RARE DISEASE
3-methylcrotonyl-CoA carboxylase deficiency
3-methylcrotonyl-CoA carboxylase deficiency
3-methylcrotonyl-CoA carboxylase deficiency
Synonyms: 3-methylcrotonylglycinuria, MCC deficiency, MCCD
Synonyms: 3-methylcrotonylglycinuria, MCC deficiency, MCCD
Synonyms: 3-methylcrotonylglycinuria, MCC deficiency, MCCD
Drug discovery
38
papers
On emerging therapies
Overview
3-methylcrotonyl-CoA carboxylase deficiency (3-MCCD) is an autosomal recessive disorder of leucine metabolism caused by mutations in MCCC1 or MCCC2 genes. Clinical presentation varies widely, ranging from asymptomatic cases (most common) to metabolic crises triggered by infections, fasting, or high-protein intake, manifesting as vomiting, hypoglycemia, lethargy, and neurological complications. Diagnosis relies on elevated C5-OH acylcarnitine in newborn screening, urinary 3-hydroxyisovaleric acid, and genetic testing. Prognosis is generally favorable with early management [1][2][5][16].
Burden
Low clinical penetrance: ~90% remain asymptomatic, but 10% risk acute metabolic decompensation with potential morbidity (e.g., seizures, coma) [5][16].
Long-term neurological sequelae (e.g., developmental delays) are rare but reported in severe, untreated cases [4][9].
Minimal lifelong burden for most patients, though symptomatic cases require ongoing dietary and metabolic surveillance [5][14].
Therapies
Asymptomatic cases: Often require no intervention beyond monitoring [1][13].
Symptomatic management: L-carnitine supplementation to correct deficiency and enhance detoxification; avoidance of fasting/prolonged catabolism [1][6][16].
Acute crises: Emergency protocols with IV glucose, acidosis correction, and temporary protein restriction [1][6][13].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
38 drug discovery papers about 3-methylcrotonyl-CoA carboxylase deficiency, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
38 drug discovery papers about 3-methylcrotonyl-CoA carboxylase deficiency, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-22 | Substrate-enhanced filamentation of 3-methylcrotonyl-CoA carboxylase in Legionella pneumophila
Abstract 3-Methylcrotonyl-CoA carboxylase (MCC) is a biotin-dependent carboxylase that metabolizes the amino acid leucine. MCC is present in bacteria, fungi, plants, and animals. In humans, its overexpression is linked to cancer, and its deficiency is linked to inborn errors of metabolism with severe consequences, so understanding its structure and function has far reaching implications. Here, we explore the MCC from Legionella pneumophila , a pathogenic bacterium with a biphasic life cycle. Our endogenous holoenzyme yielded the highest resolution cryo-EM structure of MCC to date, allowing for identification of protein components by the machine learning tool ModelAngelo, confirmed independently by mass spectrometry. We also observed enhanced filamentation of MCC upon substrate binding. We propose that this filamentation, previously observed in the eukaryotic MCCs, but not in bacterial MCCs, may be important for cellular processes such as differentiation of life cycle or cell division.
2026-04-28 | Salvia miltiorrhiza Tanshinone IIA for Mitochondrial Bioenergetics Enhancement in 3-MCC Deficiency
Tanshinone IIA activates PGC-1α and SIRT1 pathways, enhancing mitochondrial biogenesis and oxidative phosphorylation efficiency. This compound upregulates alternative fatty acid oxidation enzymes including ACOX1 and CPT1A, potentially bypassing the blocked leucine catabolism pathway while improving overall cellular energy metabolism.
2025-12-24 | Incidence of Organic Acid Disorders in 13 Million Chinese Newborns: A Systematic Review and Meta-Analysis.
