DeCure for 3-methylcrotonyl-CoA carboxylase 2 deficiency
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for 3-methylcrotonyl-CoA carboxylase 2 deficiency — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease module3-methylcrotonyl-CoA carboxylase 2 deficiency maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
approvedBiotinApproved drug
Structures already discussed alongside 3-methylcrotonyl-coa carboxylase 2 deficiency in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
methylcrotonyl-CoA carboxylase subunit 2 (MCCC2) — MCCC2 is one of the genes in this disease's Open Targets module — part of the target space DeCure's repurposing candidates point at. The protein backbone is drawn as a cartoon. The structure has biotin bound in it, shown as sticks.
Loading structure…
helix sheet btndrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8XL6 · 2.29 Å · ligand BIOTIN (BTN). Experimental structure, not a prediction.
What the evidence adds up to
Two patients with isolated 3-methylcrotonyl-CoA carboxylase deficiency had urine that contained no or only trace 3-methylcrotonylglycine, the marker considered pathognomonic for the disorder. One was a girl with trisomy 21 detected by newborn screening with an elevated 5‑carbon hydroxycarnitine species; the other came to attention at five months with failure to thrive and developmental delay. Both had elevated 3-hydroxyisovaleric acid in urine but no demonstrable 3-methylcrotonylglycine. Enzyme studies in cultured fibroblasts showed residual activities of 5–7% and 12% of the median control value. Incorporation of 14C‑isovaleric acid into intact fibroblasts was essentially normal, suggesting the overall pathway was at least partially functional and potentially explaining the absence of the urinary marker. Mutation analysis of MCCA and MCCB genes showed both patients were compound heterozygous for a missense mutation, MCCB‑c.1015G→A (p.V339M), and a second mutation that leads to undetectable MCCB messenger RNA. The authors warn that absent or trace 3-methylcrotonylglycine raises the potential for misdiagnosis when relying solely on urine organic acid analysis by gas chromatography‑mass spectrometry.
A 2023 case report describes a child diagnosed at 12 months of age with bi‑allelic mutations in MCCC2. Newborn screening had not revealed any abnormalities. The child presented with recurrent viral infections and non‑specific gastrointestinal symptoms—vomiting, hematochezia, and gaseous abdominal distention. Evaluation for underlying immunodeficiency was unremarkable. The authors note that the condition is typically diagnosed by newborn screening and that patients diagnosed later generally present with metabolic disturbances, seizures, failure to thrive, or delayed development.
A separate report from 1940, which appears to be misdated or misattributed in the provided text, states that cardiac evaluation should be performed in patients with 3‑methylcrotonyl‑CoA carboxylase deficiency and that the disorder should be included in the differential diagnosis of dilatative cardiomyopathy. No patient numbers or survival data are given in that report.
No drug treatment is mentioned in any of these abstracts. What is missing is any controlled trial of a therapy, any systematic data on long‑term outcomes, and any clear stratification of patients by genotype or residual enzyme activity that might predict clinical course. The diagnostic pitfalls described also mean that prevalence estimates based on newborn screening may be incomplete.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Inherited Metabolic Disease · 2005 · 29 citations
Consanguineous 3‐methylcrotonyl‐CoA carboxylase deficiency: Early‐onset necrotizing encephalopathy with lethal outcome
AbstractA patient with a severe neonatal variant of 3-methylcrotonyl-CoA carboxylase (MCC) deficiency is reported. The first child of healthy consanguineous Turkish parents presented on the second day of life with dehydration, cyanosis, no sucking, generalized muscular hypotonia, encephalopathy, respiratory depression requiring mechanic ventilation, macrocephaly, severe acidosis and hypoglycaemia. Elevated C5-OH-carnitine in dried blood spot by tandem MS and elevated urinary excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine suggested MCC deficiency, confirmed by enzyme analysis in cultured fibroblasts. Cerebral ultrasonography and cranial CT findings revealed progressive changes such as disseminated encephalomalacia, cystic changes, ventricular dilatation and cerebral atrophy. Treatment with high-dose biotin and protein-restricted diet was ineffective and the patient died at the age of 33 days with progressive neurological deterioration. Mutation analysis revealed a homozygous mutation in the splice acceptor site of intron 15 in the MCC beta-subunit. Early-onset severe necrotizing encephalopathy should be included in the differential diagnosis of isolated MCC deficiency.
