DeCure for Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A13
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A13 — screening already-approved drugs against its 2-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 A13 maps to a 2-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 a13 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
UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 2 (B3GNT2) — B3GNT2 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 6mdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8TJC · 2.2 Å · ligand (6M)-1-[(2R)-3,3-dimethylbutan-2-yl]-6-[(5S)-5-methyl-4-oxo-5-phenyl-4,5-dihydro-1H-imidazol-2-yl]-1,3-dihydro-2H-benzimidazol-2-one (HI8). Experimental structure, not a prediction.
What the evidence adds up to
A 2001 case report describes 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 report concludes that ophthalmological assessments are important for diagnosis and follow-up in congenital muscular dystrophy.
A 2020 study of two Chinese patients with B3GALNT2 mutations and muscle-eye-brain-like phenotypes reports that patient 1, a 2-year-11-month-old girl, could walk independently for a few minutes, had a developmental quotient of 66 (mild to moderate mental retardation), normal serum creatine kinase at 10 months, and brain MRI showing polymicrogyria, white matter signal changes, cerebellum cysts, and dysplastic cerebellum and brainstem. Patient 2, a 1-year-9-month-old girl, could say one- or two-syllable words at 8 months and walk with support at 15 months, had a developmental quotient of 57 (moderate to severe mental retardation), serum creatine kinase of 565 U/L (normal <170), and brain MRI showing white matter signal changes, cerebellum dysplasia, and mildly enlarged ventricles. Neither patient had eye anomalies. The study identifies two novel mutations (c.48dupG and c.1183G>A) and notes that the relationship between mutations and enzyme activities has not been elucidated.
A 2025 study of 3 newly diagnosed Chinese patients and 28 previously reported patients with B3GALNT2-related alpha-dystroglycanopathy reports that all three new patients carried compound heterozygous variants involving one truncating and one missense mutation. Two novel mutations (c.657_658insTT and c.1384T>C) were identified. Functional studies showed that the missense mutations Y436C and C462R impaired enzymatic activity to 40–50% of wild-type levels, while splice variants caused frameshifts and likely complete loss of protein. Despite partial residual activity, all patients showed severely reduced alpha-dystroglycan glycosylation and loss of laminin binding, consistent with a functional threshold effect. Transcriptomic analysis revealed upregulation of CHST10 in two patients. The study expands the mutational spectrum and provides mechanistic insight but does not test any therapeutic intervention.
What is still missing: no drug has been tested in any of these studies; there are no clinical trials, no animal model treatment data, and no biomarker-validated patient stratification for this specific B3GALNT2 form of alpha-dystroglycanopathy. Funding for functional studies and potential therapy development remains limited.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
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.
Chinese Medical Journal · 2020 · 2 citations · open access
Novel mutations in B3GALNT2 gene causing α-dystroglycanopathy in Chinese patients
AbstractAlpha-dystroglycanopathy (α-DGP) is a subtype of congenital muscular dystrophies (CMDs) with autosomal recessive inheritance. Its main pathogenesis is the defect of post-translational O-glycosylation in α-dystroglycan (α-DG). α-DGP presents a wide clinical spectrum that ranges from the most severe CMDs such as Walker-Warburg syndrome (WWS), muscle-eye-brain disease (MEB), and Fukuyama congenital muscular dystrophy to the mildest limb-girdle muscular dystrophy. The B3GALNT2 (NM 152490) is one of the pathogenic genes of α-DGP. It encodes an enzyme that produces a unique carbohydrate structure, nitroacetylgalactosamine-β-1,3-nitroacetylglucosamine (GalNAc-β-1–3GlcNAc), which is essential for O-glycosylation of α-DG.[1] Most patients with B3GALNT2 mutations in previous studies presented with the most severe WWS or less severe MEB[2] and those with WWS generally had a very short lifespan. They universally exhibited severe muscle weakness, ocular anomalies, including congenital cataract, glaucoma, severe myopia, and optic nerve atrophy. Their brain imaging showed cobblestone lissencephaly or polymicrogyria, cerebellum cysts, and dysplasia. To date, there are rare studies on Chinese patients with B3GALNT2 gene mutations. Here, we described two Chinese patients who carried compound heterozygous mutations of B3GALNT2. They presented with MEB-like phenotypes, which were very similar to MEB but milder than it. The research protocol was reviewed and approved by the Ethics Committee of Peking University First Hospital (No. 2015[916]). Written informed consent for the research and