DeCure for Distal hereditary motor neuropathy type 7
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for distal hereditary motor neuropathy type 7 — 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 moduleDistal hereditary motor neuropathy type 7 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 distal hereditary motor neuropathy type 7 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
solute carrier family 5 member 7 (SLC5A7) — SLC5A7 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 chtdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9BFJ · 2.35 Å · ligand CHOLINE ION (CHT). Experimental structure, not a prediction.
What the evidence adds up to
A recurrent mutation in the WARS gene (c.770A>G, p.His257Arg) was identified as a novel cause of autosomal dominant distal hereditary motor neuropathy in a Taiwanese family after exome sequencing excluded mutations in common implicated genes. The same mutation was found in one additional Taiwanese pedigree and one Belgian family of Caucasian origin when 79 Taiwanese pedigrees and 163 index cases from Australian, European, and Korean families were screened. Cell transfection studies showed the mutation had a dominant-negative effect on the aminoacylation activity of tryptophanyl-tRNA synthetase, compromising protein synthesis and reducing cell viability; it also inhibited neurite outgrowth and caused neurite degeneration in neuronal cell lines and rat motor neurons. The mutation appeared to potentiate angiostatic activities of the enzyme by enhancing its interaction with vascular endothelial-cadherin.
In a cohort of 105 patients from the North of England, the prevalence of distal hereditary motor neuropathy was 2.14 per 100,000 inhabitants. Causative mutations were identified in 26 of 73 index patients (35.6%), with a diagnostic rate of 32.5% in the distal hereditary motor neuropathy subgroup, higher than the previously reported 20%. Many genes were shared between distal hereditary motor neuropathy and axonal motor Charcot-Marie-Tooth disease, suggesting identical disease mechanisms. A significant defect of neuromuscular transmission was detected in 7 cases, and potentially causative mutations were found in 4 patients with multifocal demyelinating motor neuropathy.
Distal hereditary motor neuropathy type 7, characterised by vocal cord paresis, was described in a mother and daughter from Wales whose diagnosis became apparent through initial difficulty in singing from early vocal cord dysfunction. They carried the common truncating mutation in the SLC5A7 gene. This rare neuropathy has now been identified in two apparently unrelated families in Wales. In children under 10 years of age with one parent affected by hereditary motor sensory neuropathy type I, slowed motor nerve conduction velocities were found in 17 of 36 children, with 4 children showing slowing at one year or less; clinical signs were subtle and included pes planus, distal foot wasting, weakness of ankle eversion and dorsiflexion, and areflexia.
What is still missing are large-scale natural history studies that stratify patients by specific genetic mutations, funding for clinical trials targeting the identified mechanisms such as neuromuscular transmission defects or tRNA synthetase dysfunction, and validated outcome measures sensitive enough to detect change in these rare, slowly progressive disorders.
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 · 2017 · 102 citations · open access
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.
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.
Journal of Neurology Neurosurgery & Psychiatry · 1992 · 15 citations · open access
Detection of hereditary motor sensory neuropathy type I in childhood.
AbstractClinical signs and slowed motor nerve conduction velocities were found in 17 of 36 children under 10 years of age who had one parent with hereditary motor sensory neuropathy type I (HMSN I). Four children had slowed conduction velocities at one year or less. Clinical signs were subtle and included pes planus, distal foot wasting, weakness of ankle eversion and dorsiflexion and areflexia. HMSN I can be detected reliably in children, even before one year of age.
Practical Neurology · 2016 · 10 citations · open access
Distal hereditary motor neuropathy with vocal cord paresis: from difficulty in choral singing to a molecular genetic diagnosis
AbstractPatients presenting with distal weakness can be a diagnostic challenge; the eventual diagnosis often depends upon accurate clinical phenotyping. We present a mother and daughter with a rare form of distal hereditary motor neuropathy type 7 in whom the diagnosis became apparent by initial difficulty in singing, from early vocal cord dysfunction. This rare neuropathy has now been identified in two apparently unrelated families in Wales. This family's clinical presentation is typical of distal hereditary motor neuropathy type 7, and they have the common truncating mutation in the SLC5A7 gene. Advances in genetic analysis of these rare conditions broaden our understanding of their potential molecular mechanisms and may allow more directed therapy.
CONTINUUM Lifelong Learning in Neurology · 2023 · 6 citations
Hereditary Neuropathies
AbstractOBJECTIVE: This article provides an overview of hereditary neuropathies, describes the different hereditary neuropathy subtypes and the clinical approach to differentiating between them, and summarizes their clinical management. LATEST DEVELOPMENTS: Increasingly available clinical genetic testing has broadened the clinical spectrum of hereditary neuropathy subtypes and demonstrated a significant overlap of phenotypes associated with a single gene. New subtypes such as SORD -related neuropathy and CANVAS (cerebellar ataxia, neuropathy, vestibular areflexia syndrome) have emerged. The optimization of clinical management has improved gait and motor function in the adult and pediatric populations. Novel therapeutic approaches are entering clinical trials. ESSENTIAL POINTS: Hereditary neuropathies constitute a spectrum of peripheral nerve disorders with variable degrees of motor and sensory symptoms, patterns of involvement, and clinical courses.
[Peripheral Nerve: Cause and Pathology of Inherited Peripheral Neuropathy].
AbstractInherited peripheral neuropathies (IPN) are classified as hereditary motor and sensory neuropathy (HMSN), hereditary motor neuropathy (HMN), or hereditary sensory and autonomic neuropathy (HSAN) based on clinical symptoms. Many IPN are accompanied by central nervous system disorders, such as spastic paraplegia and cerebellar ataxia. With the development of genetic analysis, the causes of IPN continue to be elucidated. This article describes the causative genes and pathologies identified to date.
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.
