No approved-drug candidate for congenital disorder of deglycosylation 1 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.
RCSB Protein Data Bank · entry 2IWZ · 1.65 Å · ligand HEXANOIC ACID (6NA). Experimental structure, not a prediction.
Congenital disorders of glycosylation (CDG) are a group of rare autosomal recessive metabolic diseases caused by mutations in over 100 genes that impair protein or lipid glycosylation. By 2004, 20 CDG subtypes had been identified, with an average of nearly one new disease reported per year since 1980. The disorders affect nearly all organs and systems, and it was recommended that CDG be considered in any child with an unexplained clinical syndrome. ALG1-CDG, caused by mutations in the β1,4 mannosyltransferase gene ALG1, was described in 39 previously unreported patients from 32 families, tripling the known patient number and adding 26 new mutations. Pathogenicity was confirmed in an alg1-deficient yeast strain, but no rank order comparison of biomarker glycosylation and patient phenotype could be established, though mutations with a lethal outcome in the first two years of life were identified. Peters’-plus syndrome, a rare autosomal recessive disorder characterised by Peters’ anomaly, short stature, cleft lip/palate, and variable central nervous system and heart defects, was identified as a CDG caused by inactivation of a β1,3-glucosyltransferase that adds glucose to O-linked fucose on thrombospondin type 1 repeats. The phenotype ranges from death in early childhood to general developmental delay with mental retardation.
For PGM1-CDG, oral D-galactose (D-gal) supplementation is a treatment that significantly improves many aspects of the disorder. In a case series of five patients, D-gal resulted in notable clinical improvement in four, though efficacy varied between patients. Significant improvement or normalisation occurred in transferrin glycosylation, liver transaminases and coagulation factors in three patients, creatine kinase levels in two, and hypoglycaemia resolved in two. 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-gal failed to improve cardiac function, which was initially abnormal in three patients, and cardiac involvement remains the biggest challenge in treating PGM1-CDG, often resulting in early death. The authors underline the importance of developing novel therapies that specifically treat the cardiac phenotype.
What is still missing are therapies that address the cardiac phenotype in PGM1-CDG, which is the most severe aspect and can cause early death. For the other CDG subtypes discussed, no treatment is reported at all. Larger, longer-term studies with consistent outcome measures are needed, and patient stratification by specific mutation or biomarker profile may be necessary to understand variable treatment responses. Funding for such rare-disease trials remains a barrier.
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.
https://doi.org/10.1097/01.mop.0000133636.56790.4aHuman 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.
https://doi.org/10.1002/humu.22983Annals 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.
https://doi.org/10.1080/07853890802301975Therapeutic 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.
https://doi.org/10.1177/26330040221150269Advances in Neonatal Care · 2012 · 11 citations
Congenital Disorder of Glycosylation
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.
https://doi.org/10.1097/anc.0b013e318241bc1bPediatric Dermatology · 2017 · 9 citations
Congenital Degos Disease: Case Report and Dermoscopic Findings
AbstractPediatric Degos disease is rare, with only 36 cases reported in the medical literature. Classically the diagnosis has been established according to pathognomonic histopathologic findings, but when these features are not present, there may be a delay in diagnosis. We report the second congenital case of Degos disease, highlighting the clinical and dermoscopic findings.
https://doi.org/10.1111/pde.13096Sage 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.
https://doi.org/10.25384/sage.c.6405105.v1Sage 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.
https://doi.org/10.25384/sage.c.6405105Disease 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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