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Jaak Jaeken - One of the best experts on this subject based on the ideXlab platform.

  • Liver involvement in Congenital Disorders of glycosylation (CDG). A systematic review of the literature
    Journal of Inherited Metabolic Disease, 2017
    Co-Authors: D. Marques-da-silva, Peter Witters, Jaak Jaeken, V. Reis Ferreira, M. Monticelli, P. Janeiro, P. A. Videira, David Cassiman
    Abstract:

    Congenital Disorders of glycosylation (CDG) are a rapidly growing family of genetic diseases caused by defects in glycosylation. Nearly 100 CDG types are known so far. Patients present a great phenotypic diversity ranging from poly- to mono-organ/system involvement and from very mild to extremely severe presentation. In this literature review, we summarize the liver involvement reported in CDG patients. Although liver involvement is present in only a minority of the reported CDG types (22 %), it can be debilitating or even life-threatening. Sixteen of the patients we collated here developed cirrhosis, 10 had liver failure. We distinguish two main groups: on the one hand, the CDG types with predominant or isolated liver involvement including MPI-CDG, TMEM199-CDG, CCDC115-CDG, and ATP6AP1-CDG, and on the other hand, the CDG types associated with liver disease but not as a striking, unique or predominant feature, including PMM2-CDG, ALG1-CDG, ALG3-CDG, ALG6-CDG, ALG8-CDG, ALG9-CDG, PGM1-CDG, and COG-CDG. This review aims to facilitate CDG patient identification and to understand CDG liver involvement, hopefully leading to earlier diagnosis, and better management and treatment.

  • electroclinical features of early onset epileptic encephalopathies in Congenital Disorders of glycosylation cdgs
    JIMD reports, 2015
    Co-Authors: Agata Fiumara, Rita Barone, Giuliana Del Campo, Pasquale Striano, Jaak Jaeken
    Abstract:

    Congenital Disorders of glycosylation (CDG) are a constantly growing group of genetic defects of glycoprotein and glycolipid glycan synthesis. CDGs are usually multisystem diseases, and in the majority of patients, there is an important neurological involvement comprising psychomotor disability, hypotonia, ataxia, seizures, stroke-like episodes, and peripheral neuropathy. To assess the incidence, among early-onset epileptic encephalopathies (EOEE), of patients with identified Congenital Disorders of glycosylation (CDG), we made a review of clinical, electrophysiological, and neuroimaging findings of 27 CDG patients focusing on seizure onset, semiology and frequency, response to antiepileptic drugs (AED), and early epileptic manifestations. Epilepsy was uncommon in PMM2-CDG (11%), while it was a main concern in other rare forms. We describe a series of patients with EOEE and genetically confirmed CDG (ALG3-CDG, ALG6-CDG, DPM2-CDG, ALG1-CDG). Epileptic seizures at onset included myoclonic and clonic fits and focal seizures. With time, patients developed recurrent and intractable seizures principally tonic–clonic seizures, infantile spasms, and myoclonic seizures. Electrophysiological correlates included focal and multifocal epileptic discharges, slowed background rhythm, and generalized epileptic activity including burst suppression pattern and status epilepticus. We propose a diagnostic flowchart for the early diagnosis of CDG in patients presenting with EOEE and suggest to perform serum transferrin IEF (or capillary zone electrophoresis) as a first-line screening in early-onset epilepsy.

  • Congenital Disorders of Glycosylation with Emphasis on Cerebellar Involvement
    Seminars in neurology, 2014
    Co-Authors: Rita Barone, Agata Fiumara, Jaak Jaeken
    Abstract:

    Congenital Disorders of glycosylation (CDG) are genetic diseases due to defective glycosylation of proteins and lipids. The authors present an update on these Disorders affecting the central nervous system with a focus on cerebellar involvement. The rate of identification of novel CDG shows an exponential increase. Some 76 CDG are actually known, not taking into account the defects in glycan-modifying proteins. Neurologic involvement is present in the large majority of CDG. Screening methods are limited to serum transferrin isoelectrofocusing (for N-glycosylation Disorders with sialic acid deficiency), and serum apolipoprotein C-III isoelectrofocusing (for core 1 mucin-type O-glycosylation Disorders). Whole exome/genome sequencing is increasingly used in the diagnostic workup of patients with CDG-X. Treatment is greatly lagging behind because only one CDG is efficiently treatable (MPI-CDG). Cerebellar involvement is an important feature of PMM2-CDG, the Congenital muscular dystrophies due to dystroglycanopathy, and SRD5A3-CDG. It has also been reported in some patients with ALG1-CDG, ALG3-CDG, ALG9-CDG, ALG6-CDG, ALG8-CDG, PIGA-CDG, DPM1-CDG, DPM2-CDG, B4GALT1-CDG, SLC35A2-CDG, COG1-CDG, COG5-CDG, COG7-CDG, and COG8-CDG.

