DeCure for Neuronopathy, distal hereditary motor, autosomal dominant 15
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for neuronopathy, distal hereditary motor, autosomal dominant 15 — 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 15 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 15 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 abstracts provided do not contain any clinical trial data or treatment outcomes for neuronopathy, distal hereditary motor, autosomal dominant 15. The 1980 study of 228 patients with hereditary motor and sensory neuropathy describes two genetically distinct types defined by median nerve motor conduction velocity above or below 38 m/s. Type I cases, with slower conduction, had a peak onset in the first decade, more frequent hand weakness, upper limb tremor, ataxia, tendon areflexia, distal sensory loss, foot and spinal deformities, and nerve thickening. Type II cases had onset most often in the second decade, sometimes delayed to the seventh, and upper limb tremor was considerably less common. In both types, males tended to be more severely affected, and asymptomatic female family members were more common.
A 2011 review of distal hereditary motor neuropathies states that 80% of patients have a mutation in an as-yet undiscovered gene, despite eleven causative genes and four loci having been identified. The review notes that many forms have minor sensory abnormalities or a significant upper-motor-neuron component, and overlap with axonal Charcot-Marie-Tooth disease, juvenile amyotrophic lateral sclerosis, and hereditary spastic paraplegia. The 1976 study of 14 families with familial motor neuron disease distinguishes three autosomal dominant types based on survival and pathology, but this is a separate disease category.
A 1995 study of 13 French families with hereditary neuropathy with liability to pressure palsies and a chromosome 17p11.2 deletion found electrophysiologic abnormalities in all 28 symptomatic and 8 asymptomatic deletion carriers, including bilateral delayed distal motor latency of the median nerve at the wrist. A 1983 population-based study of Swedish children found a prevalence of all clinical hereditary motor and sensory neuropathies of 19.0 per 100,000, with 10% of children severely disabled, 70% moderately, and 20% mildly disabled; all severely affected children belonged to the demyelinating type I group.
What is still missing for this specific autosomal dominant 15 subtype is any dedicated clinical trial, any tested therapeutic intervention, any natural history data specific to this genetic form, and any patient stratification by mutation. The abstracts confirm that most distal hereditary motor neuropathy patients lack a known genetic diagnosis, and no drug has been studied in this population.
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 · 1980 · 831 citations
THE CLINICAL FEATURES OF HEREDITARY MOTOR AND SENSORY NEUROPATHY TYPES I AND II
AbstractObservations have been made on a series of 228 patients with hereditary motor and sensory neuropathy, comprising 120 index cases and 108 affected relatives. These could be separated into genetically distinct type I and type II categories depending upon whether motor nerve conduction velocity in the median nerve was below or above 38 m s-1. These disorders constitute separate genetic subgroups within the clinical spectrum of 'peroneal muscular atrophy'. Type I cases were more numerous. Most were of autosomal dominant inheritance, but a proportion were sporadic. Four families with probable autosomal recessive inheritance were identified; these displayed significantly slower motor conduction velocity. There was a positive correlation between motor conduction velocity in the propositi and that in their relatives in the total type I group which persisted after the autosomal recessive cases had been extracted, indicating further genetic heterogeneity amongst the autosomal dominant families. No X-linked recessive families were encountered. Type I cases had a peak age of onset of symptoms during the first decade of life. In comparison with the type II cases, they displayed a greater tendency to show weakness of the hands, upper limb tremor and ataxia, generalized tendon areflexia and more extensive distal sensory loss, sometimes with acrodystrophic changes. Foot and spinal deformities were more frequent, probably due to the earlier age of onset. Nerve thickening was confined to the type I cases. The onset of symptoms was most often in the second decade in the type II cases, but in some it was delayed, even as late as the seventh decade. Most cases were again of autosomal dominant inheritance, but two probable autosomal recessive families were detected, as well as sporadic cases. Upper limb tremor also occurred in this form but was considerably less common. In both types, males tended to be more severely affected, and asymptomatic affected family members ('formes frustes') were more commonly female.
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.
Clinical, electrophysiologic, and molecular correlations in 13 families with hereditary neuropathy with liability to pressure palsies and a chromosome 17p11.2 deletion
AbstractHereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disease characterized by recurrent episodes of acute nerve palsies. We performed a clinical, electrophysiologic, and molecular study of 13 French families with HNPP associated with a chromosome 17p11.2 deletion in 36 individuals. There were electrophysiologic abnormalities in all symptomatic (n = 28) and asymptomatic (n = 8) deletion carriers, even in childhood. Bilateral delayed distal motor latency of the median nerve at the wrist, reduced sensory velocity in the palm-wrist segment, and delayed distal motor latency or reduced motor velocity in the peroneal nerve was diagnostic in at-risk relatives. This large series confirms the reliability of molecular analysis combined with a simplified electrophysiologic examination for the diagnosis of HNPP associated with 17p11.2 deletion.
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.
Annals of Human Genetics · 2001 · 3 citations · open access
Exclusion of 5 functional candidate genes for distal hereditary motor neuropathy type II (distal HMN II) linked to 12q24.3
AbstractDistal hereditary motor neuropathies (distal HMNs) are characterised by degeneration of anterior horn cells of the spinal cord resulting in muscle weakness and atrophy. Distal HMN type II is genetically linked to chromosome 12q24.3 and located within a 13 cM region flanked by markers D12S86 and D12S340. We previously excluded the human phospholipase A2 group 1B gene ( PLA2G1B ) as the disease causing gene. Here, we report the mutation analysis of five other candidate genes localised within the distal HMN II region: the cytoskeletal proteins paxillin ( PXN ) and restin ( RSN ); the acidic ribosomal phosphoprotein, large P0 subunit ( RPLP0 ); a nucleoside diphosphate kinase ( NME2B ); and the β 3 subunit of the voltage‐gated calcium channel ( CACNB3 ). DNA sequencing of the coding regions was performed but no disease causing mutations could be identified, hence excluding these five genes for distal HMN type 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.
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