Organic acid disorders (OADs) are inherited metabolic defects in the enzymes and cofactors involved in metabolic pathways. This systematic review and meta-analysis investigated the incidence and regional differences in OADs between the northern and southern regions of China. Searches of the PubMed, Embase, Web of Science, and Chinese databases (CNKI, Veipu, and Wanfang) revealed 1784 studies indexed between January 2002 and December 2024. After quality assessment and data extraction, the meta-analysis was conducted on OAD screening data from 57 studies involving 13,314,056 newborns and 1501 OAD cases in China. The seven most prevalent OADs were methylmalonic acidemia (MMA), 3-methylcrotonyl-CoA carboxylase deficiency, glutaric acidemia type I, isobutyryl-CoA dehydrogenase deficiency, isovaleric acidemia, 2-methylbutyryl-CoA dehydrogenase deficiency (2-MBD), and propionic acidemia. The meta-analysis revealed an OAD prevalence of 112.38 (95% confidence interval 106.70-118.07) per 1,000,000 newborns. The incidence of OADs and MMA was significantly higher in northern China than in southern China, whereas the incidence of 2-MBD was significantly lower in northern China than in southern China (p < 0.0001). Additionally, the ratio of MMA combined with homocystinuria to MMA was higher in northern China than in southern China (p < 0.05). These results provide valuable epidemiological insights and guidance for newborn screening for OADs in China.
2025-12-24 | Psychological Impact of Newborn Screening for 3-Methylcrotonyl-CoA Carboxylase Deficiency: The Parental Experience.
3-Methylcrotonyl-CoA carboxylase deficiency (3-MCCD) is a metabolic disorder with a wide clinical spectrum ranging from asymptomatic individuals to severe metabolic decompensation. Following the introduction of expanded newborn screening, a high number of asymptomatic individuals with 3-MCCD were identified, prompting debates about its inclusion in screening panels. In order to inform policy and healthcare decisions regarding the inclusion of 3-MCCD in newborn screening programs, we evaluated the long-term outcomes for newborns with positive results over a decade of screening experience in North-East Italy, as well as the psychological impact on their parents. Of the 336,668 newborns screened between 2014 and 2025, 9 were confirmed to be affected. These infants underwent annual clinical and biochemical assessments, including dried blood spot acylcarnitine profile, plasma free carnitine, and urinary organic acids assays. An emergency protocol was provided to all affected children to manage intercurrent illnesses. An ad hoc survey was developed to assess the psychological impact of the disease on parents. During follow-up (mean age at last visit: 4.2 years), one patient experienced metabolic decompensation during an intercurrent illness, which was promptly treated. One patient presented with growth retardation and another with transient psychomotor delay. Five patients developed carnitine deficiency, requiring supplementation. Psychological assessments revealed an initial high level of parental psychological impact, which decreased over time. All parents strongly supported the screening program. Newborn screening for 3-MCCD enabled the early identification and management of affected individuals, thereby avoiding severe metabolic decompensation. Although there is an initial psychological burden on parents, it significantly decreases over time. Therefore, the long-term benefits of newborn screening for 3-MCCD seem to outweigh the psychological drawbacks.
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.
small molecules
2026-09-22 | Substrate-enhanced filamentation of 3-methylcrotonyl-CoA carboxylase in Legionella pneumophila
Abstract 3-Methylcrotonyl-CoA carboxylase (MCC) is a biotin-dependent carboxylase that metabolizes the amino acid leucine. MCC is present in bacteria, fungi, plants, and animals. In humans, its overexpression is linked to cancer, and its deficiency is linked to inborn errors of metabolism with severe consequences, so understanding its structure and function has far reaching implications. Here, we explore the MCC from Legionella pneumophila , a pathogenic bacterium with a biphasic life cycle. Our endogenous holoenzyme yielded the highest resolution cryo-EM structure of MCC to date, allowing for identification of protein components by the machine learning tool ModelAngelo, confirmed independently by mass spectrometry. We also observed enhanced filamentation of MCC upon substrate binding. We propose that this filamentation, previously observed in the eukaryotic MCCs, but not in bacterial MCCs, may be important for cellular processes such as differentiation of life cycle or cell division.
