DeCure for Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 10
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 10 — 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 a, 10 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 a, 10 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
fukutin related protein (FKRP) — FKRP 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 cdpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6KAJ · 2.2249 Å · ligand CYTIDINE-5'-DIPHOSPHATE (CDP). Experimental structure, not a prediction.
What the evidence adds up to
In a 2006 study of 13 patients with congenital muscular dystrophy and FKRP gene mutations, five had normal intelligence and normal brain MRI, three had isolated cerebellar cysts with mental retardation, and five had cerebellar cysts plus structural brain changes ranging from focal heterotopia to marked cerebellar dysplasia and pontine hypoplasia. One of those five resembled muscle-eye-brain disease and another mild Walker-Warburg syndrome. No clear association was found between the specific FKRP mutations and the severity of central nervous system involvement; instead, the severity broadly reflected how severely α-dystroglycan glycosylation was disrupted, with expression almost absent in the muscle-eye-brain disease-like phenotype.
Transgenic mice overexpressing human LARGE showed hyperglycosylation of α-dystroglycan in skeletal and cardiac muscle, with increased laminin binding and normal expression of other dystroglycan complex components. Young mice were indistinguishable from wild-type littermates, but older mice developed a loss of force in response to eccentric exercise, though no muscle pathology was observed even in the diaphragm. The authors concluded that therapies based on LARGE upregulation and α-dystroglycan hyperglycosylation in muscle should be safe, but the force deficit in older animals indicates a subclinical effect that develops over time.
A 2018 case report noted that characteristic neuroradiological findings allowed early genetic diagnosis of muscle-eye-brain disease. A 2021 case report reiterated that congenital muscular dystrophies with brain malformations and eye abnormalities are distinguishing features of subtypes such as muscle-eye-brain disease and Walker-Warburg syndrome. A 2001 review stated there are still no curative treatment options for any congenital muscular dystrophy, and a 2013 review listed nine genes then known to cause defective α-dystroglycan glycosylation.
What is still missing: no clinical trial has tested LARGE upregulation in human patients; the transgenic mouse data show only subclinical force loss, not functional improvement; patient numbers in the natural history studies are small; and no therapy has been shown to alter the course of the brain or eye anomalies, which are the most disabling features in the severe congenital forms.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Archives of Neurology · 2006 · 104 citations · open access
Spectrum of Brain Changes in Patients With Congenital Muscular Dystrophy and FKRP Gene Mutations
AbstractOBJECTIVES: To report the spectrum of brain magnetic resonance imaging findings in 13 patients with congenital muscular dystrophy and FKRP gene mutations and to explore possible genotype-phenotype correlations. DESIGN: We retrospectively reviewed brain magnetic resonance imaging in patients with congenital muscular dystrophy and FKRP gene mutations. PATIENTS: Thirteen patients with congenital muscular dystrophy and mutations in the FKRP gene. RESULTS: Five of the 13 patients had the typical phenotype originally described for congenital muscular dystrophy (MDC1C) with normal intelligence and normal brain magnetic resonance imaging while 3 other patients had isolated cerebellar cysts and mental retardation without any other sign of posterior fossa of supratentorial abnormalities. In the remaining 5 patients cerebellar cysts were associated with structural brain changes involving the posterior fossa and the cortex, ranging from focal unilateral periventricular nodular heterotopia to marked cerebellar dysplasia and pontine hypoplasia. In 2 of these 5 patients the severity and distribution of changes resembled muscle-eye-brain disease in 1 patient who had mild Walker-Warburg syndrome. The distribution of FKRP gene mutations identified in this group of patients did not reveal any obvious association with the severity of central nervous system involvement. CONCLUSIONS: The severity of central nervous system involvement observed in our patients in contrast broadly reflected the severity of the disruption of alpha-dystroglycan glycosylation. In particular, dystroglycan expression was almost absent in the patients with muscle-eye-brain diseaselike phenotype and less severely reduced in the patients with congenital muscular dystrophy (MDC1C) with or without cerebellar cysts. This study further highlights the central role that dystroglycan has in neuronal migration.
