Overview of maple syrup urine disease
- Olaf A Bodamer, MD, PhD, FAAP, FACMG
Olaf A Bodamer, MD, PhD, FAAP, FACMG
- Park Gerald Chair in Genetics and Genomics
- Associate Chief, Genetics and Genomics
- Boston Children’s Hospital/Harvard Medical School
Maple syrup urine disease (MSUD, MIM #248600) also known as branched-chain ketoaciduria, is a disorder affecting the aliphatic or branched-chain amino acids. It is caused by a deficiency of branched-chain alpha-ketoacid dehydrogenase complex (BCKDC), the second enzyme of the metabolic pathway of the three branched-chain amino acids, leucine, isoleucine, and valine. It is characterized by psychomotor delay, feeding problems, and a maple syrup odor of the urine.
MSUD is reviewed here. A general discussion of amino acid disorders is presented separately. (See "Inborn errors of metabolism: Classification".)
MSUD occurs in approximately 1 in 86,800 to 185,000 live births [1-3]. It occurs more frequently in populations with an increased frequency of consanguinity, such as the Mennonites in Pennsylvania, where the incidence is as high as 1 in 200 births .
The branched-chain amino acids, leucine, isoleucine, and valine, are essential amino acids with hydrophobic side chains and are important precursors for gluconeogenesis, energy production, and synthesis of fatty acids and cholesterol .
In the first step of branched-chain metabolism, branched-chain amino acids are converted by cytosolic and mitochondrial branched-chain aminotransferases (BCATs) to their respective alpha-ketoacids. The alpha-ketoacids are subsequently decarboxylated by the branched-chain ketoacid dehydrogenase complex (BCKDC) to yield isovaleryl-coenzyme A (CoA), alpha-methylbutyryl-CoA, and isobutyrl-CoA, respectively, which eventually result in acetyl-CoA, acetoacetate, and succinyl-CoA (figure 1) [5,6].
Subscribers log in hereLiterature review current through: May 2017. | This topic last updated: Aug 16, 2016.References
- Naylor EW. Newborn screening in maple syrup urine disease (branched-chain ketoaciduria). In: Neonatal screening for inborn errors of metabolism, Bickel H, Guthrie R, Hammersen G (Eds), Springer Verlag, Berlin 1980. p.19.
- Chuang DT, Shih VE. Maple syrup urine disease (branched-chain ketoaciduria). In: The metabolic and molecular bases of inherited disease, 8th ed, Scriver CR, Beaudet AL, Sly WS, Valle D (Eds), McGraw-Hill, New York 2001. p.1971.
- Quental S, Vilarinho L, Martins E, et al. Incidence of maple syrup urine disease in Portugal. Mol Genet Metab 2010; 100:385.
- Morton DH, Strauss KA, Robinson DL, et al. Diagnosis and treatment of maple syrup disease: a study of 36 patients. Pediatrics 2002; 109:999.
- 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; 23:R1.
- Brosnan JT, Brosnan ME. Branched-chain amino acids: enzyme and substrate regulation. J Nutr 2006; 136:207S.
- Wang XL, Li CJ, Xing Y, et al. Hypervalinemia and hyperleucine-isoleucinemia caused by mutations in the branched-chain-amino-acid aminotransferase gene. J Inherit Metab Dis 2015; 38:855.
- Jeune M, Collombel C, Michel M, et al. [Hyperleucinisoleucinemia due to partial transamination defect associated with type 2 hyperprolinemia. Familial case of double aminoacidopathy]. Ann Pediatr (Paris) 1970; 17:349.
- Chuang DT. Maple syrup urine disease: it has come a long way. J Pediatr 1998; 132:S17.
- Scaini G, Morais MO, Galant LS, et al. Coadministration of branched-chain amino acids and lipopolysaccharide causes matrix metalloproteinase activation and blood-brain barrier breakdown. Mol Neurobiol 2014; 50:358.
- Korein J, Sansaricq C, Kalmijn M, et al. Maple syrup urine disease: clinical, EEG, and plasma amino acid correlations with a theoretical mechanism of acute neurotoxicity. Int J Neurosci 1994; 79:21.
- Zhang B, Zhao Y, Harris RA, Crabb DW. Molecular defects in the E1 alpha subunit of the branched-chain alpha-ketoacid dehydrogenase complex that cause maple syrup urine disease. Mol Biol Med 1991; 8:39.
- Patel MS, Harris RA. Mammalian alpha-keto acid dehydrogenase complexes: gene regulation and genetic defects. FASEB J 1995; 9:1164.
- Chuang DT, Shih VE. Disorders of branched chain amino acid and keto acid metabolism. In: The metabolic and molecular bases of inherited disease, Scriver CR, Beaudet AL, Sly WS, Valle D (Eds), McGraw-Hill, New York 2001.
- Fisher CW, Chuang JL, Griffin TA, et al. 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. J Biol Chem 1989; 264:3448.
- Puffenberger EG. Genetic heritage of the Old Order Mennonites of southeastern Pennsylvania. Am J Med Genet C Semin Med Genet 2003; 121C:18.
- Oyarzabal A, Martínez-Pardo M, Merinero B, et al. 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; 34:355.
