DeCure for Finnish upper limb-onset distal myopathy
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Finnish upper limb-onset distal myopathy — 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 moduleFinnish upper limb-onset distal myopathy 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
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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 finnish upper limb-onset distal myopathy 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
heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) — HNRNPA1 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 9GKF · 3.21 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
This is a report on a single Australian kindred with twelve affected members and two possibly affected members, all showing a dominant, slowly progressive distal myopathy. The weakness and wasting were symmetric, affecting the anterior upper limbs and the posterior lower limbs, with the tibialis anterior muscle spared even in advanced disease. All patients remained ambulant, and no cardiac or respiratory muscle involvement was detected. Serum creatine kinase was normal or mildly elevated. Imaging showed widespread involvement of posterior and lateral leg compartments, with proximal muscles abnormal only in advanced disease. Muscle histopathology in four patients showed either end-stage muscle or nonspecific myopathic findings without inflammation or vacuoles. Genetic analysis formally excluded all known distal myopathy phenotype genes and linkage regions, suggesting a new genetic locus.
A 2005 review of distal myopathies noted that aside from some inflammatory myopathies and very few genetic disorders, no therapies exist that make most patients with myopathies stronger. The review described a number of new clinical phenotypes and genetic loci reported in the preceding five years, and emphasised the overlap between distal myopathies, limb girdle myopathies, and hereditary inclusion body myopathies. It reported that genes and mutations had been identified for early onset (Laing) myopathy, tibial (Udd) myopathy, and distal myopathy with rimmed vacuoles (Nonaka), the latter being allelic with quadriceps-sparing hereditary inclusion body myopathy. The review held promise for eventual development of therapies.
A 2013 review on management of myopathies stated bluntly that aside from some inflammatory myopathies and very few genetic disorders, there are no therapies that make most patients with myopathies stronger. It recommended a multidisciplinary approach focused on strength therapies, supportive care, symptomatic therapies, and psychological support, noting that disease-altering therapies had proven elusive for many muscle diseases. A 2020 entry described adult-onset distal myopathy due to VCP mutation as a rare genetic disorder characterised by middle-age onset of distal leg muscle weakness and atrophy in the anterior compartment causing foot drop, without proximal or scapular weakness, and associated with rapidly progressive dementia.
No drug treatment is mentioned in any of these abstracts. What is still missing is any disease-modifying therapy for this specific distal myopathy, any clinical trial testing a drug, and any patient stratification beyond the single Australian kindred and the VCP mutation case. The genetic basis for the Australian kindred remains unidentified, and no preclinical model or drug screening has been reported.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Neurology · 2005 · 41 citations
A new dominant distal myopathy affecting posterior leg and anterior upper limb muscles
AbstractOBJECTIVE: To report a dominant, slowly progressive early onset distal myopathy with sparing of the tibialis anterior. METHODS: Twelve affected and two possibly affected members from an Australian kindred were examined and investigated by EMG, imaging studies, histopathology, and genetic analysis. RESULTS: Affected patients had a slowly progressive condition with symmetric, distal weakness and wasting of the anterior upper and posterior lower limbs, with sparing of tibialis anterior, even in advanced disease. All patients remained ambulant and there was no evidence of cardiac or respiratory muscle involvement. Serum creatine kinase levels were either normal or mildly elevated. Imaging studies showed widespread involvement of the posterior and lateral leg compartments. Proximal muscles were radiologically abnormal only in advanced disease. Muscles that were mildly affected clinically appeared normal on imaging. EMG in nine patients showed widespread myopathic changes. Muscle histopathology in four patients showed either end stage muscle or nonspecific myopathic findings without inflammation or vacuoles. Microsatellite markers for distal myopathy loci were analyzed and all known distal myopathy phenotype genes and linkage regions were formally excluded by multipoint analysis. CONCLUSIONS: The affected patients in this kindred display a clinically distinct myopathy, with selective involvement of posterior lower and anterior upper limb muscles. The genetic analysis suggests the existence of one more distal myopathy locus.
