DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for centronuclear myopathy — screening already-approved drugs against its 16-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleCentronuclear myopathy maps to a 16-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 centronuclear 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
cholinergic receptor nicotinic alpha 1 subunit (CHRNA1) — CHRNA1 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 clrdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9DMS · 1.92 Å · ligand CHOLESTEROL (CLR). Experimental structure, not a prediction.
What the evidence adds up to
A 1998 case report describes general anaesthesia for a 32-year-old woman with centronuclear myopathy who required bilateral temporomandibular joint arthroplasties. She had been wheelchair-bound since early childhood, had severe restrictive lung disease, sleep apnea requiring nocturnal bilevel pressure-assisted ventilation, and a history of gastroesophageal reflux. Muscle relaxants were avoided, and anaesthesia was induced with propofol and maintained with propofol infusion, nitrous oxide, and oxygen. No volatile agents or neuromuscular-blocking drugs were used. The patient awoke spontaneously, was extubated without incident, and was discharged on the third postoperative day. The authors note that the potential for muscle relaxants to interact with diseased muscle and the possibility of triggering malignant hyperthermia influenced the choice of anaesthetic plan.
A 2007 case report describes the successful use of regional anaesthesia in a 48-year-old woman with centronuclear myopathy who underwent excision of a large popliteal soft tissue swelling. She was morbidly obese (BMI 55), wheelchair-bound due to lower limb weakness, and had bilateral symmetrical proximal muscle weakness (Grade 3) with distal strength Grade 4–5. Combined spinal-epidural anaesthesia was performed using hyperbaric bupivacaine 0.5%. Sensory block from S1 to L1 was achieved after 15 minutes, and incremental boluses raised the upper level to T10. Haemodynamic stability was maintained without vasopressors. Surgery lasted about one hour under tourniquet. Sensory and motor function returned to preoperative level at 4.5 hours, and the patient was discharged to the ward after 6 hours with no deterioration of muscle weakness or new neurological deficit at six-week follow-up. The authors note that only four previous cases of general anaesthesia in centronuclear myopathy had been reported, all avoiding neuromuscular-blocking drugs and volatile agents, and that the effect of regional anaesthesia on disease progression in patients with prolonged immobilisation and muscle atrophy is not known.
A 2008 review states that centronuclear myopathy is an inherited neuromuscular disorder with centrally placed nuclei on muscle biopsy. The X-linked form (MTM1 gene mutations) usually presents at birth with marked weakness, hypotonia, external ophthalmoplegia, and respiratory failure, and is often fatal in infancy. Autosomal-dominant forms (DNM2 gene mutations) have a later onset and milder course; autosomal-recessive forms (BIN1 gene mutations) are intermediate in severity. The review notes that management is mainly supportive and based on a multidisciplinary approach. No drug treatment is mentioned in any of the three abstracts.
