3-methylcrotonyl-CoA carboxylase deficiency: Clinical, biochemical, enzymatic and molecular studies in 88 individuals

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• 作者：Sarah C Grünert (1) (2)
  Martin Stucki (1) (3)
  Raphael J Morscher (1)
  Terttu Suormala (1) (4)
  Celine Bürer (1)
  Patricie Burda (1)
  Ernst Christensen (5)
  Can Ficicioglu (6)
  Jürgen Herwig (7)
  Stefan K?lker (8)
  Dorothea M?slinger (9)
  Elisabetta Pasquini (10)
  René Santer (11)
  K Otfried Schwab (2)
  Bridget Wilcken (12)
  Brian Fowler (1) (4)
  Wyatt W Yue (13)
  Matthias R Baumgartner (1) (3)
  
• 关键词：3 ; Methylcrotonyl ; CoA carboxylase ; MCCC1 ; MCCC2 ; Biotin ; Inborn error ; Organic aciduria ; Newborn screening
• 刊名：Orphanet Journal of Rare Diseases
• 出版年：2012
• 出版时间：December 2012
• 年：2012
• 卷：7
• 期：1
• 全文大小：674KB
• 参考文献：1. Sweetman L, Williams JC: <strong class="a-plus-plus">Branched chain organic acidurias.strong> In / In The Metabolic & Molecular Bases of Inherited Disease. 8th edition. Edited by: Scriver CR, Beaudet AL, Sly WS, Valle D. McGraw Hill, New York; 2001:2125-163.
  2. Baumgartner MR, Almashanu S, Suormala T, Obie C, Cole RN, Packman S, Baumgartner ER, Valle D: <strong class="a-plus-plus">The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency.strong> / J Clin Invest 2001, <strong class="a-plus-plus">107:strong>495-04. class="external" href="http://dx.doi.org/10.1172/JCI11948">CrossRef
  3. Gallardo ME, Desviat LR, Rodrígues JM, Esparza-Gordillo J, Pérez-Cerdá C, Pérez B, Rodrígues-Pombo P, Criado O, Sanz R, Morton DH, / et al.: <strong class="a-plus-plus">The molecular basis of 3-methlcrotonylglycinuria, a disorder of leucine catabolsim.strong> / Am J Hum Genet 2001, <strong class="a-plus-plus">68:strong>334-46. class="external" href="http://dx.doi.org/10.1086/318202">CrossRef
  4. Holzinger A, Roschinger W, Lagler F, Mayerhofer PU, Lichtner P, Kattenfeld T, Thuy LP, Nyhan WL, Koch HG, Muntau AC, Roscher AA: <strong class="a-plus-plus">Cloning of the human MCCA and MCCB genes and mutations therein reveal the molecular cause of 3-methylcrotonyl-CoA: carboxylase deficiency.strong> / Hum Mol Genet 2001, <strong class="a-plus-plus">10:strong>1299-306. class="external" href="http://dx.doi.org/10.1093/hmg/10.12.1299">CrossRef
  5. Desviat LR, Perez-Cerda C, Perez B, Esparza-Gordillo J, Rodriguez-Pombo P, Penalva MA, Rodriguez De Cordoba S, Ugarte M: <strong class="a-plus-plus">Functional analysis of MCCA and MCCB mutations causing methylcrotonylglycinuria.strong> / Mol Genet Metab 2003, <strong class="a-plus-plus">80:strong>315. class="external" href="http://dx.doi.org/10.1016/S1096-7192(03)00130-6">CrossRef
  6. Stadler SC, Polanetz R, Maier EM, Heidenreich SC, Niederer B, Mayerhofer PU, Lagler F, Koch HG, Santer R, Fletcher JM, / et al.: <strong class="a-plus-plus">Newborn screening for 3-methylcrotonyl-CoA carboxylase deficiency: population heterogeneity of MCCA and MCCB mutations and impact on risk assessment.strong> / Hum Mutat 2006, <strong class="a-plus-plus">27:strong>748-59. class="external" href="http://dx.doi.org/10.1002/humu.20349">CrossRef
