DeCure for Neuronopathy, distal hereditary motor, autosomal dominant
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for neuronopathy, distal hereditary motor, autosomal dominant — screening already-approved drugs against its 9-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 maps to a 9-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 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
MORC family CW-type zinc finger 2 (MORC2) — MORC2 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 anpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9CDH · 1.95 Å · ligand PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER (ANP). Experimental structure, not a prediction.
What the evidence adds up to
Distal hereditary motor neuropathy is a heterogeneous group of inherited disorders defined by length-dependent, predominantly motor nerve degeneration. As of a 2011 review, eleven causative genes and four loci had been identified across autosomal dominant, recessive, and X-linked patterns, yet 80% of patients still carried a mutation in an undiscovered gene. The known genes implicated protein misfolding (HSPB1, HSPB8, BSCL2), RNA metabolism (IGHMBP2, SETX, GARS), axonal transport (HSPB1, DYNC1H1, DCTN1), and cation-channel dysfunction (ATP7A, TRPV4). No therapeutic strategies were established; the review only highlighted potential directions based on functional consequences of mutations.
In 2017, exome sequencing of a Taiwanese family with autosomal dominant distal hereditary motor neuropathy, after exclusion of common genes, identified a heterozygous mutation c.770A>G (p.His257Arg) in the cytoplasmic tryptophanyl-tRNA synthetase gene WARS. The same mutation was found in one additional Taiwanese pedigree and one Belgian family of Caucasian origin among 79 Taiwanese and 163 Australian, European, and Korean families screened. Cell transfection studies showed a dominant-negative effect on aminoacylation activity, compromising protein synthesis and reducing cell viability. The mutant also inhibited neurite outgrowth and caused neurite degeneration in neuronal cell lines and rat motor neurons, and potentiated angiostatic activities by enhancing interaction with vascular endothelial-cadherin. These findings established WARS as a novel causal gene, but no treatment or clinical trial data were reported.
A 1983 population-based study of Swedish children aged 2–15 years found a prevalence of all clinical hereditary motor and sensory neuropathies of 19.0 per 100,000, with neuronal-axonal types (HMSN II) at 11 per 100,000 and demyelinating types (HMSN I) at 8 per 100,000. Among 21 HMSN I cases and 29 HMSN II cases, autosomal dominant inheritance was inferred in 18 and 26 respectively. Disability was severe in 10% of all children, moderate in 70%, and mild in 20%; all severely affected children were in the HMSN I group, and 9 of the 10 mildly affected were in HMSN II. No treatment or intervention was studied.
What remains missing for this autosomal dominant neuronopathy is any clinical trial of a drug, any preclinical therapy tested in animal models, and any patient stratification beyond broad genetic categories. The 80% of patients without a known mutation cannot be enrolled in gene-specific studies. Funding for natural history studies and for functional assays to validate the many private variants that next-generation sequencing will uncover is lacking.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
AbstractThe distal hereditary motor neuropathies (dHMN) comprise a heterogeneous group of diseases that share the common feature of a length-dependent predominantly motor neuropathy. Many forms of dHMN have minor sensory abnormalities and/or a significant upper-motor-neuron component, and there is often an overlap with the axonal forms of Charcot-Marie-Tooth disease (CMT2) and with juvenile forms of amyotrophic lateral sclerosis and hereditary spastic paraplegia. Eleven causative genes and four loci have been identified with autosomal dominant, recessive and X-linked patterns of inheritance. Despite advances in the identification of novel gene mutations, 80% of patients with dHMN have a mutation in an as-yet undiscovered gene. The causative genes have implicated proteins with diverse functions such as protein misfolding (HSPB1, HSPB8, BSCL2), RNA metabolism (IGHMBP2, SETX, GARS), axonal transport (HSPB1, DYNC1H1, DCTN1) and cation-channel dysfunction (ATP7A and TRPV4) in motor-nerve disease. This review will summarise the clinical features of the different subtypes of dHMN to help focus genetic testing for the practising clinician. It will also review the neuroscience that underpins our current understanding of how these mutations lead to a motor-specific neuropathy and highlight potential therapeutic strategies. An understanding of the functional consequences of gene mutations will become increasingly important with the advent of next-generation sequencing and the need to determine the pathogenicity of large amounts of individual genetic data.
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.
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.
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.
