DeCure for ALG6-congenital disorder of glycosylation 1C
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for ALG6-congenital disorder of glycosylation 1C — 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 moduleALG6-congenital disorder of glycosylation 1C 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 alg6-congenital disorder of glycosylation 1c 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
The abstracts provided do not contain any drug repurposing data for ALG6-CDG. One 2003 paper on ALG6-CDG (CDG-Ic) reports that the common mutation c.998C>T (p.Ala333Val) occurs in over half of known patients, and that a frequent variant c.391T>C (p.Tyr131His) has a US population frequency of 0.0214, suggesting homozygotes could occur at roughly 1:2,200. However, one patient with homozygous p.Tyr131His had typical CDG-Ic symptoms but normal lipid-linked oligosaccharide and plasma transferrin glycosylation, leaving it unclear whether this variant causes CDG-Ic or merely contributes to symptoms. No treatment or drug is tested or proposed in that paper.
The remaining abstracts cover ALG1-CDG, ALG13-CDG, and general CDG reviews. A 2016 study of 39 unreported ALG1-CDG patients triples the known patient number and identifies 26 new mutations but could not establish a rank order of biomarker glycosylation versus phenotype. A 2025 report of three Iranian ALG1-CDG cases with a novel homozygous p.Leu375Gln variant describes a mild phenotype with survival to childhood and adulthood, seizures, developmental delay, and speech and learning disabilities; one child gained walking ability through occupational therapy. The 2023 ALG13-CDG natural history study of 14 patients found only two older than 16 years, with no surviving males over 16; six adolescent and young adult females had epilepsy, hypotonia, intellectual disability, absent speech, and required full parental support. Ketogenic diet was effective for seizures in three of four ALG13-CDG patients.
The 2021 review states that treatment options for CDG remain limited and mostly symptomatic, though some novel therapies have moved from bench to bedside. The 2024 Society for Glycobiology abstract notes that the Frontiers in CDG Consortium has launched a Natural History Study with over 300 patients and clinical trials aiming to restore glycosylation, but does not name any drug or report results. What is still missing for ALG6-CDG specifically: no drug repurposing trials have been conducted, no patient stratification by genotype or glycosylation status has been tested in a treatment context, and the functional significance of the common p.Tyr131His variant remains unresolved. Funding for targeted therapy development and natural history studies focused on ALG6-CDG is absent from the published record.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Human Mutation · 2016 · 58 citations · open access
ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients
AbstractCongenital disorders of glycosylation (CDG) arise from pathogenic mutations in over 100 genes leading to impaired protein or lipid glycosylation. ALG1 encodes a β1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date 13 mutations in 18 patients from 14 families have been described with varying degrees of clinical severity. We identified and characterized 39 previously unreported cases of ALG1-CDG from 32 families and add 26 new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2 , was seen in all 27 patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder.
Frontiers in Genetics · 2021 · 41 citations · open access
Treatment Options in Congenital Disorders of Glycosylation
AbstractDespite advances in the identification and diagnosis of congenital disorders of glycosylation (CDG), treatment options remain limited and are often constrained to symptomatic management of disease manifestations. However, recent years have seen significant advances in treatment and novel therapies aimed both at the causative defect and secondary disease manifestations have been transferred from bench to bedside. In this review, we aim to give a detailed overview of the available therapies and rising concepts to treat these ultra-rare diseases.
Identification of a frequent variant inALG6, the cause of Congenital Disorder of Glycosylation-Ic
AbstractCongenital Disorder of Glycosylation (CDG) type Ic is caused by mutations in ALG6. This gene encodes an alpha1,3 glucosyltransferase used for synthesis of the lipid linked oligosaccharide (LLO) precursor of the protein N-glycosylation pathway. CDG-Ic patients have moderate to severe psychomotor retardation, seizures, hypotonia, strabismus, and feeding difficulties. We previously identified a typical patient with a heterozygous point mutation, c.391T>C (p.Tyr131His) in ALG6. Using complementation analysis of ALG6-deficient yeast, we show that this alteration is as severe as the most common disease-causing mutation, c998C>T (p. Ala333Val), which occurs in over half of all known CDG-Ic patients. The frequency of c.391T>C (p.Tyr131His) in the US population, is 0.0214, suggesting that homozygotes would occur at a rate of& tilde;1:2,200. We identified one patient with typical CDG-Ic symptoms and a homozygous p.Tyr131His alteration in ALG6. However, in contrast to most CDG patients, her LLO and plasma transferrin glycosylation appeared normal. Thus, it is unclear whether c.391T>C causes CDG-Ic or contributes to the symptoms. Genotyping additional patients with CDG-like symptoms will be required to resolve this issue.
