DeCure for Neuronopathy, distal hereditary motor, type 5A
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for neuronopathy, distal hereditary motor, type 5A — 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 moduleNeuronopathy, distal hereditary motor, type 5A 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 neuronopathy, distal hereditary motor, type 5a 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
BSCL2 lipid droplet biogenesis associated, seipin (BSCL2) — BSCL2 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 6DS5 · 3.8 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Distal hereditary motor neuropathy type 5A is one form within a group of length‑predominant motor neuropathies that can also involve minor sensory abnormalities or upper‑motor‑neuron signs. By 2011, eleven causative genes and four loci had been identified across autosomal dominant, recessive and X‑linked patterns, but 80% of patients still had 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 specific therapy was available; the review only highlighted potential therapeutic strategies based on functional consequences of the mutations.
In 2017, exome sequencing in a Taiwanese family with autosomal dominant distal hereditary motor neuropathy, after excluding mutations in common genes, identified a heterozygous WARS mutation c.770A>G (p.His257Arg) that co‑segregated with the neuropathy. Screening 79 additional Taiwanese pedigrees and 163 index cases from Australian, European and Korean families found the same mutation in one more Taiwanese pedigree and one Belgian family of Caucasian origin. Cell transfection showed a dominant‑negative effect on TrpRS aminoacylation activity, compromising protein synthesis and reducing cell viability. The His257Arg TrpRS also inhibited neurite outgrowth and caused neurite degeneration in neuronal cell lines and rat motor neurons, and it potentiated angiostatic activities by enhancing interaction with vascular endothelial‑cadherin. These findings established WARS as a causal gene for distal hereditary motor neuropathy, but no treatment was tested.
No clinical trial data exist for any drug in this specific disease. The 2011 review noted that most patients lack a known genetic diagnosis, and the 2017 study identified WARS mutations in only a small number of families. What is missing is a sufficiently large, genetically defined patient cohort for any therapeutic trial, funding to move from cellular and animal models to human studies, and a trial design that can stratify patients by the specific gene mutation and functional pathway involved.
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.
Prevalence of hereditary motor and sensory neuropathy in Cantabria
AbstractOne hundred and forty-four patients with hereditary motor and sensory neuropathy (HMSN) were selected from within a defined area (Cantabria) in Northern Spain, from 1974 to 1984. The series comprises 49 index cases and 95 affected relatives. The prevalence ratio was 28.2 cases per 100,000. The results of the study indicate that the majority of the cases were hereditary as a dominant trait. The prevalence for the Type I HMSN cases did not differ from that of Type II cases. Previous population-surveys of these disorders are compared.
AbstractMotor neuron diseases are hereditary and acquired neurodegenerative diseases associated with selective degeneration of the upper motor neurons and lower motor neurons. Unfortunately, there is no single test that is highly sensitive and specific for motor neuron disease, with the exception of the genetic confirmation of the inherited motor neuron diseases. The diagnosis of most motor neuron diseases is based on the combination of the clinical history, physical examination, electrophysiology, imaging, and serology.
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.