publication of medical data was obtained from the patients and their parents. Patient 1 was a 2-year and 11-month-old girl who was the second child of healthy and non-consanguineous parents without a family history of neuromuscular disorders. She was born at full-term without perinatal complications. She had a poor interaction with people at 10 months of age and could not stand independently until 2 years old. Physical examination at 13 months of age showed a head circumference of 44.5 cm (<P25), proximal muscle weakness, and decreased tendon reflexes without joint contractures. At the present age, she could walk independently for a few minutes but had a wide-base gait and could not understand instructions or say any complicated words. Her neuropsychological evaluation at 10 months of age revealed that the developmental quotient (DQ) was 66, which meant mild to moderate mental retardation. The serum creatine kinase (CK) level at 10 months of age, auditory test, and fundus examination at 1 year of age were all normal. The brain magnetic resonance imaging (MRI) at 11 months of age demonstrated polymicrogyria, increased T2 signal in the white matter of cerebrum and cerebellum, mildly enlarged ventricles, cerebellum cysts, and dysplastic cerebellum and brainstem [Figure 1A].Figure 1: (A) The brain MRI of patient 1 at 11 months of age showed polymicrogyria (white arrows), abnormal signal intensity in the white matter of bilateral cerebrum and cerebellum (black arrows), cerebellum cysts (red circle), and dysplastic cerebellum and brainstem (arrowhead). (B) The brain MRI of patient 2 at 7 months of age showed mildly enlarged ventricles (white arrows), increased signals in the white matter (black arrows), brainstem, and cerebellum dysplasia (arrowheads). (C) Mutational sites of B3GALNT2 and the corresponding phenotypes. The transmembrane domain of B3GALNT2 is encoded by exon 1. The catalytic domain is encoded by exon 8–11. The numbers in the yellow inverted triangles represent our patients: 1, Patient 1; 2, Patient 2. The triangles represent mutations reported previously. MRI: Magnetic resonance imaging.Patient 2 was a 1-year and 9-month-old girl who was the first child of non-consanguineous and healthy parents. She was born at full-term without perinatal complications. She could say one- or two-syllable words at the age of 8 months, stand with assistance at the age of 1 year, and walk with support at the age of 15 months but without any progress since then. She had no ocular or auditory impairment. Psychological evaluation at 15 months of age showed the DQ was 57, which meant moderate to severe mental retardation. Physical examination showed a 45 cm (<P25) head circumference at 17 months of age. She had decreased muscle strength and no joint contractures. Her knee reflexes could be elicited bilaterally. The serum CK level at 17 months of age was 565 U/L (normal value <170 U/L). Her brain MRI at 7 months of age showed slightly increased T2 signals in the white matter of the cerebrum, brainstem, cerebellum dysplasia, and mildly enlarged ventricles [Figure 1B]. The whole exon sequencing was performed on both patients, and candidate variants were validated by Sanger sequencing in the families. If the next-generation sequencing data revealed different number of sequence reads between patients and control samples, a copy number variant (CNV) was confirmed by the quantitative polymerase chain reaction. Both patients were found to carry variants of B3GALNT2 and their parents were carriers. Patient 1 had compound heterozygous variants of c.979G>A (p.D327N) and c.1421_c.1423delCTC (p.P474del), which had been reported previously[3–5] and no CNVs [Supplementary Figure 1A, http://links.lww.com/CM9/A408]. Patient 2 harbored novel compound heterozygous variants of c.48dupG (p.L17fs) and c.1183G>A (p.G395R) [Supplementary Figure 1B, http://links.lww.com/CM9/A408]. Furthermore, she had a CNV which was a duplication of 550-kilo base pairs on chromosome 12: 94075229-94625165. According to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines, these two novel variants were predicted to be pathogenic and likely pathogenic, respectively. The CNV was not recorded in the chromosome CNVs polymorphism database of the normal population, and there was no smaller pathogenic duplication reports than this region in the DatabasE of genomiC varIation and Phenotype in Humans using Ensemble Resources database (DECIPHER). Based on the earlier evidence, its pathogenicity was considered to be uncertain. These two patients manifested early onset of muscle weakness, psychomotor, and language retardation. Together with microcephaly, brain structural abnormalities but without eye anomalies, we considered them to have MEB-like phenotypes as their presentations were relatively mild. The B3GALNT2 gene at chromosome 1q42.3 contains 12 exons and encodes approximately 500 amino acids. It comprises one transmembrane domain, one stem region, and a galactosyltransferase catalytic domain. The catalytic domain is located between amino acids 307 and 457.