoms of the condition include uncharacteristically inappropriate, extreme or erratic behaviour and moods, hallucinations, lack of appetite, weight loss,[4]anemia, diarrhea, vomiting, dehydration, lethargy,[4] oscillating hypertonia and hypotonia,[4]ataxia,[4]seizures,[4]hypoglycaemia, ketoacidosis, opisthotonus, pancreatitis,[6] rapid neurological decline, and coma.[4] Death from cerebral edema will likely occur if there is no treatment.[4] Additionally, MSUD patients experience an abnormal course of diseases in simple infections that can lead to permanent damage.[citation needed]


Maple syrup urine disease has an autosomal recessive pattern of inheritance.

Mutations in the following genes cause maple syrup urine disease:

These four genes produce proteins that work together as the branched-chain alpha-keto acid dehydrogenase complex. The complex is essential for breaking down the amino acids leucine, isoleucine, and valine. These are present in some quantity in almost all kinds of food, but in particular, protein-rich foods such as dairy products, meat, fish, soy, gluten, eggs, nuts, whole grains, seeds, avocados, algae, edible seaweed, beans, and pulses. Mutation in any of these genes reduces or eliminates the function of the enzyme complex, preventing the normal breakdown of isoleucine, leucine, and valine. As a result, these amino acids and their by-products build up in the body. Because high levels of these substances are toxic to the brain and other organs, this accumulation leads to the serious medical problems associated with maple syrup urine disease.[citation needed]

This condition has an autosomal recessive inheritance pattern, which means the defective gene is located on an autosome, and two copies of the gene – one from each parent – must be inherited to be affected by the disorder. The parents of a child with an autosomal recessive disorder are carriers of one copy of the defective gene, but are usually not affected by the disorder.[citation needed]


MSUD is a metabolic disorder caused by a deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKAD), leading to a buildup of the branched-chain amino acids (leucine, isoleucine, and valine) and their toxic by-products (ketoacids) in the blood and urine. The buildup of these BCAAS will lead to the maple syrup odor that is associated with MSUD. The BCKAD complex begins by breaking down leucine, isoleucine, and valine through the use of branch-chain aminotransferase into their relevant α-ketoacids. The second step involves the conversion of α-ketoacids into acetoacetate, acetyl-CoA, and succinyl-CoA through oxidative decarboxylation of α-ketoacids. The BCKAD complex consists of four subunits designated E1α, E1β, E2, and E3. The E3 subunit is also a component of pyruvate dehydrogenase complex and oxoglutarate dehydrogenase complex.[7] MSUD can result from mutations in any of the genes that code for these enzyme subunits, E1α, E1β, E2, and E3. Mutations of these enzyme subunits will lead to the BCKAD complex unable to break down leucine, isoleucine, and valine. The levels of these branched chain amino acids will become elevated and lead to the symptoms associated with MSUD. Glutamate levels are maintained in the brain by BCAA metabolism functions and if not properly maintained can lead to neurological problems that are seen in MSUD individuals. High levels of leucine has also been shown to affect water homeostasis within subcortical gray matter leading to cerebral edema, which occurs in MSUD patients if left untreated.[citation needed]


Prior to the easy availability of plasma amino acid measurement, diagnosis was commonly made based on suggestive symptoms and odor. Affected individuals are now often identified with characteristic elevations on plasma amino acids which do not have the characteristic odor.[4] The compound responsible for the odor is sotolon (sometimes spelled sotolone).[6]

On 9 May 2014, the UK National Screening Committee (UK NSC) announced its recommendation to screen every newborn baby in the UK for four further genetic disorders as part of its NHS Newborn Blood Spot Screening programme, including maple syrup urine disease.[8] The disease is estimated to affect 1 out of 185,000 infants worldwide and its frequency increases with certain heritages.[3]

Newborn screening for maple syrup urine disease involves analyzing the blood of 1–2 day-old newborns through tandem mass spectrometry. The blood concentration of leucine and isoleucine is measured relative to other amino acids to determine if the newborn has a high level of branched-chain amino acids. Once the newborn is 2–3 days old the blood concentration of branched-chain amino acids like leucine is greater than 1000 μmol/L and alternative screening methods are used. Instead, the newborn's urine is analyzed for levels of branched-chain alpha-hydroxyacids and alpha-ketoacids.[6]

The amount and type of enzyme activity in an affected individual with MSUD will determine which classification the affected individual will identify with:[citation needed]

  • Classic MSUD: Less than 2% of normal enzyme activity
  • Intermediate MSUD: 3-8% normal enzyme activity
  • Intermittent MSUD: 8-15% of normal enzyme activity

Thiamine-Responsive MSUD: Large doses of thiamine will increase enzyme activity.[9]


Maple syrup urine disease can be classified by its pattern of signs and symptoms, or by its genetic cause. The most common and severe form of this disease is the classic type, which appears soon after birth, and as long as it remains untreated, gives rise to progressive and unremitting symptoms. Variant forms of the disorder may become apparent only later in infancy or childhood, with typically less severe symptoms that may only appear during times of fasting, stress or illness, but still involve mental and physical problems if left untreated.[citation needed]

Sub-divisions of MSUD:[citation needed]

