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Advances and challenges in the treatment of branched-chain amino/keto acid metabolic defects

  • Branched-chain Amino Acids
  • Published:
Journal of Inherited Metabolic Disease

Summary

Disorders of branched-chain amino/keto acid metabolism encompass diverse entities, including maple syrup urine disease (MSUD), the ‘classical’ organic acidurias isovaleric acidemia (IVA), propionic acidemia (PA), methylmalonic acidemia (MMA) and, among others, rarely described disorders such as 2-methylbutyryl-CoA dehydrogenase deficiency (MBDD) or isobutyryl-CoA dehydrogenase deficiency (IBDD). Our focus in this review is to highlight the biochemical basis underlying recent advances and ongoing challenges of long-term conservative therapy including precursor/protein restriction, replenishment of deficient substrates, and the use of antioxidants and anaplerotic agents which refill the Krebs cycle. Ongoing clinical assessments of affected individuals in conjunction with monitoring of disease-specific biochemical parameters remain essential. It is likely that mass spectrometry-based ‘metabolomics’ may be a helpful tool in the future for studying complete biochemical profiles and diverse metabolic phenotypes. Prospective studies are needed to test the effectiveness of adjunct therapies such as antioxidants, ornithine-alpha-ketoglutarate (OKG) or creatine in addition to specialized diets and to optimize current therapeutic strategies in affected individuals. With the individual life-time risk and degree of severity being unknown in asymptomatic individuals with MBDD or IBDD, instructions regarding risks for metabolic stress and fasting avoidance along with clinical monitoring are reasonable interventions at the current time. Overall, it is apparent that carefully designed prospective clinical investigations and multicenter cohort-controlled trials are needed in order to leverage that knowledge into significant breakthroughs in treatment strategies and appropriate approaches.

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Abbreviations

AA:

Amino acid(s)

ACAD:

Acyl-CoA dehydrogenase

ACADSB:

Short/branched-chain acyl-CoA dehydrogenase

ArAA:

Aromatic amino acid(s)

BBB:

Blood-brain-barrier

BCAA:

Branched-chain amino acid(s)

CoA:

Coenzyme A

BCKDH:

Branched-chain alpha-keto acid dehydrogenase complex

DHA:

Docosahexaenoic acid

EFA:

Essential fatty acids

IBDD:

Isobutyryl-CoA dehydrogenase deficiency

iMSUD:

Intermediate MSUD

IVA:

Isovaleric acidemia

LNAA:

Large neutral amino acid(s)

MBDD:

2-Methylbutyryl-CoA dehydrogenase deficiency

MMA:

Methylmalonic acidemia

MSUD:

Maple syrup urine disease

MUT:

Methylmalonyl-CoA mutase

OKG:

Ornithine alpha-ketoglutarate

PA:

Propionic acidemia

PCCA:

Propionyl CoA carboxylase alpha polypeptide

References

  • Aldámiz-Echevarría L, Sanjurjo P, Elorz J, Prieto JA, Pérez C, Andrade F, Rodríguez-Soriano J (2006) Effect of docosahexaenoic acid administration on plasma lipid profile and metabolic parameters of children with methylmalonic acidaemia. J Inherit Metab Dis 29:58–63

    Article  PubMed  Google Scholar 

  • 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 100:333–338

    Article  PubMed  CAS  Google Scholar 

  • Amaral AU, Leipnitz G, Fernandes CG, Seminotti B, Schuck PF, Wajner M (2010) Alpha-Ketoisocaproic acid and leucine provoke mitochondrial bioenergetic dysfunction in rat brain. Brain Res 1324:75–84

    Article  PubMed  CAS  Google Scholar 

  • Arbeiter AK, Kranz B, Wingen AM, Bonzel KE, Dohna-Schwake C, Hanssler L, Neudorf U, Hoyer PF, Büscher R (2010) Continuous venovenous haemodialysis (CVVHD) and continuous peritoneal dialysis (CPD) in the acute management of 21 children with inborn errors of metabolism. Nephrol Dial Transplant 25:1257–1265