  • Congenital Disorders of glycosylation.
    Handbook of clinical neurology, 2013
    Co-Authors: Jaak Jaeken
    Abstract:

    Congenital Disorders of glycosylation (CDG) are genetic diseases due to defects in the synthesis or the attachment of the glycan moiety of glycoproteins and glycolipids. They can be divided into four groups: Disorders of protein N-glycosylation, Disorders of protein O-glycosylation, Disorders of lipid glycosylation, and Disorders of other glycosylation pathways and of multiple glycosylation pathways. Of the more than 40 reported CDG, some 80% are neurological or have an important neurological component. By far the most common neurological CDG is phosphomannomutase 2 deficiency. Isoelectrofocusing of serum transferrin, the most widely used screening test, picks up only CDG associated with sialic acid deficiency of N-linked glycans. Predominant neurological signs and symptoms are psychomotor retardation, epilepsy, hypotonia, hyporeflexia, strabismus, retinitis pigmentosa, polyneuropathy, myopathy, and cerebellar hypotrophy/hypoplasia. All known neurological CDG have an autosomal recessive inheritance except for IAP-CDG, an X-linked pure mental retardation syndrome. No curative or effective treatment is available for neurological CDG. Since at least 1% of the genome is involved in glycosylation, it is likely that the large majority of CDG is yet to be discovered. In 2008, a novel nomenclature was introduced using the gene symbol followed by -CDG, e.g., CDG-Ia becomes PMM2-CDG. CDG should be looked for in any unexplained neurological syndrome.

  • Congenital Disorders of glycosylation cdg it s nearly all in it
    Journal of Inherited Metabolic Disease, 2011
    Co-Authors: Jaak Jaeken
    Abstract:

    Congenital 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.

Eva Morava - One of the best experts on this subject based on the ideXlab platform.

  • Therapeutic approaches in Congenital Disorders of Glycosylation (CDG) involving N-linked glycosylation: an update
    Genetics in Medicine, 2020
    Co-Authors: Jan Verheijen, Peter Witters, Tamas Kozicz, Shawn Tahata, Eva Morava
    Abstract:

    Congenital Disorders of glycosylation (CDG) are a group of clinically and genetically heterogeneous metabolic Disorders. Over 150 CDG types have been described. Most CDG types are ultrarare Disorders. CDG types affecting N-glycosylation are the most common type of CDG with emerging therapeutic possibilities. This review is an update on the available therapies for Disorders affecting the N-linked glycosylation pathway. In the first part of the review, we highlight the clinical presentation, general principles of management, and disease-specific therapies for N-linked glycosylation CDG types, organized by organ system. The second part of the review focuses on the therapeutic strategies currently available and under development. We summarize the successful (pre-) clinical application of nutritional therapies, transplantation, activated sugars, gene therapy, and pharmacological chaperones and outline the anticipated expansion of the therapeutic possibilities in CDG. We aim to provide a comprehensive update on the treatable aspects of CDG types involving N-linked glycosylation, with particular emphasis on disease-specific treatment options for the involved organ systems; call for natural history studies; and present current and future therapeutic strategies for CDG.

  • increased clinical sensitivity and specificity of plasma protein n glycan profiling for diagnosing Congenital Disorders of glycosylation by use of flow injection electrospray ionization quadrupole time of flight mass spectrometry
    Clinical Chemistry, 2019
    Co-Authors: Jie Chen, Eva Morava, Andrew C Edmondson, Gail Ditewig Meyers, Kosuke Izumi, Amanda M Ackermann, Can Ficicioglu, Michael J Bennett
    Abstract:

    Background: Congenital Disorders of glycosylation (CDG) represent 1 of the largest groups of metabolic Disorders with >130 subtypes identified to date. The majority of CDG subtypes are Disorders of N -linked glycosylation, in which carbohydrate residues, namely, N -glycans, are posttranslationally linked to asparagine molecules in peptides. To improve the diagnostic capability for CDG, we developed and validated a plasma N -glycan assay using flow injection–electrospray ionization–quadrupole time-of-flight mass spectrometry. Methods: After PNGase F digestion of plasma glycoproteins, N -glycans were linked to a quinolone using a transient amine group at the reducing end, isolated by a hydrophilic interaction chromatography column, and then identified by accurate mass and quantified using a stable isotope-labeled glycopeptide as the internal standard. Results: This assay differed from other N -glycan profiling methods because it was free of any contamination from circulating free glycans and was semiquantitative. The low end of the detection range tested was at 63 nmol/L for disialo-biantennary N -glycan. The majority of N -glycans in normal plasma had N -glycan profiles from 19 patients with known diagnoses of 11 different CDG subtypes were generated, some of which had previously been reported to have normal N -linked protein glycosylation by carbohydrate-deficient transferrin analysis. Conclusions: The clinical specificity and sensitivity of N -glycan analysis was much improved with this method. Additional CDGs can be diagnosed that would be missed by carbohydrate-deficient transferrin analysis. The assay provides novel biomarkers with diagnostic and potentially therapeutic significance.