  1. Classic MSUD
  2. Intermediate MSUD
  3. Intermittent MSUD
  4. Thiamine-responsive MSUD

Generally, majority of patients will be classified into one of these four categories but some patients affected by MSUD do not fit the criteria for the listed sub-divisions and will be deemed unclassified MSUD.[5]


There are no methods for preventing the manifestation of the pathology of MSUD in infants with two defective copies of the BCKD gene. However, genetic counselors may consult with couples to screen for the disease via DNA testing. DNA testing is also available to identify the disease in an unborn child in the womb.[10]



Keeping MSUD under control requires careful monitoring of blood chemistry, both at home and in a hospital setting. DNPH or specialised dipsticks may be used to test the patient's urine for ketones (a sign of metabolic decompensation), when metabolic stress is likely or suspected. Fingerstick tests are performed regularly and sent to a laboratory to determine blood levels of leucine, isoleucine, and valine. Regular metabolic consultations, including blood-draws for full nutritional analysis, are recommended; especially during puberty and periods of rapid growth. MSUD management also involves a specially tailored metabolic formula, a modified diet, and lifestyle precautions such as avoiding fatigue and infections, as well as consuming regular, sufficient calories in proportion to physical stress and exertion. Without sufficient calories, catabolism of muscle protein will result in metabolic crisis. Those with MSUD must be hospitalised for intravenous infusion of sugars and nasogastric drip-feeding of formula, in the event of metabolic decompensation, or lack of appetite, diarrhea or vomiting. Food avoidance, rejection of formula and picky eating are all common problems with MSUD. Some patients may need to receive all or part of their daily nutrition through a feeding tube.[citation needed]

Toxin removal[edit]

Following diagnosis, rapid removal of excess leucine from the body reduces the impact of the disease on development. Exchange transfusion, hemodialysis, or hemofiltration may be used.[11]

Diet control[edit]

A diet with carefully controlled levels of the amino acids leucine, isoleucine, and valine must be maintained at all times in order to prevent neurological damage. Since these three amino acids occur in all natural protein, and most natural foods contain some protein, any food intake must be closely monitored, and day-to-day protein intake calculated on a cumulative basis, to ensure individual tolerance levels are not exceeded at any time. As the MSUD diet is so protein-restricted, and adequate protein is a requirement for all humans, tailored metabolic formula containing all the other essential amino acids, as well as any vitamins, minerals, omega-3 fatty acids and trace elements (which may be lacking due to the limited range of permissible foods), are an essential aspect of MSUD management. These complement the MSUD patient's natural food intake to meet normal nutritional requirements without causing harm.[12] If adequate calories cannot be obtained from natural food without exceeding protein tolerance, specialised low protein products such as starch-based baking mixtures, imitation rice and pasta may be prescribed, often alongside a protein-free carbohydrate powder added to food and/or drink, and increased at times of metabolic stress. MSUD patients with thiamine- responsive MSUD can have a higher protein intake diet with administration of high doses of thiamine, a cofactor of the enzyme that causes the condition. The typical dosage amount of thiamine-responsive MSUD depends on the enzyme activity present and can range from 10 mg - 100 mg daily.[citation needed]

Liver transplantation[edit]

Usually MSUD patients are monitored by a dietitian. Liver transplantation is a treatment option that can completely and permanently normalise metabolic function, enabling discontinuation of nutritional supplements and strict monitoring of biochemistry and caloric intake, relaxation of MSUD-related lifestyle precautions, and an unrestricted diet. This procedure is most successful when performed at a young age, and weaning from immunosuppressants may even be possible in the long run. However, the surgery is a major undertaking requiring extensive hospitalisation and rigorous adherence to a tapering regimen of medications. Following transplant, the risk of periodic rejection will always exist, as will the need for some degree of lifelong monitoring in this respect. Despite normalising clinical presentation, liver transplantation is not considered a cure for MSUD. The patient will still carry two copies of the mutated BKAD gene in each of their own cells, which will consequently still be unable to produce the missing enzyme. They will also still pass one mutated copy of the gene on to each of their biological children. As a major surgery the transplant procedure itself also carries standard risks, although the odds of its success are greatly elevated when the only indication for it is an inborn error of metabolism. In absence of a liver transplant, the MSUD diet must be adhered to strictly and permanently. However, in both treatment scenarios, with proper management, those afflicted are able to live healthy, normal lives without suffering the severe neurological damage associated with the disease.


Control of metabolism is vital during pregnancy of women with MSUD. To prevent detrimental abnormalities in development of the embryo or fetus, dietary adjustments should be made and plasma amino acid concentrations of the mother should be observed carefully and frequently. Amino acid deficiency can be detected through fetal growth, making it essential to monitor development closely.[6]


If left untreated, MSUD will lead to death due to central neurological function failure and respiratory failure. Early detection, diet low in branched-chain amino acids, and close monitoring of blood chemistry can lead to a good prognosis with little or no abnormal developments. Average intellectual development is below that of the general population and the severity of the deficit is a related to the time the condition remained undiagnosed and the effectiveness of dietary control including during metabolic crises.[11]