  7. Uematsu M, Sakamoto O, Sugawara N, Kumagai N, Morimoto T, Yamaguchi S, Hasegawa Y, Kobayashi H, Ihara K, Yoshino M, / et al.: <strong class="a-plus-plus">Novel mutations in five Japanese patients with 3-methylcrotonyl-CoA carboxylase deficiency.strong> / J Hum Genet 2007, <strong class="a-plus-plus">52:strong>1040-043. class="external" href="http://dx.doi.org/10.1007/s10038-007-0211-9">CrossRef
  8. Nguyen KV, Naviaux RK, Patra S, Barshop BA, Nyhan WL: <strong class="a-plus-plus">Novel mutations in the human MCCA and MCCB gene causing methylcrotonylglycinuria.strong> / Mol Genet Metab 2011, <strong class="a-plus-plus">102:strong>218-21. class="external" href="http://dx.doi.org/10.1016/j.ymgme.2010.10.008">CrossRef
  9. Dirik E, Yis U, Pasaoglu G, Chambaz C, Baumgartner MR: <strong class="a-plus-plus">Recurrent attacks of status epilepticus as predominant symptom in 3-methylcrotonyl-CoA carboxylase deficiency.strong> / Brain Dev 2008, <strong class="a-plus-plus">30:strong>218-20. class="external" href="http://dx.doi.org/10.1016/j.braindev.2007.08.005">CrossRef
  10. Eminoglu FT, Ozcelik AA, Okur I, Tumer L, Biberoglu G, Demir E, Hasanoglu A, Baumgartner MR: <strong class="a-plus-plus">3-Methylcrotonyl-CoA carboxylase deficiency: phenotypic variability in a family.strong> / J Child Neurol 2009, <strong class="a-plus-plus">24:strong>478-81. class="external" href="http://dx.doi.org/10.1177/0883073808324536">CrossRef
  11. Dantas MF, Suormala T, Randolph A, Coelho D, Fowler B, Valle D, Baumgartner MR: <strong class="a-plus-plus">3-Methylcrotonyl-CoA carboxylase deficiency: mutation analysis in 28 probands, 9 symptomatic and 19 detected by newborn screening.strong> / Hum Mutat 2005, <strong class="a-plus-plus">26:strong>164. class="external" href="http://dx.doi.org/10.1002/humu.9352">CrossRef
  12. Morscher RJ, Grünert SC, Bürer C, Burda P, Suormala T, Fowler B, Baumgartner MR: <strong class="a-plus-plus">A single mutation in MCCC1 or MCCC2 as a potential cause of positive screening for 3-methylcrotonyl-CoA carboxylase deficiency.strong> / Mol Genet Metab 2012, <strong class="a-plus-plus">105:strong>602-06. class="external" href="http://dx.doi.org/10.1016/j.ymgme.2011.12.018">CrossRef
  13. Naylor EW, Chace DH: <strong class="a-plus-plus">Automated tandem mass spectrometry for mass newborn screening for disorders in fatty acid, organic acid, and amino acid metabolism.strong> / J Child Neurol 1999, <strong class="a-plus-plus">14:strong>S4-.
  14. Koeberl DD, Millington DS, Smith WE, Weavil SD, Muenzer J, McCandless SE, Kishnani PS, McDonald MT, Chaing S, Boney A, / et al.: <strong class="a-plus-plus">Evaluation of 3-methylcrotonyl-CoA carboxylase deficiency detected by tandem mass spectrometry newborn screening.strong> / J Inherit Metab Dis 2003, <strong class="a-plus-plus">26:strong>25-5. class="external" href="http://dx.doi.org/10.1023/A:1024015227863">CrossRef
  15. Roscher AA, Liebl B, Fingerhut R, Olgem?ller B: <strong class="a-plus-plus">Prospective study of MS-MS newborn screening in Bavaria, Germany.strong> / J Inherit Metab Dis 2000, <strong class="a-plus-plus">23:strong>4.