  • Nutritional Therapies in Congenital Disorders of Glycosylation (CDG).
    Nutrients, 2017
    Co-Authors: Peter Witters, David Cassiman, Eva Morava
    Abstract:

    Congenital Disorders of glycosylation (CDG) are a group of more than 130 inborn errors of metabolism affecting N-linked, O-linked protein and lipid-linked glycosylation. The phenotype in CDG patients includes frequent liver involvement, especially the Disorders belonging to the N-linked protein glycosylation group. There are only a few treatable CDG. Mannose-Phosphate Isomerase (MPI)-CDG was the first treatable CDG by high dose mannose supplements. Recently, with the successful use of d-galactose in Phosphoglucomutase 1 (PGM1)-CDG, other CDG types have been trialed on galactose and with an increasing number of potential nutritional therapies. Current mini review focuses on therapies in glycosylation Disorders affecting liver function and dietary intervention in general in N-linked glycosylation Disorders. We also emphasize now the importance of early screening for CDG in patients with mild hepatopathy but also in cholestasis.

  • Congenital Disorders of glycosylation cdg quo vadis
    European Journal of Medical Genetics, 2017
    Co-Authors: Romain Peanne, Pascale De Lonlay, Eva Morava, Francois Foulquier, Uwe Kornak, Dirk Lefeber, Belen Perez, Nathalie Seta, Christian Thiel, Emile Van Schaftingen
    Abstract:

    The survey summarizes in its first part the current status of knowledge on the Congenital Disorders of Glycosylation (CDG) with regard to their phenotypic spectrum, diagnostic and therapeutic strategies, and pathophysiology. It documents the clinical and basic research activities, and efforts to involve patients and their families. In the second part, it tries to look into the future of CDG. More specific biomarkers are needed for fast CDG diagnosis and treatment monitoring. Whole genome sequencing will play an increasingly important role in the molecular diagnosis of unsolved CDG. Epigenetic defects are expected to join the rapidly expanding genetic and allelic heterogeneity of the CDG family. Novel treatments are urgently needed particularly for PMM2-CDG, the most prevalent CDG. Patient services such as apps should be developed e.g. to document the natural history and monitor treatment. Networking (EURO-CDG, the European Reference Networks (MetabERN)) is an efficient tool to disseminate knowledge and boost collaboration at all levels. The final goal is of course to improve the quality of life of the patients and their families.

  • high resolution mass spectrometry glycoprofiling of intact transferrin for diagnosis and subtype identification in the Congenital Disorders of glycosylation
    Translational Research, 2015
    Co-Authors: Monique Van Scherpenzeel, Ron A. Wevers, Eva Morava, Gerry Steenbergen, Dirk Lefeber
    Abstract:

    Diagnostic screening of the Congenital Disorders of glycosylation (CDG) generally involves isoelectric focusing of plasma transferrin, a robust method easily integrated in medical laboratories. Structural information is needed as the next step, as required for the challenging classification of Golgi glycosylation defects (CDG-II). Here, we present the use of high-resolution nano liquid chromatography-chip (C8)-quadrupole time of flight mass spectrometry (nanoLC-chip [C8]-QTOF MS) for protein-specific glycoprofiling of intact transferrin, which allows screening and direct diagnosis of a number of CDG-II defects. Transferrin was immunopurified from 10 μL of plasma and analyzed by nanoLC-chip-QTOF MS. Charge distribution raw data were deconvoluted by Mass Hunter software to reconstructed mass spectra. Plasma samples were processed from controls (n = 56), patients with known defects (n = 30), and patients with secondary (n = 6) or unsolved (n = 3) cause of abnormal glycosylation. This fast and robust method, established for CDG diagnostics, requires only 2 hours analysis time, including sample preparation and analysis. For CDG-I patients, the characteristic loss of complete N-glycans could be detected with high sensitivity. Known CDG-II defects (phosphoglucomutase 1 [PGM1-CDG], mannosyl (α-1,6-)-glycoprotein β-1,2-N-acetylglucosaminyltransferase [MGAT2-CDG], β-1,4-galactosyltransferase 1 [B4GALT1-CDG], CMP-sialic acid transporter [SLC35A1-CDG], UDP-galactose transporter [SLC35A2-CDG] and mannosyl-oligosaccharide 1,2-alpha-mannosidase [MAN1B1-CDG]) resulted in characteristic diagnostic profiles. Moreover, in the group of Golgi trafficking defects and unsolved CDG-II patients, distinct profiles were observed, which facilitate identification of the specific CDG subtype. The established QTOF method affords high sensitivity and resolution for the detection of complete glycan loss and structural assignment of truncated glycans in a single assay. The speed and robustness allow its clinical diagnostic application as a first step in the diagnostic procedure for CDG defects.

