Medicine:3-Methylcrotonyl-CoA carboxylase deficiency

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3-Methylcrotonyl-CoA carboxylase deficiency
Other names3MCC deficiency, 3-methylcrotonylglycinuria, MCC deficiency, MCCD
Methylcrotonyl coenzyme A.svg
Skeletal formula of methylcrotonyl coenzyme A
SpecialtyMedical genetics

3-Methylcrotonyl-CoA carboxylase deficiency also known as 3-Methylcrotonylglycinuria is an inborn error of leucine metabolism and is inherited through an autosomal dominant fashion.[1] 3-Methylcrotonyl-CoA carboxylase deficiency is caused by mutations in the MCCC1 gene, formerly known as MMCA, or the MCCC2 gene, formerly known as MCCB. MCCC1 encodes the a-subunits of 3-methylcrotonyl-CoA carboxylase[2] while MCCC2 encodes the b-subunits.[3] The clinical presentation of 3-Methylcrotonyl-CoA carboxylase deficiency is varied, even within members of the same family.[4]

Manifestations of 3-Methylcrotonyl-CoA carboxylase deficiency range from asymptomatic[5] to neonatal onset with extreme neurological symptoms[6] and even fatal cases.[7] 3-Methylcrotonyl-CoA carboxylase deficiency is diagnosed by increased 3-hydroxyisovaleric acid and 3-methylcrotonylglycine in the urine. 3-hydroxyisovalerylcarnitine is often found in both the urine and blood.

The diagnosis of 3-Methylcrotonyl-CoA carboxylase deficiency is confirmed by decreased enzyme activity in fibroblasts or white blood cells.[8] Although no treatment options have been proven to help manage 3-Methylcrotonyl-CoA carboxylase deficiency[9] proposed treatments include L-carnitine supplements,[10] glycine administration,[11] biotin supplements[4] and dietary restriction of leucine.[12] 3-Methylcrotonyl-CoA carboxylase deficiency is the most common organic aciduria detected by newborn screening programs in Australia ,[13] North America,[14] and Europe.[15]

Signs and symptoms

Those with 3-Methylcrotonyl-CoA carboxylase deficiency typically display normal development until 6 months to 3 years old when patients present with an acute episode. These acute episodes are typically brought on by increased protein load[16] or intercurrent infections.[7] During metabolic crisis, moderate hyperammonemia,[7] hypoglycemia, and metabolic acidosis have been noted.[17] There is a broad spectrum of clinical manifestations ranging from cardiomyopathy, developmental delays,[4] leukodystrophy, necrotizing encephalopathy, respiratory failure, hypotonia,[6] cerebral palsy and failure to thrive.[17] Carnitine deficiency is found in about 50% of cases.[18]

Over 90% of those diagnosed with 3-Methylcrotonyl-CoA carboxylase deficiency by newborn screening remain asymptomatic. The medical abnormalities that present in the few who do show symptoms are not always clearly related to 3-Methylcrotonyl-CoA carboxylase deficiency.[5] Manifestations of 3-Methylcrotonyl-CoA carboxylase deficiency vary even among family members who share a common environment and genetics.[4]

Genetics

The MCCC1 and MCCC2 genes make protein subunits that come together to form an enzyme called 3-methylcrotonyl-CoA carboxylase. This enzyme plays an essential role in breaking down proteins from the diet. Specifically, the enzyme is responsible for the fourth step in processing leucine. If a mutation in the MCCC1 or MCCC2 gene reduces or eliminates the activity of 3-methylcrotonyl-CoA carboxylase, the body is unable to process leucine properly. As a result, toxic byproducts of leucine processing build up to harmful levels, damaging the brain and nervous system. This condition is inherited in an autosomal recessive pattern.[19]

Diagnosis

3-Methylcrotonyl-CoA carboxylase deficiency is diagnosed by the detection of organic acids in urine using gas chromatography or mass spectrometry and analysis of the blood by liquid chromatography-tandem mass spectrometry.[20] 3-Methylcrotonyl-CoA carboxylase deficiency is characterized by increased 3-hydroxyisovaleric acid and 3-methylcrotonylglycine levels in the urine. The acylcarnitines profile shows elevated concentrations of 3-hydroxyisovalerylcarnitine as well as an increased ratio of 3-hydroxyisovalerylcarnitine to propionylcarnitine.[3]

Since genotype isn't predictive of phenotype,[5] DNA testing isn't necessary. However, DNA analysis may help confirm 3-Methylcrotonyl-CoA carboxylase deficiency when the diagnosis is uncertain.[9]