    Article  PubMed  Google Scholar 

  • Ballhausen D, Mittaz L, Boulat O, Bonafé L, Braissant O (2009) Evidence for catabolic pathway of propionate metabolism in CNS: expression pattern of methylmalonyl-CoA mutase and propionyl-CoA carboxylase alpha-subunit in developing and adult rat brain. Neuroscience 164:578–587

    Article  PubMed  CAS  Google Scholar 

  • Barschak AG, Sitta A, Deon M, Barden AT, Dutra-Filho CS, Wajner M, Vargas CR (2008) Oxidative stress in plasma from maple syrup urine disease patients during treatment. Metab Brain Dis 23:71–80

    Article  PubMed  CAS  Google Scholar 

  • Barschak AG, Sitta A, Deon M, Busanello EN, Coelho DM, Cipriani F, Dutra-Filho CS, Giugliani R, Wajner M, Vargas CR (2009) Amino acids levels and lipid peroxidation in maple syrup urine disease patients. Clin Biochem 42:462–466

    Article  PubMed  CAS  Google Scholar 

  • Barshes NR, Vanatta JM, Patel AJ, Carter BA, O'Mahony CA, Karpen SJ, Goss JA (2006) Evaluation and management of patients with propionic acidemia undergoing liver transplantation: a comprehensive review. Pediatr Transplant 10:773–781

    Article  PubMed  Google Scholar 

  • Brunengraber H, Roe CR (2006) Anaplerotic molecules: current and future. J Inherit Metab Dis 29:327–331

    Article  PubMed  Google Scholar 

  • 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 (2010) Phenylbutyrate therapy for maple syrup urine disease. Hum Mol Genet Nov 23 [Epub ahead of print]

  • Brusque AM, Borba Rosa R, Schuck PF, Dalcin KB, Ribeiro CA, Silva CG, Wannmacher CM, Dutra-Filho CS, Wyse AT, Briones P, Wajner M (2002) Inhibition of the mitochondrial respiratory chain complex activities in rat cerebral cortex by methylmalonic acid. Neurochem Int 40:593–601

    Article  PubMed  CAS  Google Scholar 

  • Carrillo-Carrasco N, Chandler RJ, Chandrasekaran S, Venditti CP (2010) Liver-directed recombinant adeno-associated viral gene delivery rescues a lethal mouse model of methylmalonic acidemia and provides long-term phenotypic correction. Hum Gene Ther 21:1147–1154

    Article  PubMed  CAS  Google Scholar 

  • Castorina M, Rigante D, Antuzzi D, Sciascia Cannizzaro G, Ricci R (2008) Different outcome in isovaleric acidemia might be related to unsatisfactory diet compliance. Scand J Gastroenterol 43:767–768

    Article  PubMed  Google Scholar 

  • Chandler RJ, Zerfas PM, Shanske S, Sloan J, Hoffmann V, DiMauro S, Venditti CP (2009) Mitochondrial dysfunction in mut methylmalonic acidemia. FASEB J 23:1252–1261

    Article  PubMed  CAS  Google Scholar 

  • Chandler RJ, Chandrasekaran S, Carrillo-Carrasco N, Senac JS, Hofherr S, Barry MA, Venditti CP (2010) Adeno-associated virus serotype 8 (AAV8) gene transfer rescues a neonatal lethal murine model of propionic acidemia. Hum Gene Ther Oct 15 [Epub ahead of print]

  • Cynober L (2004) Ornithine alpha-ketoglutarate as a potent precursor of arginine and nitric oxide: a new job for an old friend. J Nutr 134:2858S–2862S

    PubMed  CAS  Google Scholar 

  • De Keyzer Y, Valayannopoulos V, Benoist JF, Batteux F, Lacaille F, Hubert L, Chrétien D, Chadefeaux-Vekemans B, Niaudet P, Touati G, Munnich A, de Lonlay P (2009) Multiple OXPHOS deficiency in the liver, kidney, heart, and skeletal muscle of patients with methylmalonic aciduria and propionic aciduria. Pediatr Res 66:91–95

    Article  PubMed  Google Scholar 

  • Deodato F, Boenzi S, Santorelli FM, Dionisi-Vici C (2006) Methylmalonic and propionic aciduria. Am J Med Genet C Semin Med Genet 142C:104–112

