RARE DISEASE
2-methylbutyryl-CoA dehydrogenase deficiency
2-methylbutyryl-CoA dehydrogenase deficiency
2-methylbutyryl-CoA dehydrogenase deficiency
Synonyms: 2-methylbutyric aciduria, Developmental delay due to 2-methylbutyryl-CoA dehydrogenase deficiency, SBCAD deficiency, Short/branched-chain acyl-coA dehydrogenase deficiency
Synonyms: 2-methylbutyric aciduria, Developmental delay due to 2-methylbutyryl-CoA dehydrogenase deficiency, SBCAD deficiency, Short/branched-chain acyl-coA dehydrogenase deficiency
Synonyms: 2-methylbutyric aciduria, Developmental delay due to 2-methylbutyryl-CoA dehydrogenase deficiency, SBCAD deficiency, Short/branched-chain acyl-coA dehydrogenase deficiency
Drug discovery
0
drugs
With orphan designations
Overview
2-methylbutyryl-CoA dehydrogenase deficiency (2MBCD) is a rare autosomal recessive disorder of isoleucine metabolism caused by ACADSB gene mutations, leading to elevated C5 acylcarnitine and urinary 2-methylbutyrylglycine [1][4][14]. While often asymptomatic, clinical features may include hypotonia, developmental delay, seizures, and metabolic crises triggered by catabolic stressors [1][5][14]. Diagnosis is typically through newborn screening (tandem mass spectrometry) with confirmatory genetic testing [4][7]. Management focuses on dietary protein restriction and metabolic monitoring [3][9].
Burden
Most patients remain asymptomatic with early intervention, but untreated cases risk neurodevelopmental deficits [1][9][14]
Lifelong dietary management required, posing logistical/financial challenges [3][4][16]
Clinical heterogeneity complicates prognosis; rare cases progress to metabolic crises or autism-spectrum disorders [5][7][14]
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
22 drug discovery papers about 2-methylbutyryl-CoA dehydrogenase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
22 drug discovery papers about 2-methylbutyryl-CoA dehydrogenase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-08-21 | Large-scale newborn screening for organic acidemias in Quanzhou, China: a 10-year retrospective observational study.
Organic acidemias (OADs) are a group of congenital metabolic disorders whose incidence, disease spectrum, and genetic profiles differ greatly across countries. This study aimed to determine the characteristics of OADs in Quanzhou, China. A total of 693,797 newborns were screened for OADs from 2014 to 2023, and the acylcarnitine and genetic profiles of patients with OADs were analysed. Sixty-nine patients were confirmed to have OADs, with an overall incidence of 1/10,055 newborns. Seven types of OADs were identified, of which 18 were 2-methylbutyryl-CoA dehydrogenase deficiency (MBAD), 18 were 3-methylcrotonyl-CoA carboxylase deficiency (3-MCCD), 13 were glutaric acidemia type 1 (GA-1), nine were isobutyryl-CoA dehydrogenase deficiency (IBDD), five were isovaleric acidemia (IVA), four were methylmalonic acidemia (MMA), and two were propionic academia (PA). All but one of the patients with MBAD had elevated isovalerylcarnitine levels and corresponding ratios during screening. All patients with GA-1 had elevated glutarylcarnitine levels and corresponding ratios during screening, except for one with a low free carnitine level. The remaining patients presented with elevated acylcarnitine levels during screening and recall. Several variant hotspots were identified in the ACADSB, MCCC1, MCCC2, GCDH, ACAD8, and IVD. The overall incidence of OADs in the study population was 1/10,055 newborns, with MBAD, 3-MCCD, and GA-1 being the three most common. The acylcarnitine profiles and genetic features of most OADs have been elucidated. Our findings provide useful information for newborn screening, genetic diagnosis, and the prevention of OADs.
