DeCure for Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 12
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 12 — 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, 12 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, 12 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
calcium voltage-gated channel auxiliary subunit beta 1 (CACNB1) — CACNB1 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 r16drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 7VFS · 2.8 Å · ligand HEXADECANE (R16). Experimental structure, not a prediction.
What the evidence adds up to
In 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 periventricular nodular heterotopia to marked cerebellar dysplasia and pontine hypoplasia. One of those five had a muscle-eye-brain disease-like phenotype and one had mild Walker-Warburg syndrome. Dystroglycan expression was almost absent in the patients with the muscle-eye-brain disease-like phenotype and less severely reduced in the others. No obvious association was found between the distribution of FKRP mutations and the severity of central nervous system involvement.
Four additional patients with LARGE mutations are reported, bringing the total to 15. Brain abnormalities overshadowed the initially mild muscle phenotype in all four. Postmortem neuropathology in one patient with a homozygous Cys443 mutation showed polymicrogyria as the predominant cortical malformation, with densely festooned polymicrogyria overlaid by a continuous agyric surface. The mutation p.Glu509Lys in another patient may confer a milder phenotype. Gross deletions and rearrangements are important mutational mechanisms for LARGE.
The broader group of alpha-dystroglycanopathies includes Fukuyama congenital muscular dystrophy, MDC1C, MDC1D, muscle-eye-brain disease, Walker-Warburg syndrome, and limb-girdle muscular dystrophy 2I. Causative mutations have been described in six genes: POMT1, POMT2, POMGnT1, fukutin, FKRP, and LARGE. In one study of ten clinically well-characterised Walker-Warburg syndrome and muscle-eye-brain disease patients, only three mutations were found — one in each POMT1, POMGnT1, and POMT2 — leaving seven patients with no mutations in the five genes examined. Real-time PCR showed reduced expression of each mutated gene and a higher expression of POMT2 in the case of the POMT1 mutation.
No curative treatment options exist for patients with congenital muscular dystrophies. What is missing is a clear genetic diagnosis for many patients, functional understanding of several of the implicated genes, and any therapy that restores alpha-dystroglycan glycosylation or prevents the neuronal migration defects. Stratification by genotype and severity of brain involvement is not yet possible in a way that predicts individual outcomes.
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.
Journal of Neuropathology & Experimental Neurology · 2014 · 52 citations · open access
Clinical, Pathologic, and Mutational Spectrum of Dystroglycanopathy Caused by<i>LARGE</i>Mutations
AbstractDystroglycanopathies are a subtype of congenital muscular dystrophy of varying severity that can affect the brain and eyes, ranging from Walker-Warburg syndrome with severe brain malformation to milder congenital muscular dystrophy presentations with affected or normal cognition and later onset. Mutations in dystroglycanopathy genes affect a specific glycoepitope on α-dystroglycan; of the 14 genes implicated to date, LARGE encodes the glycosyltransferase that adds the final xylose and glucuronic acid, allowing α-dystroglycan to bind ligands, including laminin 211 and neurexin. Only 11 patients with LARGE mutations have been reported. We report the clinical, neuroimaging, and genetic features of 4 additional patients. We confirm that gross deletions and rearrangements are important mutational mechanisms for LARGE. The brain abnormalities overshadowed the initially mild muscle phenotype in all 4 patients. We present the first comprehensive postnatal neuropathology of the brain, spinal cord, and eyes of a patient with a homozygous LARGE mutation at Cys443. In this patient, polymicrogyria was the predominant cortical malformation; densely festooned polymicrogyria were overlaid by a continuous agyric surface. In view of the severity of these abnormalities, Cys443 may be a functionally important residue in the LARGE protein, whereas the mutation p.Glu509Lys of Patient 1 in this study may confer a milder phenotype. Overall, these results expand the clinical and genetic spectrum of dystroglycanopathy.
Rinsho Shinkeigaku · 2008 · 2 citations · open access
Congenital muscular dystrophy and .ALPHA.-dystroglycanopathy
AbstractCongenital muscular dystrophy (CMD) refers to a heterogeneous group of muscular dystrophies with onset during the neonatal period. Among them, some types of CMD are characterized by the association of brain malformations and ocular abnormalities. Biochemical analyses revealed altered glycosylation and decreased laminin-binding activity of alpha-dystroglycan in these disorders, therefore they are correctively called alpha-dystroglycanopathy. Recently, mutations in the genes encoding demonstrated or putative glycosyltransferases have been identified in alpha-dystroglycanopathy. Fukuyama-type CMD and MDC1C are caused by mutations in the fukutin and fukutin-related protein (FKRP) genes, respectively. Mutations in the protein O-mannose beta-1, 2-N-acetylglucosaminyltransferase (POMGnT-1) and protein O-mannosyltransferase 1 and 2 (POMT1 and POMT2) genes cause muscle-eye-brain disease and Walker-Warburg syndrome, respectively. In addition, mutations in Large gene results in MDC1D. Furthermore, recent genotype-phenotype correlation analyses have revealed that the spectrum of phenotypes caused by mutations in these genes is much wider than originally assumed. In this review, we focus on the molecular pathomechanism and diverging clinical phenotypes of alpha-dystroglycanopathy.
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.
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).
Genetics of α-dystroglycanopathies – More questions than answers
AbstractWalker-Warburg syndrome (WWS) and Muscle-eye-brain disease (MEBD) are autosomal recessive disorders belonging to the group of α-dystroglycanopathies, caused by defective O-linked glycosylation of α-dystroglycan. Consequently, the migration of neurons and the integrity of skeletal muscle are impaired, and life expectancy is reduced. The clinical spectrum of α-dystroglycanopathies is broad and does not always allow a clear clinical distinction between the various disorders. Currently, Fukuyama congenital muscular dystrophy, MDCIc, MDCId, and limb-girdle muscular dystrophy 2I are also counted among the group of α-dystroglycanopathies. Causative mutations have been described in six genes: the genes coding for putative glycosyltransferases POMT1, POMT2, PomGnT1, as well as the genes coding for Fukutin, FKRP, and Large, whose functions are not clearly defined. We examined the coding sequences of the POMT1, POMT2, PomGnT1, Fukutin, and FKRP genes from ten clinically well characterized WWS/MEBD patients. Additionally, we used real-time PCR to measure gene expression of the five genes in the patients' fibroblasts. We identified three mutations: one in each POMT1, PomGnT1, and POMT2. However, there were no mutations in the examined genes of the other seven patients. Quantification of gene expression by real-time PCR showed reduced expression of each of the three genes carrying mutations as well as a higher expression of POMT2 in the case of the POMT1 mutation. We found slight but significant alterations of gene expression in three others patients.
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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