3-hydroxyisovalerylcarnitine is also elevated in other metabolism disorders such as 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency, biotinidase deficiency, multiple carboxylase deficiency, mitochondrial acetoacetyl-CoA thiolase deficiency and malonic aciduria. 3-Methylcrotonyl-CoA carboxylase deficiency is differentiated by the lack of other urine metabolites and by measuring the activity of 3-methylcrotonyl-CoA carboxylase, biotinidase, and other biotin dependant carboxylases.[12]

Screening

It is one of the 29 conditions currently recommended for newborn screening by the American College of Medical Genetics.[21]

Treatment

Symptoms can be reduced through avoidance of leucine, an amino acid. Leucine is a component of most protein-rich foods; therefore, a low-protein diet is recommended. Some isolated cases of this disorder have responded to supplemental biotin;[22] this is not altogether surprising, consider that other biotin-related genetic disorders (such as biotinidase deficiency and holocarboxylase synthetase deficiency) can be treated solely with biotin. Individuals with these multiple carboxylase disorders have the same problem with leucine catabolism as those with 3-methylcrotonyl-CoA carboxylase deficiency.[23]

See also

References

This article incorporates public domain text from The U.S. National Library of Medicine

  1. ↑ Tuba Eminoglu, F.; Ozcelik, Aysima A.; Okur, Ilyas; Tumer, Leyla; Biberoglu, Gursel; Demir, Ercan; Hasanoglu, Alev; Baumgartner, Matthias R. (January 23, 2009). "3-Methylcrotonyl-CoA Carboxylase Deficiency: Phenotypic Variability in a Family". Journal of Child Neurology (SAGE Publications) 24 (4): 478–481. doi:10.1177/0883073808324536. ISSN 0883-0738. PMID 19339287. https://journals.sagepub.com/doi/abs/10.1177/0883073808324536. Retrieved November 27, 2023. 
  2. ↑ Baumgartner, Matthias R.; Almashanu, Shlomo; Suormala, Terttu; Obie, Cassandra; Cole, Robert N.; Packman, Seymour; Baumgartner, E. Regula; Valle, David (February 15, 2001). "The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency". Journal of Clinical Investigation (American Society for Clinical Investigation) 107 (4): 495–504. doi:10.1172/jci11948. ISSN 0021-9738. PMID 11181649. 
  3. ↑ 3.0 3.1 Holzinger, A. (June 1, 2001). "Cloning of the human MCCA and MCCB genes and mutations therein reveal the molecular cause of 3-methylcrotonyl-CoA: carboxylase deficiency". Human Molecular Genetics (Oxford University Press (OUP)) 10 (12): 1299–1306. doi:10.1093/hmg/10.12.1299. ISSN 1460-2083. PMID 11406611. https://pubmed.ncbi.nlm.nih.gov/11406611/. Retrieved November 27, 2023. 
  4. ↑ 4.0 4.1 4.2 4.3 Visser, Gepke; Suormala, Terttu; Smit, G. Peter A.; Reijngoud, Dirk-Jan; Bink-Boelkens, Margreet Th. E.; Niezen-Koning, Klary E.; Baumgartner, E. Regula (November 20, 2000). "3-Methylcrotonyl-CoA carboxylase deficiency in an infant with cardiomyopathy, in her brother with developmental delay and in their asymptomatic father". European Journal of Pediatrics (Springer Science and Business Media LLC) 159 (12): 901–904. doi:10.1007/pl00008366. ISSN 0340-6199. PMID 11131348. https://pubmed.ncbi.nlm.nih.gov/11131348/. Retrieved November 27, 2023. 
  5. ↑ 5.0 5.1 5.2 Stadler, Sonja C.; Polanetz, Roman; Maier, Esther M.; Heidenreich, Sylvia C.; Niederer, Birgit; Mayerhofer, Peter U.; Lagler, Florian; Koch, Hans-Georg et al. (2006). "Newborn screening for 3-methylcrotonyl-CoA carboxylase deficiency: population heterogeneity ofMCCA andMCCB mutations and impact on risk assessment". Human Mutation (Hindawi Limited) 27 (8): 748–759. doi:10.1002/humu.20349. ISSN 1059-7794. https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.20349. Retrieved November 27, 2023. 
