DeCure for Myopathy, myosin storage, autosomal recessive
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for myopathy, myosin storage, autosomal recessive — 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, myosin storage, autosomal recessive 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, myosin storage, autosomal recessive 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
myosin heavy chain 7 (MYH7) — MYH7 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 adpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9TPJ · 3.02 Å · ligand ADENOSINE-5'-DIPHOSPHATE (ADP). Experimental structure, not a prediction.
What the evidence adds up to
In 2005, two isolated Belgian cases of myosin storage myopathy were found to carry the same arginine 1845 tryptophan mutation in the MYH7 gene that had previously been identified in Swedish families, confirming a critical role for that residue. Myosin storage myopathy is a congenital condition defined by subsarcolemmal hyaline bodies in type 1 muscle fibres that stain positive for ATPase, indicating the presence of myosin. The 2013 German report describes the first patient from that country with myosin storage myopathy, also carrying a heterozygous R1845W missense mutation in MYH7, and presents clinical, myopathological and MRI findings for that single case.
A separate 2013 paper revisits an autosomal recessive myopathy with external ophthalmoplegia originally described in 2005 in 16 subjects from eight families in a highly inbred Arab community near Jerusalem. The condition features conjugate non-restrictive ocular motility impairment without ptosis, mild facial and limb weakness, scoliosis, and marked type 1 fibre predominance on biopsy. A genome-wide search had linked the disorder to chromosome 17p13.1-p12, but initial sequencing of MYH2 found no exonic mutations. After six additional similarly affected individuals were diagnosed from the same community, reanalysis of MYH2 in two original patients disclosed a homozygous single-base deletion in exon 19 (c.2400delG) that had been missed by a laboratory error. This truncating mutation causes a reading frame shift and premature stop codon (p.Phe801SerfsX28), likely resulting in loss of functional MyHC IIa protein. The same mutation was found in homozygosity in a previously untested patient and in heterozygosity in his unaffected mother. No MyHC IIa transcript was detected in his muscle biopsy, consistent with downregulated expression due to the truncating mutation.
The MYH2-related phenotype is now described as mild facial and limb myopathy with prominent external ophthalmoplegia of early childhood onset and slow progression. The co-occurrence of skeletal myopathy and ophthalmoplegia is explained by MyHC IIa expression in type 2A muscle fibres and in oculorotatory muscles. The infrequency of ptosis, despite MyHC IIa also being present in levator palpebrae superioris, remains unclear. The 2013 paper notes that two patients had slightly elevated creatine kinase levels, and one had a muscle biopsy reported to show no identifiable alterations. The original 2005 group and the 2013 group together include 22 affected individuals from the same community, but no treatment or intervention is tested or discussed in any of these reports.
What is still missing for these rare myopathies is any systematic trial of a therapeutic agent, any preclinical model testing a drug, and any funding directed toward drug development rather than genetic characterisation. Patient stratification by specific MYH7 or MYH2 mutation is possible but has not been used to guide a clinical trial. The natural history is slow and variable, which would complicate trial design and outcome measurement. No repurposed drug has been proposed or tested in these patient populations.
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 · 57 citations
Myosin storage myopathy: Slow skeletal myosin ( <i>MYH7</i> ) mutation in two isolated cases
AbstractMyosin storage myopathy is a congenital myopathy characterized by subsarcolemmal hyaline bodies in type 1 muscle fibers, which are ATPase positive and thus contain myosin. Mutations recently were identified in the type 1 muscle fiber myosin gene (MYH7) in Swedish and Saudi families with myosin storage myopathy. The authors have identified the arginine 1845 tryptophan mutation found in the Swedish families in two isolated Belgian cases, indicating a critical role for myosin residue arginine 1845.