    Article  PubMed  CAS  Google Scholar 

  • Dionisi-Vici C, Deodato F, Röschinger W, Rhead W, Wilcken B (2006) 'Classical' organic acidurias, propionic aciduria, methylmalonic aciduria and isovaleric aciduria: long-term outcome and effects of expanded newborn screening using tandem mass spectrometry. J Inherit Metab Dis 29:383–389

    Article  PubMed  CAS  Google Scholar 

  • Erdem E, Cayonu N, Uysalol E, Yildirmak ZY (2010) Chronic intermittent form of isovaleric acidemia mimicking diabetic ketoacidosis. J Pediatr Endocrinol Metab 23:503–505

    Article  PubMed  Google Scholar 

  • Finsterer J (2010) Treatment of mitochondrial disorders. Eur J Paediatr Neurol 14:29–44

    Article  PubMed  Google Scholar 

  • Gibson KM, Burlingame TG, Hogema B, Jakobs C, Schutgens RB, Millington D, Roe CR, Roe DS, Sweetman L, Steiner RD, Linck L, Pohowalla P, Sacks M, Kiss D, Rinaldo P, Vockley J (2000a) 2-Methylbutyryl-coenzyme A dehydrogenase deficiency: a new inborn error of L-isoleucine metabolism. Pediatr Res 47:830–833

    Article  CAS  Google Scholar 

  • Gibson KM, Ugarte M, Fukao T, Mitchell GA (2000b) Molecular and enzymatic methods for detection of genetic defects in distal pathways of branched-chain amino acid metabolism. Methods Enzymol 324:432–453

    Article  CAS  Google Scholar 

  • Gülçin I (2006) Antioxidant and antiradical activities of L-carnitine. Life Sci 78:803–811

    Article  PubMed  Google Scholar 

  • Homanics GE, Skvorak K, Ferguson C, Watkins S, Paul HS (2006) Production and characterization of murine models of classic and intermediate maple syrup urine disease. BMC Med Genet 31:7–33

    Google Scholar 

  • Hörster F, Garbade SF, Zwickler T, Aydin HI, Bodamer OA, Burlina AB, Das AM, De Klerk JB, Dionisi-Vici C, Geb S, Gökcay G, Guffon N, Maier EM, Morava E, Walter JH, Schwahn B, Wijburg FA, Lindner M, Grünewald S, Baumgartner MR, Kölker S (2009) Prediction of outcome in isolated methylmalonic acidurias: combined use of clinical and biochemical parameters. J Inherit Metab Dis 32:630–639

    Article  PubMed  Google Scholar 

  • Jouvet P, Rustin P, Taylor DL, Pocock JM, Felderhoff-Mueser U, Mazarakis ND, Sarraf C, Joashi U, Kozma M, Greenwood K, Edwards AD, Mehmet H (2000) Branched chain amino acids induce apoptosis in neural cells without mitochondrial membrane depolarization or cytochrome c release: implications for neurological impairment associated with maple syrup urine disease. Mol Biol Cell 11:1919–1932

    PubMed  CAS  Google Scholar 

  • 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 Reports 1:98

    Article  PubMed  Google Scholar 

  • Kao CH, Liu MY, Liu TT, Hsiao KJ, Cheng KH, Huang CH, Lin HY, Niu DM (2009) Growth hormone therapy in neonatal patients with methylmalonic acidemia. J Chin Med Assoc 72:462–467

    Google Scholar 

  • Koeberl DD, Young SP, Gregersen NS, Vockley J, Smith WE, Benjamin DK Jr, An Y, Weavil SD, Chaing SH, Bali D, McDonald MT, Kishnani PS, Chen YT, Millington DS (2003) Rare disorders of metabolism with elevated butyryl- and isobutyryl-carnitine detected by tandem mass spectrometry newborn screening. Pediatr Res 54:219–223

    Article  PubMed  CAS  Google Scholar 

  • Kölker S, Sauer SW, Surtees RA, Leonard JV (2006) The aetiology of neurological complications of organic acidaemias -a role for the blood-brain barrier. J Inherit Metab Dis 29:701–704

