DeCure for Mandibuloacral dysplasia with type A lipodystrophy
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for mandibuloacral dysplasia with type A lipodystrophy — 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 moduleMandibuloacral dysplasia with type A lipodystrophy 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
No approved-drug candidate for mandibuloacral dysplasia with type a lipodystrophy 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
lamin A/C (LMNA) — LMNA 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6JLB · 3.205 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Mandibuloacral dysplasia (MAD) is a rare autosomal recessive disorder with two recognised lipodystrophy patterns. In type A, subcutaneous fat is lost from the extremities while the neck and trunk are normal or slightly excessive; in type B, fat loss is more generalised, involving face, trunk and extremities. A 2003 study of six pedigrees found that affected patients from two families with type A lipodystrophy carried a homozygous R527H mutation in the LMNA gene. The other four affected subjects, all with type B lipodystrophy, had no mutation in LMNA exons or splice junctions, and RNA from two of them also showed normal sequence. Sequencing of AGPAT2, Seipin and PPARG in those four patients revealed no substantial alterations. The authors concluded that MAD is genetically and phenotypically heterogeneous and that other unmapped loci are likely involved.
A 2016 report described a 12-year-old boy with MAD type B lipodystrophy who had a novel homozygous c.1196A>G (p.Tyr399Cys) mutation in ZMPSTE24, the gene encoding a zinc metalloproteinase involved in lamin processing. Nine distinct pathogenic variants in ZMPSTE24 had previously been identified in 11 patients from nine unrelated families. The boy had typical dermatological and skeletal features, sparse hair, short stature, mild microcephaly, facial dysmorphism, and a striking failure of ossification of the interparietal region of the occipital bone. Newly recognised signs were gaze palsy and ptosis. The authors noted that delayed closure of cranial sutures and Wormian bones had been described in three patients, but an ossification failure strictly limited to the occipital bone appeared unique to MAD type B. They suggested this failure might be a useful radiological sign for diagnosis.
An earlier 1984 report of two brothers confirmed Welsh’s 1975 hypothesis of autosomal recessive inheritance and noted that the syndrome is probably often misdiagnosed. No treatment or intervention is discussed in any of these abstracts. What remains missing is any clinical trial data, any drug tested in these patients, and any systematic effort to stratify patients by genotype or lipodystrophy type. Funding for natural history studies and for developing molecular or symptomatic therapies is 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.
The Journal of Clinical Endocrinology & Metabolism · 2003 · 134 citations
Genetic and Phenotypic Heterogeneity in Patients with Mandibuloacral Dysplasia-Associated Lipodystrophy
AbstractMandibuloacral dysplasia (MAD) is a phenotypically heterogeneous, rare autosomal recessive disorder characterized by mandibular and clavicular hypoplasia, acroosteolysis, delayed closure of cranial sutures, joint contractures, and mottled cutaneous pigmentation. Patients with MAD develop two patterns of lipodystrophy: type A pattern, with loss of sc fat from the extremities and normal or slight excess in the neck and truncal regions; and type B pattern, with a more generalized loss of sc fat involving the face, trunk, and extremities. Recently, affected patients from five consanguineous Italian pedigrees with partial lipodystrophy (type A) were reported to have a homozygous R527H mutation in LMNA (lamin A/C) gene. We carried out mutational analysis of LMNA in affected patients from six pedigrees. Affected patients from two pedigrees with type A lipodystrophy had the homozygous R527H mutation in LMNA. The other four affected subjects who had type B lipodystrophy did not have any mutation in the exons and splice site junctions of LMNA; RNA extracted from lymphoblasts of two of these patients also revealed normal sequence. In these four subjects, sequencing of other known genes implicated in lipodystrophies, i.e. AGPAT2, Seipin, and PPARG also revealed no substantial alterations. We conclude that MAD is a genetically and phenotypically heterogeneous disorder. Besides LMNA gene, other as yet unmapped loci could be linked to MAD.
Mandibuloacral dysplasia: a rare progeroid syndrome Two brothers confirm autosomal recessive inheritance
AbstractMandibuloacral Dysplasia would appear to be a very rare syndrome, probably because it is usually mistakenly diagnosed. This article describes the case histories of two brothers, confirming Welsh's (1975) earlier hypothesis concerning autosomal recessive inheritance and makes certain observations which should be helpful in diagnosing this rare hereditary syndrome.
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.
