DeCure for Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency — screening already-approved drugs against its 3-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleMethylmalonic aciduria due to methylmalonyl-CoA mutase deficiency maps to a 3-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
approvedHydroxocobalaminApproved drug
Structures already discussed alongside methylmalonic aciduria due to methylmalonyl-coa mutase deficiency in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
The surface-exposed lipo-protein of BtuG2 — Hydroxocobalamin has a real, experimentally solved structure in complex with this target (PDB 8BB0, 1.5 Å). This is the drug's own deposited structure, not a prediction, and confirms it is a structurally characterised molecule rather than an untested guess.
Loading structure…
helix sheet i2adrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8BB0 · 1.5 Å · ligand Hydroxocobalamin (I2A). Experimental structure, not a prediction.
What the evidence adds up to
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency (mut type) is clinically distinct from the cblA subtype, which responds to hydroxocobalamin. In a cross-sectional European registry study of 95 mut patients and 28 cblA patients, metabolic crisis was the main presenting symptom in both groups, and age at diagnosis and biochemical disturbances during the first crisis were similar. However, at last follow-up, mut patients had significantly lower height and weight Z-scores, lower glomerular filtration rate, and more frequent chronic renal failure and neurological complications. Urine and plasma methylmalonic acid levels were significantly higher in the mut group. During the study, six mut patients died while all cblA patients survived. 98% of mut patients followed a calculated diet, and 69% received amino acid supplements; 86% of cblA patients were treated with intramuscular hydroxocobalamin, and 73% followed a calculated diet.
Two novel homozygous mutations in the MUT gene have been identified in Saudi infants presenting with sepsis-like illness, metabolic acidosis, and hyperammonemia. One infant, aged 6 days, carried a missense mutation (c.329A>G; p.Y110C) predicted to damage protein structure and function. The other, aged 3 months, carried a nonsense mutation (c.2200C>T; p.Q734X) leading to a premature stop codon. Both had elevated propionylcarnitine, urinary methylmalonic acid, 3-hydroxypropionic acid, and methylcitrate. A separate case report describes a ten-month-old infant with recurrent ketoacidosis, vomiting, dehydration, and mental retardation whose symptoms did not respond to vitamin B12; diagnosis was confirmed by MUT gene analysis.
Molecular cloning of the methylmalonyl-CoA mutase gene has provided information on primary structure, evolution, and mutations underlying the deficiency. Gene transfer studies have restored enzyme activity in deficient cells, raising the possibility of somatic gene therapy. However, no clinical trial of gene therapy in patients has been reported.
What is still missing is a large, well-funded clinical trial that can stratify mut patients by genotype and residual enzyme activity, and that tests whether any intervention—whether dietary, pharmacological, or gene-based—improves the poor renal and neurological outcomes and high mortality seen in this subgroup. The natural history data come from a registry with no randomised treatment assignment, and the molecular studies are preclinical.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Human Mutation · 1997 · 57 citations
Mutations inmut methylmalonic acidemia: Clinical and enzymatic correlations
AbstractMut methylmalonic acidemia is caused by mutations in the MUT locus encoding the enzyme methylmalonyl CoA mutase. Genotypic and phenotypic variability in this disease has been studied extensively by biochemical and somatic cell genetic techniques, by molecular cloning, and by gene transfer. Mutations have been identified that cause classic mut(o) phenotypes in which there is no detectable enzymatic activity, mut- phenotypes in which there is residual cobalamin-dependent activity, as well as a subset within both mut(o) and mut- phenotypes that exhibit interallelic complementation. These mutations illustrate the position, structure, and function of critical domains within this cobalamin-binding enzyme and provide new insights into the biochemical and clinical consequences of enzyme deficiency.
