DeCure for Congenital disorder of deglycosylation 2
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for congenital disorder of deglycosylation 2 — 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 moduleCongenital disorder of deglycosylation 2 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 congenital disorder of deglycosylation 2 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
nei like DNA glycosylase 1 (NEIL1) — NEIL1 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5ITU · 2.41 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Congenital disorders of glycosylation (CDG) are a group of rare inherited metabolic diseases, with about 20 distinct disorders identified by 2004, and roughly one new disease reported per year since 1980. The most common type is PMM2-CDG (also called Jaken syndrome), with around 800 cases described worldwide by 2019. The disorders affect nearly every organ system, and it is recommended that CDG be considered in any child with an unexplained clinical syndrome. Peters’-plus syndrome, a rare autosomal recessive disorder characterised by Peters’ anomaly of the eye, short stature, cleft lip or palate, central nervous system defects, and variable severity from early death to developmental delay with mental retardation, was identified as a CDG caused by inactivating mutations in a beta1,3-glucosyltransferase that adds glucose to O-linked fucose on thrombospondin type 1 repeats. Some CDG variants also show cutaneous manifestations, including a hanging fat sign reported in type Ia.
For PGM1-CDG, a specific subtype caused by phosphoglucomutase-1 deficiency, oral D-galactose supplementation is an available treatment. In a 2023 case series of five patients, D-galactose resulted in notable clinical improvement in four patients, but efficacy varied. Three patients showed significant improvement or normalisation of transferrin glycosylation, liver transaminases, and coagulation factors; creatine kinase levels improved in two; and hypoglycaemia resolved in two. One patient discontinued treatment due to urinary frequency and lack of clinical improvement. One patient experienced recurrent rhabdomyolysis and tachycardia even on higher doses. D-galactose failed to improve cardiac function, which was initially abnormal in three patients and remains the biggest treatment challenge in PGM1-CDG. In a 2019 report of PMM2-CDG, positive clinical and laboratory dynamics were described for the first time with inclusion of D-mannose therapy.
What is still missing are therapies that specifically address the cardiac phenotype in PGM1-CDG, where D-galactose has not shown benefit. For the majority of CDG subtypes, no effective treatment exists at all. The rarity of each disorder, the heterogeneity of clinical presentation, and the lack of large, controlled trials limit progress. Patient stratification by genetic subtype and organ-specific outcomes, along with funding for preclinical development of therapies targeting glycosylation pathways, remain absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Current Opinion in Pediatrics · 2004 · 99 citations
Congenital disorders of glycosylation: a booming chapter of pediatrics
AbstractPURPOSE OF REVIEW: The detection and identification of new congenital disorders of glycosylation continues at a rapid pace. Sine June 2003, four new congenital disorders of glycosylation have been reported, making a total of 20 diseases (on average nearly 1 disease per year since the first report in 1980; 12 of these congenital disorders of glycosylation were identified in the past 6 years). RECENT FINDINGS: Three of these newly discovered CDG are caused by defects in early steps of dolichol-linked oligosaccharide biosynthesis. Affected patients have a neurologic or a multisystem disease. The fourth new CDG is a completely new CDG type caused by a defect in an endoplasmic reticulum-Golgi shuttle protein carrying multiple glycosyltransferases and nucleotide-sugar transporters. SUMMARY: Disorders of nearly all organs and systems have been reported and continue to be reported in congenital disorders of glycosylation. Therefore, it is strongly recommended that congenital disorders of glycosylation be considered in any child with an unexplained clinical syndrome.
Annals of Medicine · 2008 · 49 citations · open access
Peters’-plus syndrome is a congenital disorder of glycosylation caused by a defect in the β1,3-glucosyltransferase that modifies thrombospondin type 1 repeats
AbstractGenetic defects in glycosyltransferases are responsible for a number of developmental defects and diseases known as congenital disorders of glycosylation (CDGs). Peters'-plus syndrome, a rare autosomal recessive disorder, is now known to be a CDG. This syndrome is characterized by a specific malformation of the eye that includes corneal opaqueness and iridocorneal adhesions (Peters' anomaly). Affected individuals are short in stature and have short limbs, and may have cleft lip/palate, defects in the central nervous system, heart, and various other organs. The phenotype varies in severity, ranging from death in early childhood to a general delay in growth and development, and is often associated with mental retardation. The mutations responsible for Peters'-plus syndrome inactivate a beta1,3-glucosyltransferase whose function is to add a glucose moiety to O-linked fucose, forming a rare glucose-beta1,3-fucose disaccharide. This disaccharide modification is specific to thrombospondin type 1 repeats (TSRs), domains found in extracellular proteins that function in cell-cell and cell-matrix interactions and signalling. Some ninety human proteins contain TSRs, but thus far the disaccharide has been demonstrated on only thrombospondin 1, properdin, F-spondin, ADAMTS-13, and ADAMTSL-1. These proteins perform essential functions in embryonic development, tissue remodelling, angiogenesis, neurogenesis, and complement activation. Identification of the beta1,3-glucosyltransferase and its substrate proteins is a key step towards understanding their roles in human development, and to uncovering the molecular and cellular mechanisms underlying the clinical manifestations of Peters'-plus syndrome.
