DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for congenital disorder of deglycosylation — screening already-approved drugs against its 3-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 maps to a 3-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 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
3-oxoacyl-ACP synthase, mitochondrial (OXSM) — OXSM 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 6nadrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 2IWZ · 1.65 Å · ligand HEXANOIC ACID (6NA). Experimental structure, not a prediction.
What the evidence adds up to
The congenital disorders of glycosylation (CDG) are a group of rare, genetically inherited metabolic diseases that have expanded from 45 known types in 2011 to a rapidly growing family. The disorders are classified into N-linked, O-linked, combined, and glycosphingolipid/glycosylphosphatidylinositol anchor synthesis defects. Clinical presentation is highly variable, ranging from mild dysmorphism to profound organ failure and early death, and can involve neurologic, cardiac, endocrine, immunologic, haematologic, gastrointestinal, and skeletal muscle systems. There is no universal or pathognomonic sign, and diagnosis relies on serum transferrin isoelectric focusing followed by molecular genetic testing.
For most CDG types, treatment is symptomatic only. An exception is phosphoglucomutase-1-CDG (PGM1-CDG), for which oral D-galactose supplementation is used. A 2023 case series of five PGM1-CDG patients reported notable clinical improvement in four, with significant improvement or normalisation of transferrin glycosylation, liver transaminases, and coagulation factors in three patients, creatine kinase levels in two, and resolution of hypoglycaemia in two. However, efficacy varied: one patient discontinued treatment due to urinary frequency and lack of improvement, and another experienced recurrent rhabdomyolysis and tachycardia even on higher doses. D-galactose failed to improve cardiac function, which was initially abnormal in three patients, and cardiac involvement remains the biggest treatment challenge, often leading to early death.
Peters’-plus syndrome, a rare autosomal recessive disorder characterised by Peters’ anomaly (corneal opaqueness and iridocorneal adhesions), short stature, cleft lip/palate, central nervous system defects, and variable severity from early death to developmental delay with mental retardation, is now known to be a CDG. It is caused by inactivating mutations in a beta1,3-glucosyltransferase that adds a glucose moiety to O-linked fucose on thrombospondin type 1 repeats. The disaccharide has been demonstrated on only five of some ninety human proteins containing these repeats, including thrombospondin 1, properdin, and ADAMTS-13, which function in embryonic development, angiogenesis, and neurogenesis.
What is still missing is specific treatment for the vast majority of CDG types, including cardiac-targeted therapies for PGM1-CDG. The rarity and phenotypic variability of these disorders make clinical trial design and patient stratification difficult, and funding for basic research into the molecular mechanisms of individual glycosylation defects 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.
Journal of Inherited Metabolic Disease · 2011 · 137 citations
Congenital disorders of glycosylation (CDG): it's (nearly) all in it!
AbstractCongenital disorders of glycosylation (CDG) is a booming class of metabolic diseases. Its number has increased nearly fourfold (to 45) since 2003, the year of the Komrower lecture, entitled 'Congenital disorders of glycosylation CDG): It's all in it!'. This paper presents an overview of recently discovered CDG and CDG phenotypes, of a diagnostic approach, of (the lack of) treatment, of CDG genetics, of a novel CDG nomenclature and classification, and of some future directions in the CDG field.
New England Journal of Medicine · 1963 · 87 citations
Abnormal Catechol Amine Metabolism in Familial Dysautonomia
AbstractFAMILIAL dysautonomia is a rare congenital disorder that occurs primarily in Jewish children.1 The more striking manifestations of the disease include reduced or absent tearing, transient skin blotching, profuse sweating, abnormal swallowing reflex and instability of temperature control. Postural hypotension is a regular finding in this syndrome although the blood pressure may rise during excitement.Riley2 has suggested that the many manifestations of familial dysautonomia may result from a singleenzyme defect. Since autonomie dysfunction is so prominent in this disorder, a defect in catechol amine metabolism may be involved. The excretion rates of catechol amine catabolites, homovanillic (HVA) and vanillyl-mandelic . . .
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.
AbstractABSTRACT: Najjar, S., Salem, G. and Idriss, Z. (Department of Pediatrics, The American University of Beirut, Beirut, Lebanon). Congenital generalized lipodystrophy. Acta Paediatr Scand, 64:273, 1975.–Six patients with congenital generalized lipodystrophy are described. They had generalized paucity of fat tissue, acanthosis nigricans, prominent superficial veins and muscle hypertrophy. They were mentally retarded. Three had corneal opacities. They had normal external genitalia and none was tall for age. Their bone age was advanced and some had minor skeletal anomalies and nephromegaly. The muscle histology on light microscopy was normal. The majority had elevated serum aldolase and to a lesser degree serum lactic dehydrogenase and creatinine phosphokinase. Four of five examined had a myopathic electromyogram. They had normal or minimally deranged liver function tests. The fatty liver infiltration in one seems to be progressive. Four had a normal and two an abnormal metyrapone test. They had an age‐dependent abnormality of growth hormone, insulin and carbohydrate homeostasis.
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.
Journal of Palliative Medicine · 2016 · 3 citations
Providing Palliative Care in Rare Pediatric Diseases: A Case Series of Three Children with Congenital Disorder of Glycosylation
AbstractPediatric palliative care providers often care for children with rare, poorly understood diseases. In addition to grappling with a life-limiting diagnosis, families face complexity in decision making stemming from the prognostic uncertainty surrounding their child's rare condition. We discuss several unique challenges, illustrated through case studies of three children who shared the rare diagnosis of congenital disorder of glycosylation.
Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) · 2022 · 3 citations · open access
Congenital disorders of glycosylation
AbstractCongenital disorders of glycosylation are a highly variable, rapidly expanding family of genetic diseases that result from defects in the synthesis of glycans. The vast majority of these monogenic diseases are inherited in an autosomal recessive way, but some types follow an autosomal dominant or X-linked inheritance. The present work aimed to review the state of the art of congenital disorders of glycosylation, including available therapeutic options, and present a simplified diagnostic approach to this group of diseases. Congenital disorders of glycosylation can be classified into four categories: N-linked glycosylation defects, O-linked glycosylation defects, combined glycosylation defects, and glycosphingolipid and glycosylphosphatidylinositol anchor synthesis defects. The phenotype may range from mild to severe, depending on disease severity. Clinical features include dysmorphic features, neurologic, dermatologic, cardiac, endocrine, immunologic, hematologic, gastrointestinal and liver involvement, and skeletal muscle abnormalities. As there is no universal or pathognomonic sign or symptom and no sensitive diagnostic test, it is of foremost importance to keep a high index of suspicion of these diseases. When a congenital disorder of glycosylation is suspected, the first step in screening is to perform serum transferrin isoelectric focusing. Molecular genetic testing is the most specific diagnostic test. Treatment is usually symptomatic, with specific treatment only available for some of these disorders. Since congenital defects of glycosylation may affect any organ at any age and have variable clinical presentation, they should be considered in the differential diagnosis of any patient with multiorgan involvement.
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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