Maple syrup urine disease (MSUD) is a rare, inherited metabolic disorder. Its prevalence in the United States population is approximately 1 newborn out of 180,000 live births. However, in populations where there is a higher frequency of consanguinity, such as the Mennonites in Pennsylvania or the Amish, the frequency of MSUD is significantly higher at 1 newborn out of 176 live births. In Austria, 1 newborn out of 250,000 live births inherits MSUD.[13] It also is believed to have a higher prevalence in certain populations due in part to the founder effect[14] since MSUD has a much higher prevalence in children of Amish, Mennonite, and Jewish descent.[15][16][17]

Research directions[edit]

Gene therapy[edit]

Gene therapy to overcome the genetic mutations that cause MSUD have already been proven safe in animals studies with MSUD. The gene therapy involves a healthy copy of the gene causing MSUD is produced and inserted into a viral vector. The adeno-associated virus vector is delivered one-time to the patient intravenously. Hepatocytes will take up vector and functional copies of the affected gene is MSUD patients will be expressed. This will allow BCAA to be broken down properly and prevent toxic build up.[18]

Phenylbutyrate therapy[edit]

Sodium phenylacetate/benzoate or sodium phenylbutyrate has been shown to reduce BCAA in a clinical trial done February 2011. Phenylbutyrate treatment reduced the blood concentration of BCAA and their corresponding BCKA in certain groups of MSUD patients and may be a possible adjunctive treatment.[19]

See also[edit]


  1. ^Podebrad F, Heil M, Reichert S, Mosandl A, Sewell AC, Böhles H (April 1999). "4,5-dimethyl-3-hydroxy-25H-furanone (sotolone)--the odour of maple syrup urine disease". Journal of Inherited Metabolic Disease. 22 (2): 107–114. doi:10.1023/A:1005433516026. PMID 10234605. S2CID 6426166.
  2. ^Ogier de Baulny H, Saudubray JM (2002). "Branched-chain organic acidurias". Semin Neonatol. 7 (1): 65–74. doi:10.1053/siny.2001.0087. PMID 12069539.
  3. ^ ab"Maple syrup urine disease". Genetics Home Reference. July 2017.
  4. ^ abcdefghij"OMIM Entry - # 248600 - MAPLE SYRUP URINE DISEASE; MSUD". Retrieved 2016-11-14.
  5. ^ abcde"NORD - Maple Syrup Urine Disease". Retrieved 13 December 2019.
  6. ^ abcdStrauss, Kevin A.; Puffenberger, Erik G.; Morton, D. Holmes (1993-01-01). Pagon, Roberta A.; Adam, Margaret P.; Ardinger, Holly H.; Wallace, Stephanie E.; Amemiya, Anne; Bean, Lora J.H.; Bird, Thomas D.; Fong, Chin-To; Mefford, Heather C. (eds.). Maple Syrup Urine Disease. Seattle (WA): University of Washington, Seattle. PMID 20301495.
  7. ^Pasquali, Marzia; Longo, Nicola (December 13, 2011). "58. Newborn screening and inborn errors of metabolism". In Burtis, Carl A.; Ashwood, Edward R.; Bruns, David E. (eds.). Tietz Textbook of Clinical Chemistry and Molecular Diagnostics (5th ed.). Elsevier Health Sciences. p. 2062. ISBN .
  8. ^"New screening will protect babies from death and disability".
  9. ^"MSUD classifications".
  10. ^"Maple Syrup Urine Disease (MSUD)". Healthline. Retrieved 2016-11-10.
  11. ^ abK. Tada; N.R.M. Buist; John Fernandes; Jean-Marie Saudubray; Georges van den Berghe (14 March 2013). Inborn Metabolic Diseases: Diagnosis and Treatment. Springer Science & Business Media. pp. 216–217. ISBN .
  12. ^Hallam P, Lilburn M, Lee PJ (2005). "A new protein substitute for adolescents and adults with maple syrup urine disease (MSUD)". J. Inherit. Metab. Dis. 28 (5): 665–672. doi:10.1007/s10545-005-0061-6. PMID 16151896. S2CID 24718350.
  13. ^"Maple Syrup Urine Disease (MSUD): Facts & Information". Disabled World. Retrieved 2016-11-10.
  14. ^Jaworski MA, Severini A, Mansour G, Konrad HM, Slater J, Henning K, Schlaut J, Yoon JW, Pak CY, Maclaren N, et al. (1989). "Genetic conditions among Canadian Mennonites: evidence for a founder effect among the old country (Chortitza) Mennonites". Clin Invest Med. 12 (2): 127–141. PMID 2706837.
  15. ^Mary Kugler, R.N. "Maple Syrup Urine Disease". Health.
  16. ^Puffenberger EG (2003). "Genetic heritage of Old Order Mennonites in southeastern Pennsylvania". Am J Med Genet C Semin Med Genet. 121 (1): 18–31. doi:10.1002/ajmg.c.20003. PMID 12888983. S2CID 25317649.
  17. ^"Maple Syrup Urine Disease (MSUD) - Jewish Genetic Disease". Retrieved 18 December 2015.
  18. ^"MSUD infographic - gene therapy". Retrieved 13 December 2019.
  19. ^Brunetti-Pierri, Nicola; Lanpher, Brendan; Erez, Ayelet; Ananieva, Elitsa A.; Islam, Mohammad; Marini, Juan C.; Sun, Qin; Yu, Chunli; Hegde, Madhuri; Li, Jun; Wynn, R. Max; Chuang, David T.; Hutson, Susan; Lee, Brendan (15 February 2011). "Phenylbutyrate therapy for maple syrup urine disease". Hum Mol Genet. 20 (4): 631–640. doi:10.1093/hmg/ddq507. PMC 3024040. PMID 21098507.