  16. Schulze A, Lindner M, Kohlmüller D, Olgem?ller K, Mayatepek E, Hoffmann GF: <strong class="a-plus-plus">Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications.strong> / Pediatrics 2003, <strong class="a-plus-plus">111:strong>1399-406. class="external" href="http://dx.doi.org/10.1542/peds.111.6.1399">CrossRef
  17. Wilcken B, Wiley V, Hammond J, Carpenter K: <strong class="a-plus-plus">Screening newborns for inborn errors of metabolism by tandem mass spectrometry.strong> / N Engl J Med 2003, <strong class="a-plus-plus">348:strong>2304-312. class="external" href="http://dx.doi.org/10.1056/NEJMoa025225">CrossRef
  18. Visser G, Suormala T, Smit GP, Reijngoud DJ, Bink-Boelkens MT, Niezen-Koning KE, Baumgartner ER: <strong class="a-plus-plus">3-methylcrotonyl-CoA carboxylase deficiency in an infant with cardiomyopathy, in her brother with developmental delay and in their asymptomatic father.strong> / Eur J Pediatr 2000, <strong class="a-plus-plus">159:strong>901-04. class="external" href="http://dx.doi.org/10.1007/PL00008366">CrossRef
  19. Bannwart C, Wermuth B, Baumgartner R, Suormala T, Wiesmann UN: <strong class="a-plus-plus">Isolated biotin-resistant deficiency of 3-methylcrotonyl-CoA carboxylase presenting as a clinically severe form in a newborn with fatal outcome.strong> / J Inherit Metab Dis 1992, <strong class="a-plus-plus">15:strong>863-68. class="external" href="http://dx.doi.org/10.1007/BF01800223">CrossRef
  20. Dodelson de Kremer R, Latini A, Suormala T, Baumgartner ER, Laróvere L, Civallero G, Guelbert N, Paschini-Capra A, Depetris-Boldini C, Mayor C: <strong class="a-plus-plus">Leukodystrophy and CSF purine abnormalities associated with isolated 3-methylcrotonyl-CoA carboxylase deficiency.strong> / Metabolic Brain Disease 2002, <strong class="a-plus-plus">17:strong>13-8. class="external" href="http://dx.doi.org/10.1023/A:1014096112916">CrossRef
  21. Baykal T, Huner Gokcay G, Ince Z, Dantas MF, Fowler B, Baumgartner MR, Can G, Demirkol M: <strong class="a-plus-plus">3-methylcrotonyl-CoA carboxylase deficiency with early onset necrotizing encephalopathy and lethal outcome.strong> / J Inherit Metab Dis 2005, <strong class="a-plus-plus">28:strong>229-33. class="external" href="http://dx.doi.org/10.1007/s10545-005-4559-8">CrossRef
  22. Gibson KM, Bennett MJ, Naylor EW, Morton DH: <strong class="a-plus-plus">3-Methylcrotonyl-coenzyme A carboxylase deficiency in Amish/Mennonite adults identified by detection of increased acylcarnitines in blood spots of their children.strong> / J Pediatr 1998, <strong class="a-plus-plus">132:strong>519-23. class="external" href="http://dx.doi.org/10.1016/S0022-3476(98)70032-0">CrossRef
  23. Baykal T, Gokcay GH, Ince Z, Dantas MF, Fowler B, Baumgartner MR, Demir F, Can G, Demirkol M: <strong class="a-plus-plus">Consanguineous 3-methylcrotonyl-CoA carboxylase deficiency: early-onset necrotizing encephalopathy with lethal outcome.strong> / J Inherit Metab Dis 2005, <strong class="a-plus-plus">28:strong>229-33. class="external" href="http://dx.doi.org/10.1007/s10545-005-4559-8">CrossRef
  24. van Hove JLK, Rutledge SL, Nada MA, Kahler SG, Millington DS: <strong class="a-plus-plus">3-Hydroxyisovalerylcarnitine in 3-methylcrotonyl-CoA carboxylase defciency.strong> / J Inherit Metab Dis 1995, <strong class="a-plus-plus">18:strong>592-01. class="external" href="http://dx.doi.org/10.1007/BF02436004">CrossRef
  25. Steen C, Baumgartner ER, Duran M, Lehnert W, Suormala T, Fingerhut R, Stehn M, Kohlschütter A: <strong class="a-plus-plus">Metabolic stroke in isolated 3-methylcrotonyl-CoA carboxylase deficiency.strong> / Eur J Pediatr 1999, <strong class="a-plus-plus">158:strong>730-33. class="external" href="http://dx.doi.org/10.1007/s004310051189">CrossRef
