DeCure for Neuronopathy, distal hereditary motor, autosomal dominant 8
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for neuronopathy, distal hereditary motor, autosomal dominant 8 — 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 moduleNeuronopathy, distal hereditary motor, autosomal dominant 8 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 neuronopathy, distal hereditary motor, autosomal dominant 8 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
transient receptor potential cation channel subfamily V member 4 (TRPV4) — TRPV4 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 2~{r}drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8T1E · 2.77 Å · ligand [(2~{R})-2-[(~{Z})-hexadec-9-enoyl]oxy-3-[oxidanyl-[2-(trimethyl-$l^{4}-azanyl)ethoxy]phosphoryl]oxy-propyl] (~{Z})-docos-13-enoate (9ZR). Experimental structure, not a prediction.
What the evidence adds up to
A recurrent mutation in the WARS gene, c.770A>G (p.His257Arg), was identified by exome sequencing in a Taiwanese family with autosomal dominant distal hereditary motor neuropathy after mutations in common implicated genes had been excluded. The same mutation was then found in one additional Taiwanese pedigree and one Belgian family of Caucasian origin when 79 Taiwanese pedigrees with inherited neuropathies and 163 index cases from Australian, European, and Korean families were screened. Cell transfection studies showed a dominant-negative effect on the aminoacylation activity of tryptophanyl-tRNA synthetase, which compromised protein synthesis and reduced cell viability. The His257Arg mutant also inhibited neurite outgrowth and caused neurite degeneration in neuronal cell lines and rat motor neurons, and in vitro analyses indicated it could potentiate angiostatic activities by enhancing interaction with vascular endothelial-cadherin.
An earlier clinical, pathologic, and genetic study of 14 families described three types of familial motor neuron disease, all apparently autosomal dominant. The first type showed rapid progressive loss of motor function with lower motor neuron signs and a course under five years, with pathology limited to anterior horn cells and pyramidal tracts. The second type was clinically identical but had additional changes in posterior columns, Clarke's column, and spinocerebellar tracts. The third type had much longer survival, usually beyond ten and sometimes over twenty years, but was otherwise similar to the second type.
A population-based study of Swedish children aged 2 to 15 found the prevalence of total peroneal muscle atrophies was 21.6 per 100,000 and of all clinical hereditary motor and sensory neuropathies was 19.0 per 100,000. Among these, de- and remyelinating types (HMSN I) constituted 8 per 100,000 and neuronal-axonal types (HMSN II) 11 per 100,000. Eighteen of 21 HMSN I cases and 26 of 29 HMSN II cases were considered autosomal dominant. Ten percent of all children were severely disabled, 70% moderately, and 20% mildly; all severely affected children were in the HMSN I group, and 9 of 10 mildly affected were in HMSN II.
What remains missing is any clinical trial testing a treatment for this specific WARS mutation, any patient stratification beyond broad neuropathy categories, and the funding to move from cell and animal models to human studies. The natural history data from 1976 and 1983 are not specific to this genetic subtype, and no drug has been proposed or tested in these abstracts.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Brain · 2017 · 102 citations · open access
A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy
AbstractDistal hereditary motor neuropathy is a heterogeneous group of inherited neuropathies characterized by distal limb muscle weakness and atrophy. Although at least 15 genes have been implicated in distal hereditary motor neuropathy, the genetic causes remain elusive in many families. To identify an additional causal gene for distal hereditary motor neuropathy, we performed exome sequencing for two affected individuals and two unaffected members in a Taiwanese family with an autosomal dominant distal hereditary motor neuropathy in which mutations in common distal hereditary motor neuropathy-implicated genes had been excluded. The exome sequencing revealed a heterozygous mutation, c.770A > G (p.His257Arg), in the cytoplasmic tryptophanyl-tRNA synthetase (TrpRS) gene (WARS) that co-segregates with the neuropathy in the family. Further analyses of WARS in an additional 79 Taiwanese pedigrees with inherited neuropathies and 163 index cases from Australian, European, and Korean distal hereditary motor neuropathy families identified the same mutation in another Taiwanese distal hereditary motor neuropathy pedigree with different ancestries and one additional Belgian distal hereditary motor neuropathy family of Caucasian origin. Cell transfection studies demonstrated a dominant-negative effect of the p.His257Arg mutation on aminoacylation activity of TrpRS, which subsequently compromised protein synthesis and reduced cell viability. His257Arg TrpRS also inhibited neurite outgrowth and led to neurite degeneration in the neuronal cell lines and rat motor neurons. Further in vitro analyses showed that the WARS mutation could potentiate the angiostatic activities of TrpRS by enhancing its interaction with vascular endothelial-cadherin. Taken together, these findings establish WARS as a gene whose mutations may cause distal hereditary motor neuropathy and alter canonical and non-canonical functions of TrpRS.
AbstractBased on a clinical, pathologic, and genetic study of 14 families, at least three types of familial motor neuron disease can be distinguished, all apparently of autosomal dominant transmission. The first is characterized by rapid, progressive loss of motor function with predominantly lower motor neuron manifestations and a course lasting less than 5 years. Pathologic changes are limited to the anterior horn cells and pyramidal tracts. The second type is clinically identical to the first, but at autopsy additional changes are found in the posterior columns, Clarke's column, and spinocerebellar tracts. The third type is characterized by a much longer survival usually beyond 10 and after more than 20 years in affected family members but is otherwise similar to the second type.
HEREDITARY MOTOR AND SENSORY NEUROPATHIES IN SWEDISH CHILDREN I
AbstractThe prevalence of hereditary motor and sensory neuropathies (HMSN) and their distribution according to the severity of the disability were studied in a population-based series of Swedish children 2-15 years old. The prevalence per 100 000 of total peroneal muscle atrophies was 21.6 and of all clinical HMSN 19.0 Among HMSN, de- and remyelinating types (HMSN I) constituted 8 per 100000 and neuronal-axonal types (HMSN II) 11. Eighteen of the 21 HMSN I cases and 26 of the 29 HMSN II were considered to represent an autosomal dominant mode of inheritance. Ten per cent of all children were severely, 70% moderately and 20% mildly disabled. All the severely affected children belonged to the HMSN I group and 9 of the 10 mildly affected to HMSN II.
Journal of Neurology Neurosurgery & Psychiatry · 1996 · 19 citations · open access
Autosomal dominant optic atrophy with asymptomatic peripheral neuropathy.
AbstractThe association between hereditary motor and sensory neuropathy (HMSN) and optic atrophy has been termed HMSN type VI. The autosomal dominant inheritance of this syndrome is reported. Three generations were affected with optic atrophy, which differed in some respects from classic dominant optic atrophy, and an asymptomatic, mainly sensory, neuropathy.
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.