External links[edit]


Wiki maple disease syrup urine


Medical condition

Other namesBlack urine disease, black bone disease, alcaptonuria
Pigmentation of the face in alkaptonuria
SpecialtyEndocrinology Edit this on Wikidata

Alkaptonuria is a rare inherited genetic disease which is caused by a mutation in the HGDgene for the enzymehomogentisate 1,2-dioxygenase (EC1.13.11.5); if a person inherits an abnormal copy from both parents (it is a recessive condition), the body accumulates an intermediate substance called homogentisic acid in the blood and tissues. Homogentisic acid and its oxidized formalkapton are excreted in the urine, giving it an unusually dark color. The accumulating homogentisic acid causes damage to cartilage (ochronosis, leading to osteoarthritis) and heart valves, as well as precipitating as kidney stones and stones in other organs. Symptoms usually develop in people over 30 years old, although the dark discoloration of the urine is present from birth.

Apart from treatment of the complications (such as pain relief and joint replacement for the cartilage damage), the drug nitisinone has been found to suppress homogentisic acid production, and research is ongoing as to whether it can improve symptoms. Alkaptonuria is a rare disease; it occurs in one in 250,000 people, but is more common in Slovakia and the Dominican Republic.[citation needed]

Signs and symptoms[edit]

Intervertebral discs calcification due to ochronosis

Patients with alkaptonuria are asymptomatic as children or young adults, but their urine may turn brown or even inky black if collected and left exposed to open air.[1] Pigmentation may be noted in the cartilage of the ear and other cartilage,[1][2] and the sclera and corneal limbus of the eye.[3]

After the age of 30, people begin to develop pain in the weight-bearing joints of the spine, hips, and knees. The pain can be severe to the point that interferes with activities of daily living and may affect the ability to work. Joint-replacement surgery (hip and shoulder) is often necessary at a relatively young age.[1] In the longer term, the involvement of the spinal joints leads to reduced movement of the rib cage and can affect breathing.[1]Bone mineral density may be affected, increasing the risk of bone fractures, and rupture of tendons and muscles may occur.[1]

Valvular heart disease, mainly calcification and regurgitation of the aortic and mitral valves, may occur, and in severe and progressive cases, valve replacement may be necessary. Irregularities in the heart rhythm and heart failure affect a significant proportion of people with alkaptonuria (40% and 10%, respectively).[1] Hearing loss affects 40% of people. Also, a propensity to developing kidney stones exists, and eventually also gallstones and stones in the prostate and salivary glands (sialolithiasis) can occur.[1]


Chemical skeletal formulaof homogentisic acid, which accumulates in the body fluids of people with alkaptonuria.

All people carry in their DNA two copies (one received from each parent) of the gene HGD, which contains the genetic information to produce the enzyme homogentisate 1,2-dioxygenase (HGD) which can normally be found in numerous tissues in the body (liver, kidney, small intestine, colon, and prostate). In people with alkaptonuria, both copies of the gene contain abnormalities that mean that the body cannot produce an adequately functioning enzyme.[4]HGD mutations are generally found in certain parts (exons 6, 8, 10, and 13), but a total of over 100 abnormalities has been described throughout the gene.[4] The normal HGD enzyme is a hexamer (it has six subunits) that are organized in two groups of three (two trimers) and contains an iron atom. Different mutations may affect the structure, function, or solubility of the enzyme.[4] Very occasionally, the disease appears to be transmitted in an autosomal-dominant fashion, where a single abnormal copy of HGD from a single parent is associated with alkaptonuria; other mechanisms or defects in other genes possibly are responsible in those cases.[4]

Pathophysiology of alkaptonuria (AKU) is due to the absence of functional homogentisate dioxygenase (HGD) in the liver.

The HGD enzyme is involved in the metabolism (chemical processing) of the aromatic amino acidsphenylalanine and tyrosine. Normally, these enter the bloodstream through protein-containing food and the natural turnover of protein in the body. Tyrosine is specifically required for a number of functions, such as hormones (e.g. thyroxine, the thyroid hormone), melanin (the dark pigment in the skin and hair), and certain proteins, but the vast majority (over 95%) is unused and is metabolized through a group of enzymes that eventually generate acetoacetate and malate.[1] In alkaptonuria, the HGD enzyme cannot metabolize the homogentisic acid (generated from tyrosine) into 4-maleylacetoacetate, and homogentisic acid levels in the blood are 100-fold higher than would normally be expected, despite the fact that a substantial amount is eliminated into the urine by the kidneys.[1]

The homogentisic acid is converted to the related substance benzoquinone acetic acid which forms polymers that resemble the skin pigment melanin. These are deposited in the collagen, a connective tissue protein, of particular tissues such as cartilage. This process is called ochronosis (as the tissue looks ochre); ochronotic tissue is stiffened and unusually brittle, impairing its normal function and causing damage.[1]


Urine of a 4-month-old baby with dark urine (on the left) after 10% ammonia and 3% silver nitrate were added. The tube in the middle is a normal control. Color change on alkalinization is not a specific test, and confirmatory investigations are needed.[1]