Transgenic Overexpression of LARGE Induces α-Dystroglycan Hyperglycosylation in Skeletal and Cardiac Muscle
AbstractBACKGROUND: LARGE is one of seven putative or demonstrated glycosyltransferase enzymes defective in a common group of muscular dystrophies with reduced glycosylation of α-dystroglycan. Overexpression of LARGE induces hyperglycosylation of α-dystroglycan in both wild type and in cells from dystroglycanopathy patients, irrespective of their primary gene defect, restoring functional glycosylation. Viral delivery of LARGE to skeletal muscle in animal models of dystroglycanopathy has identical effects in vivo, suggesting that the restoration of functional glycosylation could have therapeutic applications in these disorders. Pharmacological strategies to upregulate Large expression are also being explored. METHODOLOGY/PRINCIPAL FINDINGS: In order to asses the safety and efficacy of long term LARGE over-expression in vivo, we have generated four mouse lines expressing a human LARGE transgene. On observation, LARGE transgenic mice were indistinguishable from the wild type littermates. Tissue analysis from young mice of all four lines showed a variable pattern of transgene expression: highest in skeletal and cardiac muscles, and lower in brain, kidney and liver. Transgene expression in striated muscles correlated with α-dystroglycan hyperglycosylation, as determined by immunoreactivity to antibody IIH6 and increased laminin binding on an overlay assay. Other components of the dystroglycan complex and extracellular matrix ligands were normally expressed, and general muscle histology was indistinguishable from wild type controls. Further detailed muscle physiological analysis demonstrated a loss of force in response to eccentric exercise in the older, but not in the younger mice, suggesting this deficit developed over time. However this remained a subclinical feature as no pathology was observed in older mice in any muscles including the diaphragm, which is sensitive to mechanical load-induced damage. CONCLUSIONS/SIGNIFICANCE: This work shows that potential therapies in the dystroglycanopathies based on LARGE upregulation and α-dystroglycan hyperglycosylation in muscle should be safe.
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.
Handbook of clinical neurology · 2001 · 0 citations
Towards a Flexible information Retrieval Approach based on the Context
AbstractThe congenital muscular dystrophies are a heterogeneous group of disorders in which weakness and dystrophic pattern on muscle biopsy are present at birth or during the first months of life. This chapter reviews the most common forms of congenital muscular dystrophies, including laminin α-2 (merosin) deficiency, Ullrich congenital muscular dystrophy, fukutin-related proteinopathy, rigid spine syndrome, and glycosylation disorders of α-dystroglycan. The latter group is often associated with neuronal migration defects including lissencephaly, pachygyria, cerebellar and brainstem abnormalities, and variable ocular anomalies. Typical clinical findings and underlying genetic defects are discussed to assist in the differential diagnosis and diagnostic work-up of patients with congenital muscular dystrophies. There are still no curative treatment options for patients with congenital muscular dystrophies but regular follow-up and symptomatic care by a multidisciplinary team considering the peculiarities of each disorder are important to maintain or improve patients' quality of life.
Indian Journal of Child Health · 2021 · 0 citations · open access
Muscle eye brain disease – A rare case of congenital muscular dystrophy
AbstractCongenital muscular dystrophies are a distinct group of inherited muscle disorders that manifest within the 1st year of life accompanied by weakness, hypotonia, and developmental delay. A distinguishing feature of congenital muscular dystrophy from other muscular dystrophies is an increased association with brain malformations, particularly disorders of cortical development such as lissencephaly, pachygyria, and polymicrogyria. Moreover, some subtypes of congenital muscular dystrophies (CMDs) such as muscle eye brain disease and Walker-Warburg syndrome are more commonly associated with structural eye abnormalities apart from brain malformations. The inheritance of CMD is usually autosomal recessive except for CMD with spinal rigidity and lamin A/C abnormality and Ullrich CMD.
Alpha-dystroglycanopathies: Clinical and genetic variability
AbstractAims: Alpha-dystroglycanopathies show a broad clinical spectrum from mild limb girdle to severe congenital muscular dystrophy with brain and eye abnormalities. Currently, mutations in nine genes are known which lead to defective glycosylation of α-dystroglycan: FKTN, LARGE, FKRP, POMT1, POMT2, POMGnT1, DPM3, DPM2, WWP1, ISPD or encodes α-dystroglycan, DAG1.
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.