Isabelle Chantret - One of the best experts on this subject based on the ideXlab platform.

  • A case of fatal Type I Congenital Disorders of glycosylation (CDG I) associated with low dehydrodolichol diphosphate synthase (DHDDS) activity.
    Orphanet Journal of Rare Diseases, 2016
    Co-Authors: Sahar Sabry, Nathalie Seta, Sandrine Vuillaumier-barrot, Delphine Heron, Elodie Mintet, Magali Fasseu, Vassili Valayannopoulos, Nathalie Dorison, Cyril Mignot, Isabelle Chantret
    Abstract:

    Type I Congenital Disorders of glycosylation (CDG-I) are mostly complex multisystemic diseases associated with hypoglycosylated serum glycoproteins. A subgroup harbour mutations in genes necessary for the biosynthesis of the dolichol-linked oligosaccharide (DLO) precursor that is essential for protein N-glycosylation. Here, our objective was to identify the molecular origins of disease in such a CDG-Ix patient presenting with axial hypotonia, peripheral hypertonia, enlarged liver, micropenis, cryptorchidism and sensorineural deafness associated with hypo glycosylated serum glycoproteins. Targeted sequencing of DNA revealed a splice site mutation in intron 5 and a non-sense mutation in exon 4 of the dehydrodolichol diphosphate synthase gene (DHDDS). Skin biopsy fibroblasts derived from the patient revealed ~20 % residual DHDDS mRNA, ~35 % residual DHDDS activity, reduced dolichol-phosphate, truncated DLO and N-glycans, and an increased ratio of [2-(3)H]mannose labeled glycoprotein to [2-(3)H]mannose labeled DLO. Predicted truncated DHDDS transcripts did not complement rer2-deficient yeast. SiRNA-mediated down-regulation of DHDDS in human hepatocellular carcinoma HepG2 cells largely mirrored the biochemical phenotype of cells from the patient. The patient also harboured the homozygous ALG6(F304S) variant, which does not cause CDG but has been reported to be more frequent in PMM2-CDG patients with severe/fatal disease than in those with moderate presentations. WES did not reveal other strong candidate causal genes. We describe a patient presenting with severe multisystem disease associated with DHDDS deficiency. As retinitis pigmentosa is the only clinical sign in previously reported cases, this report broadens the spectrum of phenotypes associated with this condition.

  • guanosine diphosphate mannose glcnac2 pp dolichol mannosyltransferase deficiency Congenital Disorders of glycosylation type ik five new patients and seven novel mutations
    Journal of Medical Genetics, 2010
    Co-Authors: Thierry Dupre, H S Yaye, Le C Bizec, Lydie Burglen, Isabelle Chantret, Sandrine Vuillaumierbarrot, Cécilia Altuzarra, Alexandra Afenjar, Christine Barnerias, Pascale De Lonlay
    Abstract:

    Background In type I Congenital Disorders of glycosylation (CDG I), proteins necessary for the biosynthesis of the lipid-linked oligosaccharide (LLO) required for protein N-glycosylation are defective. A deficiency in guanosine diphosphate-mannose:GlcNAc2-PP-dolichol mannosyltransferase-1 (MT-1) causes CDG Ik (OMIM 608540), and only five patients, with severe multisystemic clinical presentations, have been described with this disease. Objective To characterise genetic, biochemical and clinical data in five new CDG Ik cases and compare these findings with those of the five previously described patients. Methods LLO biosynthesis was examined in skin biopsy fibroblasts, mannosyltransferases were assayed in microsomes prepared from these cells, and ALG1 -encoding MT-1 was sequenced at the DNA and complementary DNA levels. Clinical data for the five new patients were collated. Results Cells from five patients with non-typed CDG I revealed accumulations of GlcNAc2-PP-dolichol, the second intermediate in the biosynthesis of LLO. Assay of MT-1, -2 and -3, the first three mannosyltransferases required for extension of this intermediate, demonstrated only MT-1 to be deficient. DNA sequencing of ALG1 revealed nine different mutations, seven of which have not been previously reported. Clinical presentations are severe, with dysmorphias, CNS involvement and ocular disturbances being prevalent. Conclusions 5 patients with CDG Ik are described, and their identification reveals that in France, this disease and CDG Ib (mannose phosphate isomerase deficiency: OMIM 602579) are the most frequently diagnosed CDG I after CDG Ia (phosphomannomutase 2 deficiency: OMIM 601785) and substantiate previous observations indicating that this disease presents at the severe end of the CDG I clinical spectrum.

