DeCure for Neuronopathy, distal hereditary motor, autosomal recessive 5
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for neuronopathy, distal hereditary motor, autosomal recessive 5 — 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, autosomal recessive 5 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, autosomal recessive 5 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.
What the evidence adds up to
The distal hereditary motor neuropathies (dHMN) are a heterogeneous group of length-dependent motor neuropathies. Eleven causative genes and four loci have been identified, but 80% of patients with dHMN have a mutation in an as-yet undiscovered gene. Causative genes implicate protein misfolding, RNA metabolism, axonal transport, and cation-channel dysfunction. No drug treatment is mentioned in this 2011 review.
Six families with autosomal recessive hereditary motor and sensory neuropathy (HMSN) were described in 1980. Four were classified as HMSN type I and two as type II. The consanguinity rate was high. Compared with dominant forms, mean age of onset was significantly earlier for type II cases but did not differ for type I. Motor nerve conduction velocity was significantly lower for type I cases but did not differ for type II. Recessive type I cases tended to show greater incidence of weakness, ataxia, tendon areflexia, and scoliosis. No drug treatment is mentioned.
The PLEKHG5 gene encodes a protein that activates NFκB signalling. Mutations in this gene have been associated with distal spinal muscular atrophy IV and intermediate axonal neuropathy C, both autosomal recessive. Two families with lower motor neuron disease caused by PLEKHG5 mutations had been reported by 2020. A third family, the first nonconsanguineous, was then described with two not previously reported PLEKHG5 mutations. No drug treatment is mentioned in this 2020 report.
No drug has been tested in any clinical trial for this disease. What is missing is any funded effort to screen or repurpose existing compounds, a defined patient stratification strategy for a condition with multiple genetic causes, and the financial support to move from gene discovery to preclinical testing.
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.
Journal of Neurology Neurosurgery & Psychiatry · 1980 · 115 citations · open access
Autosomal recessive forms of hereditary motor and sensory neuropathy.
AbstractSix families are described with hereditary motor and sensory neuropathy (HMSN) of probable autosomal recessive inheritance. Four of these were classified as HMSN type I and two as type II. The consanguinity rate in this series was high, suggesting that these recessive genes are rare. In comparison with the dominantly inherited forms of these disorders, the mean age of onset was significantly earlier for the type II cases but did not differ for the type I patients. Motor nerve conduction velocity was significantly less for the type I cases but did not differ for the type II form. The recessive type I cases tended to show a greater incidence of weakness, ataxia, tendon areflexia and scoliosis than in the dominant form. The importance of differentiating such cases from Friedreich's ataxia is emphasised.
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.
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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