Abstract
Branched-chain amino acids (leucine, isoleucine and valine) are structurally related to branched-chain fatty acids. Leucine is 2-amino-4-methyl-pentanoic acid, isoleucine is 2-amino-3-methyl-pentanoic acid, and valine is 2-amino-3-methyl-butanoic acid. Similar to fatty acid oxidation, leucine and isoleucine produce acetyl-coA. Additionally, leucine generates acetoacetate and isoleucine yields propionyl-coA. Valine oxidation produces propionyl-coA, which is converted into methylmalonyl-coA and succinyl-coA. Branched-chain aminotransferase catalyzes the first reaction in the catabolic pathway of branched-chain amino acids, a reversible transamination that converts branched-chain amino acids into branched-chain ketoacids. Simultaneously, glutamate is converted in 2-ketoglutarate. The branched-chain ketoacid dehydrogenase complex catalyzes the irreversible oxidative decarboxylation of branched-chain ketoacids to produce branched-chain acyl-coA intermediates, which then follow separate catabolic pathways. Human tissue distribution and function of most of the enzymes involved in branched-chain amino acid catabolism is unknown. Congenital deficiencies of the enzymes involved in branched-chain amino acid metabolism are generally rare disorders. Some of them are associated with reduced pyruvate dehydrogenase complex activity and respiratory chain dysfunction that may contribute to their clinical phenotype. The biochemical phenotype is characterized by accumulation of the substrate to the deficient enzyme and its carnitine and/or glycine derivatives. It was established at the beginning of the twentieth century that the plasma level of the branched-chain amino acids is increased in conditions associated with insulin resistance such as obesity and diabetes mellitus. However, the potential clinical relevance of this elevation is uncertain.
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Akagawa S, Fukao T, Akagawa Y, Sasai H, Kohdera U, Kino M, Shigematsu Y, Aoyama Y, Kaneko K (2016) Japanese male siblings with 2-methyl-3-hydroxybutyryl-coa dehydrogenase deficiency (HSD10 Disease) without neurological regression. JIMD Rep. doi:10.1007/8904_2016_570
Alfardan J, Mohsen AW, Copeland S, Ellison J, Keppen-Davis L, Rohrbach M, Powell BR, Gillis J, Matern D, Kant J, Vockley J (2010) Characterization of new ACADSB gene sequence mutations and clinical implications in patients with 2-methylbutyrylglycinuria identified by newborn screening. Mol Genet Metab 100(4):333–338. doi:10.1016/j.ymgme.2010.04.014
Andresen BS, Christensen E, Corydon TJ, Bross P, Pilgaard B, Wanders RJ, Ruiter JP, Simonsen H, Winter V, Knudsen I, Schroeder LD, Gregersen N, Skovby F (2000) Isolated 2-methylbutyrylglycinuria caused by short/branched-chain acyl-CoA dehydrogenase deficiency: identification of a new enzyme defect, resolution of its molecular basis, and evidence for distinct acyl-CoA dehydrogenases in isoleucine and valine metabolism. Am J Hum Genet 67(5):1095–1103. doi:10.1086/303105
Aoyama Y, Yamamoto T, Sakaguchi N, Ishige M, Tanaka T, Ichihara T, Ohara K, Kouzan H, Kinosada Y, Fukao T (2015) Application of multiplex ligation-dependent probe amplification, and identification of a heterozygous Alu-associated deletion and a uniparental disomy of chromosome 1 in two patients with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. Int J Mol Med 35(6):1554–1560. doi:10.3892/ijmm.2015.2184
Ashby EL, Kierzkowska M, Hull J, Kehoe PG, Hutson SM, Conway ME (2016) Altered expression of human mitochondrial branched chain aminotransferase in dementia with Lewy bodies and vascular dementia. Neurochem Res. doi:10.1007/s11064-016-1855-7