- Manara R, Del Rizzo M, Burlina AP, et al. Wernicke-like encephalopathy during classic maple syrup urine disease decompensation. J Inherit Metab Dis 2012; 35:413.
- Simon E, Flaschker N, Schadewaldt P, et al. Variant maple syrup urine disease (MSUD)--the entire spectrum. J Inherit Metab Dis 2006; 29:716.
- Scriver CR, Mackenzie S, Clow CL, Delvin E. Thiamine-responsive maple-syrup-urine disease. Lancet 1971; 1:310.
- Shaag A, Saada A, Berger I, et al. Molecular basis of lipoamide dehydrogenase deficiency in Ashkenazi Jews. Am J Med Genet 1999; 82:177.
- Oglesbee D, Sanders KA, Lacey JM, et al. Second-tier test for quantification of alloisoleucine and branched-chain amino acids in dried blood spots to improve newborn screening for maple syrup urine disease (MSUD). Clin Chem 2008; 54:542.
- Bhattacharya K, Khalili V, Wiley V, et al. Newborn screening may fail to identify intermediate forms of maple syrup urine disease. J Inherit Metab Dis 2006; 29:586.
- Puckett RL, Lorey F, Rinaldo P, et al. Maple syrup urine disease: further evidence that newborn screening may fail to identify variant forms. Mol Genet Metab 2010; 100:136.
- Frazier DM, Allgeier C, Homer C, et al. Nutrition management guideline for maple syrup urine disease: an evidence- and consensus-based approach. Mol Genet Metab 2014; 112:210.
- Hoffmann B, Helbling C, Schadewaldt P, Wendel U. Impact of longitudinal plasma leucine levels on the intellectual outcome in patients with classic MSUD. Pediatr Res 2006; 59:17.
- Gouyon JB, Semama D, Prévot A, Desgres J. Removal of branched-chain amino acids and alpha-ketoisocaproate by haemofiltration and haemodiafiltration. J Inherit Metab Dis 1996; 19:610.
- Jouvet P, Poggi F, Rabier D, et al. Continuous venovenous haemodiafiltration in the acute phase of neonatal maple syrup urine disease. J Inherit Metab Dis 1997; 20:463.
- Dixon MA, Leonard JV. Intercurrent illness in inborn errors of intermediary metabolism. Arch Dis Child 1992; 67:1387.
- Puliyanda DP, Harmon WE, Peterschmitt MJ, et al. Utility of hemodialysis in maple syrup urine disease. Pediatr Nephrol 2002; 17:239.
- Suryawan A, Hawes JW, Harris RA, et al. A molecular model of human branched-chain amino acid metabolism. Am J Clin Nutr 1998; 68:72.
- Wendel U, Saudubray JM, Bodner A, Schadewaldt P. Liver transplantation in maple syrup urine disease. Eur J Pediatr 1999; 158 Suppl 2:S60.
- Bodner-Leidecker A, Wendel U, Saudubray JM, Schadewaldt P. Branched-chain L-amino acid metabolism in classical maple syrup urine disease after orthotopic liver transplantation. J Inherit Metab Dis 2000; 23:805.
- Mazariegos GV, Morton DH, Sindhi R, et al. Liver transplantation for classical maple syrup urine disease: long-term follow-up in 37 patients and comparative United Network for Organ Sharing experience. J Pediatr 2012; 160:116.
- Squires RH, Ng V, Romero R, et al. Evaluation of the pediatric patient for liver transplantation: 2014 practice guideline by the American Association for the Study of Liver Diseases, American Society of Transplantation and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Hepatology 2014; 60:362.
- Strauss KA, Mazariegos GV, Sindhi R, et al. Elective liver transplantation for the treatment of classical maple syrup urine disease. Am J Transplant 2006; 6:557.
- Shellmer DA, DeVito Dabbs A, Dew MA, et al. Cognitive and adaptive functioning after liver transplantation for maple syrup urine disease: a case series. Pediatr Transplant 2011; 15:58.
- Díaz VM, Camarena C, de la Vega Á, et al. Liver transplantation for classical maple syrup urine disease: long-term follow-up. J Pediatr Gastroenterol Nutr 2014; 59:636.
- Sundaram SS, Alonso EM, Whitington PF. Liver transplantation in neonates. Liver Transpl 2003; 9:783.
- Van Calcar SC, Harding CO, Davidson SR, et al. Case reports of successful pregnancy in women with maple syrup urine disease and propionic acidemia. Am J Med Genet 1992; 44:641.
- Grünewald S, Hinrichs F, Wendel U. Pregnancy in a woman with maple syrup urine disease. J Inherit Metab Dis 1998; 21:89.
- Wessel AE, Mogensen KM, Rohr F, et al. Management of a Woman With Maple Syrup Urine Disease During Pregnancy, Delivery, and Lactation. JPEN J Parenter Enteral Nutr 2015; 39:875.
- CLINICAL FEATURES
- Classic MSUD
- Intermediate MSUD
- Intermittent MSUD
- Thiamine-responsive MSUD
- E3-deficient MSUD
- Prenatal diagnosis
- Newborn screening
- DIFFERENTIAL DIAGNOSIS
- Dietary therapy
- Metabolic decompensation
- Liver transplantation