DeCure for Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2 — 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 moduleMuscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2 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 muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a2 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
A homozygous mutation in the DAG1 gene, p.Cys699Phe (murine counterpart p.Cys667Phe), was identified in a patient with muscle-eye-brain disease and multicystic leucodystrophy. In cellular models, this mutation caused the uncleaved dystroglycan precursor to be retained in the endoplasmic reticulum, rather than being processed normally. Small-angle X-ray scattering and biochemical experiments showed that the mutation altered the folding of the β-dystroglycan ectodomain, leading to disulfide-associated oligomerisation. This represents a novel intracellular mechanism for dystroglycanopathy, distinct from the reduced α-dystroglycan glycosylation seen in secondary forms.
A separate case report described a child with muscle-eye-brain disease who had severe visual impairment from progressive myopia and retinal degeneration, a pachygyria-type brain migration disorder with a cobblestone cortex, muscular weakness, and severe mental retardation. The authors noted that ophthalmological assessments are important for diagnosis and follow-up in congenital muscular dystrophy. Another report emphasised that muscle-eye-brain disease is a rare autosomal recessive congenital muscular dystrophy with abnormal α-dystroglycan glycosylation, presenting with early-onset muscular hypotonia and variable structural brain and eye anomalies, and that characteristic neuroradiological findings can enable early genetic diagnosis.
No treatment or intervention was tested in any of these studies. What is still missing is any preclinical or clinical work on drug repurposing for this specific mutation or pathway, as well as funding for cellular or animal models that could screen compounds capable of correcting the endoplasmic reticulum retention of the mutant dystroglycan. Patient stratification by genotype and natural history data are also lacking.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Human Mutation · 2017 · 12 citations · open access
A dystroglycan mutation (p.Cys667Phe) associated to muscle-eye-brain disease with multicystic leucodystrophy results in ER-retention of the mutant protein
AbstractDystroglycan (DG) is a cell adhesion complex composed by two subunits, the highly glycosylated α-DG and the transmembrane β-DG. In skeletal muscle, DG is involved in dystroglycanopathies, a group of heterogeneous muscular dystrophies characterized by a reduced glycosylation of α-DG. The genes mutated in secondary dystroglycanopathies are involved in the synthesis of O-mannosyl glycans and in the O-mannosylation pathway of α-DG. Mutations in the DG gene (DAG1), causing primary dystroglycanopathies, destabilize the α-DG core protein influencing its binding to modifying enzymes. Recently, a homozygous mutation (p.Cys699Phe) hitting the β-DG ectodomain has been identified in a patient affected by muscle-eye-brain disease with multicystic leucodystrophy, suggesting that other mechanisms than hypoglycosylation of α-DG could be implicated in dystroglycanopathies. Herein, we have characterized the DG murine mutant counterpart by transfection in cellular systems and high-resolution microscopy. We observed that the mutation alters the DG processing leading to retention of its uncleaved precursor in the endoplasmic reticulum. Accordingly, small-angle X-ray scattering data, corroborated by biochemical and biophysical experiments, revealed that the mutation provokes an alteration in the β-DG ectodomain overall folding, resulting in disulfide-associated oligomerization. Our data provide the first evidence of a novel intracellular mechanism, featuring an anomalous endoplasmic reticulum-retention, underlying dystroglycanopathy.
AbstractPURPOSE: To describe a child with Muscle-Eye-Brain disease (MEB), one of three types of congenital muscular dystrophy associated with ocular abnormalities. METHODS: Case report. RESULTS: The child showed severe visual impairment due to progressive myopia and retinal degeneration, a pachygyria-type of migration disorder of the brain with a nodular cortical surface, i.e. cobblestone cortex, as well as muscular weakness and severe mental retardation. CONCLUSION: Ophthalmological assessments are important to help to diagnose and follow children with congenital muscular dystrophy.
P 644. Diagnosis of Muscle–Eye–Brain Disease through Characteristic Neuroradiological Findings
AbstractBackground: Muscle–eye–brain disease MEB is a rare autosomal recessive congenital muscular dystrophy (CMD) characterized by an abnormal glycosylation of α-dystroglycan. The so-called α-dystroglycanopathies manifest with a marked clinical, biochemical, and genetical heterogeneity. Typical symptoms are early-onset muscular hypotonia with variable structural brain and eye anomalies. We present a patient with typical radiological findings which allowed us for an early genetic diagnosis and confirmation of the diagnosis MEB.
Muscular magnet resonance imaging (M-MRI) in α-Dystroglykanopathies – clinical course of two juvenile patients with LGMD2I and LGMD2M
AbstractIntroduction: α-Dystroglycanopathies are a heterogenous group of neuromuscular disorders caused by a hypoglycosilation of the membrane protein α-dystroglycan. Mutations in the genes FKRP, FCMD, POMT1, POMT2, POMGnT1 and LARGE can cause a highly variable clinical phenotype but also disclose a remarkably disease overlap. The clinical phenotype can range from severe congenital onset with brain malformations (e.g. Fukuyama muscular dystrophy) to relatively milder forms (e.g. LGMD2).
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.