  26. Ficicioglu C, Payan I: <strong class="a-plus-plus">3-Methylcrotonyl-CoA carboxylase deficiency: metabolic decompensation in a noncompliant child detected through newborn screening.strong> / Pediatrics 2006, <strong class="a-plus-plus">118:strong>2555-556. class="external" href="http://dx.doi.org/10.1542/peds.2006-1659">CrossRef
  27. Oude Luttikhuis HG, Touati G, Rabier D, Williams M, Jakobs C, Saudubray JM: <strong class="a-plus-plus">Severe hypoglycaemia in isolated 3-methylcrotonyl-CoA carboxylase deficiency; a rare, severe clinical presentation.strong> / J Inherit Metab Dis 2005, <strong class="a-plus-plus">28:strong>1136-138. class="external" href="http://dx.doi.org/10.1007/s10545-005-4545-1">CrossRef
  28. Darin N, Andersen O, Wiklund LM, Holmgren D, Holme E: <strong class="a-plus-plus">3-methylcrotonyl-CoA carboxylase deficiency and severe multiple sclerosis.strong> / Pediatr Neurol 2007, <strong class="a-plus-plus">36:strong>132-34. class="external" href="http://dx.doi.org/10.1016/j.pediatrneurol.2006.09.007">CrossRef
  29. Murayama K, Kimura M, Yamaguchi S, Shinka T, Kodama K: <strong class="a-plus-plus">Isolated 3-methylcrotonyl-CoA carboxylase deficiency in a 15-year-old girl.strong> / Brain Devel 1997, <strong class="a-plus-plus">19:strong>303. class="external" href="http://dx.doi.org/10.1016/S0387-7604(97)86920-3">CrossRef
  30. Yap S, Monavari AA, Thornton P, Naughten E: <strong class="a-plus-plus">Late infantile 3-methylcrotonyl-CoA carboxylase deficiency presenting as global developmental delay.strong> / J Inherit Metab Dis 1998, <strong class="a-plus-plus">21:strong>175-76. class="external" href="http://dx.doi.org/10.1023/A:1005372432116">CrossRef
  31. Friebel D, von der Hagen M, Baumgartner ER, Fowler B, Hahn G, Feyh P, Heubner G, Baumgartner MR, Hoffmann G: <strong class="a-plus-plus">The first case of 3-methylcrotonyl-CoA (MCC) carboxylase deficiency responsive to biotin.strong> / Neuropediatrics 2006, <strong class="a-plus-plus">37:strong>72-8. class="external" href="http://dx.doi.org/10.1055/s-2006-924024">CrossRef
  32. Ihara K, Kuromaru R, Inoue Y, Kuhara T, Matsumoto I, Yoshino M, Fukushige J: <strong class="a-plus-plus">An asymptomatic infant with isolated 3-methylcrotonyl-coenzyme: A carboxylase deficiency detected by newborn screening for maple syrup urine disease.strong> / Eur J Pediatr 1997, <strong class="a-plus-plus">156:strong>713-15. class="external" href="http://dx.doi.org/10.1007/s004310050696">CrossRef
  33. Beemer FA, Bartlett K, Duran M, Ghneim HK, Wadman SK, Bruinvis L, Ketting D: <strong class="a-plus-plus">Isolated biotin-resistant 3-methylcrotonyl-CoA carboxylase deficiency in two sibs.strong> / Eur J Pediatr 1982, <strong class="a-plus-plus">138:strong>351-54. class="external" href="http://dx.doi.org/10.1007/BF00442517">CrossRef
  34. Mourmans J, Bakkeren J, de Jong J, Wevers R, van Diggelen OP, Suormala T, Baumgartner R, Wendel U: <strong class="a-plus-plus">Isolated (biotin-resistant) 3-methylcrotonyl-CoA carboxylase deficiency: Four sibs devoid of pathology.strong> / J Inherit Metab Dis 1995, <strong class="a-plus-plus">18:strong>643-45. class="external" href="http://dx.doi.org/10.1007/BF02436014">CrossRef
  35. Pearson MA, Aleck KA, Heidenreich RA: <strong class="a-plus-plus">Benign clinical presentation of 3-methylglycinuria.strong> / J Inherit Metab Dis 1995, <strong class="a-plus-plus">18:strong>640-41. class="external" href="http://dx.doi.org/10.1007/BF02436012">CrossRef