    Article  PubMed  Google Scholar 

  • Loots DT (2009) Abnormal tricarboxylic acid cycle metabolites in isovaleric acidaemia. J Inherit Metab Dis 32:403–411

    Article  PubMed  CAS  Google Scholar 

  • Loots DT, Erasmus E, Mienie LJ (2005) Identification of 19 new metabolites induced by abnormal amino acid conjugation in isovaleric acidemia. Clin Chem 51:1510–1512

    Article  PubMed  CAS  Google Scholar 

  • Martin-Requero A, Corkey BE, Cerdan S, Walajtys-Rode E, Parrilla RL, Williamson JR (1983) Interactions between alpha-ketoisovalerate metabolism and the pathways of gluconeogenesis and urea synthesis in isolated hepatocytes. J Biol Chem 258:3673–3681

    PubMed  CAS  Google Scholar 

  • Matern D, He M, Berry SA, Rinaldo P, Whitley CB, Madsen PP, van Calcar SC, Lussky RC, Andresen BS, Wolff JA, Vockley J (2003) Prospective diagnosis of 2-methylbutyryl-CoA dehydrogenase deficiency in the Hmong population by newborn screening using tandem mass spectrometry. Pediatrics 112:74–78

    Article  PubMed  Google Scholar 

  • Mazer LM, Yi SH, Singh RH (2010) Docosahexaenoic acid status in females of reproductive age with maple syrup urine disease. J Inherit Metab Dis 33:121–127

    Article  PubMed  CAS  Google Scholar 

  • Mc Guire PJ, Lim-Melia E, Diaz GA, Raymond K, Larkin A, Wasserstein MP, Sansaricq C (2008) Combined liver-kidney transplant for the management of methylmalonic aciduria: a case report and review of the literature. Mol Genet Metab 93:22–29

    Article  PubMed  CAS  Google Scholar 

  • Mc Guire PJ, Parikh A, Diaz GA (2009) Profiling of oxidative stress in patients with inborn errors of metabolism. Mol Genet Metab 98:173–180

    Article  PubMed  CAS  Google Scholar 

  • Miyazaki T, Ohura T, Kobayashi M, Shigematsu Y, Yamaguchi S, Suzuki Y, Hata I, Aoki Y, Yang X, Minjares C, Haruta I, Uto H, Ito Y, Müller U (2001) Fatal propionic acidemia in mice lacking propionyl-CoA carboxylase and its rescue by postnatal, liver-specific supplementation via a transgene. J Biol Chem 276:35995–35999

    Article  PubMed  CAS  Google Scholar 

  • Morton DH, Strauss KA, Robinson DL, Puffenberger EG, Kelley RI (2002) Diagnosis and treatment of maple syrup disease: a study of 36 patients. Pediatrics 109:999–1008

    Article  PubMed  Google Scholar 

  • Murín R, Hamprecht B (2008) Metabolic and regulatory roles of leucine in neural cells. Neurochem Res 33:279–284

    Article  PubMed  Google Scholar 

  • Nasser M, Javaheri H, Fedorowicz Z, Noorani Z (2009) Carnitine supplementation for inborn errors of metabolism. Cochrane Database Syst Res Apr 15:CD006659

    Google Scholar 

  • Ogier de Baulny H, Saudubray JM (2002) Branched-chain organic acidurias. Semin Neonatol 7:65–74

    Article  PubMed  CAS  Google Scholar 

  • 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 9:108–116

    Article  PubMed  CAS  Google Scholar 

  • Ribas GS, Manfredini V, de Mari JF, Wayhs CY, Vanzin CS, Biancini GB, Sitta A, Deon M, Wajner M, Vargas CR (2010) Reduction of lipid and protein damage in patients with disorders of propionate metabolism under treatment: a possible protective role of L-carnitine supplementation. Int J Dev Neurosci 28:127–132

    Article  PubMed  CAS  Google Scholar 

  • Ribeiro CA, Sgaravatti AM, Rosa RB, Schuck PF, Grando V, Schmidt AL, Ferreira GC, Perry ML, Dutra-Filho CS, Wajner M (2008) Inhibition of brain energy metabolism by the branched-chain amino acids accumulating in maple syrup urine disease. Neurochem Res 33:114–124