2025-07-06 | Metabolic rerouting of valine and isoleucine oxidation increases survival in zebrafish models of disorders of propionyl-CoA metabolism
Branched-chain amino acid (BCAA) oxidation is a multistep process leading to the formation of acetyl-CoA and propionyl-CoA. The syndromes associated with disturbed BCAA oxidation are clinically and biochemically heterogenous. While the common organic acidemias, propionic (PA) and methylmalonic acidemia (MMA), arise from deficient activity of propionyl-CoA carboxylase and methylmalonyl-CoA mutase and are life-threatening conditions with limited treatment options, isobutyryl-CoA dehydrogenase (IBD), and 2-methylbutyryl-CoA dehydrogenase (2-MBD) deficiencies manifest as biochemical traits, with no associated symptoms or consistent metabolic phenotypes. To assess whether the proximal interruption of valine and isoleucine oxidation might represent an approach to treat MMA and PA, we investigated the effects of loss of function of acad8 (encoding IBD) and acadsb (encoding 2-MBD), singly and doubly, on biochemical and morphological findings of zebrafish models of pccb-related propionic acidemia (PA) and mmut methylmalonic acidemia (MMA). Although acad8-/-;acadsb-/- double mutants showed growth failure and early mortality, the proximal interruption of valine and isoleucine oxidation in double (pccb/acad8, pccb/acadsb, mmut/acad8, mmut/acadsb) and triple (pccb/acad8/acadsb, mmut/acad8/acadsb) homozygous mutants improved pccb-/- and mmut-/- survival and reduced propionate-derived toxic metabolites, supporting the rationale for pursuing modulation of IBD and 2-MBD activity as a strategy to reduce the metabolic load and improve clinical outcomes in PA and MMA.
2023-09-08 | Acyl-CoA dehydrogenase substrate promiscuity: Challenges and opportunities for development of substrate reduction therapy in disorders of valine and isoleucine metabolism.
Toxicity of accumulating substrates is a significant problem in several disorders of valine and isoleucine degradation notably short-chain enoyl-CoA hydratase (ECHS1 or crotonase) deficiency, 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, propionic acidemia (PA), and methylmalonic aciduria (MMA). Isobutyryl-CoA dehydrogenase (ACAD8) and short/branched-chain acyl-CoA dehydrogenase (SBCAD, ACADSB) function in the valine and isoleucine degradation pathways, respectively. Deficiencies of these acyl-CoA dehydrogenase (ACAD) enzymes are considered biochemical abnormalities with limited or no clinical consequences. We investigated whether substrate reduction therapy through inhibition of ACAD8 and SBCAD can limit the accumulation of toxic metabolic intermediates in disorders of valine and isoleucine metabolism. Using analysis of acylcarnitine isomers, we show that 2-methylenecyclopropaneacetic acid (MCPA) inhibited SBCAD, isovaleryl-CoA dehydrogenase, short-chain acyl-CoA dehydrogenase and medium-chain acyl-CoA dehydrogenase, but not ACAD8. MCPA treatment of wild-type and PA HEK-293 cells caused a pronounced decrease in C3-carnitine. Furthermore, deletion of ACADSB in HEK-293 cells led to an equally strong decrease in C3-carnitine when compared to wild-type cells. Deletion of ECHS1 in HEK-293 cells caused a defect in lipoylation of the E2 component of the pyruvate dehydrogenase complex, which was not rescued by ACAD8 deletion. MCPA was able to rescue lipoylation in ECHS1 KO cells, but only in cells with prior ACAD8 deletion. SBCAD was not the sole ACAD responsible for this compensation, which indicates substantial promiscuity of ACADs in HEK-293 cells for the isobutyryl-CoA substrate. Substrate promiscuity appeared less prominent for 2-methylbutyryl-CoA at least in HEK-293 cells. We suggest that pharmacological inhibition of SBCAD to treat PA should be investigated further.