Potential Misdiagnosis of 3-Methylcrotonyl-Coenzyme A Carboxylase Deficiency Associated With Absent or Trace Urinary 3-Methylcrotonylglycine
AbstractWe report 2 patients with isolated 3-methylcrotonyl-coenzyme A carboxylase deficiency whose urine was devoid of, or contained only trace, 3-methylcrotonylglycine, the pathognomonic marker for this disorder. The first patient, a girl with trisomy 21, was detected through newborn screening with an elevated 5 carbon hydroxycarnitine species level, and the second patient came to clinical attention at the age of 5 months because of failure to thrive and developmental delay. Investigation of urinary organic acids revealed an elevated 3-hydroxyisovaleric acid level but no demonstrable 3-methylcrotonylglycine in both patients. Enzyme studies in cultured fibroblasts confirmed isolated 3-methylcrotonyl-coenzyme A carboxylase deficiency with residual activities of 5% to 7% and 12% of the median control value, respectively. Incorporation of 14C-isovaleric acid into intact fibroblasts was essentially normal, showing that the overall pathway was at least partially functional and potentially explaining the absence of 3-methylcrotonylglycine in urine. Mutation analysis of the MCCA and MCCB genes revealed that both patients were compound heterozygous for a missense mutation, MCCB-c.1015G-->A (p.V339M), and a second mutation that leads to undetectable MCCB messenger (poly A+) RNA. Absent or trace 3-methylcrotonylglycine levels in urine raises the potential for misdiagnosis in the clinical biochemical genetics laboratory based solely on urine organic acid analysis using combined gas chromatography-mass spectrometry.
AbstractOBJECTIVE: To explore the molecular mechanism for a boy suspected with 3-methylcrotonyl-CoA carboxylase deficiency by neonatal screening. METHODS: PCR and Sanger sequencing were used to identify potential mutations of MCCC1 and MCCC2 genes. SIFT and Polyphen-2 software was used to predict the effect of variant on the protein function and conservation of the variant across various species. Human Splicing Finder and Swiss-PdbViewer4.1.0 were applied to analyze the possible mechanism of the variant. RESULTS: For the proband, a compound heterozygous mutation was discovered in the MCCC1 gene, namely c.539G>T (p.G180V) and c.704_711del (p.A235Vfs*4), which were inherited from his father and mother, respectively. The two mutations have disrupted the protein conformation, which in turn may impact the function of MCC protein. CONCLUSION: The compound heterozygous mutations of the MCCC1 gene may contribute to the 3-methylcrotonyl-CoA carboxylase deficiency manifested by the patient.
Thermal reaction and hydrogenation of coal. VII. Effects of the ratio of hydrogen to coal
AbstractIn order to understand the phenotypic spectrum of this rare disorder, cardiac evaluation should be made in patients with 3-methylcrotonyl-CoA carboxylase deficiency. Biochemical and clinical investigations have also to be performed in their parents and siblings. In addition, 3-methylcrotonyl-CoA carboxylase deficiency should be included in the differential diagnosis of dilatative cardiomyopathy.
A Unique Presentation of 3-Methylcrotonyl-CoA Carboxylase Deficiency
Abstract3-methylcrotonyl-CoA carboxylase deficiency is an autosomal recessive disorder resulting in impaired leucine metabolism. The condition is typically diagnosed with newborn screening; patients diagnosed at a later stage generally present with symptoms including metabolic disturbances, seizures, failure to thrive, or delayed development. We present the case of a child diagnosed at 12 months of age who was noted to have recurrent viral infections and nonspecific gastrointestinal symptoms of vomiting, hematochezia, and gaseous distention of the abdomen. Newborn screening did not reveal any abnormalities. Evaluation for underlying immunodeficiency was unremarkable; genetic testing revealed bi-allelic mutations in MCCC2, a known association of 3-methylcrotonyl-CoA carboxylase deficiency. It is important to consider genetic disorders when evaluating patients even if the newborn screening is unremarkable.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
