DeCure for Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 — 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 moduleInclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 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 inclusion body myopathy with early-onset paget disease with or without frontotemporal dementia 2 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
heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1) — HNRNPA2B1 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 5WWG · 2.03 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
A French case report describes a patient who developed progressive limb weakness in his fifties, eventually becoming wheelchair-bound, followed by acute behavioural changes including irritability, severe anxiety and major depression that led to psychiatric hospitalisation. Aphasia and executive function impairment led to a diagnosis of the behavioural form of frontotemporal dementia. Genetic testing confirmed the R155H mutation in the VCP gene, the most frequent of 18 known mutations. The report notes that inclusion body myopathy has a mean onset at 42 years, Paget’s disease of bone at around 40 years, and frontotemporal dementia at a mean of 55 years, appearing nearly ten years later than muscle or bone disease. Frontotemporal dementia is seen in about one third of patients, and Paget’s disease in about half, though less common in Japanese patients.
A separate case report describes a 50-year-old man with a two-year history of progressive proximal and distal limb weakness unresponsive to steroids and IVIg. His creatine kinase was mildly elevated, EMG showed myopathic changes, and MRI of the thighs revealed marked atrophy with fatty replacement. Muscle biopsy showed myopathic changes with vacuoles and inclusions and no inflammation. A bone scan was normal. Genetic testing found a heterozygous mutation at codon 97 of the VCP gene (c.G290A, p.G97E). His brother had myopathy and Paget’s disease, and his father had undiagnosed muscle weakness. This case demonstrates that VCP mutations can cause inclusion body myopathy without Paget’s disease or dementia, and that phenotypes can differ even within the same family.
Muscle weakness is the most common symptom, with onset around age 40, and affected muscles are variable, sometimes leading to misdiagnosis as limb girdle muscular dystrophy or GNE myopathy. Muscle pathology shows cytoplasmic and nuclear inclusions, rimmed vacuoles, disorganised myofibrils, and neurogenic changes. The VCP protein is involved in protein quality control via proteasome and autophagy, mitochondrial quality control, and cell proliferation. The disease is not as rare as previously thought, but its complicated clinical findings make diagnosis difficult. No treatment data are reported in any of these abstracts. What is missing are prospective natural history studies, validated biomarkers for disease progression, and any clinical trial testing a drug that targets VCP pathology or its downstream effects.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Brazilian Journal of Medical and Biological Research · 2011 · 26 citations · open access
A Brazilian family with hereditary inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia
AbstractInclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD) is a progressive and usually misdiagnosed autosomal dominant disorder. It is clinically characterized by a triad of features: proximal and distal myopathy, early onset Paget disease of bone (PDB), and frontotemporal dementia (FTD). It is caused by missense mutations in the valosin-containing protein (VCP) gene. We describe here the clinical and molecular findings of the first Brazilian family identified with IBMPFD. Progressive myopathy affecting the limb girdles was detected by clinical examination followed by muscle biopsy and creatine kinase measurement. PDB was suggested after anatomopathological bone examination and FTD was diagnosed by clinical, neuropsychological and language evaluations. Brain magnetic resonance revealed severe atrophy of the anterior temporal lobes, including the hippocampi. A R93C mutation in VCP was detected by direct sequencing screening in subject W (age 62) and in his mother. Four more individuals diagnosed with "dementia" were reported in this family. We also present a comprehensive genotype-phenotype correlation analysis of mutations in VCP in 182 patients from 29 families described in the literature and show that while IBM is a conspicuously penetrant symptom, PDB has a lower penetrance when associated with mutations in the AAAD1 domain and FTD has a lower penetrance when associated with mutations in the Junction (L1-D1) domain. Furthermore, the R93C mutation is likely to be associated with the penetrance of all the clinical symptoms of the triad.