Axler O, Holmquist P (2014) Intermittent maple syrup urine disease: two case reports. Pediatrics 133(2):e458–e460. doi:10.1542/peds.2013-0427
Barash V, Mandel H, Sella S, Geiger R (1990) 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: biochemical studies and family investigation of four generations. J Inherit Metab Dis 13(2):156–164
Battaile KP, Nguyen TV, Vockley J, Kim JJ (2004) Structures of isobutyryl-CoA dehydrogenase and enzyme-product complex: comparison with isovaleryl- and short-chain acyl-CoA dehydrogenases. J Biol Chem 279(16):16526–16534. doi:10.1074/jbc.M400034200
Baumgartner MR, Almashanu S, Suormala T, Obie C, Cole RN, Packman S, Baumgartner ER, Valle D (2001) The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency. J Clin Investig 107(4):495–504. doi:10.1172/jci11948
Bledsoe RK, Dawson PA, Hutson SM (1997) Cloning of the rat and human mitochondrial branched chain aminotransferases (BCATm). Biochim Biophys Acta 1339(1):9–13
Bodner-Leidecker A, Wendel U, Saudubray JM, Schadewaldt P (2000) Branched-chain l-amino acid metabolism in classical maple syrup urine disease after orthotopic liver transplantation. J Inherit Metab Dis 23(8):805–818
Borthwick JA, Ancellin N, Bertrand SM, Bingham RP, Carter PS, Chung CW, Churcher I, Dodic N, Fournier C, Francis PL, Hobbs A, Jamieson C, Pickett SD, Smith SE, Somers DO, Spitzfaden C, Suckling CJ, Young RJ (2016) Structurally diverse mitochondrial branched chain aminotransferase (BCATm) leads with varying binding modes identified by fragment screening. J Med Chem 59(6):2452–2467. doi:10.1021/acs.jmedchem.5b01607
Brunetti-Pierri N, Lanpher B, Erez A, Ananieva EA, Islam M, Marini JC, Sun Q, Yu C, Hegde M, Li J, Wynn RM, Chuang DT, Hutson S, Lee B (2011) Phenylbutyrate therapy for maple syrup urine disease. Hum Mol Genet 20(4):631–640. doi:10.1093/hmg/ddq507
Catanzano F, Ombrone D, Di Stefano C, Rossi A, Nosari N, Scolamiero E, Tandurella I, Frisso G, Parenti G, Ruoppolo M, Andria G, Salvatore F (2010) The first case of mitochondrial acetoacetyl-CoA thiolase deficiency identified by expanded newborn metabolic screening in Italy: the importance of an integrated diagnostic approach. J Inherit Metab Dis 33(Suppl 3):S91–S94. doi:10.1007/s10545-009-9028-3
Chambliss KL, Gray RG, Rylance G, Pollitt RJ, Gibson KM (2000) Molecular characterization of methylmalonate semialdehyde dehydrogenase deficiency. J Inherit Metab Dis 23(5):497–504
Chuang DT, Chuang JL, Wynn RM (2006) Lessons from genetic disorders of branched-chain amino acid metabolism. J Nutr 136(1 Suppl):243s–249s
Cloppenborg T, Janzen N, Wagner H, Steuerwald U, Peter M, Das A (2014) Application of a second-tier newborn screening assay for c5 isoforms. JIMD Rep 13:23–26. doi:10.1007/8904_2013_275
Daum RS, Scriver CR, Mamer OA, Delvin E, Lamm P, Goldman H (1973) An inherited disorder of isoleucine catabolism causing accumulation of alpha-methylacetoacetate and alpha-methyl-beta -hydroxybutyrate, and intermittent metabolic acidosis. Pediatr Res 7(3):149–160. doi:10.1203/00006450-197303000-00007
Ensenauer R, Niederhoff H, Ruiter JP, Wanders RJ, Schwab KO, Brandis M, Lehnert W (2002) Clinical variability in 3-hydroxy-2-methylbutyryl-CoA dehydrogenase deficiency. Ann Neurol 51(5):656–659. doi:10.1002/ana.10169
Ensenauer R, Vockley J, Willard JM, Huey JC, Sass JO, Edland SD, Burton BK, Berry SA, Santer R, Grunert S, Koch HG, Marquardt I, Rinaldo P, Hahn S, Matern D (2004) A common mutation is associated with a mild, potentially asymptomatic phenotype in patients with isovaleric acidemia diagnosed by newborn screening. Am J Hum Genet 75(6):1136–1142. doi:10.1086/426318