Journal of Inherited Metabolic Disease · 2020 · 39 citations · open access
Delineating the clinical spectrum of isolated methylmalonic acidurias: <scp><i>cblA</i></scp> and <i>mut</i>
AbstractINTRODUCTION: Long-term outcome is postulated to be different in isolated methylmalonic aciduria caused by mutations in the MMAA gene (cblA type) compared with methylmalonyl-CoA mutase deficiency (mut), but case definition was previously difficult. METHOD: Cross-sectional analysis of data from the European Registry and Network for Intoxication type Metabolic Diseases (Chafea no. December 1, 2010). RESULTS: Data from 28 cblA and 95 mut patients in most cases confirmed by mutation analysis (including 4 new mutations for cblA and 19 new mutations for mut). Metabolic crisis is the predominant symptom leading to diagnosis in both groups. Biochemical disturbances during the first crisis were similar in both groups, as well as the age at diagnosis. Z scores of body height and body weight were similar in both groups at birth, but were significantly lower in the mut group at the time of last visit. Glomerular filtration rate was significantly higher in cblA; and as a consequence, chronic renal failure and related complications were significantly less frequent and renal function could be preserved even in older patients. Neurological complications were predominantly found in the mut subgroup. Methylmalonic acidemia (MMA) levels in urine and plasma were significantly lower in cblA. 27/28 cblA patients were reported to be responsive to cobalamin, only 86% of cblA patients were treated with i.m. hydroxocobalamin. In total, 73% of cblA and 98% of mut patients followed a calculated diet with amino acid supplements in 27% (cblA) and 69% (mut). During the study interval, six patients from the mut group died, while all cblA patients survived. CONCLUSION: Although similar at first, cblA patients respond to hydroxocobalamin treatment, subsequently show significantly lower levels of MMA and a milder course than mut patients.
Perspectives on methylmalonic acidemia resulting from molecular cloning of methylmalonyl CoA mutase
AbstractMethylmalonyl CoA mutase deficiency (methylmalonic acidemia) has been a paradigm for biochemical and somatic cell genetic approaches to human disease. Recently, genes encoding this enzyme have been cloned from several species. These studies have provided information about the primary structure and evolution of this enzyme, the mutations which underlie its deficiency state, and the structure-function determinants which are required for its activity. Gene transfer studies now permit restitution of this enzyme to genetically deficient cells and may enable somatic gene therapy to be undertaken. Molecular genetic studies not only provide more detailed information about this enzyme, but introduce new perspectives on the molecular mechanisms and dynamics of its function and raise new questions about the dyshomeostatic consequences of its deficiency.
Saudi Medical Journal · 2015 · 5 citations · open access
Identification of 2 novel homozygous mutations in the methylmalonyl-CoA mutase gene in Saudi patients
AbstractThe aim of this report is to analyze the clinical features, and mutations of the methylmalonyl CoA mutase (MUT) gene in 2 patients with methylmalonic aciduria (MMA) attending King Saud University Medical City, Riyadh, Saudi Arabia in January 2014. The infants aged 6 days (patient 1) and 3 months (patient 2) with sepsis-like picture, metabolic acidosis, and hyperammonemia were presented. Investigations revealed high propionylcarnitine (C3), elevated urinary methylmalonic acids, 3-hydroxypropionic acids and methylcitrate, consistent with MMA. Sanger-sequencing detected a homozygous novel mutation (c.329A>G; p.Y110C) in the MUT gene in patient 1 and a heterozygous in parents. This mutation is predicted to have a damaging effect on the protein structure and function. In patient 2, we detected a novel homozygous nonsense mutation (c.2200C>T; p.Q734X) and a heterozygous in parents. This mutation leads to a premature stop-codon at codon 734 of the MUT gene. We identified 2 novel mutations in the MUT gene causing isolated MMA.
AbstractIsolated methylmalonic acidemia (AMR) is an inborn error of metabolism due to an enzymatic deficit in methylmalonyl-CoA mutase. AMR lead to increased methylmalonic acid in plasma and urine without hyperhomocysteinemia. The clinical signs are recurrent episodes of ketoacidosis and bouts of vomiting, dehydration and mental retardation. These symptoms do not respond to the administration of vitamin B12. We report a case of a ten-months-old infant to whom the diagnosis was suspected in the presence of a metabolic acidosis, hyperammonemia, without hepatic impairment and ketosis. The chromatography of organic acids showed elevated methylmalonic acid levels. Molecular genetics allowed confirming the diagnosis of deficit in methylmalonyl-CoA mutase demonstrating the genetic abnormality of the gene MUT.
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.