Cutaneous Findings in Congenital Disorders of Glycosylation: The Hanging Fat Sign
AbstractThe congenital disorders of glycosylation are a group of rare metabolic disorders with predominantly neurologic findings. Some variants of this disorder also exhibit cutaneous manifestations. We report a patient with a congenital disorder of glycosylation type Ia, the most common form, with emphasis on the cutaneous findings of this type, and summarize the cutaneous findings in the other forms of the disorder.
Therapeutic Advances in Rare Disease · 2023 · 11 citations · open access
Novel insights into the phenotype and long-term D-gal treatment in PGM1-CDG: a case series
AbstractPhosphoglucomutase-1-congenital disorder of glycosylation (PGM1-CDG) (OMIM: 614921) is a rare autosomal recessive inherited metabolic disease caused by the deficiency of the PGM1 enzyme. Like other CDGs, PGM1-CDG has a multisystemic presentation. The most common clinical findings include liver involvement, rhabdomyolysis, hypoglycemia, and cardiac involvement. Phenotypic severity can vary, though cardiac presentation is usually part of the most severe phenotype, often resulting in early death. Unlike the majority of CDGs, PGM1-CDG has a treatment: oral D-galactose (D-gal) supplementation, which significantly improves many aspects of the disorder. Here, we describe five PGM1-CDG patients treated with D-gal and report both on novel clinical symptoms in PGM1-CDG as well as the effects of the D-gal treatment. D-gal resulted in notable clinical improvement in four patients, though the efficacy of treatment varied between the patients. Furthermore, there was a significant improvement or normalization in transferrin glycosylation, liver transaminases and coagulation factors in three patients, creatine kinase (CK) levels in two, while hypoglycemia resolved in two patients. One patient discontinued the treatment due to urinary frequency and lack of clinical improvement. Furthermore, one patient experienced recurrent episodes of rhabdomyolysis and tachycardia even on higher doses of therapy. D-gal also failed to improve the cardiac function, which was initially abnormal in three patients, and remains the biggest challenge in treating PGM1-CDG. Together, our findings expand the phenotype of PGM1-CDG and underline the importance of developing novel therapies that would specifically treat the cardiac phenotype in PGM1-CDG.
AbstractCongenital disorders of glycosylation (CDG) are a group of rare genetically inherited disorders that involve the malfunction of attaching sugar molecules to lipids, proteins, or other organic molecules through an enzymatic process. The resulting defect in glycoprotein and glycolipid synthesis often has a heterogeneous range of multisystemic effects ranging from mild dysmorphism to profound organ failure and subsequent death. There are 2 types of CDG, type I and type II, with multiple subtypes within each. This column is a case presentation about an infant who presented with CDG type Ik.
Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics) · 2019 · 0 citations · open access
Congenital disorder of glycosilation PMM2-CDG
AbstractCongenital glycosylation disorders represent a group of genetically determined diseases which violate the synthesis and addition of glycans to glycoproteins and glycolipids, and also the synthesis of glycosylphosphatidyl inositol. The most common defects are the defects of protein N-glycosylation. Jaken syndrome, a congenital disorder of PMM2-CDG glycosylation, is the most commonly diagnosed type (about 800 cases worldwide). However, there are only a few descriptions of clinical cases in the Russian literature. The article presents a clinical observation of a child with this type of congenital glycosylation disorder due to a defect in phosphomannomtase 2 (PMM2 gene). The diagnose was based on the combination of clinical, laboratory and instrumental data: a characteristic phenotype, hyperinsulinism, delayed physical and psychomotor development, neurological manifestations, coagulopathy, liver damage, exudative enteropathy, abnormal forms of transferrin, PMM2 gene mutations associated with Jaken’s syndrome. For the first time the authors described positive clinical and laboratory dynamics due to the inclusion of D-mannose to the therapy for this type of congenital glycosylation disorder.
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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