Erdem E, Cayonu N, Uysalol E, Yildirmak ZY (2010) Chronic intermittent form of isovaleric acidemia mimicking diabetic ketoacidosis. J Pediatr Endocrinol Metab 23(5):503–505
Ferdinandusse S, Waterham HR, Heales SJ, Brown GK, Hargreaves IP, Taanman JW, Gunny R, Abulhoul L, Wanders RJ, Clayton PT, Leonard JV, Rahman S (2013) HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase. Orphanet J Rare Dis 8:188. doi:10.1186/1750-1172-8-188
Ferdinandusse S, Friederich MW, Burlina A, Ruiter JP, Coughlin CR 2nd, Dishop MK, Gallagher RC, Bedoyan JK, Vaz FM, Waterham HR, Gowan K, Chatfield K, Bloom K, Bennett MJ, Elpeleg O, Van Hove JL, Wanders RJ (2015) Clinical and biochemical characterization of four patients with mutations in ECHS1. Orphanet J Rare Dis 10:79. doi:10.1186/s13023-015-0290-1
Forsyth R, Vockley CW, Edick MJ, Cameron CA, Hiner SJ, Berry SA, Vockley J, Arnold GL (2016) Outcomes of cases with 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency—report from the inborn errors of metabolism information system. Mol Genet Metab 118(1):15–20. doi:10.1016/j.ymgme.2016.02.002
Frazier DM, Allgeier C, Homer C, Marriage BJ, Ogata B, Rohr F, Splett PL, Stembridge A, Singh RH (2014) Nutrition management guideline for maple syrup urine disease: an evidence- and consensus-based approach. Mol Genet Metab 112(3):210–217. doi:10.1016/j.ymgme.2014.05.006
Fu Z, Runquist JA, Forouhar F, Hussain M, Hunt JF, Miziorko HM, Kim JJ (2006) Crystal structure of human 3-hydroxy-3-methylglutaryl-CoA Lyase: insights into catalysis and the molecular basis for hydroxymethylglutaric aciduria. J Biol Chem 281(11):7526–7532. doi:10.1074/jbc.M506880200
Fukao T, Scriver CR, Kondo N (2001) The clinical phenotype and outcome of mitochondrial acetoacetyl-CoA thiolase deficiency (beta-ketothiolase or T2 deficiency) in 26 enzymatically proved and mutation-defined patients. Mol Genet Metab 72(2):109–114. doi:10.1006/mgme.2000.3113
Fukao T, Horikawa R, Naiki Y, Tanaka T, Takayanagi M, Yamaguchi S, Kondo N (2010a) A novel mutation (c.951C>T) in an exonic splicing enhancer results in exon 10 skipping in the human mitochondrial acetoacetyl-CoA thiolase gene. Mol Genet Metab 100(4):339–344. doi:10.1016/j.ymgme.2010.03.012
Fukao T, Nguyen HT, Nguyen NT, Vu DC, Can NT, Pham AT, Nguyen KN, Kobayashi H, Hasegawa Y, Bui TP, Niezen-Koning KE, Wanders RJ, de Koning T, Nguyen LT, Yamaguchi S, Kondo N (2010b) A common mutation, R208X, identified in Vietnamese patients with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. Mol Genet Metab 100(1):37–41. doi:10.1016/j.ymgme.2010.01.007
Fukao T, Mitchell G, Sass JO, Hori T, Orii K, Aoyama Y (2014) Ketone body metabolism and its defects. J Inherit Metab Dis 37(4):541–551. doi:10.1007/s10545-014-9704-9
Ganetzky RD, Bloom K, Ahrens-Nicklas R, Edmondson A, Deardorff MA, Bennett MJ, Ficicioglu C (2016) ECHS1 deficiency as a cause of severe neonatal lactic acidosis. JIMD Rep 30:33–37. doi:10.1007/8904_2016_538
Gibson KM, Breuer J, Nyhan WL (1988) 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: review of 18 reported patients. Eur J Pediatr 148(3):180–186
Gilbert-Barness E, Barness LA (1999) Isovaleric acidemia with promyelocytic myeloproliferative syndrome. Pediatr Dev Pathol 2(3):286–291
Goto M, Miyahara I, Hirotsu K, Conway M, Yennawar N, Islam MM, Hutson SM (2005) Structural determinants for branched-chain aminotransferase isozyme-specific inhibition by the anticonvulsant drug gabapentin. J Biol Chem 280(44):37246–37256. doi:10.1074/jbc.M506486200
Grunert SC, Stucki M, Morscher RJ, Suormala T, Burer C, Burda P, Christensen E, Ficicioglu C, Herwig J, Kolker S, Moslinger D, Pasquini E, Santer R, Schwab KO, Wilcken B, Fowler B, Yue WW, Baumgartner MR (2012a) 3-methylcrotonyl-CoA carboxylase deficiency: clinical, biochemical, enzymatic and molecular studies in 88 individuals. Orphanet J Rare Dis 7:31. doi:10.1186/1750-1172-7-31