  • a deficiency in dolichyl p glucose glc1man9glcnac2 pp dolichyl α3 glucosyltransferase defines a new subtype of Congenital Disorders of glycosylation
    Journal of Biological Chemistry, 2003
    Co-Authors: Isabelle Chantret, Thierry Dupre, Sandrine Vuillaumierbarrot, Christophe Delenda, Stephanie Bucher, Julia Dancourt, Olivier Danos, Helene Ogier De Baulny, Celine Peletan, Nathalie Seta
    Abstract:

    The underlying causes of type I Congenital Disorders of glycosylation (CDG I) have been shown to be mutations in genes encoding proteins involved in the biosynthesis of the dolichyl-linked oligosaccharide (Glc(3)Man(9)GlcNAc(2)-PP-dolichyl) that is required for protein glycosylation. Here we describe a CDG I patient displaying gastrointestinal problems but no central nervous system deficits. Fibroblasts from this patient accumulate mainly Man(9)GlcNAc(2)-PP-dolichyl, but in the presence of castanospermine, an endoplasmic reticulum glucosidase inhibitor Glc(1)Man(9)GlcNAc(2)-PP-dolichyl predominates, suggesting inefficient addition of the second glucose residue onto lipid-linked oligosaccharide. Northern blot analysis revealed the cells from the patient to possess only 10-20% normal amounts of mRNA encoding the enzyme, dolichyl-P-glucose:Glc(1)Man(9)GlcNAc(2)-PP-dolichyl alpha3-glucosyltransferase (hALG8p), which catalyzes this reaction. Sequencing of hALG8 genomic DNA revealed exon 4 to contain a base deletion in one allele and a base insertion in the other. Both mutations give rise to premature stop codons predicted to generate severely truncated proteins, but because the translation inhibitor emetine was shown to stabilize the hALG8 mRNA from the patient to normal levels, it is likely that both transcripts undergo nonsense-mediated mRNA decay. As the cells from the patient were successfully complemented with wild type hALG8 cDNA, we conclude that these mutations are the underlying cause of this new CDG I subtype that we propose be called CDG Ih.

  • Congenital Disorders of glycosylation type ig is defined by a deficiency in dolichyl p mannose man7glcnac2 pp dolichyl mannosyltransferase
    Journal of Biological Chemistry, 2002
    Co-Authors: Isabelle Chantret, Thierry Dupre, Christophe Delenda, Stephanie Bucher, Julia Dancourt, Anne Barnier, Aude Charollais, Delphine Heron, B Badermeunier, Olivier Danos
    Abstract:

    Abstract Type I Congenital Disorders of glycosylation (CDG I) are diseases presenting multisystemic lesions including central and peripheral nervous system deficits. The disease is characterized by under-glycosylated serum glycoproteins and is caused by mutations in genes encoding proteins involved in the stepwise assembly of dolichol-oligosaccharide used for proteinN-glycosylation. We report that fibroblasts from a type I CDG patient, born of consanguineous parents, are deficient in their capacity to add the eighth mannose residue onto the lipid-linked oligosaccharide precursor. We have characterized cDNA corresponding to the human ortholog of the yeast geneALG12 that encodes the dolichyl-P-Man:Man7GlcNAc2-PP-dolichyl α6-mannosyltransferase that is thought to accomplish this reaction, and we show that the patient is homozygous for a point mutation (T571G) that causes an amino acid substitution (F142V) in a conserved region of the protein. As the pathological phenotype of the fibroblasts of the patient was largely normalized upon transduction with the wild type gene, we demonstrate that the F142V substitution is the underlying cause of this new CDG, which we suggest be called CDG Ig. Finally, we show that the fibroblasts of the patient are capable of the direct transfer of Man7GlcNAc2 from dolichol onto protein and that this N-linked structure can be glucosylated by UDP-glucose:glycoprotein glucosyltransferase in the endoplasmic reticulum.

Gert Matthijs - One of the best experts on this subject based on the ideXlab platform.