If the diagnosis of alkaptonuria is suspected, it can be confirmed or excluded by collecting urine for 24 hours and determining the amount of homogentisic acid by means of chromatography. No assay of HGA in blood has been validated.[1] The Genetic Testing Registry is used for maintaining information about the genetic test for alkaptonuria.[5]

The severity of the symptoms and response to treatment can be quantified through a validated questionnaire titled the AKU Severity Score Index. This assigns scores to the presence of particular symptoms and features, such as the presence of eye and skin pigmentation, joint pain, heart problems, and organ stones.[1]


No treatment modality has been unequivocally demonstrated to reduce the complications of alkaptonuria. Main treatment attempts have focused on preventing ochronosis through the reduction of accumulating homogentisic acid. Such commonly recommended treatments include large doses of ascorbic acid (vitamin C) or dietary restriction of amino acids phenylalanine and tyrosine. However, vitamin C treatment does not have definitively proven effectiveness[1] and protein restriction (which can be difficult to adhere to) has not shown to be effective in clinical studies.[1]

Several studies have suggested that the herbicide nitisinone may be effective in the treatment of alkaptonuria. Nitisinone inhibits the enzyme 4-hydroxyphenylpyruvate dioxygenase, responsible for converting tyrosine to homogentisic acid, thereby blocking the production and accumulation of HGA. Nitisinone has been used for some time at much higher doses in the treatment of type I tyrosinemia. Nitisinone treatment has been shown to cause a larger than 95% reduction in plasma and urinary HGA.[1] The main drawback is accumulation of tyrosine, the long-term risks of which are unknown; a particular concern exists about damage to the cornea of the eye. Long-term use requires frequent monitoring for complications.[1]


Alkaptonuria does not appear to affect life expectancy, although the latest study on the topic is from 1985.[1] The main impact is on quality of life; many people with alkaptonuria have disabling symptoms such as pain, poor sleep, and breathing symptoms. These generally start in the fourth decade. The typical age at requiring joint replacement surgery is 50–55 years.[1]


In most ethnic groups, the prevalence of alkaptonuria is between 1:100,000 and 1:250,000.[4] In Slovakia and the Dominican Republic, the disease is much more common, with prevalence estimated at 1:19,000 people.[4] As for Slovakia, this is not the result of a single mutation, but due to a group of 12 mutations in specific "hot spots" of the HGD gene.[4] The Slovakian clustering probably arose in a small area in the northwest of the country and spread after the 1950s due to migration.[4]


Alkaptonuria was one of the four diseases described by Archibald Edward Garrod, as being the result of the accumulation of intermediates due to metabolic deficiencies. He linked ochronosis with the accumulation of alkaptans in 1902,[4][6] and his views on the subject, including its mode of heritance, were summarized in a 1908 Croonian Lecture at the Royal College of Physicians.[4][7][8]

The defect was narrowed down to homogentisic acid oxidase deficiency in a study published in 1958.[4][9] The genetic basis was elucidated in 1996, when HGD mutations were demonstrated.[4][10]

A 1977 study showed that an ochronotic Egyptian mummy had probably suffered from alkaptonuria.[11][12]

Research directions[edit]

Research collaborations by several national centres have been established to find a more definitive treatment for alkaptonuria. This has included studies on the use of nitisinone and investigations into antioxidants to inhibit ochronosis.[4] The ideal treatment would replace HGD enzyme function without accumulating other substances.[1]

See also[edit]


  1. ^ abcdefghijklmnopqrstRanganath LR, Jarvis JC, Gallagher JA (May 2013). "Recent advances in management of alkaptonuria (invited review; best practice article)". J. Clin. Pathol. 66 (5): 367–73. doi:10.1136/jclinpath-2012-200877. PMID 23486607.
  2. ^Speeckaert R, Van Gele M, Speeckaert MM, Lambert J, van Geel N (July 2014). "The biology of hyperpigmentation syndromes". Pigment Cell Melanoma Res. 27 (4): 512–24. doi:10.1111/pcmr.12235. PMID 24612852.
  3. ^Lindner, Moritz; Bertelmann, Thomas (2014-01-30). "On the ocular findings in ochronosis: a systematic review of literature". BMC Ophthalmology. 14 (1): 12. doi:10.1186/1471-2415-14-12. ISSN 1471-2415. PMC 3915032. PMID 24479547.
  4. ^ abcdefghijklmZatkova A (December 2011). "An update on molecular genetics of Alkaptonuria (AKU)". J. Inherit. Metab. Dis. 34 (6): 1127–36. doi:10.1007/s10545-011-9363-z. PMID 21720873.
  5. ^Anonymous (18 March 2016). "Alkaptonuria". Retrieved 17 April 2018.
  6. ^Garrod AE (1902). "The incidence of alkaptonuria: a study in clinical individuality". Lancet. 2 (4137): 1616–20. doi:10.1016/S0140-6736(01)41972-6. PMC 2230159. PMID 8784780. Reproduced in Garrod AE (2002). "The incidence of alkaptonuria: a study in chemical individuality. 1902 classical article". Yale Journal of Biology and Medicine. 75 (4): 221–31. PMC 2588790. PMID 12784973.
  7. ^Garrod AE (1908). "The Croonian lectures on inborn errors of metabolism: lecture II: alkaptonuria". Lancet. 2 (4428): 73–79. doi:10.1016/s0140-6736(01)78041-5.
  8. ^Garrod AE (1909). "Inborn errors of metabolism". Oxford University Press. OL 7116744M.
  9. ^La Du BN, Zannoni VG, Laster L, Seegmiller JE (1 January 1958). "The nature of the defect in tyrosine metabolism in alcaptonuria". Journal of Biological Chemistry. 230 (1): 251–60. PMID 13502394. Archived from the original(PDF) on 31 May 2008. Retrieved 3 December 2007.
  10. ^Fernández-Cañón JM, Granadino B, Beltrán-Valero de Bernabé D, et al. (1996). "The molecular basis of alkaptonuria". Nature Genetics. 14 (1): 19–24. doi:10.1038/ng0996-19. PMID 8782815.
  11. ^Stenn FF, Milgram JW, Lee SL, Weigand RJ, Veis A (1977). "Biochemical identification of homogentisic acid pigment in an ochronotic egyptian mummy". Science. 197 (4303): 566–68. Bibcode:1977Sci...197..566S. doi:10.1126/science.327549. PMID 327549.
  12. ^Lee, SL.; Stenn, FF. (Jul 1978). "Characterization of mummy bone ochronotic pigment". JAMA. 240 (2): 136–38. doi:10.1001/jama.1978.03290020058024. PMID 351220.

