DeCure for Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis 1
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis 1 — 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 moduleMyopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis 1 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 myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis 1 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
Of 66 patients with unprovoked rhabdomyolysis, 32 had myopathic electromyography. A definitive diagnosis was reached in 15 patients: 11 with myopathic EMG and 4 without. Genetic testing identified the cause in all 12 patients who had it, including 5 with normal muscle biopsy and 3 with nonmyopathic EMG. Diagnoses included seven metabolic and eight nonmetabolic myopathies — five muscular dystrophies and three ryanodine receptor 1 myopathies. Patients with myopathic EMG were more likely to have baseline weakness, elevated baseline creatine kinase, and nonmetabolic myopathies, but nonmyopathic EMG did not rule out an underlying myopathy. The authors concluded that genetic testing should be first-tier after unprovoked rhabdomyolysis.
Drug-induced myopathy can range from asymptomatic creatine kinase elevation and myalgia to life-threatening rhabdomyolysis. In one 12-week trial of ezetimibe and fenofibrate, no measured creatine kinase elevations exceeded 10 times the upper limit of normal, no myopathy was reported, and myalgia incidence was low and similar across groups: 3.1% for placebo, 1.6% for ezetimibe alone, 1.1% for fenofibrate alone, and 1.6% for the combination. No elevations more than five times the upper limit of normal with or without symptoms occurred in any group. The protocol specified discontinuation for persistent five-fold or greater elevations with muscle symptoms, and for persistent 10-fold or greater elevations with or without symptoms.
A 30-year-old man with post-exercise myalgias and hyperCKemia had a creatine kinase level of 70,000 after swimming and was diagnosed with rhabdomyolysis. Genetic testing revealed a heterozygous variant in the GYG1 gene, associated with polyglucosan body myopathy type 2. He had no acute kidney injury and his creatine kinase returned to basal levels with rest. His brother had three rhabdomyolysis episodes. The authors noted that homozygous or compound heterozygous GYG1 variants cause a disease with a range of phenotypes from exercise intolerance to progressive proximal weakness with cardiac involvement, and that heterozygous variants may present with a mild phenotype.
A 32-year-old man with generalized myalgias, proximal muscle weakness, dark urine, and elevated creatine phosphokinase was diagnosed with rhabdomyolysis. He developed acute renal failure requiring hemodialysis. Muscle biopsy showed marked fiber degeneration and necrosis without inflammation, consistent with necrotizing autoimmune myopathy. Antibodies to HMG-CoA reductase were positive in significant titers. He was treated with intravenous corticosteroids and his muscle weakness improved. The authors noted that necrotizing autoimmune myopathy is most commonly associated with statin use, malignancy, or connective tissue disorders, though the majority are idiopathic. What is still missing is a unified diagnostic pathway that integrates genetic testing, drug history, and autoantibody screening in a cost-effective way, and prospective trials to determine whether early identification of specific genetic or autoimmune causes changes long-term outcomes such as renal failure or progressive weakness.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Muscle & Nerve · 2024 · 7 citations · open access
The utility of electrodiagnostic testing in unprovoked rhabdomyolysis in the era of next‐generation sequencing
AbstractINTRODUCTION/AIMS: Rhabdomyolysis is an etiologically heterogeneous, acute necrosis of myofibers characterized by transient marked creatine kinase (CK) elevation associated with myalgia, muscle edema, and/or weakness. The study aimed to determine the role of electrodiagnostic (EDX) testing relative to genetic testing and muscle biopsy in patients with unprovoked rhabdomyolysis in identifying an underlying myopathy. METHODS: EDX database was reviewed to identify unprovoked rhabdomyolysis patients who underwent EDX testing between January 2012 and January 2022. Each patient's clinical profile, EDX findings, muscle pathology, laboratory, and genetic testing results were analyzed. RESULTS: Of 66 patients identified, 32 had myopathic electromyography (EMG). Muscle biopsy and genetic testing were performed in 41 and 37 patients, respectively. A definitive diagnosis was achieved in 15 patients (11 myopathic EMG and 4 nonmyopathic EMG; p = .04) based on abnormal muscle biopsy (4/11 patients) or genetic testing (12/12 patients, encompassing 5 patients with normal muscle biopsy and 3 patients with nonmyopathic EMG). These included seven metabolic and eight nonmetabolic myopathies (five muscular dystrophies and three ryanodine receptor 1 [RYR1]-myopathies). Patients were more likely to have baseline weakness (p < .01), elevated baseline CK (p < .01), and nonmetabolic myopathies (p = .03) when myopathic EMG was identified. DISCUSSION: Myopathic EMG occurred in approximately half of patients with unprovoked rhabdomyolysis, more likely in patients with weakness and elevated CK at baseline. Although patients with myopathic EMG were more likely to have nonmetabolic myopathies, nonmyopathic EMG did not exclude myopathy, and genetic testing was primarily helpful to identify an underlying myopathy. Genetic testing should likely be first-tier diagnostic testing following unprovoked rhabdomyolysis.