2026-04-28 | Salvia miltiorrhiza Tanshinone IIA for Mitochondrial Bioenergetics Enhancement in 3-MCC Deficiency
Tanshinone IIA activates PGC-1α and SIRT1 pathways, enhancing mitochondrial biogenesis and oxidative phosphorylation efficiency. This compound upregulates alternative fatty acid oxidation enzymes including ACOX1 and CPT1A, potentially bypassing the blocked leucine catabolism pathway while improving overall cellular energy metabolism.
2025-12-24 | Incidence of Organic Acid Disorders in 13 Million Chinese Newborns: A Systematic Review and Meta-Analysis.
Organic acid disorders (OADs) are inherited metabolic defects in the enzymes and cofactors involved in metabolic pathways. This systematic review and meta-analysis investigated the incidence and regional differences in OADs between the northern and southern regions of China. Searches of the PubMed, Embase, Web of Science, and Chinese databases (CNKI, Veipu, and Wanfang) revealed 1784 studies indexed between January 2002 and December 2024. After quality assessment and data extraction, the meta-analysis was conducted on OAD screening data from 57 studies involving 13,314,056 newborns and 1501 OAD cases in China. The seven most prevalent OADs were methylmalonic acidemia (MMA), 3-methylcrotonyl-CoA carboxylase deficiency, glutaric acidemia type I, isobutyryl-CoA dehydrogenase deficiency, isovaleric acidemia, 2-methylbutyryl-CoA dehydrogenase deficiency (2-MBD), and propionic acidemia. The meta-analysis revealed an OAD prevalence of 112.38 (95% confidence interval 106.70-118.07) per 1,000,000 newborns. The incidence of OADs and MMA was significantly higher in northern China than in southern China, whereas the incidence of 2-MBD was significantly lower in northern China than in southern China (p < 0.0001). Additionally, the ratio of MMA combined with homocystinuria to MMA was higher in northern China than in southern China (p < 0.05). These results provide valuable epidemiological insights and guidance for newborn screening for OADs in China.
2025-12-24 | Psychological Impact of Newborn Screening for 3-Methylcrotonyl-CoA Carboxylase Deficiency: The Parental Experience.
3-Methylcrotonyl-CoA carboxylase deficiency (3-MCCD) is a metabolic disorder with a wide clinical spectrum ranging from asymptomatic individuals to severe metabolic decompensation. Following the introduction of expanded newborn screening, a high number of asymptomatic individuals with 3-MCCD were identified, prompting debates about its inclusion in screening panels. In order to inform policy and healthcare decisions regarding the inclusion of 3-MCCD in newborn screening programs, we evaluated the long-term outcomes for newborns with positive results over a decade of screening experience in North-East Italy, as well as the psychological impact on their parents. Of the 336,668 newborns screened between 2014 and 2025, 9 were confirmed to be affected. These infants underwent annual clinical and biochemical assessments, including dried blood spot acylcarnitine profile, plasma free carnitine, and urinary organic acids assays. An emergency protocol was provided to all affected children to manage intercurrent illnesses. An ad hoc survey was developed to assess the psychological impact of the disease on parents. During follow-up (mean age at last visit: 4.2 years), one patient experienced metabolic decompensation during an intercurrent illness, which was promptly treated. One patient presented with growth retardation and another with transient psychomotor delay. Five patients developed carnitine deficiency, requiring supplementation. Psychological assessments revealed an initial high level of parental psychological impact, which decreased over time. All parents strongly supported the screening program. Newborn screening for 3-MCCD enabled the early identification and management of affected individuals, thereby avoiding severe metabolic decompensation. Although there is an initial psychological burden on parents, it significantly decreases over time. Therefore, the long-term benefits of newborn screening for 3-MCCD seem to outweigh the psychological drawbacks.
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.
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