[1] Five Iranian siblings who carried homozygous mutations of p.D327N manifested much milder than our patient 1. They only had psychomotor and language retardation and non-specific cerebral white matter change. They had no brain structural deformity or ocular anomalies except that they all had epilepsy. Strikingly, their muscle involvement was much milder than those reported previously.[4] The manifestations of one Swedish patient with mutations of p.D327N and p.E65fs∗ were very similar to our patient 1.[5] It seems that p.D327N affects protein function slightly despite it is located in the catalytic domain. The mutation p.P474del combined with p.S25Cfs∗38 had been reported to cause severe MEB.[3] Although p.P474del is outside the catalytic domain, it is a conservative site in many species. Thus, it is probably the mutation p.P474del that contributes to the severity of clinical manifestations in patient 1 rather than p.D327N. The severities of clinical manifestations may depend on the degree of impairment in the protein function caused by the mutation rather than the region in which the mutation is located. The missense mutation p.G395R and the frameshift mutation p.L17fs of patient 2 are novel and located in the catalytic and the transmembrane domain, respectively. Both sites are conservative, and the frameshift mutation may produce truncated protein. We summarized all the reported mutations and their corresponding phenotypes in Figure 1C. In conclusion, these two Chinese patients with B3GALNT2 gene mutations expand the mutational and phenotypic spectrum of α-DGP. The relationship between these mutations and their effects on enzyme activities had not been elucidated. Further studies are necessary to investigate the pathogenicity of these mutations and their molecular mechanisms. Acknowledgements The authors deeply appreciate the families who participated in this study. Funding This study was supported by the Development Program of China (No. 2016YFC0901505), National Natural Science Foundation of China (No. 81571220), and Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases (No. BZ0317). Conflicts of interest None.
Congenital Muscular Dystrophy-Dystroglycanopathy (MDDGA1) in a Consanguineous Family with Compound Heterozygous Mutations of the POMT1 Gene and Variable Clinical Severity
AbstractBackground/Purpose: Congenital muscular dystrophies-dystroglycanopathies with brain and eye anomalies (MDDGA) are genetically heterogeneous autosomal recessive disorders with characteristic brain and eye malformations and congenital muscular dystrophy. We report on a consanguineous family with two sisters with MDDGA1 in which homozygosity mapping failed to elucidate the causal mutation.
Journal of Neuromuscular Diseases · 2025 · 0 citations · open access
Pathogenic mechanisms and clinical insights into <i>B3GALNT2</i> -related alpha-dystroglycanopathies
AbstractBackground B3GALNT2 mutations cause α-dystroglycanopathy (α-DGP), a rare condition characterized by muscular dystrophy, brain malformations, and developmental delay. However, its pathogenic mechanisms remain poorly understood. To date, limited cases have been reported, and the pathogenic mechanisms remain incompletely understood. Methods Clinical and genetic data from 3 newly diagnosed Chinese patients and 28 patients previously diagnosed with B3GALNT2 -related α-DGP were analyzed. Using patient-derived fibroblasts, α-dystroglycan (α-DG) glycosylation and laminin-binding capacity were assessed by immunoblotting, laminin overlay and immunofluorescence. B3GALNT2 mRNA and protein levels were quantified by real-time PCR and immunoblotting. Enzymatic activity was measured using purified recombinant B3GALNT2 proteins. Differentially expressed genes were identified via an mRNA microarray. Results All three patients carried compound heterozygous variants involving one truncating and one missense mutation. Two novel mutations (c.657_658insTT and c.1384T > C) were identified. Functional studies confirmed that the missense mutations (Y436C and C462R) impaired enzymatic activity to 40–50% of wild-type levels, while splice variants caused frameshifts and likely complete loss of protein. Despite partial residual activity, all patients showed severely reduced α-DG glycosylation and loss of laminin binding, consistent with a functional threshold effect. Transcriptomic analysis revealed upregulation of CHST10 in two patients. Conclusions This study expands the mutational spectrum of B3GALNT2 -related α-DGP and provides mechanistic insight into the pathogenicity of novel variants. Our findings support a functional threshold model for B3GALNT2 activity in α-DG glycosylation and suggest CHST10 as a potential transcriptional responder to glycosylation defects. These results deepen the understanding of B3GALNT2 -related dystroglycanopathies and may inform future diagnostic and therapeutic strategies.
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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