  36. Arnold GL, Koeberl DD, Matern D, Barshop B, Braverman N, Burton B, Cederbaum S, Fiegenbaum A, Garganta C, Gibson J, / et al.: <strong class="a-plus-plus">A Delphi-based consensus clinical practice protocol for the diagnosis and management of 3-methylcrotonyl CoA carboxylase deficiency.strong> / Mol Genet Metab 2008, <strong class="a-plus-plus">93:strong>363-70. class="external" href="http://dx.doi.org/10.1016/j.ymgme.2007.11.002">CrossRef
  37. Boneh A, Baumgartner M, Hayman M, Peters H: <strong class="a-plus-plus">Methylcrotonyl-CoA carboxylase (MCC) deficiency associated with severe muscle pain and physical disability in an adult.strong> / J Inherit Metab Dis 2005, <strong class="a-plus-plus">28:strong>1139-140. class="external" href="http://dx.doi.org/10.1007/s10545-005-0163-1">CrossRef
  38. Pinto L, Zen P, Rosa R, Paskulin G, Perla A, Barea L, Baumgartner MR, Dantas MF, Fowler B, Giugliani R, / et al.: <strong class="a-plus-plus">Isolated 3-methylcrotonyl-coenzyme A carboxylase deficiency in a child with metabolic stroke.strong> / J Inherit Metab Dis 2006, <strong class="a-plus-plus">29:strong>205-06. class="external" href="http://dx.doi.org/10.1007/s10545-006-0188-0">CrossRef
  39. Wolfe LA, Fiegold DN, Vockley J, Walters N, Chambaz C, Suormala T, Koch HG, Matern D, Barshop BA, Cropcho LJ, Baumgartner MR, Gibson KM: <strong class="a-plus-plus">Potential misdiagnosis of 3-methylcrotonyl-CoA carboxylase deficiency associated with absent or trace urinary 3-methylcrotonylglycine.strong> / Pediatrics 2007, <strong class="a-plus-plus">120:strong>e1135-e1340. class="external" href="http://dx.doi.org/10.1542/peds.2007-0674">CrossRef
  40. Suormala T, Wick H, Bonjour JP, Baumgartner ER: <strong class="a-plus-plus">Rapid differential diagnosis of carboxylase deficiencies and evaluation for biotin-responsiveness in a single blood sample.strong> / Clin Chim Acta 1985, <strong class="a-plus-plus">145:strong>151-62. class="external" href="http://dx.doi.org/10.1016/0009-8981(85)90282-7">CrossRef
  41. Stucki M, Suormala T, Fowler B, Valle D, Baumgartner MR: <strong class="a-plus-plus">Cryptic exon activation by disruption of exon splice enhancer: novel mechanism causing 3-methylcrotonyl-CoA carboxylase deficiency.strong> / J Biol Chem 2009, <strong class="a-plus-plus">284:strong>28953-8957. class="external" href="http://dx.doi.org/10.1074/jbc.M109.050674">CrossRef
  42. Ensenauer R, Vockley J, Willard JM, Huey JC, Sass JO, Edland SD, Burton BK, Berry SA, Santer R, Grunert S, / et al.: <strong class="a-plus-plus">A common mutation is associated with a mild, potentially asymptomatic phenotype in patients with isovaleric acidemia diagnosed by newborn screening.strong> / Am J Hum Genet 2004, <strong class="a-plus-plus">75:strong>1136-142. class="external" href="http://dx.doi.org/10.1086/426318">CrossRef
  43. Maier EM, Liebl B, Roschinger W, Nennstiel-Ratzel U, Fingerhut R, Olgemoller B, Busch U, Krone N, v Kries R, Roscher AA: <strong class="a-plus-plus">Population spectrum of ACADM genotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency.strong> / Hum Mutat 2005, <strong class="a-plus-plus">25:strong>443-52. class="external" href="http://dx.doi.org/10.1002/humu.20163">CrossRef
  44. Baumgartner MR, Dantas MF, Suormala T, Almashanu S, Giunta C, Friebel D, Gebhardt B, Fowler B, Hoffmann GF, Baumgartner ER, Valle D: <strong class="a-plus-plus">Isolated 3-methylcrotonyl-CoA carboxylase deficiency: evidence for an allele-specific dominant negative effect and responsiveness to biotin therapy.strong> / Am J Hum Genet 2004, <strong class="a-plus-plus">75:strong>790-00. class="external" href="http://dx.doi.org/10.1086/425181">CrossRef