Grunert SC, Wendel U, Lindner M, Leichsenring M, Schwab KO, Vockley J, Lehnert W, Ensenauer R (2012b) Clinical and neurocognitive outcome in symptomatic isovaleric acidemia. Orphanet J Rare Dis 7:9. doi:10.1186/1750-1172-7-9
Haack TB, Jackson CB, Murayama K, Kremer LS, Schaller A, Kotzaeridou U, de Vries MC, Schottmann G, Santra S, Buchner B, Wieland T, Graf E, Freisinger P, Eggimann S, Ohtake A, Okazaki Y, Kohda M, Kishita Y, Tokuzawa Y, Sauer S, Memari Y, Kolb-Kokocinski A, Durbin R, Hasselmann O, Cremer K, Albrecht B, Wieczorek D, Engels H, Hahn D, Zink AM, Alston CL, Taylor RW, Rodenburg RJ, Trollmann R, Sperl W, Strom TM, Hoffmann GF, Mayr JA, Meitinger T, Bolognini R, Schuelke M, Nuoffer JM, Kolker S, Prokisch H, Klopstock T (2015) Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement. Ann Clin Transl Neurol 2(5):492–509. doi:10.1002/acn3.189
Holzinger A, Roschinger W, Lagler F, Mayerhofer PU, Lichtner P, Kattenfeld T, Thuy LP, Nyhan WL, Koch HG, Muntau AC, Roscher AA (2001) Cloning of the human MCCA and MCCB genes and mutations therein reveal the molecular cause of 3-methylcrotonyl-CoA: carboxylase deficiency. Hum Mol Genet 10(12):1299–1306
Hull J, Hindy ME, Kehoe PG, Chalmers K, Love S, Conway ME (2012) Distribution of the branched chain aminotransferase proteins in the human brain and their role in glutamate regulation. J Neurochem 123(6):997–1009. doi:10.1111/jnc.12044
Ijlst L, Loupatty FJ, Ruiter JP, Duran M, Lehnert W, Wanders RJ (2002) 3-Methylglutaconic aciduria type I is caused by mutations in AUH. Am J Hum Genet 71(6):1463–1466. doi:10.1086/344712
Indo Y, Kitano A, Endo F, Akaboshi I, Matsuda I (1987) Altered kinetic properties of the branched-chain alpha-keto acid dehydrogenase complex due to mutation of the beta-subunit of the branched-chain alpha-keto acid decarboxylase (E1) component in lymphoblastoid cells derived from patients with maple syrup urine disease. J Clin Investig 80(1):63–70. doi:10.1172/jci113064
Islam MM, Wallin R, Wynn RM, Conway M, Fujii H, Mobley JA, Chuang DT, Hutson SM (2007) A novel branched-chain amino acid metabolon. Protein-protein interactions in a supramolecular complex. J Biol Chem 282(16):11893–11903. doi:10.1074/jbc.M700198200
Janssen U, Davis EM, Le Beau MM, Stoffel W (1997) Human mitochondrial enoyl-CoA hydratase gene (ECHS1): structural organization and assignment to chromosome 10q26.2-q26.3. Genomics 40(3):470–475. doi:10.1006/geno.1996.4597
Kanavin OJ, Woldseth B, Jellum E, Tvedt B, Andresen BS, Stromme P (2007) 2-methylbutyryl-CoA dehydrogenase deficiency associated with autism and mental retardation: a case report. J Med Case Rep 1:98. doi:10.1186/1752-1947-1-98
Ko FJ, Nyhan WL, Wolff J, Barshop B, Sweetman L (1991) 3-Hydroxyisobutyric aciduria: an inborn error of valine metabolism. Pediatr Res 30(4):322–326. doi:10.1203/00006450-199110000-00006
Korman SH, Yang SY (2007) HSD17B10 replaces HADH2 as the approved designation for the gene mutated in 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency. Mol Genet Metab 91(1):115. doi:10.1016/j.ymgme.2007.01.001
Kurimoto K, Fukai S, Nureki O, Muto Y, Yokoyama S (2001) Crystal structure of human AUH protein, a single-stranded RNA binding homolog of enoyl-CoA hydratase. Structure 9(12):1253–1263
Lambrecht A, Pichard S, Maurey H, Segarra NG, Drunat S, Acquaviva-Bourdain C, Passemard S, Benoist JF, Fauret-Amsellem AL, Schiff M (2015) Angelman syndrome and isovaleric acidemia: what is the link? Mol Genet Metab Rep 3:36–38. doi:10.1016/j.ymgmr.2015.03.004
