DeCure for Neuronopathy, distal hereditary motor, type 5C
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for neuronopathy, distal hereditary motor, type 5C — 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 5C 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 5c 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
The 2011 review of distal hereditary motor neuropathies (dHMN) notes that 80% of patients have a mutation in an as-yet undiscovered gene. Eleven causative genes and four loci had been identified at that time. The review describes protein misfolding, RNA metabolism, axonal transport and cation-channel dysfunction as implicated mechanisms, but no specific drug or therapy is tested or recommended in the paper.
A 2017 cohort study of 105 patients from the North of England found the prevalence of dHMN to be 2.14 affected individuals per 100,000 inhabitants (95% confidence interval 1.62–2.66). Causative mutations were identified in 26 of 73 index patients (35.6%), and the diagnostic rate in the dHMN subgroup was 32.5%, higher than the previously reported 20%. The study detected a significant defect of neuromuscular transmission in 7 cases and identified potentially causative mutations in 4 patients with multifocal demyelinating motor neuropathy. The authors suggest that abnormal neuromuscular transmission in some genetic forms provides a treatable target, but no treatment is tested or recommended in this paper.
A 2020 case report describes a third family with lower motor neuron disease caused by mutations in PLEKHG5, the first nonconsanguineous family. Two not previously reported PLEKHG5 mutations were found. The gene encodes a protein that activates the nuclear factor kappa B (NFκB) signalling pathway. The report confirms and extends previous findings linking PLEKHG5 mutations to lower motor neuron disease, but no drug or therapy is tested.
No drug is mentioned in any of these three abstracts. What is missing for any potential therapy in dHMN type 5C specifically is a clear molecular target validated in patients, a trial design that accounts for the genetic heterogeneity (80% of patients still lack a known mutation), and funding to move from the observation of neuromuscular transmission defects or NFκB pathway involvement to a clinical trial. Patient stratification by genotype and electrophysiological subtype would be required before any drug could be tested.
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.
AbstractOBJECTIVE: To study the prevalence, molecular cause, and clinical presentation of hereditary motor neuropathies in a large cohort of patients from the North of England. METHODS: Detailed neurologic and electrophysiologic assessments and next-generation panel testing or whole exome sequencing were performed in 105 patients with clinical symptoms of distal hereditary motor neuropathy (dHMN, 64 patients), axonal motor neuropathy (motor Charcot-Marie-Tooth disease [CMT2], 16 patients), or complex neurologic disease predominantly affecting the motor nerves (hereditary motor neuropathy plus, 25 patients). RESULTS: The prevalence of dHMN is 2.14 affected individuals per 100,000 inhabitants (95% confidence interval 1.62-2.66) in the North of England. Causative mutations were identified in 26 out of 73 index patients (35.6%). The diagnostic rate in the dHMN subgroup was 32.5%, which is higher than previously reported (20%). We detected a significant defect of neuromuscular transmission in 7 cases and identified potentially causative mutations in 4 patients with multifocal demyelinating motor neuropathy. CONCLUSIONS: Many of the genes were shared between dHMN and motor CMT2, indicating identical disease mechanisms; therefore, we suggest changing the classification and including dHMN also as a subcategory of Charcot-Marie-Tooth disease. Abnormal neuromuscular transmission in some genetic forms provides a treatable target to develop therapies.
Annals of Clinical and Translational Neurology · 2020 · 6 citations · open access
Novel <i>PLEKHG5</i> mutations in a patient with childhood‐onset lower motor neuron disease
AbstractThe PLEKHG5 gene encodes a protein that activates the nuclear factor kappa B (NFκB) signaling pathway. Mutations in this gene have been associated with distal spinal muscular atrophy IV and intermediate axonal neuropathy C, both with an autosomal recessive mode of inheritance. Two families with low motor neuron disease (LMND) caused by mutations in PLEKHG5 have been reported to date. We present a third LMND family, the first nonconsanguineous, due to two not previously reported PLEKHG5 mutations. Our results confirm and extend previous findings linking PLEKHG5 mutations to lower motor neuron diseases.
Muscular hypotonia, joint contractures and elevated creatin kinase level as main symptoms for Congenital muscular dystrophy 1A (MDC 1A/congenital muscular dystrophy with laminin α 2 (merosin) deficiency)
AbstractIntroduction: congenital muscular dystrophies (MDC) are hereditary myopathies characterized by congenital muscular hypotonia, delayed motor development and early onset of progressive muscle weakness. Dystrophic patterns are found in muscular biopsy. Some forms are associated with affections of the brain or eyes. Incidental rate is ca. 2.5–4.5×(10–5). The congenital muscular dystrophy with laminin α 2 -deficiency (MDC1A) counts ca. 30 to 40% of all MDC in Europe. A defect of laminin α 2 affects primarily the basement membrane of the muscular cell.
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.