Case Reports in Neurology · 2013 · 14 citations · open access
Psychiatric Presentation of Frontotemporal Dementia Associated with Inclusion Body Myopathy due to the VCP Mutation (R155H) in a French Family
AbstractINTRODUCTION: Inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia (IBMPFD) is a rare late-onset autosomal dominant disorder due to a mutation of the valosin-containing protein (VCP) gene. CASE REPORT: We report the case of a patient who developed progressive weakness of the limbs in his fifties, until he was confined to a wheelchair. At that time, he developed acute behavioural changes including irritability, severe anxiety and major depression, which led to him being hospitalised in a psychiatric hospital. He also suffered from aphasia and executive function impairment, which helped us to diagnose a behavioural form of frontotemporal dementia (FTD). The diagnosis of IBMPFD due to a mutation in the VCP gene was confirmed by a genetic study of the VCP gene (R155H mutation). DISCUSSION: THE CLINICAL DIAGNOSIS OF IBMPFD IS SUGGESTED BY THE PRESENCE OF AT LEAST ONE OF THREE MAJOR MANIFESTATIONS AS FOLLOWS: inclusion body myopathy (mean onset at 42 years of age), Paget's disease of the bone and FTD (mean onset at 55 years of age). It is mostly the behavioural form of FTD (behavioural changes, executive dysfunction and aphasia). One interesting finding in our report is the predominance of the psychiatric symptoms at the beginning of the behavioural changes, which led to the diagnosis of FTD. The diagnosis of IBMPFD was confirmed by the genetic study: the R155H mutation found on exon 5 domain CDC48 is the most frequent of the 18 known mutations in the VCP gene.
Rinsho Shinkeigaku · 2013 · 2 citations · open access
Inclusion body myopathy with Paget’s disease of bone and frontotemporal dementia
AbstractInclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) is an autosomal dominant disease caused by mutations in the VCP gene. VCP encodes a well-conserved multifunctional protein, valosin containing protein (VCP), which has important roles in protein quality control via proteasome and autophagy, protein aggregation, quality control of mitochondria, cell proliferation, and so on. Clinically, muscle weakness is the most common symptom of which disease onset is around 40 years. Affected muscles are variable, and the patients are sometimes diagnosed as limb girdle muscular dystrophy or GNE myopathy. Muscle pathology shows characteristic features including cytoplasmic/nuclear inclusions, rimmed vacuoles, and disorganized myofibrills, together with neurogenic changes. Paget's disease of bone is reported to be observed in a half of the patients around the age of 40 years, but less common in Japanese patients. Frontotemporal dementia is seen around one third of the patients which appears nearly 10 years later than muscle or bone disease. In addition to cognitive dysfunctions, motor neuron involvement and cerebellar signs were also seen in our series. IBMPFD is not so rare disease as previously thought, but complicate clinical findings may make its diagnosis difficult.
Hereditary Inclusion Body Myopathy without Paget Disease and Frontotemporal Dementia Associated with Valosin-Containing Protein Mutation: A Case Report (P5.074)
AbstractOBJECTIVE: To describe a case of IBM associated with a VCP gene mutation in a patient with classic weakness but without Paget’s disease and dementia, and with a positive family history of IBMPFD. BACKGROUND: Inclusion body myopathy with early onset Paget's disease and frontotemporal dementia (IBMPFD) is a rare autosomal dominant myopathy caused by mutations in the valosin-containing protein (VCP) gene. Muscle biopsy shows variable myopathic features with ubiquitinated inclusions that co-localize with VCP and TDP-43 inclusions due to impairment of protein degradation pathways. IBMPFD is characterized by 3 main features: myopathy, Paget's disease of bone, and frontotemporal dementia. DESIGN/METHODS: A 50-year-old man presented with a 2-year history of progressive proximal and distal limb weakness, which was unresponsive to steroids and IVIg. Family history revealed a brother with myopathy and Paget’s disease and a deceased father with history of undiagnosed muscle weakness of similar distribution. RESULTS: His creatine kinase was mildly elevated. Needle EMG demonstrated classic myopathic changes. Magnetic resonance imaging of the thighs revealed marked atrophy with liposubstitution of several muscle groups. Muscle biopsy showed myopathic changes with vacuoles and inclusions, and no inflammation. A bone scan did not show any abnormality. Genetic testing revealed a heterozygous mutation at codon 97 of the VCP gene resulting in exchange of amino acid glycine for glutamic acid (c.G290A, p.G97E). SUMMARY/CONCLUSIONS: The aforementioned VCP gene mutation is associated with variable IBMPFD phenotypes, which can differ even amongst family members. Familial IBMPFD and VCP testing should be considered in atypical sporadic IBM-like patients, whose weakness is associated with extramuscular features, and those with family history of myopathy.
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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