  • rft1 cdg deafness as a novel feature of Congenital Disorders of glycosylation
    Journal of Inherited Metabolic Disease, 2009
    Co-Authors: Jaak Jaeken, Gert Matthijs, Thierry Hennet, Francois Foulquier, Micha A Haeuptle, Wendy Vleugels, Luc Regal, C Corchia, Nathalie Goemans, Carlo Dionisivici
    Abstract:

    Congenital Disorders of glycosylation (CDG) are genetic diseases due to defects in the synthesis of glycans and in the attachment of glycans to lipids and proteins. Actually, some 42 CDG are known including defects in protein N-glycosylation, in protein O-glycosylation, in lipid glycosylation, and in multiple and other glycosylation pathways. Most CDG are multisystem diseases and a large number of signs and symptoms have already been reported in CDG. An exception to this is deafness. This symptom has not been observed as a consistent feature in CDG. In 2008, a novel defect was identified in protein N-glycosylation, namely in RFT1. This is a defect in the assembly of N-glycans. RFT1 is involved in the transfer of Man5GlcNAc2-PP-Dol from the cytoplasmic to the luminal side of the endoplasmic reticulum. According to the novel nomenclature (non-italicized gene symbol followed by -CDG) this defect is named RFT1-CDG. Recently, three other patients with RFT1-CDG have been reported and here we report two novel patients. Remarkably, all six patients with RFT1-CDG show sensorineural deafness as part of a severe neurological syndrome. We conclude that RFT1-CDG is the first ‘deafness-CDG’. CDG should be included in the work-up of Congenital, particularly syndromic, hearing loss.

  • deficiencies in subunits of the conserved oligomeric golgi cog complex define a novel group of Congenital Disorders of glycosylation
    Molecular Genetics and Metabolism, 2008
    Co-Authors: Renate Zeevaert, Francois Foulquier, Jaak Jaeken, Gert Matthijs
    Abstract:

    Processing of the glycan structures on glycoproteins by different glycosylation enzymes depends on, among other, the non-uniform distribution of these enzymes within the Golgi stacks. This compartmentalization is achieved by a balance between anterograde and retrograde vesicular trafficking. If the balance is disturbed, the glycosylation machinery is mislocalized, which can cause Congenital Disorders of Glycosylation type II (CDG-II), as illustrated by the identification of Congenital defects in the Conserved Oligomeric Golgi (COG) complex in humans. We collected findings from different COG deficient cell types, such as CHO, yeast and human fibroblasts to hypothesize about structure and function of the COG complex, and compared the phenotypes and genotypes of the patients known with a COG deficiency. Among 35 CDG-II patients we found 5 patients with a COG defect. COG defects are a novel group of CDG-II with deficient N- as well as O-glycosylation.

  • detailed glycan analysis of serum glycoproteins of patients with Congenital Disorders of glycosylation indicates the specific defective glycan processing step and provides an insight into pathogenesis
    Glycobiology, 2003
    Co-Authors: Michael Butler, Dulce Quelhas, Laura Vilarinho, Gert Matthijs, Hubert Carchon, Alison J Critchley, Holger F Hebestreit, Richard G Hibbert, Elisa Leao Teles, E Schollen
    Abstract:

    The fundamental importance of correct protein glycosylation is abundantly clear in a group of diseases known as Congenital Disorders of glycosylation (CDGs). In these diseases, many biological functions are compromised, giving rise to a wide range of severe clinical conditions. By performing detailed analyses of the total serum glycoproteins as well as isolated transferrin and IgG, we have directly correlated aberrant glycosylation with a faulty glycosylation processing step. In one patient the complete absence of complex type sugars was consistent with ablation of GlcNAcTase II activity. In another CDG type II patient, the identification of specific hybrid sugars suggested that the defective processing step was cell type-specific and involved the mannosidase III pathway. In each case, complementary serum proteome analyses revealed significant changes in some 31 glycoproteins, including components of the complement system. This biochemical approach to charting diseases that involve alterations in glycan processing provides a rapid indicator of the nature, severity, and cell type specificity of the suboptimal glycan processing steps; allows links to genetic mutations; indicates the expression levels of proteins; and gives insight into the pathways affected in the disease process.

  • Congenital Disorders of Glycosylation: A Review
    Pediatric Research, 2002
    Co-Authors: Stephanie Grunewald, Gert Matthijs, Jaak Jaeken
    Abstract:

    Congenital Disorders of glycosylation (CDGs) are a rapidly growing group of inherited Disorders caused by defects in the synthesis and processing of the asparagine(ASN)-linked oligosaccharides of glycoproteins. The first CDG patients were described in 1980. Fifteen years later, a phosphomannomutase deficiency was found as the basis of the most frequent type, CDG-Ia. In recent years several novel types have been identified. The N -glycosylation pathway is highly conserved from yeast to human, and the rapid progress in this field can largely be attributed to the systematic application of the knowledge of yeast mutants. Up to now, eight diseases have been characterized, resulting from enzyme or transport defects in the cytosol, endoplasmic reticulum, or Golgi compartment. CDGs affect all organs and particularly the CNS, except for CDG-Ib, which is mainly a hepatic-intestinal disease.