American Journal of Medical Genetics Part A · 2023 · 12 citations · open access
Long‐term outcomes in <scp>ALG13‐Congenital Disorder of Glycosylation</scp>
AbstractALG13-CDG is a rare X-linked disorder of N-linked glycosylation. Given the lack of long-term outcome data in ALG13-CDG, we collected natural history data and reviewed individuals surviving to young adulthood with confirmed pathogenic variants in ALG13 in our own cohort and in the literature. From the 14 ALG13-CDG patients enrolled into our Frontiers of Congenital Disorders of Glycosylation Consortium natural history study only two patients were older than 16 years; one of these two females is so far unreported. From the 52 patients described in the medical literature with confirmed pathogenic variants in ALG13 only five patients were older than 16 years (all females), in addition to the new, unreported patient from our natural history study. Two male patients have died due to ALG13-CDG, and there were no surviving males older than 16 years with a confirmed ALG13-CDG diagnosis. Our adolescent and young adult cohort of six patients presented with epilepsy, muscular hypotonia, speech, and developmental delay. Intellectual disability was present in all female patients with ALG13-CDG. Unreported features included ataxia, neuropathy, and severe gastrointestinal symptoms requiring G/J tube placement. In addition, two patients from our natural history study developed unilateral hearing loss. Skeletal abnormalities were found in four patients, including osteopenia and scoliosis. Major health problems included persistent seizures in three patients. Ketogenic diet was efficient for seizures in three out of four patients. Although all patients were mobile, they all had severe communication problems with mostly absent speech and were unable to function without parental support. In summary, long-term outcome in ALG13-CDG includes gastrointestinal and skeletal involvement in addition to a chronic, mostly non-progressive neurologic phenotype.
Egyptian Journal of Medical Human Genetics · 2025 · 1 citations · open access
ALG1-congenital disorder of glycosylation: report of clinical and genetic features of three new cases and review of literature
AbstractAbstract Background The ALG1-congenital disorder of glycosylation condition is a rare autosomal recessive disorder with approximately 80 patients reported worldwide up to now. This disorder is caused by a deficiency of β1,4 mannosyltransferase due to the pathogenic variants within the ALG1 gene which leads to impaired protein glycosylation. This disorder usually causes multiorgan damage. This is the first report of ALG1-CDG cases from Iran who are bearing a novel variant in a homozygote state. Case presentation The clinical and molecular features of three cases have been described. All three cases in this study had experienced seizures at a young age and had developmental delays. They were suffering from speech and learning disabilities, and in one case, cerebral atrophy was also present. Although they all had walking problems, the youngest case gained the ability to walk by occupational therapy. Additionally, they all survived to childhood and adulthood which indicates a mild phenotype. Despite several years of delayed diagnosis, a novel variant p.Leu375Gln was identified in the cases in homozygous form through whole exome sequencing, which ultimately established a diagnosis. The pathogenic effect of the novel variant was assessed computationally. It has been evaluated using prediction tools including SIFT, Poly-Phen2, and Mutation taster. The protein homology modeling was performed, and the variant effect on hydrogen bonds and protein stability was assessed. Conclusion The findings of this study expand our knowledge of clinical and genetic features of ALG1-CDG and present the significant role of next-generation sequencing technologies in the diagnosis of rare disorders.
AbstractCongenital disorders of glycosylation (CDG) are a group of rare monogenic human disorders caused by defects in the genes encoding the proteins that generate, attach, and modify glycans, thus disrupting cellular glycosylation machinery. Over 200 CDG caused by disruptions of 189 different genes are currently known. The multi-system disease manifestations of the CDG disorders highlight the importance of glycosylation across the organ systems. Clinical manifestations of CDG tend to group among genes contributing to the same glycosylation pathways, suggesting shared pathophysiology related to the glycosylation disruptions. However, the underlying glycosylation disruptions and pathophysiologic mechanisms responsible for specific CDG clinical manifestations have been determined for only a few hypoglycosylated proteins. The Frontiers in CDG Consortium (FCDGC) is an international network of clinical sites, laboratories, and patient advocacy groups established in 2019 to improve clinical symptoms, quality of life, and life expectancy for individuals with CDG. FCDGC seeks to answer decades of unresolved questions, address knowledge gaps, develop and validate new biochemical diagnostic techniques and therapeutic biomarkers, and explore novel therapeutic options for CDG. Over the past 5 years, FCDGC has launched a Natural History Study with over 300 CDG patients, discovered novel biomarkers suggesting new mechanisms of disease, and launched clinical trials aiming to restore appropriate glycosylation and targeting newly identified potential mechanisms of disease. Technical advances in glycobiology are making it increasingly possible to comprehensively catalog glycoproteomic data and to probe functional impact of altered glycosylation. My laboratory applies glycoproteomic technologies to samples from human subjects and genetic model systems to identify glycosylation abnormalities and unlock new insights from translational glycobiology. Current findings and accomplishments highlight the ongoing bottlenecks and knowledge gaps at intersections of glycobiology and clinical care requiring further investigation.
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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