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

Orphanet Journal of Rare Diseases

Matthias R Baumgartner⁴  Wyatt W Yue¹  Brian Fowler⁸  Bridget Wilcken⁶  K Otfried Schwab⁹  René Santer^1,11  Elisabetta Pasquini^1,10  Dorothea Möslinger²  Stefan Kölker^1,13  Jürgen Herwig^1,12  Can Ficicioglu³  Ernst Christensen⁷  Patricie Burda⁵  Celine Bürer⁵  Terttu Suormala⁸  Raphael J Morscher⁵  Martin Stucki⁴  Sarah C Grünert⁹ 

[1] Structural Genomics Consortium, University of Oxford, Oxford, UK;Department of Pediatric and Adolescent Medicine, University Hospital Vienna, Vienna, Austria;Children’s Hospital of Philadelphia, University of Pennsylvania, Perelman School of Medicine, Section of Biochemical Genetics, Philadelphia, Pennsylvania, USA;Zürich Center for Integrative Human Physiology (ZHIP), University of Zürich, Zürich, Switzerland;Division of Metabolism and Children’s Research Center (CRC), University Children’s Hospital Zurich, Steinwiesstraße 75, 8032, Zurich, Switzerland;Department of Biochemical Genetics, The Children's Hospital at Westmead, Sydney, New South Wales, Australia;Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark;Metabolic Unit, University Children's Hospital, Basel, Switzerland;Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany;Metabolic and Muscular Unit, Clinic of Pediatric Neurology, Meyer Children's Hospital, Florence, Italy;Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;University Children’s Hospital Frankfurt, Frankfurt, Germany;Division of Inherited Metabolic Diseases, University Children's Hospital, Heidelberg, Germany

关键词: Newborn screening;    Organic aciduria;    Inborn error;    Biotin;    MCCC2;    MCCC1;    3-Methylcrotonyl-CoA carboxylase;   