    Article  PubMed  CAS  Google Scholar 

  • Ribeiro CA, Leipnitz G, Amaral AU, de Bortoli G, Seminotti B, Wajner M (2009) Creatine administration prevents Na+, K+-ATPase inhibition induced by intracerebroventricular administration of isovaleric acid in cerebral cortex of young rats. Brain Res 1262:81–88

    Article  PubMed  CAS  Google Scholar 

  • Richard E, Jorge-Finnigan A, Garcia-Villoria J, Merinero B, Desviat LR, Gort L, Briones P, Leal F, Pérez-Cerdá C, Ribes A, Ugarte M, Pérez B, MMACHC Working Group (2009) Genetic and cellular studies of oxidative stress in methylmalonic aciduria (MMA) cobalamin deficiency type C (cblC) with homocystinuria (MMACHC). Hum Mutat 30:1558–1566

    Article  PubMed  CAS  Google Scholar 

  • Roe CR, Cederbaum SD, Roe DS, Mardach R, Galindo A, Sweetman L (1998) Isolated isobutyryl-CoA dehydrogenase deficiency: an unrecognized defect in human valine metabolism. Mol Genet Metab 65:264–271

    Article  PubMed  CAS  Google Scholar 

  • Sass JO, Ensenauer R, Röschinger W, Reich H, Steuerwald U, Schirrmacher O, Engel K, Häberle J, Andresen BS, Mégarbané 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 93:30–35

    Article  PubMed  CAS  Google Scholar 

  • Sass JO, Sander S, Zschocke J (2004) Isobutyryl-CoA dehydrogenase deficiency: isobutyrylglycinuria and ACAD8 gene mutations in two infants. J Inherit Metab Dis 27:741–745

    Article  PubMed  CAS  Google Scholar 

  • Saudubray JM, Nassogne MC, de Lonlay P, Touati G (2002) Clinical approach to inherited metabolic disorders in neonates: an overview. Semin Neonatol 7:3–15

    Article  PubMed  CAS  Google Scholar 

  • Sauer SW, Okun JG, Hoffmann GF, Koelker S, Morath MA (2008) Impact of short- and medium-chain organic acids, acylcarnitines, and acyl-CoAs on mitochondrial energy metabolism. Biochim Biophys Acta 1777:1276–1282

    Article  PubMed  CAS  Google Scholar 

  • Sauer SW, Opp S, Haarmann A, Okun JG, Kölker S, Morath MA (2009) Long-term exposure of human proximal tubule cells to hydroxycobalamin[c-lactam] as a possible model to study renal disease in methylmalonic acidurias. J Inherit Metab Dis 32:720–727

    Article  PubMed  CAS  Google Scholar 

  • Sauer SW, Opp S, Mahringer A, Kamiński MM, Thiel C, Okun JG, Fricker G, Morath MA, Kölker S (2010) Glutaric aciduria type I and methylmalonic aciduria: simulation of cerebral import and export of accumulating neurotoxic dicarboxylic acids in in vitro models of the blood-brain barrier and the choroid plexus. Biochim Biophys Acta 1802:552–560

    PubMed  CAS  Google Scholar 

  • Scholl-Bürgi S, Sass JO, Heinz-Erian P, Amann E, Haberlandt E, Albrecht U, Ertl C, Sigl SB, Lagler F, Rostasy K, Karall D (2010) Changes in plasma amino acid concentrations with increasing age in patients with propionic acidemia. Amino Acids 38:1473–1481

    Article  PubMed  Google Scholar 

  • Schuck PF, Rosa RB, Pettenuzzo LF, Sitta A, Wannmacher CM, Wyse AT, Wajner M (2004) Inhibition of mitochondrial creatine kinase activity from rat cerebral cortex by methylmalonic acid. Neurochem Int 45:661–667

    Article  PubMed  CAS  Google Scholar 

  • Schwab MA, Sauer SW, Okun JG, Nijtmans LG, Rodenburg RJ, van den Heuvel LP, Dröse S, Brandt U, Hoffmann GF, Ter Laak H, Kölker S, Smeitink JA (2006) Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins. Biochem J 398:107–112