Leung AA, Chan AK, Ezekowitz JA, Leung AK (2009) A case of dilated cardiomyopathy associated with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) lyase deficiency. Case Rep Med 2009:183125. doi:10.1155/2009/183125
Litwer S, Herring WJ, Danner DJ (1989) Reversion of the maple syrup urine disease phenotype of impaired branched chain alpha-ketoacid dehydrogenase complex activity in fibroblasts from an affected child. J Biol Chem 264(25):14597–14600
Loupatty FJ, van der Steen A, Ijlst L, Ruiter JP, Ofman R, Baumgartner MR, Ballhausen D, Yamaguchi S, Duran M, Wanders RJ (2006) Clinical, biochemical, and molecular findings in three patients with 3-hydroxyisobutyric aciduria. Mol Genet Metab 87(3):243–248. doi:10.1016/j.ymgme.2005.09.019
Loupatty FJ, Clayton PT, Ruiter JP, Ofman R, Ijlst L, Brown GK, Thorburn DR, Harris RA, Duran M, Desousa C, Krywawych S, Heales SJ, Wanders RJ (2007) Mutations in the gene encoding 3-hydroxyisobutyryl-CoA hydrolase results in progressive infantile neurodegeneration. Am J Hum Genet 80(1):195–199. doi:10.1086/510725
Luis PB, Ruiter JP, Ijlst L, Tavares de Almeida I, Duran M, Mohsen AW, Vockley J, Wanders RJ, Silva MF (2011) Role of isovaleryl-CoA dehydrogenase and short branched-chain acyl-CoA dehydrogenase in the metabolism of valproic acid: implications for the branched-chain amino acid oxidation pathway. Drug Metab Dispos 39(7):1155–1160. doi:10.1124/dmd.110.037606
Mack M, Schniegler-Mattox U, Peters V, Hoffmann GF, Liesert M, Buckel W, Zschocke J (2006) Biochemical characterization of human 3-methylglutaconyl-CoA hydratase and its role in leucine metabolism. FEBS J 273(9):2012–2022. doi:10.1111/j.1742-4658.2006.05218.x
Maeda Y, Ito T, Ohmi H, Yokoi K, Nakajima Y, Ueta A, Kurono Y, Togari H, Sugiyama N (2008) Determination of 3-hydroxyisovalerylcarnitine and other acylcarnitine levels using liquid chromatography-tandem mass spectrometry in serum and urine of a patient with multiple carboxylase deficiency. J Chromatogr B Anal Technol Biomed Life Sci 870(2):154–159. doi:10.1016/j.jchromb.2007.11.037
Marcadier JL, Smith AM, Pohl D, Schwartzentruber J, Al-Dirbashi OY, Majewski J, Ferdinandusse S, Wanders RJ, Bulman DE, Boycott KM, Chakraborty P, Geraghty MT (2013) Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria. Orphanet J Rare Dis 8:98. doi:10.1186/1750-1172-8-98
Matsuda I, Nobukuni Y, Mitsubuchi H, Indo Y, Endo F, Asaka J, Harada A (1990) 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 172(2):646–651
Mazariegos GV, Morton DH, Sindhi R, Soltys K, Nayyar N, Bond G, Shellmer D, Shneider B, Vockley J, Strauss KA (2012) 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 160(1):116-21.e1. doi:10.1016/j.jpeds.2011.06.033
Mels CM, Jansen van Rensburg P, van der Westhuizen FH, Pretorius PJ, Erasmus E (2011) Increased excretion of c4-carnitine species after a therapeutic acetylsalicylic Acid dose: evidence for an inhibitory effect on short-chain Fatty Acid metabolism. ISRN Pharmacol 2011:851870. doi:10.5402/2011/851870
Minkler PE, Stoll MS, Ingalls ST, Kerner J, Hoppel CL (2015) Quantitative acylcarnitine determination by UHPLC-MS/MS—going beyond tandem MS acylcarnitine “profiles”. Mol Genet Metab 116(4):231–241. doi:10.1016/j.ymgme.2015.10.002
Mitchell GA, Robert MF, Hruz PW, Wang S, Fontaine G, Behnke CE, Mende-Mueller LM, Schappert K, Lee C, Gibson KM, Miziorko HM (1993) 3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL). Cloning of human and chicken liver HL cDNAs and characterization of a mutation causing human HL deficiency. J Biol Chem 268(6):4376–4381