2022-11-22 | Acyl-CoA dehydrogenase substrate promiscuity limits the potential for development of substrate reduction therapy in disorders of valine and isoleucine metabolism
Abstract Toxicity of accumulating substrates is a significant problem in several disorders of valine and isoleucine degradation notably short-chain enoyl-CoA hydratase (ECHS1 or crotonase) deficiency, 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, propionic acidemia (PA) and methylmalonic aciduria (MMA). Isobutyryl-CoA dehydrogenase (ACAD8) and short/branched-chain acyl-CoA dehydrogenase (SBCAD, ACADSB ) function in the valine and isoleucine degradation pathways, respectively. Deficiencies of these acyl-CoA dehydrogenase (ACAD) enzymes are considered biochemical abnormalities with limited or no clinical consequences. We investigated whether substrate reduction therapy through inhibition of ACAD8 and SBCAD can limit the accumulation of toxic metabolic intermediates in disorders of valine and isoleucine metabolism. Using analysis of acylcarnitine isomers, we show that 2-methylenecyclopropaneacetic acid (MCPA) inhibited SBCAD, isovaleryl-CoA dehydrogenase, short-chain acyl-CoA dehydrogenase and medium-chain acyl-CoA dehydrogenase, but not ACAD8. MCPA treatment of wild-type and PA HEK-293 cells caused a pronounced decrease in C3-carnitine. Furthermore, deletion of ACADSB in HEK-293 cells led to an equally strong decrease in C3-carnitine when compared to wild-type cells. Deletion of ECHS1 in HEK-293 cells caused a defect in lipoylation of the E2 component of the pyruvate dehydrogenase complex, which was not rescued by ACAD8 deletion. MCPA was able to rescue lipoylation in ECHS1 KO cells, but only in cells with prior ACAD8 deletion. SBCAD was not the sole ACAD responsible for this compensation, which indicates substantial promiscuity of ACADs in HEK-293 cells for the isobutyryl-CoA substrate. Substrate promiscuity appeared less prominent for 2-methylbutyryl-CoA at least in HEK-293 cells. We suggest that pharmacological inhibition of SBCAD to treat PA should be investigated further.
2020-11-24 | Genetic dissection of the mitochondrial lipoylation pathway in yeast
ABSTRACT Background Lipoylation of 2-ketoacid dehydrogenases is essential for mitochondrial function in eukaryotes. While the basic principles of the lipoylation processes have been worked out, we still lack a thorough understanding of the details of this important post-translational modification pathway. Here we used yeast as a model organism to characterize substrate usage by the highly conserved eukaryotic octanoyl/lipoyl transferases in vivo and queried how amenable the lipoylation system is to supplementation with exogenous substrate. Results We show that the requirement for mitochondrial fatty acid synthesis to provide substrates for lipoylation of the 2-ketoacid dehydrogenases can be bypassed by supplying the cells with free lipoic acid (LA) or octanoic acid (C8) and a mitochondrially targeted fatty acyl/lipoyl activating enzyme. We also provide evidence that the S. cerevisiae lipoyl transferase Lip3, in addition to transferring LA from the glycine cleavage system H protein to the pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (KGD) E2 subunits, can transfer this cofactor from the PDH complex to the KGD complex. In support of yeast as a model system for human metabolism, we demonstrate that the human octanoyl/lipoyl transferases can substitute for their counterparts in yeast to support respiratory growth and protein lipoylation. Like the wild-type yeast enzyme, the human lipoyl transferase LIPT1 responds to LA supplementation in the presence of the activating enzyme LplA. Conclusions In the yeast model system, the eukaryotic lipoylation pathway can use free LA and C8 as substrates when fatty/lipoic acid activating enzymes are targeted to mitochondria. Lip3 LA transferase has a wider substrate specificity than previously recognized. We show that these features of the lipoylation mechanism in yeast are conserved in mammalian mitochondria. Our findings have important implications for the development of effective therapies for the treatment of LA or mtFAS deficiency-related disorders.
small molecules
2025-08-21 | Large-scale newborn screening for organic acidemias in Quanzhou, China: a 10-year retrospective observational study.
Organic acidemias (OADs) are a group of congenital metabolic disorders whose incidence, disease spectrum, and genetic profiles differ greatly across countries. This study aimed to determine the characteristics of OADs in Quanzhou, China. A total of 693,797 newborns were screened for OADs from 2014 to 2023, and the acylcarnitine and genetic profiles of patients with OADs were analysed. Sixty-nine patients were confirmed to have OADs, with an overall incidence of 1/10,055 newborns. Seven types of OADs were identified, of which 18 were 2-methylbutyryl-CoA dehydrogenase deficiency (MBAD), 18 were 3-methylcrotonyl-CoA carboxylase deficiency (3-MCCD), 13 were glutaric acidemia type 1 (GA-1), nine were isobutyryl-CoA dehydrogenase deficiency (IBDD), five were isovaleric acidemia (IVA), four were methylmalonic acidemia (MMA), and two were propionic academia (PA). All but one of the patients with MBAD had elevated isovalerylcarnitine levels and corresponding ratios during screening. All patients with GA-1 had elevated glutarylcarnitine levels and corresponding ratios during screening, except for one with a low free carnitine level. The remaining patients presented with elevated acylcarnitine levels during screening and recall. Several variant hotspots were identified in the ACADSB, MCCC1, MCCC2, GCDH, ACAD8, and IVD. The overall incidence of OADs in the study population was 1/10,055 newborns, with MBAD, 3-MCCD, and GA-1 being the three most common. The acylcarnitine profiles and genetic features of most OADs have been elucidated. Our findings provide useful information for newborn screening, genetic diagnosis, and the prevention of OADs.