  • Congenital Disorders of glycosylation
    Annual review of genomics and human genetics, 2001
    Co-Authors: Jacques Jaeken, Gert Matthijs
    Abstract:

    Congenital Disorders of glycosylation (CDG) are a rapidly growing group of genetic diseases that are due to defects in the synthesis of glycans and in the attachment of glycans to other compounds. Most CDG are multisystem diseases that include severe brain involvement. The CDG causing sialic acid deficiency of N-glycans can be diagnosed by isoelectrofocusing of serum sialotransferrins. An efficient treatment, namely oral D-mannose, is available for only one CDG (CDG-Ib). In many patients with CDG, the basic defect is unknown (CDG-x). Glycan structural analysis, yeast genetics, and knockout animal models are essential tools in the elucidation of novel CDG. Eleven primary genetic glycosylation diseases have been discovered and their basic defects identified: six in the N-glycan assembly, three in the N-glycan processing, and two in the O-glycan (glycosaminoglycan) assembly. This review summarizes their clinical, biochemical, and genetic characteristics and speculates on further developments in this field.

Hudson H. Freeze - One of the best experts on this subject based on the ideXlab platform.

  • glycosyltransferase genes that cause monogenic Congenital Disorders of glycosylation are distinct from glycosyltransferase genes associated with complex diseases
    Glycobiology, 2018
    Co-Authors: Hiren J Joshi, Hudson H. Freeze, Lars Hansen, Yoshiki Narimatsu, Bernard Henrissat, Eric P Bennett, Hans H Wandall, Henrik Clausen, Katrine T Schjoldager
    Abstract:

    Glycosylation of proteins, lipids and proteoglycans in human cells involves at least 167 identified glycosyltransferases (GTfs), and these orchestrate the biosynthesis of diverse types of glycoconjugates and glycan structures. Mutations in this part of the genome-the GTf-genome-cause more than 58 rare, monogenic Congenital Disorders of glycosylation (CDGs). They are also statistically associated with a large number of complex phenotypes, diseases or predispositions to complex diseases based on Genome-Wide Association Studies (GWAS). CDGs are extremely rare and often with severe medical consequences. In contrast, GWAS are likely to identify more common genetic variations and generally involve less severe and distinct traits. We recently confirmed that structural defects in GTf genes are extremely rare, which seemed at odds with the large number of GWAS pointing to GTf-genes. To resolve this issue, we surveyed the GTf-genome for reported CDGs and GWAS candidates; we found little overlap between the two groups of genes. Moreover, GTf-genes implicated by CDG or GWAS appear to constitute different classes with respect to their: (i) predicted roles in glycosylation pathways; (ii) potential for partial redundancy by closely homologous genes; and (iii) transcriptional regulation as evaluated by RNAseq data. Our analysis suggest that more complex traits are caused by dysregulation rather than structural deficiency of GTfs, which suggests that some glycosylation reactions may be predicted to be under tight regulation for fine-tuning of important biological functions.

  • Perspectives on Glycosylation and Its Congenital Disorders.
    Trends in Genetics, 2018
    Co-Authors: Bobby G. Ng, Hudson H. Freeze
    Abstract:

    Congenital Disorders of glycosylation (CDG) are a rapidly expanding group of metabolic Disorders that result from abnormal protein or lipid glycosylation. They are often difficult to clinically diagnose because they broadly affect many organs and functions and lack clinical uniformity. However, recent technological advances in next-generation sequencing have revealed a treasure trove of new genetic Disorders, expanded the knowledge of known Disorders, and showed a critical role in infectious diseases. More comprehensive genetic tools specifically tailored for mammalian cell-based models have revealed a critical role for glycosylation in pathogen–host interactions, while also identifying new CDG susceptibility genes. We highlight recent advancements that have resulted in a better understanding of human glycosylation Disorders, perspectives for potential future therapies, and mysteries for which we continue to seek new insights and solutions.

