Isolated beta-methylcrotonyl-CoA carboxylase deficiency

Barry Wolf MD PhD (Dr. Wolf of Lurie Children's Hospital of Chicago has no relevant financial relationships to disclose.)
Originally released February 7, 1994; last updated January 12, 2020; expires January 12, 2023

This article includes discussion of isolated beta-methylcrotonyl-CoA carboxylase deficiency and beta-methylcrotonyl-CoA carboxylase deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


The author explains that based on the results of newborn screening, confirmed individuals with isolated beta-methylcrotonyl-CoA carboxylase deficiency often have mild biochemical phenotypes. When neonates are found with elevated C5-OH metabolites on newborn screening and only a single mutation in the carboxylase genes is identified, their mothers should be tested to exclude the possibility that they have isolated beta-methylcrotonyl-CoA carboxylase deficiency.

Key points


• Beta-methylcrotonyl-CoA carboxylase deficiency, an inherited metabolic disorder, usually presents during early childhood with neurologic symptoms, metabolic acidosis, and organic aciduria.


• Some individuals with beta-methylcrotonyl-CoA carboxylase deficiency can exhibit mild symptoms, whereas others have severe symptoms.


• Children with beta-methylcrotonyl-CoA carboxylase deficiency can be identified by tandem mass spectroscopy on newborn screening or they may be identified later by the characteristic organic aciduria when they are symptomatic.


• Although beta-methylcrotonyl-CoA carboxylase is a biotin-dependent enzyme, individuals with the disorder do not usually respond to biotin therapy.


• Individuals with beta-methylcrotonyl-CoA carboxylase deficiency are usually treated with a low-protein or leucine-restricted, high-carbohydrate diet and carnitine supplementation.

Historical note and terminology

In the early 1970s 2 children were described with beta-methylcrotonyl-glycinuria (Eldjarn et al 1970; Gompertz et al 1971; Gompertz et al 1973). These children had slightly different symptoms, but could be differentiated by their responses to biotin supplementation. One improved markedly with biotin treatment (Gompertz et al 1971; Gompertz et al 1973), whereas the other did not and was considered to be biotin-resistant (Eldjarn et al 1970; Stokke et al 1972). Both were thought or shown to have beta-methylcrotonyl-CoA carboxylase deficiency (Tanaka and Isselbacher 1970). Other patients with beta-methylcrotonyl-glycinuria were subsequently reported, and almost all were biotin-responsive. These biotin-responsive patients were subsequently shown to have metabolites consistent with deficiencies of all 3 of the mitochondrial carboxylases; this was confirmed enzymatically in most of these children. They were designated as having multiple carboxylase deficiency (Sweetman et al 1977; Wolf 1992). Few of the children with beta-methylcrotonyl-glycinuria were shown to have beta-methylcrotonyl-CoA carboxylase deficiency with the normal activities of the other mitochondrial carboxylases. They were considered to have isolated beta-methylcrotonyl-CoA carboxylase deficiency. Since then, about a dozen children with isolated beta-methylcrotonyl-CoA carboxylase deficiency with a variety of clinical features have been reported. All have failed to respond to biotin therapy.

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