Current Opinion in Neurology · 2005 · 27 citations
Distal myopathies
AbstractPURPOSE OF REVIEW: The distal myopathies are a heterogeneous group of disorders that pose a challenge to both the clinician and geneticist. This article summarizes the findings of recent clinical, genetic and molecular studies and the current diagnostic approach to this group of patients. RECENT FINDINGS: Publications over the past 5 years describe a number of new clinical phenotypes and genetic loci and further emphasize the overlap in clinical phenotype between a number of these disorders and between the distal and limb girdle myopathies and hereditary inclusion body myopathies. Recent studies have led to the identification of the genes and mutations responsible for early onset (Laing) myopathy and tibial (Udd) myopathy, and for distal myopathy with rimmed vacuoles (Nonaka), which has been shown to be allelic with quadriceps sparing hereditary inclusion body myopathy (IBM2), and have elucidated the underlying pathogenetic mechanisms in these conditions. New diagnostic approaches using magnetic resonance imaging, and a blood-based assay for dysferlin deficiency, have also been reported. SUMMARY: These findings have important implications for future genetic linkage and gene expression studies and for the diagnostic approach to patients with a distal myopathy phenotype. They also hold promise for the eventual development of therapies for this group of disorders.
Distal myopathy with rimmed vacuoles and inflammation: A genetically proven case
AbstractDistal myopathy with rimmed vacuoles (DMRV) is a major entity of distal myopathy. It is an autosomal recessive disorder and is due to mutations in the GNE gene that regulates the synthesis of sialic acid. Although reported predominantly from Japan, cases have been reported from other parts of the world. We report the first genetically proven case of DMRV from India in a 23-year-old male with gradual onset, progressive distal weakness of both lower limbs with features of inflammation in muscle biopsy.
CONTINUUM Lifelong Learning in Neurology · 2013 · 11 citations
Multidisciplinary Approach to the Management of Myopathies
AbstractPURPOSE OF REVIEW: Aside from some inflammatory myopathies and very few genetic disorders, there are no therapies that make most patients with myopathies stronger. Consequently, the management of these patients can be frustrating for patients and their families as well as the clinicians taking care of them. Treatment of these patients must involve a comprehensive approach focused on limiting the secondary effects of skeletal muscle weakness, managing comorbidities associated with specific diseases, and, most importantly, optimizing patients' functional abilities and quality of life in terms of their ability to accomplish activities of daily living. While the approach to each patient differs depending on their disease, certain common themes can be addressed in each patient. This review highlights an approach centered on four conceptual themes ("the Four S's"): Strength therapies, Supportive care, Symptomatic therapies, and pSychological support. RECENT FINDINGS: Although relatively few well-designed studies have been done that highlight conservative management of patients with various myopathies, an emerging literature helps guide the clinician in certain key areas, especially in relation to cardiac and pulmonary management of these patients. SUMMARY: While disease-altering therapies have proven elusive for many muscle diseases, a multimodal approach to the conservative and supportive care of these patients can markedly improve their quality of life. Pharmacologic treatment options for specific myopathies will not be addressed in this article but are covered elsewhere in this issue of CONTINUUM.
AbstractOpe n Pe e r Re v ie w on Qe ios Ope n Pe e r Re v ie w on Qe ios Adult-onset distal myopathy due to VCP mutation INSERM Source INSERM.(1999).Orphanet: an online rare disease and orphan drug data base.Adultonset distal myopathy due to VCP mutation.ORPHA:329478 Adult-onset distal myopathy due to VCP mutation is a rare, genetic distal myopathy disorder characterized by middle age-onset of distal leg muscle weakness, atrophy in the anterior compartment resulting in foot drop, without proximal or scapular skeletal muscle weakness.Rapidly progressive dementia
Indian Journal of Anaesthesia · 2014 · 0 citations · open access
Anaesthetic management of a case of distal myopathy