2025-07-06 | Metabolic rerouting of valine and isoleucine oxidation increases survival in zebrafish models of disorders of propionyl-CoA metabolism
Branched-chain amino acid (BCAA) oxidation is a multistep process leading to the formation of acetyl-CoA and propionyl-CoA. The syndromes associated with disturbed BCAA oxidation are clinically and biochemically heterogenous. While the common organic acidemias, propionic (PA) and methylmalonic acidemia (MMA), arise from deficient activity of propionyl-CoA carboxylase and methylmalonyl-CoA mutase and are life-threatening conditions with limited treatment options, isobutyryl-CoA dehydrogenase (IBD), and 2-methylbutyryl-CoA dehydrogenase (2-MBD) deficiencies manifest as biochemical traits, with no associated symptoms or consistent metabolic phenotypes. To assess whether the proximal interruption of valine and isoleucine oxidation might represent an approach to treat MMA and PA, we investigated the effects of loss of function of acad8 (encoding IBD) and acadsb (encoding 2-MBD), singly and doubly, on biochemical and morphological findings of zebrafish models of pccb-related propionic acidemia (PA) and mmut methylmalonic acidemia (MMA). Although acad8-/-;acadsb-/- double mutants showed growth failure and early mortality, the proximal interruption of valine and isoleucine oxidation in double (pccb/acad8, pccb/acadsb, mmut/acad8, mmut/acadsb) and triple (pccb/acad8/acadsb, mmut/acad8/acadsb) homozygous mutants improved pccb-/- and mmut-/- survival and reduced propionate-derived toxic metabolites, supporting the rationale for pursuing modulation of IBD and 2-MBD activity as a strategy to reduce the metabolic load and improve clinical outcomes in PA and MMA.
2023-09-08 | Acyl-CoA dehydrogenase substrate promiscuity: Challenges and opportunities for development of substrate reduction therapy in disorders of valine and isoleucine metabolism.
Toxicity of accumulating substrates is a significant problem in several disorders of valine and isoleucine degradation notably short-chain enoyl-CoA hydratase (ECHS1 or crotonase) deficiency, 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, propionic acidemia (PA), and methylmalonic aciduria (MMA). Isobutyryl-CoA dehydrogenase (ACAD8) and short/branched-chain acyl-CoA dehydrogenase (SBCAD, ACADSB) function in the valine and isoleucine degradation pathways, respectively. Deficiencies of these acyl-CoA dehydrogenase (ACAD) enzymes are considered biochemical abnormalities with limited or no clinical consequences. We investigated whether substrate reduction therapy through inhibition of ACAD8 and SBCAD can limit the accumulation of toxic metabolic intermediates in disorders of valine and isoleucine metabolism. Using analysis of acylcarnitine isomers, we show that 2-methylenecyclopropaneacetic acid (MCPA) inhibited SBCAD, isovaleryl-CoA dehydrogenase, short-chain acyl-CoA dehydrogenase and medium-chain acyl-CoA dehydrogenase, but not ACAD8. MCPA treatment of wild-type and PA HEK-293 cells caused a pronounced decrease in C3-carnitine. Furthermore, deletion of ACADSB in HEK-293 cells led to an equally strong decrease in C3-carnitine when compared to wild-type cells. Deletion of ECHS1 in HEK-293 cells caused a defect in lipoylation of the E2 component of the pyruvate dehydrogenase complex, which was not rescued by ACAD8 deletion. MCPA was able to rescue lipoylation in ECHS1 KO cells, but only in cells with prior ACAD8 deletion. SBCAD was not the sole ACAD responsible for this compensation, which indicates substantial promiscuity of ACADs in HEK-293 cells for the isobutyryl-CoA substrate. Substrate promiscuity appeared less prominent for 2-methylbutyryl-CoA at least in HEK-293 cells. We suggest that pharmacological inhibition of SBCAD to treat PA should be investigated further.
