DeCure for Methylmalonic aciduria and homocystinuria type cblD
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for methylmalonic aciduria and homocystinuria type cblD — screening already-approved drugs against its 2-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 cblD maps to a 2-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
No approved-drug candidate for methylmalonic aciduria and homocystinuria type cbld is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
metabolism of cobalamin associated C (MMACHC) — MMACHC is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet b12drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3SOM · 2.4 Å · ligand COBALAMIN (B12). Experimental structure, not a prediction.
What the evidence adds up to
Methylmalonic aciduria and homocystinuria type cblD is a rare autosomal recessive disorder of vitamin B12 metabolism caused by mutations in the MMADHC gene. A 2014 study using immortalised patient fibroblasts defined three mutation classes: null mutations N-terminal to Met116 cause isolated methylmalonic aciduria (cblD-MMA) due to adenosylcobalamin deficiency; null mutations across the C-terminus (p.Y140-R250) cause combined methylmalonic aciduria and homocystinuria (cblD-MMA/HC); and missense mutations in a conserved C-terminal region (p.D246-L259) cause isolated homocystinuria (cblD-HC). Testing 20 mutations across p.P154-S287 identified a region (p.R197-D226) responsible for methylcobalamin synthesis that gave a cellular phenotype similar to cblD-HC. Mutations between p.D226-D246 and directly C-terminal to p.L259-R266 produced intermediate phenotypes. C-terminal truncation of more than 20 amino acids resulted in a cblD-MMA/HC-like phenotype, while truncation of 10 to 20 amino acids gave a cblD-HC-like phenotype.
A 2006 study of 77 Chinese patients with methylmalonic aciduria found that 46 (59.7%) had the combined form with homocystinemia, a higher proportion than reported in other countries. Neonatal and infantile onset was associated with greater severity. Among 17 patients with onset after 3 years of age, 16 had combined disease. Nine of the combined-disease patients completely recovered with normal intelligence, and seven improved with a mild handicap. A 2015 case report described an 18-year-old with a history of epilepsy who presented with acute renal failure requiring renal replacement therapy and was diagnosed with the cblC variant of combined methylmalonic acidemia and homocystinuria, not cblD.
A 2019 review noted that among the three most frequent homocystinurias (CBS deficiency, cblC deficiency, and severe MTHFR deficiency), cblC deficiency specifically presents with hematological alterations such as megaloblastic anaemia, thrombocytopenia, neutropenia, and life-threatening microangiopathy. Patients with remethylation defects typically do not have ectopia lentis, bone disturbances, tall stature, or osteoporosis. A 2012 evaluation reported that elevated urea and urinary methylmalonic acid are predictors of adverse outcomes in patients with methylmalonic acidemia with homocystinuria, and their combination provided the most accurate predictive tool.
What is still missing: no clinical trial data exist for cblD specifically; the 2014 study was limited to immortalised fibroblasts and did not test any therapeutic intervention; no patient stratification by mutation type has been prospectively validated; and funding for natural history studies or drug screening in cblD patient-derived models remains absent.
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 Inborn Errors of Metabolism and Screening · 2019 · 20 citations · open access
Three Main Causes of Homocystinuria: CBS, cblC and MTHFR Deficiency. What do they Have in Common?
AbstractGenetic homocystinurias are a group of inborn errors of metabolism that result in the massive excretion of homocysteine (Hcy) in the urine due to Hcy accumulation in the body, usually causing neurological and cardiovascular complications. The three most frequent causes are classical homocystinuria [deficiency of cystathionine beta-synthase (CBS)], methylmalonic aciduria with homocystinuria, cblC type (cblC deficiency) and severe methylenetetrahydrofolate reductase (MTHFR) deficiency. In this review, we highlight the similarities and differences among these disorders. Briefly, their joint manifestation is the accumulation of tHcy, however, the other sulfur amino acids show various and even invers profiles. Vascular disease, developmental delay and seizures are found in all homocystinurias, nevertheless, the complications of CNS differ in a wide variety of presentations and severities and are apparently less pronounced in CBS deficiency. Moreover, patients with remethylation defects typically do not present ectopia lentis and bone disturbances, tall stature and osteoporosis. Whereas hematological alterations, such as megaloblastic anemia, thrombocytopenia neutropenia and life-threatening microangiopathy, are specific findings of cblC deficiency.