Others  :  864379
DOI  :  10.1186/1750-1172-7-31

 received in 2012-02-02, accepted in 2012-04-10,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Grünert et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Sweetman L, Williams JC: Branched chain organic acidurias. 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; 2001:2125-2163.
• [2]Baumgartner MR, Almashanu S, Suormala T, Obie C, Cole RN, Packman S, Baumgartner ER, Valle D: The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency. J Clin Invest 2001, 107:495-504.
• [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.: The molecular basis of 3-methlcrotonylglycinuria, a disorder of leucine catabolsim. Am J Hum Genet 2001, 68:334-346.
• [4]Holzinger A, Roschinger W, Lagler F, Mayerhofer PU, Lichtner P, Kattenfeld T, Thuy LP, Nyhan WL, Koch HG, Muntau AC, Roscher AA: Cloning of the human MCCA and MCCB genes and mutations therein reveal the molecular cause of 3-methylcrotonyl-CoA: carboxylase deficiency. Hum Mol Genet 2001, 10:1299-1306.
• [5]Desviat LR, Perez-Cerda C, Perez B, Esparza-Gordillo J, Rodriguez-Pombo P, Penalva MA, Rodriguez De Cordoba S, Ugarte M: Functional analysis of MCCA and MCCB mutations causing methylcrotonylglycinuria. Mol Genet Metab 2003, 80:315.
• [6]Stadler SC, Polanetz R, Maier EM, Heidenreich SC, Niederer B, Mayerhofer PU, Lagler F, Koch HG, Santer R, Fletcher JM, et al.: Newborn screening for 3-methylcrotonyl-CoA carboxylase deficiency: population heterogeneity of MCCA and MCCB mutations and impact on risk assessment. Hum Mutat 2006, 27:748-759.
• [7]Uematsu M, Sakamoto O, Sugawara N, Kumagai N, Morimoto T, Yamaguchi S, Hasegawa Y, Kobayashi H, Ihara K, Yoshino M, et al.: Novel mutations in five Japanese patients with 3-methylcrotonyl-CoA carboxylase deficiency. J Hum Genet 2007, 52:1040-1043.
• [8]Nguyen KV, Naviaux RK, Patra S, Barshop BA, Nyhan WL: Novel mutations in the human MCCA and MCCB gene causing methylcrotonylglycinuria. Mol Genet Metab 2011, 102:218-221.
• [9]Dirik E, Yis U, Pasaoglu G, Chambaz C, Baumgartner MR: Recurrent attacks of status epilepticus as predominant symptom in 3-methylcrotonyl-CoA carboxylase deficiency. Brain Dev 2008, 30:218-220.
• [10]Eminoglu FT, Ozcelik AA, Okur I, Tumer L, Biberoglu G, Demir E, Hasanoglu A, Baumgartner MR: 3-Methylcrotonyl-CoA carboxylase deficiency: phenotypic variability in a family. J Child Neurol 2009, 24:478-481.
• [11]Dantas MF, Suormala T, Randolph A, Coelho D, Fowler B, Valle D, Baumgartner MR: 3-Methylcrotonyl-CoA carboxylase deficiency: mutation analysis in 28 probands, 9 symptomatic and 19 detected by newborn screening. Hum Mutat 2005, 26:164.
• [12]Morscher RJ, Grünert SC, Bürer C, Burda P, Suormala T, Fowler B, Baumgartner MR: A single mutation in MCCC1 or MCCC2 as a potential cause of positive screening for 3-methylcrotonyl-CoA carboxylase deficiency. Mol Genet Metab 2012, 105:602-606.
• [13]Naylor EW, Chace DH: Automated tandem mass spectrometry for mass newborn screening for disorders in fatty acid, organic acid, and amino acid metabolism. J Child Neurol 1999, 14:S4-8.
• [14]Koeberl DD, Millington DS, Smith WE, Weavil SD, Muenzer J, McCandless SE, Kishnani PS, McDonald MT, Chaing S, Boney A, et al.: Evaluation of 3-methylcrotonyl-CoA carboxylase deficiency detected by tandem mass spectrometry newborn screening. J Inherit Metab Dis 2003, 26:25-35.
• [15]Roscher AA, Liebl B, Fingerhut R, Olgemöller B: Prospective study of MS-MS newborn screening in Bavaria, Germany. J Inherit Metab Dis 2000, 23:4.
• [16]Schulze A, Lindner M, Kohlmüller D, Olgemöller K, Mayatepek E, Hoffmann GF: Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications. Pediatrics 2003, 111:1399-1406.
• [17]Wilcken B, Wiley V, Hammond J, Carpenter K: Screening newborns for inborn errors of metabolism by tandem mass spectrometry. N Engl J Med 2003, 348:2304-2312.
• [18]Visser G, Suormala T, Smit GP, Reijngoud DJ, Bink-Boelkens MT, Niezen-Koning KE, Baumgartner ER: 3-methylcrotonyl-CoA carboxylase deficiency in an infant with cardiomyopathy, in her brother with developmental delay and in their asymptomatic father. Eur J Pediatr 2000, 159:901-904.
• [19]Bannwart C, Wermuth B, Baumgartner R, Suormala T, Wiesmann UN: Isolated biotin-resistant deficiency of 3-methylcrotonyl-CoA carboxylase presenting as a clinically severe form in a newborn with fatal outcome. J Inherit Metab Dis 1992, 15:863-868.
• [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: Leukodystrophy and CSF purine abnormalities associated with isolated 3-methylcrotonyl-CoA carboxylase deficiency. Metabolic Brain Disease 2002, 17:13-18.
• [21]Baykal T, Huner Gokcay G, Ince Z, Dantas MF, Fowler B, Baumgartner MR, Can G, Demirkol M: 3-methylcrotonyl-CoA carboxylase deficiency with early onset necrotizing encephalopathy and lethal outcome. J Inherit Metab Dis 2005, 28:229-233.
• [22]Gibson KM, Bennett MJ, Naylor EW, Morton DH: 3-Methylcrotonyl-coenzyme A carboxylase deficiency in Amish/Mennonite adults identified by detection of increased acylcarnitines in blood spots of their children. J Pediatr 1998, 132:519-523.