  45. Jitrapakdee S, Wallace JC: <strong class="a-plus-plus">The biotin enzyme family: conserved structural motifs and domain rearrangements.strong> / Current Protein Pept Sci 2003, <strong class="a-plus-plus">4:strong>217-29. class="external" href="http://dx.doi.org/10.2174/1389203033487199">CrossRef
  46. Huang CS, Ge P, Zhou ZH, Tong L: <strong class="a-plus-plus">An unanticipated architecture of the 750-kDa alpha(6)beta(6) holoenzyme of 3-methylcrotonyl-CoA carboxylase.strong> / Nature 2011, <strong class="a-plus-plus">481:strong>219-23. class="external" href="http://dx.doi.org/10.1038/nature10691">CrossRef
  
• 作者单位：Sarah C Grünert (1) (2)
  Martin Stucki (1) (3)
  Raphael J Morscher (1)
  Terttu Suormala (1) (4)
  Celine Bürer (1)
  Patricie Burda (1)
  Ernst Christensen (5)
  Can Ficicioglu (6)
  Jürgen Herwig (7)
  Stefan K?lker (8)
  Dorothea M?slinger (9)
  Elisabetta Pasquini (10)
  René Santer (11)
  K Otfried Schwab (2)
  Bridget Wilcken (12)
  Brian Fowler (1) (4)
  Wyatt W Yue (13)
  Matthias R Baumgartner (1) (3)
  
  1. Division of Metabolism and Children’s Research Center (CRC), University Children’s Hospital Zurich, Steinwiesstra?e 75, 8032, Zurich, Switzerland
  2. Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany
  3. Zürich Center for Integrative Human Physiology (ZHIP), University of Zürich, Zürich, Switzerland
  4. Metabolic Unit, University Children’s Hospital, Basel, Switzerland
  5. Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark
  6. Perelman School of Medicine, Section of Biochemical Genetics, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  7. University Children’s Hospital Frankfurt, Frankfurt, Germany
  8. Division of Inherited Metabolic Diseases, University Children’s Hospital, Heidelberg, Germany
  9. Department of Pediatric and Adolescent Medicine, University Hospital Vienna, Vienna, Austria
  10. Metabolic and Muscular Unit, Clinic of Pediatric Neurology, Meyer Children’s Hospital, Florence, Italy
  11. Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  12. Department of Biochemical Genetics, The Children’s Hospital at Westmead, Sydney, New South Wales, Australia
  13. Structural Genomics Consortium, University of Oxford, Oxford, UK
  

文摘

Background Isolated 3-methylcrotonyl-CoA carboxylase (MCC) deficiency is an autosomal recessive disorder of leucine metabolism caused by mutations in MCCC1 or MCCC2 encoding the α and β subunit of MCC, respectively. The phenotype is highly variable ranging from acute neonatal onset with fatal outcome to asymptomatic adults. Methods We report clinical, biochemical, enzymatic and mutation data of 88 MCC deficient individuals, 53 identified by newborn screening, 26 diagnosed due to clinical symptoms or positive family history and 9 mothers, identified following the positive newborn screening result of their baby. Results Fifty-seven percent of patients were asymptomatic while 43% showed clinical symptoms, many of which were probably not related to MCC deficiency but due to ascertainment bias. However, 12 patients (5 of 53 identified by newborn screening) presented with acute metabolic decompensations. We identified 15 novel MCCC1 and 16 novel MCCC2 mutant alleles. Additionally, we report expression studies on 3 MCCC1 and 8 MCCC2 mutations and show an overview of all 132 MCCC1 and MCCC2 variants known to date. Conclusions Our data confirm that MCC deficiency, despite low penetrance, may lead to a severe clinical phenotype resembling classical organic acidurias. However, neither the genotype nor the biochemical phenotype is helpful in predicting the clinical course.