Clinical and Biochemical Studies on Chinese Patients With Methylmalonic Aciduria
AbstractMethylmalonic aciduria is a common organic aciduria disease. Recently, gas chromatography-mass spectrometry has been used to diagnose methylmalonic aciduria in China. Often, however, the diagnosis of methylmalonic aciduria is delayed because of a lack of technical expertise and the limited experience of general clinicians in China. In this study, the natural history, clinical features, and outcome of 77 Chinese patients with methylmalonic aciduria were investigated. Of the 77 patients, 31 (40.3%) had isolated methylmalonic aciduria and 46 (59.7%) had methylmalonic aciduria combined with homocystinemia. Thus, we observed a higher rate of the combined disease than studies conducted in other countries, suggesting that it might be more common in China. Total plasma homocysteine measurement might enable differential diagnoses of methylmalonic aciduria to be distinguished. The clinical spectrum of these 77 patients with methylmalonic aciduria ranged from neonatal death and severe symptoms to benign asymptomatic organic aciduria. Neonatal and infantile onset, which was a characteristic of the majority of cases, was associated with a greater severity relative to later-onset cases. Among the 17 cases who had onset after 3 years of age, only 1 patient had isolated methylmalonic aciduria and 16 had combined methylmalonic aciduria and homocystinemia. Nine of the patients with combined methylmalonic aciduria and homocystinemia completely recovered and exhibited normal intelligence, whereas seven improved, with a mild handicap.
Journal of Inherited Metabolic Disease · 2014 · 18 citations · open access
Characterization of functional domains of the <i>cblD</i> (MMADHC) gene product
AbstractIn humans vitamin B12 (cobalamin, Cbl) must be converted into two coenzyme forms, methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl), in order to maintain intracellular homeostasis of homocysteine and methylmalonic acid, respectively. Previously we have shown that in cblD patients three types of MMADHC mutations exist: 1) null mutations N-terminal to Met116 cause isolated methylmalonic aciduria (cblD-MMA) due to AdoCbl deficiency; 2) null mutations across the C-terminus (p.Y140-R250) cause combined methylmalonic aciduria and homocystinuria (cblD-MMA/HC) due to AdoCbl and MeCbl deficiency; 3) missense mutations in a conserved C-terminal region (p.D246-L259) cause isolated homocystinuria (cblD-HC) due to MeCbl deficiency. To better understand the domain boundaries related to MeCbl formation, we made selected point mutations and C-terminal truncations in MMADHC and tested rescue of MeCbl and AdoCbl synthesis in immortalized cblD-MMA/HC patient fibroblasts. Testing 20 mutations (15 missense and five C-terminal truncations) across p.P154-S287 revealed the presence of a region (p.R197-D226) responsible for MeCbl synthesis, which gave a similar cellular phenotype as cblD-HC. Further, mutation of the polypeptide stretch between the new and patient defined regions (p.D226-D246) and directly C-terminal to the patient region (p.L259-R266), gave cellular phenotypes intermediate to those of cblD-HC and cblD-MMA/HC. Finally, C-terminal truncation of more than 20 amino acids resulted in a cblD-MMA/HC like cellular phenotype, while truncation of between ten and 20 amino acids resulted in a cblD-HC like cellular phenotype. These data suggest that specific regions of MMADHC are involved in differential regulation of AdoCbl and MeCbl synthesis and help better define the boundaries of these regions.
[Combined methylmalonic acidemia and homocystinuria; a case report].
AbstractCombined methylmalonic acidemia and homocystinuria is an inborn error of metabolism of vitamin B12 or cobalamin. It's a rare autosomal recessive disease in which there are several variants depending on the pathogenesis of the metabolic disorder (cblC, cblD, cblF and cblJ). The more frequent and more severe is the cblC variant, which usually manifests in the first months of life, although some cases have been reported at the beginning of adulthood. A proper diagnosis and effective therapeutic approach is fundamental. We report the case of a patient of 18 years with a history of epilepsy who consults for acute renal failure requiring renal replacement therapy and diagnosed with combined methylmalonic acidemia and homocystinuria cblC variant.
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.
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.