    Article  PubMed  CAS  Google Scholar 

  • Simon E, Flaschker N, Schadewaldt P, Langenbeck U, Wendel U (2006) Variant maple syrup urine disease (MSUD)-the entire spectrum. J Inherit Metab Dis 29:716–724

    Article  PubMed  CAS  Google Scholar 

  • Skvorak KJ, Hager EJ, Arning E, Bottiglieri T, Paul HS, Strom SC, Homanics GE, Sun Q, Jansen EE, Jakobs C, Zinnanti WJ, Gibson KM (2009a) Hepatocyte transplantation (HTx) corrects selected neurometabolic abnormalities in murine intermediate maple syrup urine disease (iMSUD). Biochim Biophys Acta 1792:1004–1010

    CAS  Google Scholar 

  • Skvorak KJ, Paul HS, Dorko K, Marongiu F, Ellis E, Chace D, Ferguson C, Gibson KM, Homanics GE, Strom SC (2009b) Hepatocyte transplantation improves phenotype and extends survival in a murine model of intermediate maple syrup urine disease. Mol Ther 17:1266–1273

    Article  CAS  Google Scholar 

  • Solano AF, Leipnitz G, De Bortoli GM, Seminotti B, Amaral AU, Fernandes CG, Latini AS, Dutra-Filho CS, Wajner M (2008) Induction of oxidative stress by the metabolites accumulating in isovaleric acidemia in brain cortex of young rats. Free Radic Res 42:707–715

    Article  PubMed  CAS  Google Scholar 

  • Spiekerkoetter U, Lindner M, Santer R, Grotzke M, Baumgartner MR, Boehles H, Das A, Haase C, Hennermann JB, Karall D, de Klerk H, Knerr I, Koch HG, Plecko B, Röschinger W, Schwab KO, Scheible D, Wijburg FA, Zschocke J, Mayatepek E, Wendel U (2009) Treatment recommendations in long-chain fatty acid oxidation defects: consensus from a workshop. J Inherit Metab Dis 32:498–505

    Article  PubMed  CAS  Google Scholar 

  • Stewart PM, Walser M (1980) Failure of the normal ureagenic response to amino acids in organic acid-loaded rats. Proposed mechanism for the hyperammonemia of propionic and methylmalonic acidemia. J Clin Invest 66:484–492

    Article  PubMed  CAS  Google Scholar 

  • Strauss KA, Mazariegos GV, Sindhi R, Squires R, Finegold DN, Vockley G, Robinson DL, Hendrickson C, Virji M, Cropcho L, Puffenberger EG, McGhee W, Seward LM, Morton DH (2006) Elective liver transplantation for the treatment of classical maple syrup urine disease. Am J Transplant 6:557–564

    Article  PubMed  CAS  Google Scholar 

  • Strauss KA, Wardley B, Robinson D, Hendrickson C, Rider NL, Puffenberger EG, Shelmer D, Moser AB, Morton DH (2010) Classical maple syrup urine disease and brain development: principles of management and formula design. Mol Genet Metab 99:333–345

    Article  PubMed  CAS  Google Scholar 

  • Szeto HH (2006) Mitochondria-targeted peptide antioxidants: novel neuroprotective agents. AAPS J 8:E521–E531

    Article  PubMed  CAS  Google Scholar 

  • Touati G, Valayannopoulos V, Mention K, de Lonlay P, Jouvet P, Depondt E, Assoun M, Souberbielle JC, Rabier D, Ogier de Baulny H, Saudubray JM (2006) Methylmalonic and propionic acidurias: management without or with a few supplements of specific amino acid mixture. J Inherit Metab Dis 29:288–298

    Article  PubMed  CAS  Google Scholar 

  • Van Calcar SC, Gleason LA, Lindh H, Hoffman G, Rhead W, Vockley G, Wolff JA, Durkin MS (2007) 2-methylbutyryl-CoA dehydrogenase deficiency in Hmong infants identified by expanded newborn screen. WMJ 106:12–15

    PubMed  Google Scholar 

  • Vockley J, Ensenauer R (2006) Isovaleric acidemia: new aspects of genetic and phenotypic heterogeneity. Am J Med Genet C Semin Med Genet 142C:95–103