External links[edit]

Maple Syrup Urine Disease (MSUD)

Maple Syrup Urine Disease (MSUD)

Maple Syrup Urine Disorder (MSUD) also known as BCKD deficiency, Branched-chain alpha-keto acid dehydrogenase deficiency, and Branched-Chain Ketoaciduria Ketoacidemia is an inherited disorder in which the body is unable to process certain amino acids (protein building blocks) properly. The disease appears at infancy and may be lethal if proper precautions are not taken. Discovered by John Menkes in 1954, this disorder affects one in every 185,000 newborns. MSUD is characterized by sweet smelling, low viscosity urine. This disease is carried throughout ones entire lifetime. The three forms of MSUD run from mild to extreme and can cause everything from a slight annoyance to comas and brain damage.


The disease was discovered in 1954 by Dr. John Menkes. Menkes reported a family that had four infants die within the first three months of life. The oddity is that all of the dead infants had urine that smelled like maple syrup, thus the name Maple Syrup Urine Disorder came to be. In 1960 Dr. J. Dancis found that in branched-chain amino acids and their corresponding alpha-keto acids there were pathogenetic compounds. He found an enzymatic defect in MSUD was at the level of the decarboxylation of the branched-chain amino acids. Around this time SE Snyderman came up with the first diet that could positively affect MSUD by decreasing the intake of branched-chain amino acids. In 1971, Scriver reported the first case of thiamine-responsive MSUD. The branched-chain alpha-keto acid dehydrogenase (BCKD) complex was purified and characterized in 1978.


Maple Syrup Urine Disease is classified by its pattern of signs and symptoms, which become apparent within three to four days after birth. These symptoms include: loss of appetite, fussiness, and sweet-smelling urine. There is a classic form of MSUD and several less common forms, each varying in its severity and characteristic features. The classic signs and symptoms include; developmental delay, avoiding food, coma, feeding difficultly, lethargy, seizures, urine that smells like maple syrup, and vomiting. If a child with MSUD is not treated, life threatening metabolic crisis can occur. It may cause damage to the brain resulting in mental retardation, and may present seizures, coma, and death within the first few months of life. Children diagnosed early before severe symptoms appear have a chance for normal intelligence with strict diet care. [1][2]


The underlying mechanism causing Maple Syrup Urine Disease is based on the mutations in BCKA, BCKDHA, DBT, and DLD genes. These genes are responsible for making the enzymes called 2-oxoisovalerate dehydrogenase alpha, 2-oxoisovalerate dehydrogenase beta, and lipoamide acyltransferase. These genes also provide the information for making the protein complex essential for breaking down the amino acids leucine, isoleucine, and valine. Defects in any of the six subunits that make up the BCKD protein complex can cause the development of MSUD. The most common defect is caused by a mutation in a gene on chromosome 19 that encodes the alpha subunit of the BCKD complex (BCKDHA). The mutations of these genes reduce and or eliminate their function preventing the normal breakdown of the amino acids. Since they are not being broken down they accumulate in the urine, along with their metabolites (alpha-ketoacids) to give the distinctive sweet smelling urine common in those with MSUD. The build up of the amino acids and their by-products, along with accumulation in urine, also build up in the blood causing high levels of these substances which can then become toxic to the brain as well as other organs. These high levels lead to the serious medical problems and symptoms association with maple syrup urine disease. If the symptoms go left untreated they may end up with dangerously high levels of these amino acids in their blood, causing the rapid degeneration of brain cells and even death. [1] [3] [4] [5]

MSUD.jpgAutosomal recessive.jpg

en. Google Images(Accessed on Nov 30,2009)


