Friederike Hoerster MD (Dr. Hoerster of University Children's Hospital in Heidelberg, Germany, has no relevant financial relationships to disclose.)
Georg F Hoffmann MD (Dr. Hoffmann of the University Center for Child and Adolescent Medicine in Heidelberg has no relevant financial relationships to disclose.)
Tyler Reimschisel MD, editor. (Dr. Reimschisel of Vanderbilt University has received contracted research grants from Shire.)
Originally released September 19, 2003; last updated August 29, 2018; expires August 29, 2021

This article includes discussion of 3-alpha-methylcrotonylglycinuria, 3-alpha-methylcrotonyl-CoA carboxylase 1 deficiency, 3-alpha-methylcrotonyl-CoA carboxylase 2 deficiency, 3-alpha-methylcrotonyl-CoA carboxylase alpha deficiency, 3-alpha-methylcrotonyl-CoA carboxylase beta deficiency, 3-alpha-methylcrotonylglycinemia I, 3-alpha-methylcrotonylglycinemia II, 3-alpha-methylcrotonylglycinuria I, 3-alpha-methylcrotonylglycinuria II, 3-methylcrotonylglycinemia, 3-methylcrotonylglycinuria, 3MCC deficiency, MCCA deficiency, MCCB deficiency, MCCC1 deficiency, and MCCC2 deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


In this clinical article, the authors describe the different manifestations of this inborn error of leucine catabolism and explain pathophysiology, disease diagnosis, and treatment. 3-alpha-methylcrotonylglycinuria appears to be the most common as well as 1 of the most puzzling of the organoacidopathies. Clinical presentations range from severe neonatal metabolic decompensation and lethal outcome to mostly asymptomatic adults never diagnosed nor treated. This review explains the current knowledge and management of this disease, which can present to pediatricians, neurologists, and internists.

Historical note and terminology

3-alpha-methylcrotonylglycinuria is an inborn error of leucine catabolism due to a deficiency of 3-methylcrotonyl-CoA carboxylase. As the enzyme requires biotin as a cofactor, the isolated enzymatic defect must be differentiated from other forms of methylcrotonylglycinuria caused by deficiencies in the biotin pathway (biotinidase and holocarboxylase synthetase deficiencies). The disease has a wide range of manifestations. Infants may already develop severe metabolic crisis, ketoacidosis, and vomiting that may lead to coma and death without appropriate treatment. On the other hand, most individuals remain symptom-free for life. The key metabolites leading to diagnosis are 3-hydroxyisovaleric acid and 3-methylcrotonylglycine in urine and 3-hydroxyisovalerylcarnitine in plasma.

The first case reports of 3-alpha-methylcrotonylglycinuria date from 1970, and it was postulated that 3-methylcrotonyl-CoA carboxylase was deficient (Sweetman and Williams 2001). By now the enzyme 3-methylcrotonyl-CoA carboxylase has been recognized to be composed of 2 nonidentical subunits. The respective genes were identified in 2001: Gallardo and coworkers as well as Baumgartner and coworkers localized the gene for the alpha-subunit to 3q25-q27 and the gene for the beta-subunit to 5q12-q13 (Baumgartner et al 2001; Gallardo et al 2001). Several pathologic mutations in both genes have been described. Gallardo and colleagues also reported an unexpectedly high incidence of biochemical markers of this disorder through newborn screening programs (Gallardo et al 2001).

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