What is still missing: no clinical trials of any drug for centronuclear myopathy are reported in these abstracts. There is no evidence on disease-modifying therapy, no data on patient stratification by genotype, and no funding for interventional studies. The literature consists only of anaesthesia case reports and a review of natural history.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Anesthesiology · 1998 · 13 citations
General Anesthesia for a Patient with Centronuclear (Myotubular) Myopathy
Abstract(Gottschalk) Assistant Professor, Department of Anesthesia, University of Pennsylvania School of Medicine.(Heiman-Patterson) Professor, Department of Neurology, Allegheny University of the Health Sciences, Graduate Division.(deQuevedo) Resident in Anesthesia, Department of Anesthesia, University of Pennsylvania School of Medicine.(Quinn) Associate Professor and Chairman, Department of Oral and Maxillofacial Surgery, University of Pennsylvania School of Dental Medicine.CENTRONUCLEAR myopathy [1-4]is a rare congenital myopathy characterized by progressive muscle weakness. We report a case of general anesthesia for a patient with this.A 32-yr-old woman with centronuclear myopathy was scheduled for bilateral arthroplasties for treatment of ankylosis of the temporomandibular joints. For several years before surgery, she had progressive ankylosis with decreasing range of motion of her mandible. Oral intake was possible only through a small straw, and oropharyngeal secretions could be cleared only with a small soft suction catheter.The diagnosis of centronuclear myopathy was made at 6 yr of age and was reported in the literature as one of the first examples of this myopathy. [5]Because of the disease she was wheelchair-bound at an early age. Subsequently restrictive lung disease and asthma developed with multiple episodes of bronchitis and pneumonia necessitating hospital admission. Although pulmonary function testing indicated severe restrictive lung disease, the arterial blood gas levels were normal. The patient had sleep apnea necessitating nasal bilevel pressure-assisted ventilation at night. A sleep study performed previously in the year while undergoing nasal bilevel pressure-assisted ventilation showed multiple oxygen desaturations throughout the night, with 53 events below 90% to as low as 68%. She also had a history of gastroesophageal reflux, but was without cardiac, hepatic, renal or other neuromuscular disorders. At the time of admission, medications included theophylline, terfenadine, and prednisone. She was allergic to sulfa, dust, pig hair, cow hide, and tree pollen.Surgical history included correction of strabismus at 4 yr of age, bilateral ptosis repair at 6 yr of age, and bilateral Achilles tendon release at 12 yr of age, all performed uneventfully during general anesthesia. One year before admission, the patient underwent temporomandibular joint surgery at another institution, where she required emergent oral intubation for apnea after premedication with droperidol and fentanyl.Physical examination revealed a thin woman in a wheelchair who became mildly short of breath while speaking. She was unable to open her mouth. Her chest was scoliotic with breath sounds decreased bilaterally. Wheezes were absent. Muscle strength was 3/5 in all extremities.Before surgery, the anesthesia machine was flushed with oxygen. At arrival in the operating room, glycopyrrolate was administered, and airway anesthesia was obtained using topical lidocaine and percutaneous superior laryngeal nerve blocks. After uneventful nasal fiberoptic intubation with a 6.0-mm nasal R.A.E. endotracheal tube, general anesthesia was induced with propofol and maintained with a propofol infusion, nitrous oxide, and oxygen. No additional intravenous medications were administered at any time, except for ketorolac 1 h before emergence.Bilateral coronoidectomies with bilateral arthroplasty with eminectomies were performed without difficulty. The surgical sites were infiltrated with bupivacaine by the surgeon. The patient awoke and was transported to the postanesthesia care unit while breathing spontaneously. After uneventful extubation, she was placed on nasal bilevel pressure-assisted ventilation at her usual settings. The remainder of her postoperative course was unremarkable, and she was discharged on the third postoperative day.Centronuclear myopathy was first described in 1966. [6]It presents in early childhood with slowly progressive weakness of the extraocular, facial, neck, and limb muscles. [1-4]Because of the histologic resemblance of the diseased muscle to fetal myotubes, this disorder originally was called myotubular myopathy. However, the similarity between fetal myotubes and diseased muscle tissue is not complete, and the term centronuclear myopathy, which refers to the large number of centrally placed nuclei in specimens of diseased muscle, is preferred. As more cases were reported, it became clear that there was considerable heterogeneity with respect to presentation, severity, histology, and inheritance. The reported cases included several with severe X-linked disease for which the term myotubular myopathy is used by some authors. [1]Although the pattern of inheritance helps to distinguish the different variants, [7]the clinical presentation of each is similar enough to consider as a single disease.Autosomal dominant and autosomal recessive forms of centronuclear myopathy often are divided, although imperfectly, with respect to the age of onset. [1]The early-onset form is the most common, follows an autosomal recessive pattern