AbstractSir, Congenital myopathies are a group of rare genetic disorders characterized by a defect in the contractile apparatus of the myocytes.[1] We describe the case of a patient with distal myopathy taken up for total abdominal hysterectomy under general anesthesia as patient refused for neuraxial blockade. A 36-years-old female patient diagnosed to have abdominal leiomyosarcoma was planned for total abdominal hysterectomy under general anesthesia. On evaluation the patient gave a history of progressive weakness and thinning of distal aspect of both upper and lower limbs for the last 10 years. She had not sought any medical attention for these complaints. On examination, she was thin built with a BMI of 20. She was haemodynamically stable and had an adequate airway. She had atrophy of distal hand muscles with bilateral claw hands. She also had bilateral foot drop with a high stepping gait [Figure 1a and b]. Deep tendon reflexes, sensory nervous system, cranial nerves and spine examination were normal. Her routine investigations, chest X-ray and ECG were normal. Electrophysiological studies were suggestive of distal myopathy with normal proximal muscles and sensory system.Figure 1: Distal myopathy (with clawing of hand and foot drop) (a) Clawing of hand. (b) Foot dropTab. alprazolam 0.25 mg was given the night before the surgery and adequate blood products were arranged. In the operation theatre, before taking the patient in, all vapourizers were removed from anaesthesia workstation. Soda lime, breathing circuit and face mask were changed. After securing peripheral intravenous line and attaching standard monitors, we started intravenous induction with midazolam 1 mg, fentanyl 60 μcg and 1% propofol 60 mg. After loss of verbal response, we started neuromuscular monitoring with train of four (TOF) and gave atracurium 15 mg. After obtaining no response to TOF, airway was secured with proseal laryngeal mask airway (LMA) of size 3 and post induction monitoring included capnography, nasopharyngeal temperature and TOF count. Maintenance of anesthesia was with with O2/N2O and intravenous propofol infusion at 30-50 μcg/kg/min. Top up doses of atracurium was guided intraoperatively with the TOF count of 3 to achieve adequate muscle relaxation. Haemodynamics and respiratory parameters were maintained within the normal limits throughout the procedure. Thirty minutes before the end of the surgery, diclofenac 1.5 mg/kg and ondansetron 10 μcg/kg were given. At the end of the surgery, neuromuscular blockade was reversed with normal doses of neostigmine and glycopyrrolate and when TOF ratio was ≥0.9, proseal LMA was removed. Post operative period was uneventful. Anaesthetic management of patients with muscle diseases is challenging. In addition to unpredictable sporadic responses, such as rhabdomyolysis and metabolic stimulation, more predictable risks are associated with respiratory and bulbar muscle weakness, myocardial involvement, and difficult airway anatomy. To identify and minimize risk, a thorough preoperative workup is indispensable.[23] If regional anesthesia is planned, a preoperative assessment of peripheral sensory nerve dysfunction should be considered. Increased sensitivity to respiratory-depressant drugs should be anticipated and where possible, doses should be titrated to the desired effect. Even with the most careful anaesthetic management, postoperative ventilatory support may be required and, therefore, postoperative intensive care unit availability should be planned. Baseline serum potassium and creatine kinase (CK) concentrations to assess muscle membrane integrity, family history, cardiac function test and other syndromic features must be sought. It is possible that high baseline values may be associated with increased risk of profound perioperative rhabdomyolysis, whereas the baseline value per se is required to differentiate perioperative rhabdomyolysis from preexisting muscle damage.[3] All anesthetic techniques and drugs are associated with increased risk in patients with myopathies.[45] General anaesthesia performed as total intravenous anaesthesia or regional anaesthesia are equally safe. Inhalation agents especially halothane are not recommended because they may trigger a malignant hyperthermia (MH)-like syndrome.[6] Consideration should be given to the use of short-acting opioids to avoid the possibility of postoperative ventilation. Use of depolarizing neuromuscular blocking drugs should be generally discouraged in patients with neuromuscular diseases.[46] The depolarizing muscle relaxants might trigger MH, and prolonged depolarization leads to potassium release and calcium influx. Although theoretically reversal of neuromuscular block with anticholinesterases in patients with neuromuscular diseases may produce the similar situation, it was not observed in our case. So it can be recommended to use the normal dosage of reversal in such patients. The recent introduction of cyclodextrin reversal drugs (such as sugammadex) provides an attractive alternative in these circumstances. Succinylcholine may also cause acute profound rhabdomyolysis in patients susceptible to MH and those with myopathies. If neuromuscular blockade is required, a non-depolarizing neuromuscular blocking drug should be used, keeping in mind that patients with myopathies may show increased sensitivity to these drugs. On the basis of cardiac evaluation, there may be an indication for invasive monitoring and use of inotropes in patients with identified cardiac involvement.[5] Strength and range of motion can deteriorate rapidly after surgery and immobilization, and anaesthesia can unmask subclinical respiratory failure.[7] So, patients should be mobilized as soon as possible after surgery.[8]
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.