Mock DM, Stratton SL, Horvath TD, Bogusiewicz A, Matthews NI, Henrich CL, Dawson AM, Spencer HJ, Owen SN, Boysen G, Moran JH (2011) Urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine increases in response to a leucine challenge in marginally biotin-deficient humans. J Nutr 141(11):1925–1930. doi:10.3945/jn.111.146126
Molloy AM, Pangilinan F, Mills JL, Shane B, O’Neill MB, McGaughey DM, Velkova A, Abaan HO, Ueland PM, McNulty H, Ward M, Strain JJ, Cunningham C, Casey M, Cropp CD, Kim Y, Bailey-Wilson JE, Wilson AF, Brody LC (2016) A common polymorphism in HIBCH influences methylmalonic acid concentrations in blood independently of cobalamin. Am J Hum Genet 98(5):869–882. doi:10.1016/j.ajhg.2016.03.005
Nakagawa J, Waldner H, Meyer-Monard S, Hofsteenge J, Jeno P, Moroni C (1995) AUH, a gene encoding an AU-specific RNA binding protein with intrinsic enoyl-CoA hydratase activity. Proc Natl Acad Sci USA 92(6):2051–2055
Nguyen TV, Andresen BS, Corydon TJ, Ghisla S, Abd-El Razik N, Mohsen AW, Cederbaum SD, Roe DS, Roe CR, Lench NJ, Vockley J (2002) Identification of isobutyryl-CoA dehydrogenase and its deficiency in humans. Mol Genet Metab 77(1–2):68–79
Nobukuni Y, Mitsubuchi H, Endo F, Matsuda I (1989) Complete primary structure of the transacylase (E2b) subunit of the human branched chain alpha-keto acid dehydrogenase complex. Biochem Biophys Res Commun 161(3):1035–1041
Nobukuni Y, Mitsubuchi H, Akaboshi I, Indo Y, Endo F, Yoshioka A, Matsuda I (1991) Maple syrup urine disease. Complete defect of the E1 beta subunit of the branched chain alpha-ketoacid dehydrogenase complex due to a deletion of an 11-bp repeat sequence which encodes a mitochondrial targeting leader peptide in a family with the disease. J Clin Invest 87(5):1862–1866. doi:10.1172/JCI115209
Novarino G, El-Fishawy P, Kayserili H, Meguid NA, Scott EM, Schroth J, Silhavy JL, Kara M, Khalil RO, Ben-Omran T, Ercan-Sencicek AG, Hashish AF, Sanders SJ, Gupta AR, Hashem HS, Matern D, Gabriel S, Sweetman L, Rahimi Y, Harris RA, State MW, Gleeson JG (2012) Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science 338(6105):394–397. doi:10.1126/science.1224631
Ofman R, Ruiter JP, Feenstra M, Duran M, Poll-The BT, Zschocke J, Ensenauer R, Lehnert W, Sass JO, Sperl W, Wanders RJ (2003) 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency is caused by mutations in the HADH2 gene. Am J Hum Genet 72(5):1300–1307
Oglesbee D, He M, Majumder N, Vockley J, Ahmad A, Angle B, Burton B, Charrow J, Ensenauer R, Ficicioglu CH, Keppen LD, Marsden D, Tortorelli S, Hahn SH, Matern D (2007) Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency. Genet Med 9(2):108–116. doi:10.1097/GIM.0b013e31802f78d6
Otulakowski G, Robinson BH (1987) Isolation and sequence determination of cDNA clones for porcine and human lipoamide dehydrogenase. Homology to other disulfide oxidoreductases. J Biol Chem 262(36):17313–17318
Pena L, Angle B, Burton B, Charrow J (2012) Follow-up of patients with short-chain acyl-CoA dehydrogenase and isobutyryl-CoA dehydrogenase deficiencies identified through newborn screening: one center’s experience. Genet Med 14(3):342–347. doi:10.1038/gim.2011.9
Peters H, Buck N, Wanders R, Ruiter J, Waterham H, Koster J, Yaplito-Lee J, Ferdinandusse S, Pitt J (2014) ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism. Brain 137(Pt 11):2903–2908. doi:10.1093/brain/awu216
Peters H, Ferdinandusse S, Ruiter JP, Wanders RJ, Boneh A, Pitt J (2015) Metabolite studies in HIBCH and ECHS1 defects: implications for screening. Mol Genet Metab 115(4):168–173. doi:10.1016/j.ymgme.2015.06.008
Rhead WJ, Tanaka K (1980) Demonstration of a specific mitochondrial isovaleryl-CoA dehydrogenase deficiency in fibroblasts from patients with isovaleric acidemia. Proc Natl Acad Sci USA 77(1):580–583