Since MDSU is a genetic disorder, new strives are being taken to detect the disease early on. A new screening type can uses tandem mass spectrometry (MS/MS) for screening newborns for various inherited diseases, one of which is MSUD. The screening process can detect the presence of the disease; however, it is still questionable how cost effective the screening is. This new screening can detect the incidence of each disease at birth, the severity of disease, the responsiveness to treatment, accuracy (sensitivity, specificity and positive predictive rates) of screening for all different metabolic disorders, and mortality. The next step for the disease is to make AAAs on site or even mobile. Like the disorder, Diabetes, MSUD needs to be monitored throughout the day. As of now the only way to keep track of the amount amino acids in a patient’s body is by using an Amino Acid Analyzer (AAA) which are located in very few hospitals. The Amino Acid Analyzer is a piece of equipment that will enable better care for patients who have metabolic conditions involving protein metabolism. These disorders include Phenylketonuria (PKU), Maple Syrup Urine Disease (MSUD), Urea Cycle Disorders (UCD), and more. The machines run about 85,000 dollars to make, and cost increases with use and employees to run it. So steps are being taken to “shrink” the AAA and make it more cost efficient so sufferers of MSUD can test anywhere like patients of diabetes. Donations to this cause can be made at . [6]

Current Research

Since the disorder is more genetic new strives are being taken to detect the disease early on. A new screening type can use the use of tandem mass spectrometry (MS/MS) for screening newborns for inherited diseases one of which is MSUD. The screening can detect the presence, however, it is still questionable how cost effective the screening is. This new screening can detect the incidence of each disease at birth, the severity of disease, the responsiveness to treatment, accuracy (sensitivity, specificity and positive predictive rates) of screening for all different metabolic disorders, and mortality. There are also three large grants out from the NIH to study MSUD but no information has been released on any new positive outcomes. [7]


There is no cure for MSUD and even when the strict diet treatment regiment is fallowed stress may cause a sudden rise in amino acids and cause coma, neurological damage, and even death. (This can also be brought on by sudden or severe illness.)

Despite MSUD’s devastating effects children with MSUD have still grown up into healthy adults and productive members of society. [1]



[1] Maple Syrup Urine Disease (MSUD). 2005 < >

[2] Maple Syrup Urine Disease. 2009. <>

[3] Maple Syrup Urine Disease. 2008. <>

[4] Genes and Disease. Maple Syrup Urine Disease. 2007 <>

[5] Medline Plus. Maple Syrup Urine Diease. 2009 <>

[6] National Organization for Rare Disorders. 2007. Maple Syrup Urine disease. <>

[7]Centre for Reviews and Dissemination. 2007. NHS Economic Evaluation Database (NHS EED). <>


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Structural highlights


[ODBA_HUMAN] Defects in BCKDHA are a cause of maple syrup urine disease type IA (MSUD1A) [MIM:248600]. MSUD is an autosomal recessive disorder characterized by mental and physical retardation, feeding problems, and a maple syrup odor to the urine.[1][2][3][4][5][6][7][8] [ODBB_HUMAN] Defects in BCKDHB are the cause of maple syrup urine disease type IB (MSUD1B) [MIM:248600]. MSUD is an autosomal recessive disorder characterized by mental and physical retardation, feeding problems, and a maple syrup odor to the urine.[9][10][11]


[ODBA_HUMAN] The branched-chain alpha-keto dehydrogenase complex catalyzes the overall conversion of alpha-keto acids to acyl-CoA and CO(2). It contains multiple copies of three enzymatic components: branched-chain alpha-keto acid decarboxylase (E1), lipoamide acyltransferase (E2) and lipoamide dehydrogenase (E3). [ODBB_HUMAN] The branched-chain alpha-keto dehydrogenase complex catalyzes the overall conversion of alpha-keto acids to acyl-CoA and CO(2). It contains multiple copies of three enzymatic components: branched-chain alpha-keto acid decarboxylase (E1), lipoamide acyltransferase (E2) and lipoamide dehydrogenase (E3).

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

BACKGROUND: Mutations in components of the extraordinarily large alpha-ketoacid dehydrogenase multienzyme complexes can lead to serious and often fatal disorders in humans, including maple syrup urine disease (MSUD). In order to obtain insight into the effect of mutations observed in MSUD patients, we determined the crystal structure of branched-chain alpha-ketoacid dehydrogenase (E1), the 170 kDa alpha(2)beta(2) heterotetrameric E1b component of the branched-chain alpha-ketoacid dehydrogenase multienzyme complex. RESULTS: The 2.7 A resolution crystal structure of human E1b revealed essentially the full alpha and beta polypeptide chains of the tightly packed heterotetramer. The position of two important potassium (K(+)) ions was determined. One of these ions assists a loop that is close to the cofactor to adopt the proper conformation. The second is located in the beta subunit near the interface with the small C-terminal domain of the alpha subunit. The known MSUD mutations affect the functioning of E1b by interfering with the cofactor and K(+) sites, the packing of hydrophobic cores, and the precise arrangement of residues at or near several subunit interfaces. The Tyr-->Asn mutation at position 393-alpha occurs very frequently in the US population of Mennonites and is located in a unique extension of the human E1b alpha subunit, contacting the beta' subunit. CONCLUSIONS: Essentially all MSUD mutations in human E1b can be explained on the basis of the structure, with the severity of the mutations for the stability and function of the protein correlating well with the severity of the disease for the patients. The suggestion is made that small molecules with high affinity for human E1b might alleviate effects of some of the milder forms of MSUD.