of inheritance, and can be seen in white and black patients. It may present at birth and may be severe enough to produce respiratory distress at that time. It is slowly progressive, but most patients die or are wheelchair-bound by the second or third decade of life. The development of scoliosis with restrictive lung disease is the most important physiologic manifestation of the disease's progress. [8]As with our patient, the association of ptosis and strabismus may increase the likelihood of surgical procedures during childhood. Seizures, some degree of mental retardation, psychosis, or other central nervous system disorders will develop in many children. Congenital lesions of the heart and cardiomyopathy occasionally are described. [2]A high, arched palate may be present.Late-onset centronuclear myopathy follows an autosomal dominant pattern. It usually becomes apparent by the third decade of life. [1-4]The progress of the late-onset form is slower than that of the early-onset form but can still leave some patients wheelchair-bound by the sixth decade of life. The degree of defect can become worse during pregnancy.In centronuclear myopathy, serum creatine kinase concentrations usually are normal, although mild elevations are sometimes seen with the early-onset form of the disease. [1]Changes consistent with myopathy are observed on the electromyogram. However, conduction velocities of the motor nerves are normal. Electroencephalographic abnormalities have been noted in several patients with the early-onset form of the disease before clinically apparent seizure activity begins.Some authors use the term myotubular myopathy for the severe nonprogressive X-linked form of centro-nuclear myopathy in which few of the boys born with this disorder are able to overcome the marked respiratory distress present at birth. [1-4]Although males are severely affected, asymptomatic mothers have been identified using muscle biopsy. Micrognathia is one of several dysmorphic features that may be present in these patients. Serum creatine kinase concentrations usually are normal. The results of the electromyographic examination are consistent with myopathy, and conduction along the motor nerves is normal. In patients with X-linked myotubular myopathy, molecular biologic techniques have shown mutations in the gene encoding the protein myotubularin. [9,10]In this patient, several issues directly related to the myopathy influenced the choice of an anesthetic plan. These were the potential for muscle relaxants to interact with the diseased muscle tissue [11]and the possibility of triggering malignant hyperthermia. [12]Muscle relaxation was avoided and a nontriggering anesthetic was used. The severe restrictive lung disease, sleep apnea, difficult airway secondary to ankylosis of the temporomandibular joints, history of bronchospasm, and gastroesophageal reflux also were of concern.We conclude that patients with centronuclear myopathy can be treated successfully using an anesthetic plan that directly addresses the presence of the underlying myopathy and the associated decrements in physiologic function.The authors thank David S. Smith, M.D., Ph.D. for suggestions and comments.
AbstractCentronuclear myopathy (CNM) is an inherited neuromuscular disorder characterised by clinical features of a congenital myopathy and centrally placed nuclei on muscle biopsy.The incidence of X-linked myotubular myopathy is estimated at 2/100000 male births but epidemiological data for other forms are not currently available.The clinical picture is highly variable. The X-linked form usually gives rise to a severe phenotype in males presenting at birth with marked weakness and hypotonia, external ophthalmoplegia and respiratory failure. Signs of antenatal onset comprise reduced foetal movements, polyhydramnios and thinning of the ribs on chest radiographs; birth asphyxia may be the present. Affected infants are often macrosomic, with length above the 90th centile and large head circumference. Testes are frequently undescended. Both autosomal-recessive (AR) and autosomal-dominant (AD) forms differ from the X-linked form regarding age at onset, severity, clinical characteristics and prognosis. In general, AD forms have a later onset and milder course than the X-linked form, and the AR form is intermediate in both respects.Mutations in the myotubularin (MTM1) gene on chromosome Xq28 have been identified in the majority of patients with the X-linked recessive form, whilst AD and AR forms have been associated with mutations in the dynamin 2 (DNM2) gene on chromosome 19p13.2 and the amphiphysin 2 (BIN1) gene on chromosome 2q14, respectively. Single cases with features of CNM have been associated with mutations in the skeletal muscle ryanodine receptor (RYR1) and the hJUMPY (MTMR14) genes.Diagnosis is based on typical histopathological findings on muscle biopsy in combination with suggestive clinical features; muscle magnetic resonance imaging may complement clinical assessment and inform genetic testing in cases with equivocal features. Genetic counselling should be offered to all patients and families in whom a diagnosis of CNM has been made.The main differential diagnoses include congenital myotonic dystrophy and other conditions with severe neonatal hypotonia.Management of CNM is mainly supportive, based on a multidisciplinary approach. Whereas the X-linked form due to MTM1 mutations is often fatal in infancy, dominant forms due to DNM2 mutations and some cases of the recessive BIN1-related form appear to be associated with an overall more favourable prognosis.
