Ketoaciduria Research Paper
Review
Branched-chain Ketoaciduria (Maple Syrup Urine Disease), and Its Effect on the Breakdown of Amino Acids in the Human Body
David Holkesvik
INTRODUCTION: Branched-chain ketoaciduria, more commonly known as Maple syrup urine disease (MSUD) is a metabolic disorder that causes toxic buildup of un-broken down branched-chain amino acids or ketoacids. Passed on autosomal recessively, mutations in specific genes hinder or stop the enzyme complex responsible for normal breakdown of three amino acids found in protein-rich foods from working. The buildup of these toxic ketoacids leads to brain damage and eventually death in the affected infant if left untreated (Ogier de Baulny and Saudubray 2002). Although relatively rare in the general …show more content…
population (1/185,000 live births), prevalence in certain ethnic populations are much higher due the founder effect (as high as 1/10). This review will cover the causes, diagnosis/symptoms, genetic prevalence, and ethical issues regarding MSUD.
CAUSES:
MSUD stems from a disruption of the branched-chain alpha-keto acid dehydrogenase complex. This complex, consisting of four subunits E1α, E1β, E2, and E3, is responsible for the breakdown the amino acids leucine, isoleucine, and valine, which exist in many protein-rich foods. The four subunits of the complex are coded by the genes BCKDHA, BCKDHB, DBT, and DLD. Each of these genes code for a single subunit, and any mutation occurring in both alleles encoding a subunit will result in the disorder (Podebrad et al 1999). No other phenotype has been known to be associated with these mutations. Although the most common mutation is found on the BCKDHA gene on the 19th chromosome, mutations on any of the four genes result in indistinguishable consequences (Strauss et al. 2013). In other words, a mutation on any one of the genes translates to a non-functional branched-chain alpha-ketoacid dehydrogenase complex that does not produce the necessary enzymes for normal breakdown of protiens.
DIAGNOSIS/SYMPTOMS
There are a few, relatively easy ways to test for MSUD.
However if an affected child is not diagnosed within 7-10 days coma, and central respiratory failure is imminent. Since all diagnoses are made on newborn children finding of this genetic disease relies on completely on physical irregularities. The most obvious way to tell is by the smell of the infant’s urine which has a distinct sweet smell (hence maple syrup urine disease) due to the excess amount of ketoacids in the urine (Pasquali and Marzia. 2011). The sweet smell in the urine is usually detectable 12 hours after birth and is the first sign the child is affected. Another, perhaps more modern, method of diagnosis is testing plasma for elevated concentrations of branched-chain amino acids (leucine, isoleucine, and valine) using quantitative plasma amino acid analysis. This technique simply compares the ratios of the three possibly affected amino acids to other essential and non-essential amino acids and look for irregularities. The elevated levels of leucine, isoleucine, and valine are detectable 12-24 hours after birth (Hallam et al. 2005). If the infant is left untreated, the physical ramification of the acute leucinemia (leucine poisoning) and ketonuria (ketoacid poisoning) can cause vomiting, dehydration, lethargy, seizures, pancreatitis, coma, and eventually
death.
GENETIC PREVELANCE MSUD is passed on as an autosomal recessive gene. This means the defective gene is located on an autosome and one copy of the gene must be received from each parent. Although worldwide the condition only effects approximately 1/180,000 infants born, much higher rates of the disease have been found in populations of Amish, Mennonite, and Jewish communities. As an example, Mennonite populations of Pennsylvania, Kentucky, New York, Indiana, Wisconsin, Michigan, Iowa, and Missouri have been found to have an average MSUD affected infant rate of 1/380 and have been found as high as 1/10 (Jaworski et al. 1989). This high rate in specific populations is due to the founder effect, which is the loss of genetic variation due to establishment of a large population by very few individuals.
ETHICAL ISSUES One ethical issue which has come about indirectly from MSUD is the use of outsiders to prevent genetic disease. Amish communities have long since been plagued by numerous genetic disorders including dwarfism, alzheimers, macular degeneration, and many metabolic disorders the deadliest of which is MSUD (McKushick and Victor 2012). Due to the prevalence of these genetic diseases, community members have pushed for what is called “new bloodlines”. The continuous rise of unhealthy children due to inbreeding has pushed Amish women to find non-Amish men to negate the influence of the poor gene pool hence “new bloodlines”. This has caused a division in the Amish community between those who ban this method and those who advocate it for the health of their children. In conclusion, maple syrup urine disease is a rare and fatal disease if left untreated. Although the prevalence of this disorder is rare among the general public, it still plagues specific communities due to the founder effect. This fatal disease, however, is easily treatable if spotted early and cared for with precision. Overall this genetic disorder has been understood for some time, yet still remains to be an interesting and terrible affliction.
References:
Podebrad, F., M. Heil, S. Reichert, A. Mosandl, A.C. Sewell, and H. Bohles., 1999 4,5-Dimethyl-3-hydroxy-2[5H]-furanone (sotolone) — The Odour of Maple Syrup Urine Disease. Journal of Inherited Metabolic Disease 22.2: 107-14. Print.
Strauss, Kevin A., MD, Erik G. Puffenberger, PhD, and D. Holmes Morton, MD., 2013 Maple Syrup Urine Disease. GeneReviews,. Web. .
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.
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. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics (5th ed.). Elsevier Health Sciences. p. 2062. ISBN 978-1-4160-6164-9.
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
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
McKushick, Victor., 2013 Medical Genetic Research on the Amish: From Genetic Tourism to Community Health Centers. Albert Einstein College of Medicine 28.1: n. pag. Print.