Robinson BH, Sherwood WG, Taylor J, Balfe JW, Mamer OA (1979) Acetoacetyl CoA thiolase deficiency: a cause of severe ketoacidosis in infancy simulating salicylism. J Pediatr 95(2):228–233
Roe CR, Millington DS, Maltby DA (1986) Identification of 3-methylglutarylcarnitine. A new diagnostic metabolite of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency. J Clin Invest 77(4):1391–1394. doi:10.1172/jci112446
Roe CR, Cederbaum SD, Roe DS, Mardach R, Galindo A, Sweetman L (1998a) Isolated isobutyryl-CoA dehydrogenase deficiency: an unrecognized defect in human valine metabolism. Mol Genet Metab 65(4):264–271. doi:10.1006/mgme.1998.2758
Roe CR, Struys E, Kok RM, Roe DS, Harris RA, Jakobs C (1998b) Methylmalonic semialdehyde dehydrogenase deficiency: psychomotor delay and methylmalonic aciduria without metabolic decompensation. Mol Genet Metab 65(1):35–43. doi:10.1006/mgme.1998.2737
Roschinger W, Millington DS, Gage DA, Huang ZH, Iwamoto T, Yano S, Packman S, Johnston K, Berry SA, Sweetman L (1995) 3-Hydroxyisovalerylcarnitine in patients with deficiency of 3-methylcrotonyl CoA carboxylase. Clin Chim Acta 240(1):35–51
Sass JO, Ensenauer R, Roschinger W, Reich H, Steuerwald U, Schirrmacher O, Engel K, Haberle J, Andresen BS, Megarbane A, Lehnert W, Zschocke J (2008) 2-Methylbutyryl-coenzyme A dehydrogenase deficiency: functional and molecular studies on a defect in isoleucine catabolism. Mol Genet Metab 93(1):30–35. doi:10.1016/j.ymgme.2007.09.002
Sass JO, Walter M, Shield JP, Atherton AM, Garg U, Scott D, Woods CG, Smith LD (2012) 3-Hydroxyisobutyrate aciduria and mutations in the ALDH6A1 gene coding for methylmalonate semialdehyde dehydrogenase. J Inherit Metab Dis 35(3):437–442. doi:10.1007/s10545-011-9381-x
Schottmann G, Sarpong A, Lorenz C, Weinhold N, Gill E, Teschner L, Ferdinandusse S, Wanders RJ, Prigione A, Schuelke M (2016) A movement disorder with dystonia and ataxia caused by a mutation in the HIBCH gene. Mov Disord 31(11):1733–1739. doi:10.1002/mds.26704
Seaver LH, He XY, Abe K, Cowan T, Enns GM, Sweetman L, Philipp M, Lee S, Malik M, Yang SY (2011) A novel mutation in the HSD17B10 gene of a 10-year-old boy with refractory epilepsy, choreoathetosis and learning disability. PLoS One 6(11):e27348. doi:10.1371/journal.pone.0027348
She P, Van Horn C, Reid T, Hutson SM, Cooney RN, Lynch CJ (2007) Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism. Am J Physiol Endocrinol Metab 293(6):E1552–E1563. doi:10.1152/ajpendo.00134.2007
Stiles AR, Ferdinandusse S, Besse A, Appadurai V, Leydiker KB, Cambray-Forker EJ, Bonnen PE, Abdenur JE (2015) Successful diagnosis of HIBCH deficiency from exome sequencing and positive retrospective analysis of newborn screening cards in two siblings presenting with Leigh’s disease. Mol Genet Metab 115(4):161–167. doi:10.1016/j.ymgme.2015.05.008
Suryawan A, Hawes JW, Harris RA, Shimomura Y, Jenkins AE, Hutson SM (1998) A molecular model of human branched-chain amino acid metabolism. Am J Clin Nutr 68(1):72–81
Tajima G, Sakura N, Yofune H, Dwi Bahagia Febriani A, Nishimura Y, Sakamoto A, Ono H, Shigematsu Y, Kobayashi M (2005) Establishment of a practical enzymatic assay method for determination of isovaleryl-CoA dehydrogenase activity using high-performance liquid chromatography. Clin Chim Acta 353(1–2):193–199. doi:10.1016/j.cccn.2004.11.007
Tanaka K, Budd MA, Efron ML, Isselbacher KJ (1966) Isovaleric acidemia: a new genetic defect of leucine metabolism. Proc Natl Acad Sci USA 56(1):236–242