  6. ↑ 6.0 6.1 Baykal, T.; Gokcay, G. Huner; Ince, Z.; Dantas, M. F.; Fowler, B.; Baumgartner, M. R.; Demir, F.; Can, G. et al. (2005). "Consanguineous 3-methylcrotonyl-CoA carboxylase deficiency: Early-onset necrotizing encephalopathy with lethal outcome". Journal of Inherited Metabolic Disease (Wiley) 28 (2): 229–233. doi:10.1007/s10545-005-4559-8. ISSN 0141-8955. PMID 15877210. https://pubmed.ncbi.nlm.nih.gov/15877210/. Retrieved November 27, 2023. 
  7. ↑ 7.0 7.1 7.2 Bannwart, C.; Wermuth, B.; Baumgartner, R.; Suormala, T.; Wiesmann, U. N. (April 21, 1992). "Isolated biotin-resistant deficiency of 3-methylcrotonyl-CoA carboxylase presenting as a clinically severe form in a newborn with fatal outcome". Journal of Inherited Metabolic Disease (Wiley) 15 (6): 863–868. doi:10.1007/bf01800223. ISSN 0141-8955. PMID 1293382. https://pubmed.ncbi.nlm.nih.gov/1293382/. Retrieved November 27, 2023. 
  8. ↑ Röschinger, Wulf; Millington, David S.; Gage, Douglas A.; Huang, Zhi-H.; Iwamoto, Takeo; Yano, Shoji; Packman, Seymour; Johnston, Kay et al. (1995). "3-Hydroxyisovalerylcarnitine in patients with deficiency of 3-methylcrotonyl CoA carboxylase". Clinica Chimica Acta (Elsevier BV) 240 (1): 35–51. doi:10.1016/0009-8981(95)06126-2. ISSN 0009-8981. PMID 8582058. https://www.sciencedirect.com/science/article/abs/pii/0009898195061262. Retrieved November 27, 2023. 
  9. ↑ 9.0 9.1 Arnold, Georgianne L.; Koeberl, Dwight D.; Matern, Dietrich; Barshop, Bruce; Braverman, Nancy; Burton, Barbara; Cederbaum, Stephen; Fiegenbaum, Annette et al. (2008). "A Delphi-based consensus clinical practice protocol for the diagnosis and management of 3-methylcrotonyl CoA carboxylase deficiency". Molecular Genetics and Metabolism (Elsevier BV) 93 (4): 363–370. doi:10.1016/j.ymgme.2007.11.002. ISSN 1096-7192. https://www.sciencedirect.com/science/article/abs/pii/S1096719207005975. Retrieved November 27, 2023. 
  10. ↑ Fries, Melissa H.; Rinaldo, Piero; Schmidt-Sommerfeld, Eberhard; Jurecki, Elena; Packman, Seymour (1996). "Isovaleric acidemia: Response to a leucine load after three weeks of supplementation with glycine, L-carnitine, and combined glycine-carnitine therapy". The Journal of Pediatrics (Elsevier BV) 129 (3): 449–452. doi:10.1016/s0022-3476(96)70081-1. ISSN 0022-3476. PMID 8804338. https://pubmed.ncbi.nlm.nih.gov/8804338/. Retrieved November 27, 2023. 
  11. ↑ Rutledge, S. L.; Berry, G. T.; Stanley, C. A.; van Hove, J. L. K.; Millington, D. (March 30, 1994). "Glycine and L-carnitine therapy in 3-methylcrotonyl-CoA carboxylase deficiency". Journal of Inherited Metabolic Disease (Wiley) 18 (3): 299–305. doi:10.1007/bf00710419. ISSN 0141-8955. PMID 7474896. https://pubmed.ncbi.nlm.nih.gov/7474896/. Retrieved November 27, 2023. 
  12. ↑ 12.0 12.1 Koeberl, D. D.; Millington, D. S.; Smith, W. E.; Weavil, S. D.; Muenzer, J.; McCandless, S. E.; Kishnani, P. S.; McDonald, M. T. et al. (2003). "Evaluation of 3-methylcrotonyl-CoA carboxylase deficiency detected by tandem mass spectrometry newborn screening". Journal of Inherited Metabolic Disease (Wiley) 26 (1): 25–35. doi:10.1023/a:1024015227863. ISSN 0141-8955. PMID 12872837. https://onlinelibrary.wiley.com/doi/abs/10.1023/A:1024015227863. Retrieved November 27, 2023. 
  13. ↑ Wilcken, Bridget; Wiley, Veronica; Hammond, Judith; Carpenter, Kevin (June 5, 2003). "Screening Newborns for Inborn Errors of Metabolism by Tandem Mass Spectrometry". New England Journal of Medicine (Massachusetts Medical Society) 348 (23): 2304–2312. doi:10.1056/nejmoa025225. ISSN 0028-4793. PMID 12788994. 