2022-11-22 | Acyl-CoA dehydrogenase substrate promiscuity limits the potential for development of substrate reduction therapy in disorders of valine and isoleucine metabolism
Abstract Toxicity of accumulating substrates is a significant problem in several disorders of valine and isoleucine degradation notably short-chain enoyl-CoA hydratase (ECHS1 or crotonase) deficiency, 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, propionic acidemia (PA) and methylmalonic aciduria (MMA). Isobutyryl-CoA dehydrogenase (ACAD8) and short/branched-chain acyl-CoA dehydrogenase (SBCAD, ACADSB ) function in the valine and isoleucine degradation pathways, respectively. Deficiencies of these acyl-CoA dehydrogenase (ACAD) enzymes are considered biochemical abnormalities with limited or no clinical consequences. We investigated whether substrate reduction therapy through inhibition of ACAD8 and SBCAD can limit the accumulation of toxic metabolic intermediates in disorders of valine and isoleucine metabolism. Using analysis of acylcarnitine isomers, we show that 2-methylenecyclopropaneacetic acid (MCPA) inhibited SBCAD, isovaleryl-CoA dehydrogenase, short-chain acyl-CoA dehydrogenase and medium-chain acyl-CoA dehydrogenase, but not ACAD8. MCPA treatment of wild-type and PA HEK-293 cells caused a pronounced decrease in C3-carnitine. Furthermore, deletion of ACADSB in HEK-293 cells led to an equally strong decrease in C3-carnitine when compared to wild-type cells. Deletion of ECHS1 in HEK-293 cells caused a defect in lipoylation of the E2 component of the pyruvate dehydrogenase complex, which was not rescued by ACAD8 deletion. MCPA was able to rescue lipoylation in ECHS1 KO cells, but only in cells with prior ACAD8 deletion. SBCAD was not the sole ACAD responsible for this compensation, which indicates substantial promiscuity of ACADs in HEK-293 cells for the isobutyryl-CoA substrate. Substrate promiscuity appeared less prominent for 2-methylbutyryl-CoA at least in HEK-293 cells. We suggest that pharmacological inhibition of SBCAD to treat PA should be investigated further.
2020-11-24 | Genetic dissection of the mitochondrial lipoylation pathway in yeast
ABSTRACT Background Lipoylation of 2-ketoacid dehydrogenases is essential for mitochondrial function in eukaryotes. While the basic principles of the lipoylation processes have been worked out, we still lack a thorough understanding of the details of this important post-translational modification pathway. Here we used yeast as a model organism to characterize substrate usage by the highly conserved eukaryotic octanoyl/lipoyl transferases in vivo and queried how amenable the lipoylation system is to supplementation with exogenous substrate. Results We show that the requirement for mitochondrial fatty acid synthesis to provide substrates for lipoylation of the 2-ketoacid dehydrogenases can be bypassed by supplying the cells with free lipoic acid (LA) or octanoic acid (C8) and a mitochondrially targeted fatty acyl/lipoyl activating enzyme. We also provide evidence that the S. cerevisiae lipoyl transferase Lip3, in addition to transferring LA from the glycine cleavage system H protein to the pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (KGD) E2 subunits, can transfer this cofactor from the PDH complex to the KGD complex. In support of yeast as a model system for human metabolism, we demonstrate that the human octanoyl/lipoyl transferases can substitute for their counterparts in yeast to support respiratory growth and protein lipoylation. Like the wild-type yeast enzyme, the human lipoyl transferase LIPT1 responds to LA supplementation in the presence of the activating enzyme LplA. Conclusions In the yeast model system, the eukaryotic lipoylation pathway can use free LA and C8 as substrates when fatty/lipoic acid activating enzymes are targeted to mitochondria. Lip3 LA transferase has a wider substrate specificity than previously recognized. We show that these features of the lipoylation mechanism in yeast are conserved in mammalian mitochondria. Our findings have important implications for the development of effective therapies for the treatment of LA or mtFAS deficiency-related disorders.
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