DeCure for DK1-congenital disorder of glycosylation
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for DK1-congenital disorder of glycosylation — 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 moduleDK1-congenital disorder of glycosylation 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 dk1-congenital disorder of glycosylation 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
Congenital disorders of glycosylation (CDG) are a family of multisystem diseases in which the synthesis or attachment of glycans to proteins and lipids is deficient. More than 130 congenital defects of glycosylation are now known, and the molecular bases for approximately 60 disorders, affecting roughly 800 individuals, had been identified by 2013. Two thirds of known CDGs are associated with intellectual disability, and most affected individuals need support services throughout their lives. The initial clinical presentation varies significantly between individuals, even between affected siblings. Specific therapy is available only for MPI-CDG and SLC35C2-CDG; for all other forms, including DPAGT1-CDG, no disease-modifying treatment exists.
DPAGT1-CDG, a rare autosomal recessive disorder, is caused by pathogenic variants in the DPAGT1 gene. A 2015 case report describes a newborn female with arthrogryposis multiplex due to fetal akinesia secondary to DPAGT1-CDG, with intrauterine growth restriction, bilateral cataracts, multiple joint contractures, ventilator-dependent central respiratory depression, delayed myelination, and an incomplete cerebellar vermis. A 2023 report adds two new paediatric patients: an 8-month-old boy with a homozygous novel variant (p.Phe113Leu) who had congenital cataract at one month, dysmorphic findings, and epilepsy; and a 13-year-old female with compound heterozygous variants whose symptoms appeared later with more prominent muscle weakness, behavioural disorder, and dysmorphic findings but no epilepsy. The 2023 authors note that cholinesterase inhibitor therapy was found effective against muscle weakness in some patients, and they started pyridostigmine in the patient with more pronounced muscle weakness and saw benefit. Seventeen previous cases of DPAGT1-CDG had been reported by 2015, including two with multiple contractures.
A 2023 clinical case report describes a boy aged 1 year and 10 months diagnosed with CDG type 1b (phosphomannoisomerase deficiency), noting that the absence of clear, specific clinical manifestations leads to untimely recognition and treatment. The authors state that life-threatening changes involving all organ systems are observed in newborns and older children with CDG, including respiratory distress syndrome, intracranial haemorrhages in full-term newborns, long-term gastrointestinal dysfunction, and life-threatening bacterial infections. The child’s final diagnosis was determined by exome sequencing, which revealed heterozygous carrier status for the EXTL3 and MFSD8 genes. The report concludes that dynamic observation by a paediatrician and geneticist is needed to monitor physical and neuropsychological development.
What is still missing: no therapy exists for DPAGT1-CDG or for the vast majority of CDG subtypes; the 2023 pyridostigmine observation is limited to one patient and addresses only muscle weakness, not the multisystem disease course. No controlled trials have been conducted. Patient numbers remain vanishingly small, and no systematic stratification by genotype or clinical severity has been attempted. Funding for natural history studies and for any drug-repurposing screen is 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.
Oxford University Press eBooks · 2017 · 212 citations
Congenital Disorders of Glycosylation
AbstractCongenital disorders of glycosylation (CDG) comprise a family of multisystem diseases in which N- and O-linked glycosylation and glypiation of a variety of proteins and lipids is deficient. The hypoglycosylation of multiple glycoconjugates impairs normal development of the brain (and other organs), and is associated with both episodic and chronic organ dysfunction. Developmental disorders; seizures; strokelike episodes (and stroke); hearing and visual loss; peripheral neuropathy; coagulopathy; and immune, liver, endocrine, cardiac, and cutaneous manifestations may occur in varying combinations. Specific therapy is available for MPI-CDG and SLC35C2-CDG. Most forms of O-linked CDG affect muscle; these include congenital muscular dystrophies and limb girdle dystrophies.
Developmental Disabilities Research Reviews · 2013 · 28 citations
Congenital disorders of glycosylation and intellectual disability
AbstractThe congenital disorders of glycosylation (CDG) are a rapidly growing group of inborn errors of metabolism that result from defects in the synthesis of glycans. Glycosylation is a major post-translational protein modification and an estimated 2% of the human genome encodes proteins for glycosylation. The molecular bases for the current 60 disorders, affecting approximately 800 individuals, have been identified, many in the last 5 years. CDG should be considered in any multi-system syndrome or single tissue disorder not explained by the identification of another disorder. The initial clinical presentation varies significantly among individuals, even between affected siblings. However, two thirds of the known CDGs are associated with intellectual disabilities and most affected individuals need support services throughout their lives. Additional disorders of glycosylation are likely to be characterized over time.
American Journal of Medical Genetics Part A · 2015 · 18 citations
Fetal akinesia deformation sequence due to a congenital disorder of glycosylation
AbstractCongenital disorders of Glycosylation (CDG) are increasingly emerging as a major underlying etiology for patients with complex neurogenetic malformations and dysmorphic features. We describe a newborn female with arthrogryposis multiplex due to fetal akinesia secondary to CDG-DPAGT1. Pregnancy was complicated by reduced fetal movements. At birth, the patient was evaluated for intrauterine growth restriction, bilateral cataracts, and multiple joint contractures. She had markedly reduced spontaneous movements, hypotonia, weak cry, and poor suck. She had ventilator-dependent central respiratory depression. Brain MRI showed delayed myelination and an incomplete cerebellar vermis. Transferrin isoelectric focusing was suggestive of a type I congenital disorder of glycosylation. Sequencing revealed a homozygous missense mutation in dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1), exon 3, p.Leu118Val, consistent with DPAGT1-CDG. There have been seventeen previously reported cases of DPAGT1-CDG, including two similar cases with multiple contractures. This case highlights the importance of considering congenital disorders of glycosylation in the differential diagnosis for arthrogryposis.
