DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for distal myopathy — screening already-approved drugs against its 19-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleDistal myopathy maps to a 19-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 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
membrane metalloendopeptidase (MME) — MME 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 ft8drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6SUK · 1.75 Å · ligand Omapatrilat (FT8). Experimental structure, not a prediction.
What the evidence adds up to
Distal myopathies are a group of genetic primary muscle disorders defined by weakness beginning in the hands or feet. Nearly 20 genes have been linked to autosomal dominant forms, four to autosomal recessive forms, and five can cause either pattern. A digenic mechanism has also been described: rare pathogenic mutations in SQSTM1, previously associated with Paget disease of bone, cause a distal myopathy only when combined with a common polymorphism in TIA1. The clinical presentation is highly variable: age of onset ranges from early childhood to adulthood, and the distribution of weakness differs between upper and lower limbs. Histological findings range from non-specific myopathic changes to myofibrillar disarray and rimmed vacuoles. Despite this genetic and clinical heterogeneity, all distal myopathies are progressive muscular dystrophies that involve loss of muscle fibres.
One Finnish family with autosomal dominant distal myopathy had onset between 32 and 45 years, presenting with hand clumsiness and a steppage gait from foot drop. Weakness involved the small hand muscles, gluteus medius, and both anterior and posterior leg compartments, later spreading to forearm muscles, triceps, infraspinatus, and proximal lower limbs. Asymmetry was common. Serum creatine kinase was normal or mildly elevated, and muscle biopsy showed rimmed vacuoles and dystrophic changes. This phenotype did not link to the known loci for Welander distal myopathy or tibial muscular dystrophy. In the broader literature, similar phenotypes can arise from different genetic defects, and the same defect — for example, dysferlin gene mutations — can produce either a distal myopathy (Miyoshi myopathy) or a limb-girdle muscular dystrophy (LGMD2B).
Nonaka myopathy, also called distal myopathy with rimmed vacuoles, is an autosomal recessive, slowly progressive condition. Over 150 cases have been reported across the Middle East, Japan, and Europe. One 33-year-old woman presented with symmetrical distal weakness in all four limbs and was diagnosed after neurophysiology, muscle biopsy, and genetic analysis; she was managed conservatively with physiotherapy. No drug therapy was described in any of the abstracts. The review articles note that the identification of causative genes has clarified some mechanisms but has not yet led to treatments. What remains missing are therapies for any form of distal myopathy, along with the clinical trials, patient stratification, and funding needed to develop them.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
PubMed · 2020 · 57 citations · open access
Panorama of the distal myopathies.
AbstractDistal myopathies are genetic primary muscle disorders with a prominent weakness at onset in hands and/or feet. The age of onset (from early childhood to adulthood), the distribution of muscle weakness (upper versus lower limbs) and the histological findings (ranging from nonspecific myopathic changes to myofibrillar disarrays and rimmed vacuoles) are extremely variable. However, despite being characterized by a wide clinical and genetic heterogeneity, the distal myopathies are a category of muscular dystrophies: genetic diseases with progressive loss of muscle fibers. Myopathic congenital arthrogryposis is also a form of distal myopathy usually caused by focal amyoplasia. Massive parallel sequencing has further expanded the long list of genes associated with a distal myopathy, and contributed identifying as distal myopathy-causative rare variants in genes more often related with other skeletal or cardiac muscle diseases. Currently, almost 20 genes (ACTN2, CAV3, CRYAB, DNAJB6, DNM2, FLNC, HNRNPA1, HSPB8, KHLH9, LDB3, MATR3, MB, MYOT, PLIN4, TIA1, VCP, NOTCH2NLC, LRP12, GIPS1) have been associated with an autosomal dominant form of distal myopathy. Pathogenic changes in four genes (ADSSL, ANO5, DYSF, GNE) cause an autosomal recessive form; and disease-causing variants in five genes (DES, MYH7, NEB, RYR1 and TTN) result either in a dominant or in a recessive distal myopathy. Finally, a digenic mechanism, underlying a Welander-like form of distal myopathy, has been recently elucidated. Rare pathogenic mutations in SQSTM1, previously identified with a bone disease (Paget disease), unexpectedly cause a distal myopathy when combined with a common polymorphism in TIA1. The present review aims at describing the genetic basis of distal myopathy and at summarizing the clinical features of the different forms described so far.
