DeCure for PGM1-congenital disorder of glycosylation
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for PGM1-congenital disorder of glycosylation — 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 modulePGM1-congenital disorder of glycosylation 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 pgm1-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.
Molecular view
phosphoglucomutase 1 (PGM1) — PGM1 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 5JN5 · 1.75 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
PGM1-CDG is a rare autosomal recessive disorder caused by deficiency of the PGM1 enzyme. The most common clinical findings include liver involvement, rhabdomyolysis, hypoglycaemia, and cardiac involvement. Cardiac presentation is usually part of the most severe phenotype and often results in early death. Unlike the majority of CDGs, PGM1-CDG has a treatment: oral D-galactose supplementation. A 2023 case series of five PGM1-CDG patients treated with D-galactose reported notable clinical improvement in four patients, though efficacy varied. There was significant improvement or normalisation of transferrin glycosylation, liver transaminases and coagulation factors in three patients, creatine kinase levels in two, and hypoglycaemia resolved in two patients. One patient discontinued treatment due to urinary frequency and lack of clinical improvement. One patient experienced recurrent episodes of rhabdomyolysis and tachycardia even on higher doses. D-galactose failed to improve cardiac function, which was initially abnormal in three patients, and this remains the biggest challenge in treating PGM1-CDG.
Over 200 CDG caused by disruptions of 189 different genes are now known. The Frontiers in CDG Consortium, established in 2019, has launched a natural history study with over 300 CDG patients, discovered novel biomarkers, and launched clinical trials aiming to restore appropriate glycosylation and target newly identified mechanisms of disease. Despite these advances, treatment options for CDG in general remain limited and are often constrained to symptomatic management. For PGM1-CDG specifically, D-galactose improves many aspects of the disorder but does not treat the cardiac phenotype, which is the most severe and potentially fatal manifestation.
What is still missing are therapies that specifically target the cardiac phenotype in PGM1-CDG, as D-galactose supplementation alone is insufficient for heart-related issues. The underlying glycosylation disruptions and pathophysiological mechanisms responsible for specific clinical manifestations have been determined for only a few hypoglycosylated proteins. Ongoing bottlenecks include the need for better patient stratification, validated therapeutic biomarkers, and clinical trial designs that can address the variable treatment responses seen even within small patient groups.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Glycobiology · 2001 · 158 citations
Update and perspectives on congenital disorders of glycosylation
AbstractDefects in nine genes of the N-linked glycosylation pathway cause congenital disorders of glycosylation (CDGs) and serious medical consequences. Although glycobiology is seldom featured in a general medical education, an increasing number of physicians are becoming acquainted with the field because it directly impacts patient diagnosis and care. Medical practice and attitudes will change in the postgenomic era, and glycobiology has an opportunity to be a cornerstone of part of that new perspective. This review of recent developments in the CDG field describes the biochemical and molecular basis of these disorders, describes successful experimental approaches, and points out a few perspectives on current problems. The broad, multisystemic presentations of these patients emphasize that glycobiology is very much a general medical science, cutting across many traditional medical specialties. The glycobiology community is well poised to provide novel perspectives for the dedicated clinicians treating both well-known and emerging human diseases.
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.
Journal of Inherited Metabolic Disease · 2008 · 21 citations
Congenital disorders of glycosylation—a challenging group of IEMs
AbstractCongenital disorders of glycosylation (CDG) are a rapidly growing group of inherited errors of metabolism (IEMs) due to an impairment of one or several glycosylation pathways. During recent years over 30 CDG subtypes have been identified at a molecular and biochemical level. The clinical manifestations in CDG are heterogeneous and may be highly variable within the same subtype and even among affected siblings. Novel insights into the extremely complex glycosylation pathways have necessitated several reclassifications of the group of CDG. Today CDG comprise not only the formerly known multisystem glycosylation defects but also some tissue-specific glycosylation defects, implicating a different diagnostic work-up depending on the underlying glycosylation defect. In 2007 the expanding group of CDG is an enormous challenge to all specialists working in the field of IEMs. This review gives a brief overview about the expanded group of CDG and summarizes the main implications for clinicians.
American Journal of Medical Genetics Part A · 2008 · 19 citations
Clinical phenotype correlates to glycoprotein phenotype in a sib pair with CDG‐Ia
AbstractCongenital disorder of glycosylation (CDG) type Ia (PMM2 mutations) is the most common genetic disorder of protein N-glycosylation. The wide clinical spectrum with mild to severe impairment of neurological function and extensive allelic heterogeneity hamper phenotype-genotype comparison. We report on two male adult siblings with the PMM2 mutations c. 385G > A (p.V129M) and c. 422G > A (p.R141H) and partially different clinical phenotype. Patient 2 has a more severe degree of neurological and systemic involvement and a more pronounced decrease in levels of serum glycoproteins. MALDI-TOF mass spectrometry of serum transferrin and alpha-1-antitrypsin shows more pronounced glycosylation defects in the more severely affected patient. Glycoproteomic analysis may reveal differences in CDG-Ia patients with different disease severity and might endorse clinical characterization of CDG-Ia patients.
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.
Sage Journals Data · 2023 · 0 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.Plain Language Summary<b>An update on benefits and challenges of treating PGM1-CDG with galactose</b>PGM1-CDG is a rare genetic disorder that affects glycosylation, an important biochemical process happening in every cell of the body. Because glycosylation is essential for correct functioning of the cells and happens in every tissue and organ, patients with PGM1-CDG can have a variety of symptoms affecting many different organs. Main symptoms include low blood glucose levels, hyperinsulinism, bleeding disorder, liver, muscle, heart problems, and so on. This disorder is usually diagnosed based on the genetic testing, patient’s symptoms, and transferrin glycosylation test, which detects abnormalities in glycosylation in blood. So far, more than 60 patients have been reported. Unlike many genetic disorders, PGM1-CDG has a treatment in the form of a sugar called galactose, which naturally occurs in milk, and can treat many symptoms of the disorder. The patients are advised to take it every day by mouth in the form of powder. Here, we describe five more patients with PGM1-CDG, who were treated with galactose. Each of the patients had novel symptoms and they responded to the treatment differently, which helps us to better understand the disorder and the effects of therapy better. We found that many symptoms improved or normalized; however, some patients experienced persistent symptoms and even adverse events that made them stop treatment. Unfortunately, we did not observe any improvement of heart-related issues. Given that heart issues are the most severe aspect of PGM1-CDG and can result in early death, therapies that target heart issues in PGM1-CDG are still necessary. In conclusion, we describe novel aspects of PGM1-CDG, which will help understand and diagnose the disorder better, and highlight the importance of developing new therapies for this disorder that would specifically treat the heart.
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.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