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.
Molecular Syndromology · 2023 · 6 citations · open access
DPAGT1-CDG: Report of Two New Pediatric Patients and Brief Review of the Literature
AbstractIntroduction: Congenital glycosylation disorders are multisystem diseases with heterogeneous clinical manifestations caused by defects in the synthesis of the glycan moiety of glycoproteins or glycolipids or the binding of glycans to proteins and lipids. DPAGT1 (UDP-GlcNAc: dolichol phosphate N-acetylglucosamine-1-phosphotransferase) is an initiating protein in the biosynthetic pathway of dolichol-linked oligosaccharides required for protein N-glycosylation. Pathogenic variants in DPAGT1 (UDP-GlcNAc: dolichol phosphate N-acetylglucosamine-1-phosphotransferase) gene cause a rare type of congenital glycosylation disorder called DPAGT1-CDG (formerly CDG-Ij) (OMIM #608093). It is a rare autosomal recessive disease or a milder version with congenital myasthenic syndrome known as DPAGT1-CMS. A severe disease course with hypotonia, cataracts, skeletal deformities, resistant epilepsy, intellectual disability, global developmental delay, premature death has been described in most patients with DPAGT1-CDG. Patient Presentation: We describe two patients with variants in the DPAGT1 gene: an 8-month-old boy with a homozygous, missense DPAGT1:c.339T>G (p.Phe113Leu) novel variant and a 13-year-old female patient with compound heterozygous variants, DPAGT1:c.466C>T (p.Arg156Cys, R156C) and DPAGT1:c.161+5G>A. While the 8-month-old patient was diagnosed with congenital cataract at the age of 1 month, had dysmorphic findings, and epilepsy, clinical symptoms in the other patient appeared later but with more prominent muscle weakness, behavioral disorder, dysmorphic findings, and no epilepsy. Discussion: Cholinesterase inhibitor therapy was found to be effective in patients against muscle weakness, supporting DPAGT1 deficiency as the underlying etiology. We started pyridostigmine treatment in our patient with more pronounced muscle weakness, and we saw its benefit. We aimed to present our patients diagnosed with DPAGT1-CDG due to different variants in the same gene and different clinical presentations, treatment and to compare them with other patients in the literature.
Актуальні проблеми сучасної медицини Вісник Української медичної стоматологічної академії · 2023 · 1 citations · open access
CONGENITAL DISORDER OF GLYCOSYRATION TYPE 1B (CDG-1B SYNDROME, PHOSPHOMANNOISOMERASE DEFICIENCY): A CLINICAL CASE
AbstractA clinical case of my own observation of a boy A., aged 1 year and 10 months, with the diagnosis: congenital glycosylation disorder type 1b (CDG 1b syndrome, phosphomannoisomerase deficiency) is presented. The writing of this article is due to the difficulties of diagnosis, which are associated with the multisystemic clinical manifestations in the form of rather non-specific pathological conditions and the lack of information about this rare pathology. Congenital glycosylation defects are a group of genetically determined diseases in which the synthesis or attachment of glycans to glycoproteins and glycolipids is violated, as well as the formation of glycosylphosphatidylinositol. More than 130 congenital defects of glycosylation are known. According to literature data, in case of congenital glycosylation defects in newborns and older children, life-threatening changes in the body are observed, which include disorders on the part of all organs and systems that contribute to disorders of physical and neuropsychological development. Recently, more and more cases of the debut of congenital glycosylation defects have been described immediately after birth in the form of a syndrome of respiratory disorders; intracranial hemorrhages in full-term newborns; long-term dysfunction of the gastrointestinal tract; life-threatening bacterial infections. The absence of clear, specific clinical manifestations of the disease leads to untimely recognition and treatment of the disease in children after birth and contributes to the violation of their development. The child's final diagnosis is determined by the results of a molecular genetic examination: exome sequencing: a heterozygous carrier of the EXTL3, MFSD8 genes takes place here. A conclusion was made about the need for dynamic observation of the boy by a pediatrician and geneticist in order to monitor physical and neuropsychological development.
The Skeletal Manifestations of Deranged Glycosylation
AbstractThe congenital disorders of glycosylation (CDG) are a rapidly expanding disease group with protean presentations in which the skeletal manifestations are often not appreciated. In this brief review we will discuss the skeletal manifestation of CDG patients, their potential clinical and functional impact on the CDG child and their family, and consider possible underlying mechanisms of these skeletal manifestations.
Molecular and functional insights into clinical disease phenotypes associated with a primary skeletal dysplasia phenotype eg. achondrogenesis type 1A, provides invaluable, mechanistic understanding to pathology in defects associated with primary and secondary glycan deficiencies.
Galter Health Sciences Library, Northwestern University · 2000 · 0 citations · open access
Congenital Glycosylation Type Ic Disorder
AbstractClinical and biochemical characteristics of congenital disorder of glycosylation type Ic (CDG-Ic) are reported in 8 patients studied at Heinrich-Heine University Dusseldorf, Germany; University of Leuven, Belgium; University of Zurich, Switzerland; University Hospital Nijmegen; Sophia Childrens Hospital, Rotterdam; and Ignatius Hospital, Breda, The Netherlands.
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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