DeCure for Methylmalonic aciduria and homocystinuria type cblC
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for methylmalonic aciduria and homocystinuria type cblC — screening already-approved drugs against its 6-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 and homocystinuria type cblC maps to a 6-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 and homocystinuria type cblc 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
A patient with methylmalonic aciduria and homocystinuria type cblC was identified at eight months of age, malnourished, hypotonic, and with macrocytic anaemia. Serum vitamin B12 was markedly increased, folate above normal, and urinary homocystine and methylmalonic acid were elevated. Fibroblast activity of N5-methyltetrahydrofolate:homocysteine methyltransferase was reduced to about 10% of concurrent controls. A course of hydroxocobalamin therapy produced a 90% reduction in methylmalonic acid excretion and normalisation of brain stem auditory and visual evoked potentials. The 1986 report supports monitoring methylmalonic acid for therapeutic response and using electrophysiologic studies to objectively monitor treatment.
A 2022 review of adult-onset cblC deficiency collected 45 cases, including a new patient aged 45 years. Symptoms included neurological, psychiatric, renal, ophthalmic, and thromboembolic presentations. In all cases intramuscular hydroxycobalamin was reported effective in reversing symptoms. The authors note that adult onset disease is often misdiagnosed due to poor awareness, and suggest it be considered in patients with atypical haemolytic uraemic syndrome, unexplained renal decline, idiopathic neuropathies, spinal cord degeneration, ataxias, recurrent thrombosis, or visual field defects. They recommend plasma homocysteine measurement as the first-line test and inclusion of cobalamin pathway genes in gene panels for atypical haemolytic uraemic syndrome and chronic kidney disorders.
A 2015 case report describes a four-month-old male with failure to thrive, pancytopenia, and neurological disturbance. A 2012 evaluation found that elevated urea and urinary methylmalonic acid predict adverse outcomes in patients with newborn onset, and that the combination of these two measures provided the most accurate predictive tool.
What is still missing is systematic prospective data on long-term outcomes in treated adult-onset patients, standardised protocols for monitoring and dosing of hydroxocobalamin across age groups, and prospective trials that stratify patients by genotype and age of onset to determine whether the reported reversal of symptoms is sustained or partial.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Neuropediatrics · 1986 · 28 citations
A Cobalamin Metabolic Defect with Homocystinuria, Methylmalonic Aciduria and Macrocytic Anemia*
AbstractWe have identified a patient with methylmalonic aciduria and homocystinuria due to a defect in cobalamin metabolism of the cb1C type mutant. At the time of admission at eight months of age the patient was malnourished, hypotonic and had macrocytic anemia. Neonatal screening for hypermethioninemia associated with homocystinuria had been normal. Serum vitamin B12 was markedly increased and folate concentration was above normal, as were urinary homocystine and methylmalonic acid. The patient had abnormal brain stem auditory and visual evoked potentials. Fibroblast activity of N5-methyltetrahydrofolate: homocysteine methyltransferase was reduced to approximately 10% of concurrent controls. A course of therapy with hydroxocobalamin resulted in a 90% reduction in excretion of methylmalonic acid and normalization of the evoked potentials. These studies support the efficacy of hydroxocobalamin therapy in this disease, suggest that methylmalonic acid may be the most appropriate metabolite to monitor for therapeutic response, and in importance of electrophysiologic studies in character in objectively monitoring the response to treatment metabolic disease.
Leadership in Neurodevelopmental Disabilities Program Year 1 Evaluation Report
AbstractThe patients of methylmalonic acidemia with homocystinuria tend to have an adverse outcome if they have newborn onsets. Elevated urea and urinary methylmalonic acid are predictors of adverse outcomes for the patients. They show similar effect for predicting severe adverse prognosis. The combination of methylmalonic acid in urine concentration and urea in serum concentration provided the most accurate predictive tool.
Adult-onset CblC deficiency: a challenging diagnosis involving different adult clinical specialists
AbstractAbstract Background Methylmalonic aciduria and homocystinuria, CblC type (OMIM #277400) is the most common disorder of cobalamin intracellular metabolism, an autosomal recessive disease, whose biochemical hallmarks are hyperhomocysteinemia, methylmalonic aciduria and low plasma methionine. Despite being a well-recognized disease for pediatricians, there is scarce awareness of its adult presentation. A thorough analysis and discussion of cobalamin C defect presentation in adult patients has never been extensively performed. This article reviews the published data and adds a new case of the latest onset of symptoms ever described for the disease. Results We present the emblematic case of a 45-year-old male, describing the diagnostic odyssey he ventured through to get to the appropriate treatment and molecular diagnosis. Furthermore, available clinical, biochemical and molecular data from 22 reports on cases and case series were collected, resulting in 45 adult-onset CblC cases, including our own. We describe the onset of the disease in adulthood, encompassing neurological, psychiatric, renal, ophthalmic and thromboembolic symptoms. In all cases treatment with intramuscular hydroxycobalamin was effective in reversing symptoms. From a molecular point of view adult patients are usually compound heterozygous carriers of a truncating and a non-truncating variant in the MMACHC gene. Conclusion Adult onset CblC disease is a rare disorder whose diagnosis can be delayed due to poor awareness regarding its presenting insidious symptoms and biochemical hallmarks. To avoid misdiagnosis, we suggest that adult onset CblC deficiency is acknowledged as a separate entity from pediatric late onset cases, and that the disease is considered in the differential diagnosis in adult patients with atypical hemolytic uremic syndromes and/or slow unexplained decline in renal function and/or idiopathic neuropathies, spinal cord degenerations, ataxias and/or recurrent thrombosis and/or visual field defects, maculopathy and optic disc atrophy. Plasma homocysteine measurement should be the first line for differential diagnosis when the disease is suspected. To further aid diagnosis, it is important that genes belonging to the intracellular cobalamin pathway are included within gene panels routinely tested for atypical hemolytic uremic syndrome and chronic kidney disorders.
Journal of Pediatric Neurology · 2015 · 0 citations
Combined methylmalonic aciduria and homocystinuria
AbstractCombined methylmalonic aciduria and homocystinuria is a very rare disease caused by a defect in the synthesis of two cofactors in cobalamin dependent reactions, i.e. adenosylcobalamin and methylcobalamin, active forms of vitamin B12. Early onset disease consists of neurological, hematological and gastrointestinal abnormalities seen in the first year of life and some minor face abnormalities (long philtrum, wide forehead, big and low set ears, long face). Here we report a 4-month-old male with failure to thrive, pancytopenia and neurological disturbance.
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.
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