Indian Journal of Rheumatology · 2019 · 2 citations · open access
Drug-Induced Myopathy
AbstractA number of medications, including very commonly used ones, have been described as causing myopathy. Drug-induced myopathy is defined as an acute or subacute adverse effect of a drug on the muscular system, which may range from asymptomatic increase in serum creatine kinase and simple myalgias to life-threatening rhabdomyolysis. It is necessary for the treating physician to recognize these manifestations early and manage promptly; in order to prevent treatment-related morbidity and mortality. A PubMed search was conducted using the MeSH terms “drug AND myopathy” and “drug AND rhabdomyolysis.” The consensus of the authors was sought to finalize a group of 60 articles for further review. With the large number of drugs available to the treating physician today, and the significant drug interactions that can occur, knowledge about the various drugs causing myopathy, their characteristic features if any, and the optimal management of these adverse effects is imperative.
European Heart Journal · 2005 · 1 citations · open access
Ezetimibe coadministered with fenofibrate: some safety questions: reply
AbstractWe thank Dr Borja for interest in our work1 and this letter allows us to expand on the criteria related to creatine kinase (CK) elevations used in our study. First, it is important to state that there were no measured CK elevations more than 10 times upper limit of normal (ULN), no reports of myopathy, and that the incidence of myalgia was low and similar among all four treatment groups (3.1% for placebo, 1.6% for ezetimibe 10 mg/d, 1.1% for fenofibrate 160 mg/d, and 1.6% for fenofibrate 160 mg/d plus ezetimibe 10 mg/d) over 12 weeks.1 Additionally, there were no measured elevations in CK more than five times ULN with or without symptoms with any treatment (one patient in the fenofibrate plus ezetimibe group had one measured CK level between three and five times ULN). The CK criteria used in the current protocol for retesting and discontinuing patients are the same as those used in all lipid lowering protocols over the past several years by Merck & Co., Inc. and Merck–Schering Plough Pharmaceutical. Although the criteria developed by the ACC/AHA/NHLBI2 appear reasonable, the CK criteria used in the current protocol have been used extensively during the development of lovastatin, simvastatin, ezetimibe, and ezetimibe/simvastatin. Word counts imposed by the journal allow us only to summarize the details for all procedures used in this study. Subsequently, we describe in detail the procedures for monitoring and handling elevations in CK used in our study. According to the protocol, the central laboratory will notify an investigational site if CK is more than five times ULN, and the site will then contact the patient for a retest within 3 days of the first blood draw. At the follow-up visit, a patient's history will be evaluated: for potential drug interaction with known inhibitors or substrates of CYP3A4; for any recent unusual and/or strenuous exercise, trauma, or intramuscular injections prior to blood draw; and to rule out myocardial ischaemia. As per the protocol, all patients with elevated CK levels will be followed until resolution. The following criteria for CK elevations were used in this study: Conflict of interest: M.F. has no conflict of interest to declare. M.J.D., Y.B.M., and B.G. are employees of Merck & Co., Inc. and may hold stocks or stock options in Merck & Co., Inc. Patients with persistent (two consecutive) CK elevations five-fold or more WITH muscle symptoms were discontinued. Patients with persistent CK elevations more than 10-fold WITH or WITHOUT muscle symptoms were discontinued. Patients with a persistent CK elevation five-fold or more and less than 10-fold WITHOUT muscle symptoms may at the discretion of the investigator and with patient monitoring, remain on study drug until a repeat CK is obtained. Patients with a single CK elevation 10-fold or more WITH muscle symptoms interrupted study drug and had a follow-up CK within 3 days. Patients with a single CK elevation 10-fold or more WITHOUT muscle symptoms may at the discretion of the investigator and with patient monitoring, remain on study drug until a repeat CK is obtained.