  14. ↑ Naylor, Edwin W.; Chace, Donald H. (1999). "Automated Tandem Mass Spectrometry for Mass Newborn Screening for Disorders in Fatty Acid, Organic Acid, and Amino Acid Metabolism". Journal of Child Neurology (SAGE Publications) 14 (1_suppl): S4–S8. doi:10.1177/0883073899014001021. ISSN 0883-0738. PMID 10593560. https://pubmed.ncbi.nlm.nih.gov/10593560/. Retrieved November 27, 2023. 
  15. ↑ Schulze, Andreas; Lindner, Martin; Kohlmüller, Dirk; Olgemöller, Katharina; Mayatepek, Ertan; Hoffmann, Georg F. (June 1, 2003). "Expanded Newborn Screening for Inborn Errors of Metabolism by Electrospray Ionization-Tandem Mass Spectrometry: Results, Outcome, and Implications". Pediatrics (American Academy of Pediatrics (AAP)) 111 (6): 1399–1406. doi:10.1542/peds.111.6.1399. ISSN 0031-4005. PMID 12777559. https://pubmed.ncbi.nlm.nih.gov/12777559/. Retrieved November 27, 2023. 
  16. ↑ Beemer, F. A.; Bartlett, K.; Duran, M.; Ghneim, H. K.; Wadman, S. K.; Bruinvis, L.; Ketting, D. (1982). "Isolated biotin-resistant 3-methylcrotonyl-CoA carboxylase deficiency in two sibs". European Journal of Pediatrics (Springer Science and Business Media LLC) 138 (4): 351–354. doi:10.1007/bf00442517. ISSN 0340-6199. PMID 7128647. https://pubmed.ncbi.nlm.nih.gov/7128647/. Retrieved November 27, 2023. 
  17. ↑ 17.0 17.1 Oude Luttikhuis, H. G. M.; Touati, G.; Rabier, D.; Williams, M.; Jakobs, C.; Saudubray, J. M. (2005). "Severe hypoglycaemia in isolated 3-methylcrotonyl-CoA carboxylase deficiency; a rare, severe clinical presentation". Journal of Inherited Metabolic Disease (Wiley) 28 (6): 1136–1138. doi:10.1007/s10545-005-4545-1. ISSN 0141-8955. PMID 16435207. https://pubmed.ncbi.nlm.nih.gov/16435207/. Retrieved November 27, 2023. 
  18. ↑ Forsyth, RaeLynn; Vockley, Catherine Walsh; Edick, Mathew J.; Cameron, Cynthia A.; Hiner, Sally J.; Berry, Susan A.; Vockley, Jerry; Arnold, Georgianne L. (2016). "Outcomes of cases with 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency — Report from the Inborn Errors of Metabolism Information System". Molecular Genetics and Metabolism (Elsevier BV) 118 (1): 15–20. doi:10.1016/j.ymgme.2016.02.002. ISSN 1096-7192. PMID 27033733. 
  19. ↑ "3-methylcrotonyl-CoA carboxylase deficiency: MedlinePlus Genetics". October 1, 2008. https://medlineplus.gov/genetics/condition/3-methylcrotonyl-coa-carboxylase-deficiency/. 
  20. ↑ Fonseca, Helena; Azevedo, Luisa; Serrano, Catarina; Sousa, Carmen; Marcão, Ana; Vilarinho, Laura (2016). "3-Methylcrotonyl-CoA carboxylase deficiency: Mutational spectrum derived from comprehensive newborn screening". Gene (Elsevier BV) 594 (2): 203–210. doi:10.1016/j.gene.2016.09.003. ISSN 0378-1119. PMID 27601257. https://www.sciencedirect.com/science/article/abs/pii/S0378111916307077. Retrieved November 27, 2023. 
  21. ↑ "ACT Sheets and Algorithms". https://www.acmg.net/ACMG/Medical-Genetics-Practice-Resources/ACT_Sheets_and_Algorithms.aspx. 
  22. ↑ Baumgartner, Matthias R.; Dantas, M.Fernanda; Suormala, Terttu; Almashanu, Shlomo; Giunta, Cecilia; Friebel, Dolores; Gebhardt, Boris; Fowler, Brian et al. (2004). "Isolated 3-Methylcrotonyl-CoA Carboxylase Deficiency: Evidence for an Allele-Specific Dominant Negative Effect and Responsiveness to Biotin Therapy". The American Journal of Human Genetics 75 (5): 790–800. doi:10.1086/425181. PMID 15359379. 
  23. ↑ Thomsen, Jákup Andreas; Lund, Allan Meldgaard; Olesen, Jess Have; Mohr, Magni; Rasmussen, Jan (2014). "Is l-Carnitine Supplementation Beneficial in 3-Methylcrotonyl-CoA Carboxylase Deficiency?". JIMD Reports. 21. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 79–88. doi:10.1007/8904_2014_393. ISBN 978-3-662-47171-5. 

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