Crystal structure of human branched-chain alpha-ketoacid dehydrogenase and the molecular basis of multienzyme complex deficiency in maple syrup urine disease.,AEvarsson A, Chuang JL, Wynn RM, Turley S, Chuang DT, Hol WG Structure. 2000 Mar 15;8(3):277-91. PMID:10745006[12]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also


  1. ↑ Dariush N, Fisher CW, Cox RP, Chuang DT. Structure of the gene encoding the entire mature E1 alpha subunit of human branched-chain alpha-keto acid dehydrogenase complex. FEBS Lett. 1991 Jun 17;284(1):34-8. PMID:2060625
  2. ↑ Chuang JL, Fisher CR, Cox RP, Chuang DT. Molecular basis of maple syrup urine disease: novel mutations at the E1 alpha locus that impair E1(alpha 2 beta 2) assembly or decrease steady-state E1 alpha mRNA levels of branched-chain alpha-keto acid dehydrogenase complex. Am J Hum Genet. 1994 Aug;55(2):297-304. PMID:8037208
  3. ↑ Zhang B, Edenberg HJ, Crabb DW, Harris RA. Evidence for both a regulatory mutation and a structural mutation in a family with maple syrup urine disease. J Clin Invest. 1989 Apr;83(4):1425-9. PMID:2703538 doi:
  4. ↑ Matsuda I, Nobukuni Y, Mitsubuchi H, Indo Y, Endo F, Asaka J, Harada A. A T-to-A substitution in the E1 alpha subunit gene of the branched-chain alpha-ketoacid dehydrogenase complex in two cell lines derived from Menonite maple syrup urine disease patients. Biochem Biophys Res Commun. 1990 Oct 30;172(2):646-51. PMID:2241958
  5. ↑ Fisher CR, Fisher CW, Chuang DT, Cox RP. Occurrence of a Tyr393----Asn (Y393N) mutation in the E1 alpha gene of the branched-chain alpha-keto acid dehydrogenase complex in maple syrup urine disease patients from a Mennonite population. Am J Hum Genet. 1991 Aug;49(2):429-34. PMID:1867199
  6. ↑ Fisher CR, Chuang JL, Cox RP, Fisher CW, Star RA, Chuang DT. Maple syrup urine disease in Mennonites. Evidence that the Y393N mutation in E1 alpha impedes assembly of the E1 component of branched-chain alpha-keto acid dehydrogenase complex. J Clin Invest. 1991 Sep;88(3):1034-7. PMID:1885764 doi:
  7. ↑ Nobukuni Y, Mitsubuchi H, Hayashida Y, Ohta K, Indo Y, Ichiba Y, Endo F, Matsuda I. Heterogeneity of mutations in maple syrup urine disease (MSUD): screening and identification of affected E1 alpha and E1 beta subunits of the branched-chain alpha-keto-acid dehydrogenase multienzyme complex. Biochim Biophys Acta. 1993 Nov 25;1225(1):64-70. PMID:8161368
  8. ↑ Chuang JL, Davie JR, Chinsky JM, Wynn RM, Cox RP, Chuang DT. Molecular and biochemical basis of intermediate maple syrup urine disease. Occurrence of homozygous G245R and F364C mutations at the E1 alpha locus of Hispanic-Mexican patients. J Clin Invest. 1995 Mar;95(3):954-63. PMID:7883996 doi:
  9. ↑ Nobukuni Y, Mitsubuchi H, Hayashida Y, Ohta K, Indo Y, Ichiba Y, Endo F, Matsuda I. Heterogeneity of mutations in maple syrup urine disease (MSUD): screening and identification of affected E1 alpha and E1 beta subunits of the branched-chain alpha-keto-acid dehydrogenase multienzyme complex. Biochim Biophys Acta. 1993 Nov 25;1225(1):64-70. PMID:8161368
  10. ↑ Edelmann L, Wasserstein MP, Kornreich R, Sansaricq C, Snyderman SE, Diaz GA. Maple syrup urine disease: identification and carrier-frequency determination of a novel founder mutation in the Ashkenazi Jewish population. Am J Hum Genet. 2001 Oct;69(4):863-8. Epub 2001 Aug 16. PMID:11509994 doi:S0002-9297(07)61141-0
  11. ↑ Wang YP, Qi ML, Li TT, Zhao YJ. Two novel mutations in the BCKDHB gene (R170H, Q346R) cause the classic form of maple syrup urine disease (MSUD). Gene. 2012 Apr 25;498(1):112-5. doi: 10.1016/j.gene.2012.01.082. Epub 2012 Feb 3. PMID:22326532 doi:10.1016/j.gene.2012.01.082
  12. ↑ AEvarsson A, Chuang JL, Wynn RM, Turley S, Chuang DT, Hol WG. Crystal structure of human branched-chain alpha-ketoacid dehydrogenase and the molecular basis of multienzyme complex deficiency in maple syrup urine disease. Structure. 2000 Mar 15;8(3):277-91. PMID:10745006

Categories: Human | Large Structures | AEvarsson, A | Chuang, D T | Chuang, J L | Hol, W G.J | Turley, S | Wynn, R M | Branched-chain alpha-keto acid dehydrogenase | Oxidoreductase | Thdp-binding fold


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