Arquivos de Neuro-Psiquiatria · 2024 · 0 citations · open access
GYG1 gene mutation causing a mild phenotype of polyglucosan body myopathy type 2
AbstractA 30-year-old man presented to the neuromuscular disease clinic reporting post-exercise myalgias and hyperCKnemia. His condition was first noted at the age of 20 when he experienced myalgia and muscle weakness after swimming. The patient was, on occasion, referred to the emergency department, where laboratory tests revealed a creatine kinase (CK) level of 70.000, and he was diagnosed with rhabdomyolysis. He denied having had an acute kidney injury at that moment and reported that the CK eventually returned to basal levels with rest. The patient is a doctor and kept track of his CK levels through the following years. He noticed that he often experiences hyperCKemia, frequently asymptomatic, following physical exercise. The patient reported that his brother had three episodes of rhabdomyolysis during his life. Neurological examination was normal during the consult, and a genetic panel for rhabdomyolysis was requested for diagnosis, which revealed a potentially pathogenic heterozygous variant in the GYG1 gene - NM_004130.4(GYG1):c.304G>C (p.Asp102His), associated with myopathy with polyglucosan bodies type II (PGB2). The GYG1 gene encodes the isoform glycogenin-1, a protein involved in glycogen biosynthesis. Pathogenic variations in the GYG1 gene may result in reduced, absent, or functionally abnormal glycogenin-1 protein, leading to defective glycogen synthesis, glycogen depletion in skeletal muscle, and abnormal glycogen accumulation in cardiac muscle. Homozygous or compound heterozygous variants in GYG1 are associated with PGB2, a genetic disease characterized by different clinical phenotypes, ranging from exercise intolerance to progressive proximal weakness with cardiac involvement. The clinicopathological spectrum of GYG1 disease is rapidly expanding. Most cases illustrate a slowly progressive proximal myopathy with or without cardiac involvement starting in adulthood. However, distal, asymmetric, or isolated facial weakness, fluctuating weakness, exertional myalgia, and exercise intolerance are also described. Our patient experienced recurrent episodes of exercise-induced rhabdomyolysis associated with a probably pathogenic heterozygous variant in the GYG1 gene, probably representing a milder clinical phenotype of PGB2. He was instructed to avoid intense physical exercises, and genetic counseling was advised. Heterozygous variants of the GYG1 gene may present with a mild clinical phenotype of PGB2 disease. This case highlights the need to correlate clinical phenotypes and gene variants while investigating possible genetic diagnosis because mutations in the same gene may present with a broad range of clinical spectra.
A Rare Case of Idiopathic Autoimmune Necrotizing Myopathy Presenting with Rhabdomyolysis
AbstractDear Editor, Necrotizing autoimmune myopathy (NAM) is a rare entity among the idiopathic inflammatory myopathies. We report an interesting case of NAM presenting with rhabdomyolysis, hence this letter to the editor. A 32-year-old male, without prior co-morbidities presented with generalized myalgias for 1 month, which were initially limited to thighs and arms, later progressed to involve legs and forearms. They gradually increased in intensity. He complained of dark-colored urine, burning micturition, and generalized painful swelling of the body for 3 days before presenting to the emergency department. On examination, he had proximal more than distal muscle weakness. Musculoskeletal system examination showed diffuse subcutaneous edema and muscle tenderness over both extremities. Rest of the systemic examination was within normal limits. In view of symptoms of muscle pain, weakness, muscle swelling, presence of dark-colored urine, elevated lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) levels, the patient was worked up for rhabdomyolysis. Urine for myoglobin was positive. A thorough history regarding drug abuse, alcohol intake, medications such as statins and strenuous exercise was taken. Infectious causes of rhabdomyolysis were ruled out. Blood and urine cultures were negative. Serology for connective tissue disorders and acylcarnitine levels for lipid storage disorders were negative.[1] Patient developed acute renal failure and required hemodialysis during hospital course. Magnetic Resonance Imaging (MRI) of muscle was done for targeted muscle biopsy which showed diffuse muscle edema. Muscle biopsy showed muscle fibers with marked fiber degeneration and necrosis with myophagocytosis, characteristically without inflammation [Figure 1]. These findings were consistent with NAM. Antibodies to 3Hydroxy-3methyl-glutaryl-Coenzyme-A (HMGCoA) reductase were sent which were positive in significant titers confirming the diagnosis. The patient was treated with intravenous corticosteroids and his muscle weakness began to improve.Figure 1: (a and b) The muscle biopsy showing fibre necrosis without inflammation. H and E × 100. (c) The necrotic fibres highlighted on oxidative stains. NADH × 100Idiopathic inflammatory myopathies include polymyositis, dermatomyositis, sporadic inclusion body myositis, and necrotizing autoimmune myopathy. Their presentation is usually subacute or chronic with proximal muscle weakness and other systemic manifestations.[2] NAM is most commonly associated with statin use, malignancy, or connective tissue disorders though majority are idiopathic. Muscle biopsy is characteristic which typically shows little or no inflammation.[3] Autoantibodies to HMGCoA reductase are relatively specific for NAM, their titers co-relate with disease severity and those positive have a better response to therapy.[4] NAM is treated with a combination of intravenous immunoglobulins, corticosteroids, and other immunosuppressants but treatment is individualized based on response to therapy. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
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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