A distinct phenotype of distal myopathy in a large Finnish family
AbstractOBJECTIVES: The authors carried out clinical, histopathologic, immunocytochemical, electrophysiologic, and imaging investigations and molecular genetic analysis in seven patients with distal myopathy belonging to a Finnish family. RESULTS: The disease showed autosomal dominant inheritance. Age at onset ranged from 32 to 45 years. The first symptoms for referral were clumsiness with the hands and frequent stumbling from a steppage gait. Muscle weakness was characterized by early involvement of the small muscles of the hands, gluteus medium, and both anterior and posterior muscle compartments of the legs. The disease progressed to involve other intrinsic muscles of the hands, as well as the forearm muscles, triceps and infraspinatus, and proximal lower limbs. Asymmetry of muscle involvement was common. EMG showed myopathic features, serum CK was normal or slightly elevated, and muscle biopsy showed many rimmed vacuoles and dystrophic changes. There was no evidence of linkage to Welander distal myopathy or tibial muscular dystrophy loci. CONCLUSION: These patients may have a distinct distal myopathy. Genome-wide scan is undertaken in order to identify the disease locus.
Journal of Neurology Neurosurgery & Psychiatry · 1999 · 28 citations · open access
Distal myopathies: clinical and molecular diagnosis and classification
AbstractThe distal myopathies are a clinically and pathologically heterogeneous group of genetic disorders in which the distal muscles of the upper or lower limbs are selectively or disproportionately affected. Although there is some uncertainty as to the actual diagnosis, the first case description of distal myopathy is usually attributed to Gowers in 1902.1 However, it was not until the landmark publication by Welander in 19512 describing a large cohort of patients with a dominantly transmitted late onset familial form of distal myopathy in Sweden, that this group of disorders became firmly established. Other dominant and recessive forms with distinctive clinical phenotypes and muscle pathology have since been recognised, particularly in Finland and Japan.3-6 Linkage to chromosome 14q11 was first reported in an Australian family with early onset autosomal dominant distal myopathy in 19957 and genetic linkage has since also been described in the other five major forms of distal myopathy8-11 (table 1). To date, the responsible gene has been identified in only one of these (Miyoshi myopathy), in which mutations have been found in the dysferlin gene at chromosome 2p12–14.13
View this table:
Table 1
Classification and distinguishing features of the major forms of distal myopathies
Comparison of the different forms of distal myopathy has shown considerable phenotypic variability, both in terms of the age at which symptoms first develop and the pattern of differential involvement of the limb muscles and of other muscle groups such as those of the neck and face. Moreover, it has been recognised that similar phenotypes may result from different genetic defects and conversely, that certain defects such as the dysferlin gene mutations may be associated with different clinical phenotypes including one form of limb girdle muscular dystrophy (LGMD2B).12 13 At the histological level, several of the distal myopathies are characterised by the …
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.
Neurology India · 2008 · 19 citations · open access
Distal myopathies a review: Highlights on distal myopathies with rimmed vacuoles
AbstractDistal myopathies are a group of heterogeneous disorders classified into one broad category due to the presentation of weakness involving the distal skeletal muscles. The recent years have witnessed increasing efforts to identify the causative genes for distal myopathies. The identification of few causative genes made the broad classification of these diseases under "distal myopathies" disputable and added some enigma to why distal muscles are preferentially affected. Nevertheless, with the clarification of the molecular basis of specific conditions, additional clues have been uncovered to understand the mechanism of each condition. This review will give a synopsis of the common distal myopathies, presenting salient facts regarding the clinical, pathological, and molecular aspects of each disease. Distal myopathy with rimmed vacuoles, or Nonaka myopathy, will be discussed in more detail.
BMJ Case Reports · 2019 · 1 citations · open access
Slowly progressive distal muscle weakness: neuropathy or myopathy?
AbstractNonaka myopathy is an autosomal recessive and slowly progressive distal myopathy. It is part of a rare group of myopathies predominantly affecting the distal limb musculature. Over 150 cases have been reported across the Middle East, Japan and Europe. We report the case of a 33-year-old woman presenting with symmetrical upper and lower limb weakness, most severely affecting the distal muscle groups. After extensive neurological investigation including neurophysiology, muscle biopsy and genetic analysis, she was finally diagnosed with Nonaka myopathy and treated conservatively with physiotherapy.
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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