Sign Up for a Free Account
  • Updated 09.28.2023
  • Released 09.19.2003
  • Expires For CME 09.28.2026




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 one 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. Very few affected infants 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 (48). The enzyme 3-methylcrotonyl-CoA carboxylase is now recognized to be composed of two different 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 (04; 19). Several pathologic mutations in both genes have been described. Gallardo and colleagues also reported an unexpectedly high incidence of biochemical markers of this disorder detected in newborn screening programs (19).

This is an article preview.
Start a Free Account
to access the full version.

  • Nearly 3,000 illustrations, including video clips of neurologic disorders.

  • Every article is reviewed by our esteemed Editorial Board for accuracy and currency.

  • Full spectrum of neurology in 1,200 comprehensive articles.

  • Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660



ISSN: 2831-9125