Regional anaesthesia in a patient with centronuclear (myotubular) myopathy
AbstractWe wish to report the successful use of regional anaesthesia in a patient with centronuclear (myotubular) myopathy. Centronuclear myopathy is a rare type of congenital myopathy, characterised by the presence of a high proportion of small myofibres with central nuclei. It can be associated with scoliosis and cardiomyopathy [1, 2]. Patients with myopathies can be extremely sensitive to non-depolarising neuromuscular blocking drugs [3] and may have an increased risk of developing malignant hyperthermia [4]. A 48-year-old female patient with centronuclear myopathy presented for excision of large soft tissue swelling in the popliteal region measuring 20 cm × 20 cm. She was morbidly obese with a body mass index of 55 and was wheelchair bound due to her lower limb weakness. She had bilateral, symmetrical muscle weakness, more marked proximally (Grade 3) than distally (Grade 4–5). Her deep tendon reflexes were depressed uniformly in both upper and lower limbs. Examination of her sensory system revealed no abnormality. Combined spinal-epidural anaesthesia was planned as the surgery was in the lower limb, the duration of the surgery was unknown and this technique was least likely to interfere with respiration. The back-up plan was awake fibreoptic intubation and general anaesthesia using total intravenous anaesthesia without neuromuscular-blocking drugs. Following the administration of Hartmann's solution 500 ml as a preload, the epidural space was identified, using a 16-gauge Tuohy needle and loss of resistance to saline, at a depth of 8 cm from the skin. A 25-gauge pencil-point spinal needle was introduced and the subarachnoid space was identified by the flow of clear cerebrospinal fluid. Two milliitres of hyperbaric bupivacaine 0.5% was injected through the spinal needle. An epidural catheter was inserted through the Tuohy needle, and subsequent aspiration of CSF (as confirmed by glucose content of 2.1 mmol.l−1) through the catheter revealed subarachnoid placement of the catheter. The catheter was left in the subarachnoid space. A sensory block (to cold spray) extending from S1 to L1 was achieved after 15 min. Two 0.5-ml incremental boluses of hyperbaric 0.5% bupivacaine were administered through the spinal catheter, which led to an upper sensory block level at T10. Haemodynamic stability was maintained throughout the procedure without the use of vasopressors to maintain the blood pressure. Surgery was carried out under a tourniquet and lasted for about 1 h. The spinal catheter was removed at the end of operation and the patient was transferred to the post anaesthesia care unit (PACU). Both sensory and motor function returned to the pre-operative level at 4.5 h. The patient was returned to the ward after 6 h and further postoperative recovery was uneventful. She did not develop any postdural puncture headache. She was followed up 6 weeks later and there was no deterioration of muscle weakness or any new neurological deficit. Information on anaesthetic management of patients with centronuclear myopathy is scarce, with only four reported cases where general anaesthesia was administered without using neuromuscular-blocking drugs or volatile anaesthetic agents [2, 4–6]. The effect of regional anaesthesia on the progression of the disease in a patient likely to have prolonged immobilisation and muscle atrophy is not known [4]. However, there are reports of the successful use regional anaesthesia and analgesia in patients with various types of myopathy demonstrating the safety and efficacy of regional anaesthesia and analgesia [7, 8]. This case illustrates the safe use of regional anaesthesia in a patient with centronuclear myopathy.
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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