• [23]Baykal T, Gokcay GH, Ince Z, Dantas MF, Fowler B, Baumgartner MR, Demir F, Can G, Demirkol M: Consanguineous 3-methylcrotonyl-CoA carboxylase deficiency: early-onset necrotizing encephalopathy with lethal outcome. J Inherit Metab Dis 2005, 28:229-233.
• [24]van Hove JLK, Rutledge SL, Nada MA, Kahler SG, Millington DS: 3-Hydroxyisovalerylcarnitine in 3-methylcrotonyl-CoA carboxylase defciency. J Inherit Metab Dis 1995, 18:592-601.
• [25]Steen C, Baumgartner ER, Duran M, Lehnert W, Suormala T, Fingerhut R, Stehn M, Kohlschütter A: Metabolic stroke in isolated 3-methylcrotonyl-CoA carboxylase deficiency. Eur J Pediatr 1999, 158:730-733.
• [26]Ficicioglu C, Payan I: 3-Methylcrotonyl-CoA carboxylase deficiency: metabolic decompensation in a noncompliant child detected through newborn screening. Pediatrics 2006, 118:2555-2556.
• [27]Oude Luttikhuis HG, Touati G, Rabier D, Williams M, Jakobs C, Saudubray JM: Severe hypoglycaemia in isolated 3-methylcrotonyl-CoA carboxylase deficiency; a rare, severe clinical presentation. J Inherit Metab Dis 2005, 28:1136-1138.
• [28]Darin N, Andersen O, Wiklund LM, Holmgren D, Holme E: 3-methylcrotonyl-CoA carboxylase deficiency and severe multiple sclerosis. Pediatr Neurol 2007, 36:132-134.
• [29]Murayama K, Kimura M, Yamaguchi S, Shinka T, Kodama K: Isolated 3-methylcrotonyl-CoA carboxylase deficiency in a 15-year-old girl. Brain Devel 1997, 19:303.
• [30]Yap S, Monavari AA, Thornton P, Naughten E: Late infantile 3-methylcrotonyl-CoA carboxylase deficiency presenting as global developmental delay. J Inherit Metab Dis 1998, 21:175-176.
• [31]Friebel D, von der Hagen M, Baumgartner ER, Fowler B, Hahn G, Feyh P, Heubner G, Baumgartner MR, Hoffmann G: The first case of 3-methylcrotonyl-CoA (MCC) carboxylase deficiency responsive to biotin. Neuropediatrics 2006, 37:72-78.
• [32]Ihara K, Kuromaru R, Inoue Y, Kuhara T, Matsumoto I, Yoshino M, Fukushige J: An asymptomatic infant with isolated 3-methylcrotonyl-coenzyme: A carboxylase deficiency detected by newborn screening for maple syrup urine disease. Eur J Pediatr 1997, 156:713-715.
• [33]Beemer FA, Bartlett K, Duran M, Ghneim HK, Wadman SK, Bruinvis L, Ketting D: Isolated biotin-resistant 3-methylcrotonyl-CoA carboxylase deficiency in two sibs. Eur J Pediatr 1982, 138:351-354.
• [34]Mourmans J, Bakkeren J, de Jong J, Wevers R, van Diggelen OP, Suormala T, Baumgartner R, Wendel U: Isolated (biotin-resistant) 3-methylcrotonyl-CoA carboxylase deficiency: Four sibs devoid of pathology. J Inherit Metab Dis 1995, 18:643-645.
• [35]Pearson MA, Aleck KA, Heidenreich RA: Benign clinical presentation of 3-methylglycinuria. J Inherit Metab Dis 1995, 18:640-641.
• [36]Arnold GL, Koeberl DD, Matern D, Barshop B, Braverman N, Burton B, Cederbaum S, Fiegenbaum A, Garganta C, Gibson J, et al.: A Delphi-based consensus clinical practice protocol for the diagnosis and management of 3-methylcrotonyl CoA carboxylase deficiency. Mol Genet Metab 2008, 93:363-370.
• [37]Boneh A, Baumgartner M, Hayman M, Peters H: Methylcrotonyl-CoA carboxylase (MCC) deficiency associated with severe muscle pain and physical disability in an adult. J Inherit Metab Dis 2005, 28:1139-1140.
• [38]Pinto L, Zen P, Rosa R, Paskulin G, Perla A, Barea L, Baumgartner MR, Dantas MF, Fowler B, Giugliani R, et al.: Isolated 3-methylcrotonyl-coenzyme A carboxylase deficiency in a child with metabolic stroke. J Inherit Metab Dis 2006, 29:205-206.
• [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: Potential misdiagnosis of 3-methylcrotonyl-CoA carboxylase deficiency associated with absent or trace urinary 3-methylcrotonylglycine. Pediatrics 2007, 120:e1135-e1340.
• [40]Suormala T, Wick H, Bonjour JP, Baumgartner ER: Rapid differential diagnosis of carboxylase deficiencies and evaluation for biotin-responsiveness in a single blood sample. Clin Chim Acta 1985, 145:151-162.
• [41]Stucki M, Suormala T, Fowler B, Valle D, Baumgartner MR: Cryptic exon activation by disruption of exon splice enhancer: novel mechanism causing 3-methylcrotonyl-CoA carboxylase deficiency. J Biol Chem 2009, 284:28953-28957.
• [42]Ensenauer R, Vockley J, Willard JM, Huey JC, Sass JO, Edland SD, Burton BK, Berry SA, Santer R, Grunert S, et al.: A common mutation is associated with a mild, potentially asymptomatic phenotype in patients with isovaleric acidemia diagnosed by newborn screening. Am J Hum Genet 2004, 75:1136-1142.
• [43]Maier EM, Liebl B, Roschinger W, Nennstiel-Ratzel U, Fingerhut R, Olgemoller B, Busch U, Krone N, v Kries R, Roscher AA: Population spectrum of ACADM genotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency. Hum Mutat 2005, 25:443-452.
• [44]Baumgartner MR, Dantas MF, Suormala T, Almashanu S, Giunta C, Friebel D, Gebhardt B, Fowler B, Hoffmann GF, Baumgartner ER, Valle D: Isolated 3-methylcrotonyl-CoA carboxylase deficiency: evidence for an allele-specific dominant negative effect and responsiveness to biotin therapy. Am J Hum Genet 2004, 75:790-800.
• [45]Jitrapakdee S, Wallace JC: The biotin enzyme family: conserved structural motifs and domain rearrangements. Current Protein Pept Sci 2003, 4:217-229.
• [46]Huang CS, Ge P, Zhou ZH, Tong L: An unanticipated architecture of the 750-kDa alpha(6)beta(6) holoenzyme of 3-methylcrotonyl-CoA carboxylase. Nature 2011, 481:219-223.