Branched-chain Ketoaciduria (Maple Syrup Urine Disease), and Its Effect on the Breakdown of Amino Acids in the Human Body
David Holkesvik
INTRODUCTION: Branched-chain ketoaciduria, more commonly known as Maple syrup urine disease (MSUD) is a metabolic disorder that causes toxic buildup of un-broken down branched-chain amino acids or ketoacids. Passed on autosomal recessively, mutations in specific genes hinder or stop the enzyme complex responsible for normal breakdown of three amino acids found in protein-rich foods from working. The buildup of these toxic ketoacids leads to brain damage and eventually death in the affected infant if left untreated (Ogier de Baulny and Saudubray 2002). Although relatively rare in the general …show more content…
population (1/185,000 live births), prevalence in certain ethnic populations are much higher due the founder effect (as high as 1/10). This review will cover the causes, diagnosis/symptoms, genetic prevalence, and ethical issues regarding MSUD.
CAUSES:
MSUD stems from a disruption of the branched-chain alpha-keto acid dehydrogenase complex. This complex, consisting of four subunits E1α, E1β, E2, and E3, is responsible for the breakdown the amino acids leucine, isoleucine, and valine, which exist in many protein-rich foods. The four subunits of the complex are coded by the genes BCKDHA, BCKDHB, DBT, and DLD. Each of these genes code for a single subunit, and any mutation occurring in both alleles encoding a subunit will result in the disorder (Podebrad et al 1999). No other phenotype has been known to be associated with these mutations. Although the most common mutation is found on the BCKDHA gene on the 19th chromosome, mutations on any of the four genes result in indistinguishable consequences (Strauss et al. 2013). In other words, a mutation on any one of the genes translates to a non-functional branched-chain alpha-ketoacid dehydrogenase complex that does not produce the necessary enzymes for normal breakdown of protiens.
DIAGNOSIS/SYMPTOMS
There are a few, relatively easy ways to test for MSUD.
However if an affected child is not diagnosed within 7-10 days coma, and central respiratory failure is imminent. Since all diagnoses are made on newborn children finding of this genetic disease relies on completely on physical irregularities. The most obvious way to tell is by the smell of the infant’s urine which has a distinct sweet smell (hence maple syrup urine disease) due to the excess amount of ketoacids in the urine (Pasquali and Marzia. 2011). The sweet smell in the urine is usually detectable 12 hours after birth and is the first sign the child is affected. Another, perhaps more modern, method of diagnosis is testing plasma for elevated concentrations of branched-chain amino acids (leucine, isoleucine, and valine) using quantitative plasma amino acid analysis. This technique simply compares the ratios of the three possibly affected amino acids to other essential and non-essential amino acids and look for irregularities. The elevated levels of leucine, isoleucine, and valine are detectable 12-24 hours after birth (Hallam et al. 2005). If the infant is left untreated, the physical ramification of the acute leucinemia (leucine poisoning) and ketonuria (ketoacid poisoning) can cause vomiting, dehydration, lethargy, seizures, pancreatitis, coma, and eventually
death.
GENETIC PREVELANCE MSUD is passed on as an autosomal recessive gene. This means the defective gene is located on an autosome and one copy of the gene must be received from each parent. Although worldwide the condition only effects approximately 1/180,000 infants born, much higher rates of the disease have been found in populations of Amish, Mennonite, and Jewish communities. As an example, Mennonite populations of Pennsylvania, Kentucky, New York, Indiana, Wisconsin, Michigan, Iowa, and Missouri have been found to have an average MSUD affected infant rate of 1/380 and have been found as high as 1/10 (Jaworski et al. 1989). This high rate in specific populations is due to the founder effect, which is the loss of genetic variation due to establishment of a large population by very few individuals.
ETHICAL ISSUES One ethical issue which has come about indirectly from MSUD is the use of outsiders to prevent genetic disease. Amish communities have long since been plagued by numerous genetic disorders including dwarfism, alzheimers, macular degeneration, and many metabolic disorders the deadliest of which is MSUD (McKushick and Victor 2012). Due to the prevalence of these genetic diseases, community members have pushed for what is called “new bloodlines”. The continuous rise of unhealthy children due to inbreeding has pushed Amish women to find non-Amish men to negate the influence of the poor gene pool hence “new bloodlines”. This has caused a division in the Amish community between those who ban this method and those who advocate it for the health of their children. In conclusion, maple syrup urine disease is a rare and fatal disease if left untreated. Although the prevalence of this disorder is rare among the general public, it still plagues specific communities due to the founder effect. This fatal disease, however, is easily treatable if spotted early and cared for with precision. Overall this genetic disorder has been understood for some time, yet still remains to be an interesting and terrible affliction.
References:
Podebrad, F., M. Heil, S. Reichert, A. Mosandl, A.C. Sewell, and H. Bohles., 1999 4,5-Dimethyl-3-hydroxy-2[5H]-furanone (sotolone) — The Odour of Maple Syrup Urine Disease. Journal of Inherited Metabolic Disease 22.2: 107-14. Print.
Strauss, Kevin A., MD, Erik G. Puffenberger, PhD, and D. Holmes Morton, MD., 2013 Maple Syrup Urine Disease. GeneReviews,. Web. .
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.
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. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics (5th ed.). Elsevier Health Sciences. p. 2062. ISBN 978-1-4160-6164-9.
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
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
McKushick, Victor., 2013 Medical Genetic Research on the Amish: From Genetic Tourism to Community Health Centers. Albert Einstein College of Medicine 28.1: n. pag. Print.