    Article  PubMed  CAS  Google Scholar 

  • Wajner M, Latini A, Wyse AT, Dutra-Filho CS (2004) The role of oxidative damage in the neuropathology of organic acidurias: insights from animal studies. J Inherit Metab Dis 27:427–448

    Article  PubMed  CAS  Google Scholar 

  • Walrand S (2010) Ornithine alpha-ketoglutarate: could it be a new therapeutic option for sarcopenia? J Nutr Health Aging 14:570–577

    Article  PubMed  CAS  Google Scholar 

  • Wikoff WR, Gangoiti JA, Barshop BA, Siuzdak G (2007) Metabolomics identifies perturbations in human disorders of propionate metabolism. Clin Chem 53:2169–2176

    Article  PubMed  CAS  Google Scholar 

  • Wu JY, Kao HJ, Li SC, Stevens R, Hillman S, Millington D, Chen YT (2004) ENU mutagenesis identifies mice with mitochondrial branched-chain aminotransferase deficiency resembling human maple syrup urine disease. J Clin Invest 113:434–440

    PubMed  CAS  Google Scholar 

  • Yang L, Zhao K, Calingasan NY, Luo G, Szeto HH, Beal MF (2009) Mitochondria targeted peptides protect against 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine neurotoxicity. Antioxid Redox Signal 11:2095–2104

    Article  PubMed  CAS  Google Scholar 

  • Yannicelli S, Acosta PB, Velazquez A, Bock HG, Marriage B, Kurczynski TW, Miller M, Korson M, Steiner RD, Rutledge L, Bernstein L, Chinsky J, Galvin-Parton P, Arnold GL (2003) Improved growth and nutrition status in children with methylmalonic or propionic acidemia fed an elemental medical food. Mol Genet Metab 80:181–188

    Article  PubMed  CAS  Google Scholar 

  • Yannicelli S (2006) Nutrition therapy of organic acidaemias with amino acid-based formulas: emphasis on methylmalonic and propionic acidaemia. J Inherit Metab Dis 29:281–287

    Article  PubMed  CAS  Google Scholar 

  • Zand DJ, Brown KM, Lichter-Konecki U, Campbell JK, Salehi V, Chamberlain JM (2008) Effectiveness of a clinical pathway for the emergency treatment of patients with inborn errors of metabolism. Pediatrics 122:1191–1195

    Article  PubMed  Google Scholar 

  • Zinnanti WJ, Lazovic J, Griffin K, Skvorak KJ, Paul HS, Homanics GE, Bewley MC, Cheng KC, Lanoue KF, Flanagan JM (2009) Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease. Brain 132:903–918

    Article  PubMed  Google Scholar 

  • Zwickler T, Lindner M, Aydin HI, Baumgartner MR, Bodamer OA, Burlina AB, Das AM, DeKlerk JB, Gökcay G, Grünewald S, Guffon N, Maier EM, Morava E, Geb S, Schwahn B, Walter JH, Wendel U, Wijburg FA, Müller E, Kölker S, Hörster F (2008) Diagnostic work-up and management of patients with isolated methylmalonic acidurias in European metabolic centres. J Inherit Metab Dis 31:361–367

    Article  PubMed  CAS  Google Scholar 

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  1. Children’s and Adolescents’ Hospital, Otto-Heubner Centrum, Pediatric Metabolic Unit, Charité - Universitätsmedizin, Berlin, Germany

    Ina Knerr & Natalie Weinhold

  2. Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Jerry Vockley

  3. Department of Biological Sciences, Michigan Technological University, Houghton, MI, USA

    K. Michael Gibson

  4. Otto-Heubner-Centrum für Kinder- und Jugendmedizin, Pädiatrische Stoffwechselmedizin, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, D-13353, Berlin, Germany

    Ina Knerr

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  1. Ina Knerr
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Correspondence to Ina Knerr.

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Communicated by Jörn Oliver Sass

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Knerr, I., Weinhold, N., Vockley, J. et al. Advances and challenges in the treatment of branched-chain amino/keto acid metabolic defects. J Inherit Metab Dis 35, 29–40 (2012). https://doi.org/10.1007/s10545-010-9269-1

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