MYH2 mutation in recessive myopathy with external ophthalmoplegia linked to chromosome 17p13.1-p12
AbstractSir, in 2005, we described a new autosomal recessive myopathy with external ophthalmoplegia in 16 subjects of eight families from a large and highly inbred Arab community near Jerusalem (Lossos et al., 2005). Characteristic clinical features of this disorder include conjugate non-restrictive ocular motility impairment without ptosis, mild facial and limb muscle weakness and scoliosis. The major pathological finding on skeletal muscle biopsy was marked Type 1 fibre predominance. A genome-wide search for areas of homozygosity identified linkage with chromosome 17p13.1-p12 markers defining a critical region of 12 cM encompassing an ordered cluster of six myosin heavy-chain genes. Direct sequencing of the MYH2, reported by that time to be involved in autosomal-dominant myosin heavy-chain (MyHC) IIa myopathy (Martinsson et al., 2000), showed no exonic mutations, and the genetic cause of this disorder remained unknown. Since then, we have diagnosed six additional similarly affected individuals from the same community (Table 1). The four male and two female subjects were referred for neurological examination because of external ophthalmoplegia (n = 3) or for unrelated reasons (essential tremor, epilepsy or diabetic peripheral neuropathy; n = 1 each) at age 18–45 years. All presented the typical ocular motility limitation in the horizontal and vertical planes, always greatest in the upgaze and often associated with forehead contraction but without ptosis. The distribution of mild [Medical Research Council (MRC) grade 4] facial (n = 6) and limb (n = 4) muscle weakness and atrophy was always symmetrical and relatively homogenous, most prominent proximally in the upper limbs, thus confirming our original description. Given the slow progression of muscular weakness, the age of onset could not be precisely ascertained. However, parents of the two youngest patients described slow eye movements since early childhood. Two patients had slightly elevated creatine kinase level, and one had muscle biopsy reported to show no identifiable alterations but unavailable for our review. Main clinical findings in the original (Lossos et al., 2005) and the present groups of patients with recessive myopathy and external ophthalmoplegia a MRC grading: 4 = movement against variable resistance. NA = not available. Main clinical findings in the original (Lossos et al., 2005) and the present groups of patients with recessive myopathy and external ophthalmoplegia a MRC grading: 4 = movement against variable resistance. NA = not available. Because of similarities to the recently described recessive myopathy with ophthalmoplegia and absence of Type 2A muscle fibres (Tajsharghi et al., 2010), the entire coding sequence of MYH2 was reanalysed on genomic DNA samples from two affected subjects from the original group of patients. Polymerase chain reaction (PCR) conditions and sequence analysis were performed as described (Tajsharghi et al., 2005). A homozygous single-base deletion, probably missed before by a laboratory error, was disclosed in exon 19 (c.2400delG, GGG>GGT), leading to a reading frame shift and a premature stop codon (p.Phe801SerfsX28). This truncating mutation is likely to result in loss of functional MyHC IIa protein and adds to the list of truncating MYH2 mutations previously described in compound heterozygosity (Tajsharghi et al., 2010). The same mutation was identified in homozygosity in a previously untested patient and in heterozygosity in his clinically unaffected mother, thus confirming recessive segregation. In addition, the relative expression of different MyHC isoforms was analysed as described (Tajsharghi et al., 2010) using complementary DNA extracted from his skeletal muscle biopsy originally performed for diagnosis. No MyHC IIa transcript was detected (Fig. 1) consistent with down regulated expression of MyHC IIa, probably related to the truncating effect of the MYH2 mutation. The studies were approved by the national and institutional review boards. Quantitative analysis of skeletal muscle myosin heavy-chain transcripts showing expression of MyHC I (slow/beta cardiac) but not of MyHC IIa or MyHC IIx in a deltoid muscle sample of a patient homozygous for the c.2400delG MYH2 mutation. Our findings strongly confirm the evolving MYH2-related clinical phenotype with mild facial and limb myopathy associated with prominent external ophthalmoplegia of early childhood onset and slow progression. The fact that MyHC IIa is expressed in Type 2A muscle fibres and in oculorotatory muscles (Kjellgren et al., 2003) explains the co-occurrence of skeletal myopathy and ophthalmoplegia. Because MyHC IIa is also present in levator palpebrae superioris (Kjellgren et al., 2003), the infrequency of ptosis (Martinsson et al., 2000; Lossos et al., 2005; Tajsharghi et al., 2010) is unclear but may be related to the distinct organization of fibres in this muscle (Kjellgren et al., 2006). Swedish Research Council (to A.O. and H.T.); Agnes Ginges Fund for Human Neurogenetics (to A.L. and Z.A.).
Fortschritte der Neurologie · Psychiatrie · 2013 · 0 citations
L'abitante e il viaggiatore
AbstractMyopathies with pathological protein aggregates comprise a numerically significant group of sporadic and hereditary muscle disorders. A rare disease entity within the group of protein aggregate myopathies is the myosin storage myopathy, which is caused by heterozygous mutations in the MYH7 gene which encodes the slow/beta-myosin heavy chain. We report the clinical, myopathological and MRI findings in the first German patient suffering from a myosin storage myopathy due to a heterozygous R 1845W missense mutation.
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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