Taniguchi K, Nonami T, Nakao A, Harada A, Kurokawa T, Sugiyama S, Fujitsuka N, Shimomura Y, Hutson SM, Harris RA, Takagi H (1996) The valine catabolic pathway in human liver: effect of cirrhosis on enzyme activities. Hepatology 24(6):1395–1398. doi:10.1002/hep.510240614
Tiffany KA, Roberts DL, Wang M, Paschke R, Mohsen AW, Vockley J, Kim JJ (1997) Structure of human isovaleryl-CoA dehydrogenase at 2.6 A resolution: structural basis for substrate specificity. Biochemistry 36(28):8455–8464. doi:10.1021/bi970422u
Tilbrook LK, Slater J, Agarwal A, Cyriac J (2008) An unusual cause of interference in a salicylate assay caused by mitochondrial acetoacetyl-CoA thiolase deficiency. Ann Clin Biochem 45(Pt 5):524–526. doi:10.1258/acb.2008.007202
Van Calcar SC, Baker MW, Williams P, Jones SA, Xiong B, Thao MC, Lee S, Yang MK, Rice GM, Rhead W, Vockley J, Hoffman G, Durkin MS (2013) Prevalence and mutation analysis of short/branched chain acyl-CoA dehydrogenase deficiency (SBCADD) detected on newborn screening in Wisconsin. Mol Genet Metab 110(1–2):111–115. doi:10.1016/j.ymgme.2013.03.021
Wang XL, Li CJ, Xing Y, Yang YH, Jia JP (2015) Hypervalinemia and hyperleucine-isoleucinemia caused by mutations in the branched-chain-amino-acid aminotransferase gene. J Inherit Metab Dis 38(5):855–861. doi:10.1007/s10545-015-9814-z
Wortmann SB, Kluijtmans LA, Sequeira S, Wevers RA, Morava E (2014) Leucine loading test is only discriminative for 3-methylglutaconic aciduria due to AUH defect. JIMD Rep 16:1–6. doi:10.1007/8904_2014_309
Wynn RM, Davie JR, Chuang JL, Cote CD, Chuang DT (1998) Impaired assembly of E1 decarboxylase of the branched-chain alpha-ketoacid dehydrogenase complex in type IA maple syrup urine disease. J Biol Chem 273(21):13110–13118
Wynn RM, Li J, Brautigam CA, Chuang JL, Chuang DT (2012) Structural and biochemical characterization of human mitochondrial branched-chain alpha-ketoacid dehydrogenase phosphatase. J Biol Chem 287(12):9178–9192. doi:10.1074/jbc.M111.314963
Yamada K, Aiba K, Kitaura Y, Kondo Y, Nomura N, Nakamura Y, Fukushi D, Murayama K, Shimomura Y, Pitt J, Yamaguchi S, Yokochi K, Wakamatsu N (2015) Clinical, biochemical and metabolic characterisation of a mild form of human short-chain enoyl-CoA hydratase deficiency: significance of increased N-acetyl-S-(2-carboxypropyl)cysteine excretion. J Med Genet 52(10):691–698. doi:10.1136/jmedgenet-2015-103231
Yang SY, He XY, Miller D (2007) HSD17B10: a gene involved in cognitive function through metabolism of isoleucine and neuroactive steroids. Mol Genet Metab 92(1–2):36–42. doi:10.1016/j.ymgme.2007.06.001
Yoo EH, Cho HJ, Ki CS, Lee SY (2007) Isobutyryl-CoA dehydrogenase deficiency with a novel ACAD8 gene mutation detected by tandem mass spectrometry newborn screening. Clin Chem Lab Med 45(11):1495–1497. doi:10.1515/cclm.2007.317
Yun JW, Jo KI, Woo HI, Lee SY, Ki CS, Kim JW, Song J, Lee DH, Lee YW, Park HD (2015) A novel ACAD8 mutation in asymptomatic patients with isobutyryl-CoA dehydrogenase deficiency and a review of the ACAD8 mutation spectrum. Clin Genet 87(2):196–198. doi:10.1111/cge.12350
Zschocke J, Ruiter JP, Brand J, Lindner M, Hoffmann GF, Wanders RJ, Mayatepek E (2000) Progressive infantile neurodegeneration caused by 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency: a novel inborn error of branched-chain fatty acid and isoleucine metabolism. Pediatr Res 48(6):852–855. doi:10.1203/00006450-200012000-00025
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Adeva-Andany, M.M., López-Maside, L., Donapetry-García, C. et al. Enzymes involved in branched-chain amino acid metabolism in humans. Amino Acids 49, 1005–1028 (2017). https://doi.org/10.1007/s00726-017-2412-7
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DOI: https://doi.org/10.1007/s00726-017-2412-7