  • mitotic intragenic recombination a mechanism of survival for several Congenital Disorders of glycosylation
    American Journal of Human Genetics, 2016
    Co-Authors: Megan S Kane, Hudson H. Freeze, Mariska Davids, Christopher S Adams, Lynne A Wolfe, Helen Winghong Cheung, Andrea L Gropman, Yan Huang, David R Adams, William A Gahl
    Abstract:

    Congenital Disorders of glycosylation (CDGs) are Disorders of abnormal protein glycosylation that affect multiple organ systems. Because most CDGs have been described in only a few individuals, our understanding of the associated phenotypes and the mechanisms of individual survival are limited. In the process of studying two siblings, aged 6 and 11 years, with MOGS-CDG and biallelic MOGS (mannosyl-oligosaccharide glucosidase) mutations (GenBank: NM_006302.2; c.[65C>A; 329G>A] p.[Ala22Glu; Arg110His]; c.[370C>T] p.[Gln124(∗)]), we noted that their survival was much longer than the previous report of MOGS-CDG, in a child who died at 74 days of age. Upon mutation analysis, we detected multiple MOGS genotypes including wild-type alleles in their cultured fibroblast and peripheral blood DNA. Further analysis of DNA from cultured fibroblasts of six individuals with compound heterozygous mutations of PMM2 (PMM2-CDG), MPI (MPI-CDG), ALG3 (ALG3-CDG), ALG12 (ALG12-CDG), DPAGT1 (DPAGT1-CDG), and ALG1 (ALG1-CDG) also identified multiple genotypes including wild-type alleles for each. Droplet digital PCR showed a ratio of nearly 1:1 wild-type to mutant alleles for most, but not all, mutations. This suggests that mitotic recombination contributes to the survival and the variable expressivity of individuals with compound heterozygous CDGs. This also provides an explanation for prior observations of a reduced frequency of homozygous mutations and might contribute to increased levels of residual enzyme activity in cultured fibroblasts of individuals with MPI- and PMM2-CDGs.

  • A zebrafish model of Congenital Disorders of glycosylation with phosphomannose isomerase deficiency reveals an early opportunity for corrective mannose supplementation
    The Company of Biologists, 2013
    Co-Authors: Jaime Chu, Hudson H. Freeze, Alexander Mir, Ningguo Gao, Sabrina Rosa, Christopher Monson, Vandana Sharma, Richard Steet, Mark A. Lehrman, Kirsten C. Sadler
    Abstract:

    SUMMARY Individuals with Congenital Disorders of glycosylation (CDG) have recessive mutations in genes required for protein N-glycosylation, resulting in multi-systemic disease. Despite the well-characterized biochemical consequences in these individuals, the underlying cellular defects that contribute to CDG are not well understood. Synthesis of the lipid-linked oligosaccharide (LLO), which serves as the sugar donor for the N-glycosylation of secretory proteins, requires conversion of fructose-6-phosphate to mannose-6-phosphate via the phosphomannose isomerase (MPI) enzyme. Individuals who are deficient in MPI present with bleeding, diarrhea, edema, gastrointestinal bleeding and liver fibrosis. MPI-CDG patients can be treated with oral mannose supplements, which is converted to mannose-6-phosphate through a minor complementary metabolic pathway, restoring protein glycosylation and ameliorating most symptoms, although liver disease continues to progress. Because Mpi deletion in mice causes early embryonic lethality and thus is difficult to study, we used zebrafish to establish a model of MPI-CDG. We used a morpholino to block mpi mRNA translation and established a concentration that consistently yielded 13% residual Mpi enzyme activity at 4 days post-fertilization (dpf), which is within the range of MPI activity detected in fibroblasts from MPI-CDG patients. Fluorophore-assisted carbohydrate electrophoresis detected decreased LLO and N-glycans in mpi morphants. These deficiencies resulted in 50% embryonic lethality by 4 dpf. Multi-systemic abnormalities, including small eyes, dysmorphic jaws, pericardial edema, a small liver and curled tails, occurred in 82% of the surviving larvae. Importantly, these phenotypes could be rescued with mannose supplementation. Thus, parallel processes in fish and humans contribute to the phenotypes caused by Mpi depletion. Interestingly, mannose was only effective if provided prior to 24 hpf. These data provide insight into treatment efficacy and the broader molecular and developmental abnormalities that contribute to Disorders associated with defective protein glycosylation

  • targeted polymerase chain reaction based enrichment and next generation sequencing for diagnostic testing of Congenital Disorders of glycosylation
    Genetics in Medicine, 2011
    Co-Authors: Melanie A. Jones, Hudson H. Freeze, Shruti Bhide, Ephrem L H Chin, Devin Rhodenizer, Victor W Zhang, Jessica J Sun, Alice K Tanner, Madhuri Hegde
    Abstract:

    Purpose:Congenital Disorders of glycosylation are a heterogeneous group of Disorders caused by deficient glycosylation, primarily affecting the N-linked pathway. It is estimated that more than 40% of Congenital Disorders of glycosylation patients lack a confirmatory molecular diagnosis. The purpose