Congenital disorders of glycosylation type I leads to altered processing of N-linked glycans, as well as underglycosylation.
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ABSTRACT:
SUBMITTER: Mills P
PROVIDER: S-EPMC1222142 | biostudies-other | 2001 Oct
REPOSITORIES: biostudies-other
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Project description: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.
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Project description:Congenital disorders of glycosylation are a genetically and clinically heterogeneous group of >130 diseases caused by defects in various steps along glycan modification pathways. The vast majority of these monogenic diseases are autosomal recessive and have multi-systemic manifestations, mainly growth failure, developmental delay, facial dysmorphisms, and variable coagulation and endocrine abnormalities. Carbohydrate deficient transferrin (CDT) and protein-linked glycan analysis with mass spectrometry can diagnose some subtypes of congenital disorders of glycosylation (CDG), while many currently rely on massively parallel genomic sequencing for diagnosis. Early detection is important, as a few of these disorders are treatable. Molecular and biochemical techniques continue to further our understanding of this rapidly expanding group of clinically and genetically diverse disorders.
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Project description:Disruption of N-linked glycosylation has a broad impact on proper glycosylation of nascent glycoproteins in the endoplasmic reticulum, which affect multiple signalling pathways( by changing the stability of membrane proteins or the signalling ability of membrane receptors) and may be responsible of the fibrotic stage associated to CDG type-I. We used microarrays to characterize the global changes in gene expression in three distinct groups of CDG-I patients and we identified a common perturbation in the expression of genes encoding for proteins involved in the stress as well as in the fibrotic responses. Keywords: disease state analysis
2008-07-11 | GSE8440 | GEO
Project description:Congenital disorders of glycosylation (CDG) form a group of metabolic disorders caused by deficient glycosylation of proteins and/or lipids. Isoelectric focusing (IEF) of serum transferrin is the most common screening method to detect abnormalities of protein N-glycosylation. On the basis of the IEF profile, patients can be grouped into CDG type I or CDG type II. Several protein variants of transferrin are known that result in a shift in isoelectric point (pI). In some cases, these protein variants co-migrate with transferrin glycoforms, which complicates interpretation. In two patients with abnormal serum transferrin IEF profiles, neuraminidase digestion and subsequent IEF showed profiles suggestive of the diagnosis of CDG type I. Mass spectrometry of tryptic peptides of immunopurified transferrin, however, revealed a novel mutation at the N-glycan attachment site. In case 1, a peptide with mutation p.Asn630Thr in the 2nd glycosylation site was identified, resulting in an additional band at disialotransferrin position on IEF. After neuraminidase digestion, a single band was found at the asialotransferrin position, indistinguishable from CDG type I patients. In case 2, a peptide with mutation p.Asn432His was found. These results show the use of mass spectrometry of transferrin peptides in the diagnostic track of CDG type I.
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Project description:Disruption of N-linked glycosylation has a broad impact on proper glycosylation of nascent glycoproteins in the endoplasmic reticulum, which affect multiple signalling pathways( by changing the stability of membrane proteins or the signalling ability of membrane receptors) and may be responsible of the fibrotic stage associated to CDG type-I. We used microarrays to characterize the global changes in gene expression in three distinct groups of CDG-I patients and we identified a common perturbation in the expression of genes encoding for proteins involved in the stress as well as in the fibrotic responses. Experiment Overall Design: Primary fibroblasts, obtained from forearm skin biopsies of healthy control subjects and three distinct groups of CDG-I patients, were cultured in F12 DMEM supplemented with 4.5 g/l glucose and 10% fetal calf serum prior to RNA extraction and Hybridization on human HG 133 A Affymetrix Microarrays. To avoid bias related to the analysis of a specific CDG-I type or to a specific individual expression pattern, we have considered three patients for the CDG-Ic and -Ie group and two patients for the CDG-Ig group. Moreover the total RNA was extracted from three different independent biological replicates.
2008-10-18 | E-GEOD-8440 | biostudies-arrayexpress
Project description:Congenital disorders of glycosylation (CDG) are a group of metabolic disorders caused by deficient protein glycosylation. PMM2-CDG, the most common CDG, is caused by phosphomannomutase (PMM) deficiency. Clinical symptoms often include neurological involvement in addition to dysmorphic features, failure to thrive, cardiac failure, renal, and endocrine abnormalities. To our knowledge, lymphatic edema in CDG has not been reported. We present two cases of lymphatic edema in PMM2-CDG patients. The first patient was noted to have a larger right leg circumference at two years. Ultrasound investigations did not reveal any obvious vascular or lymphatic malformation. The swelling increased in size over time. At 12 years, lymphoscintigraphy revealed decreased lymphatic draining in both legs, which was more profound in the right leg. The second patient was treated for pulmonary stenosis at age 2 months. Postoperative, the patient suffered from protein-losing enteropathy, hypothyroidism, recurrent bacterial infections, and bilateral lymphatic edema. General condition improved after thyroxin treatment and albumin infusions; however, the bilateral pedal and leg edema remained unresolved. Contrast studies of the lymphatic system showed bilateral hypoplasia distal to the knees. Although both children had secondary factors worsening lymphatic edema in PMM2-CDG, hypoalbuminemia, recurrent infections, cardiac failure, and endocrine abnormalities could not fully explain the clinical features. The additional factors were treated successfully but the therapy did not resolve the lymphatic edema. Based on the abnormal imaging studies of the lymphatic system, we propose that lymphatic vessel hypoplasia is the major cause for lymphatic edema in our patients with PMM2-CDG.
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Project description:Despite 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.
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Project description:A "state of the Art" lecture titled "Hemostatic Defects in Congenital Disorders of Glycosylation" was presented at the ISTH 2022 congress. Congenital disorders of glycosylation (CDGs) are rare, inherited, metabolic diseases. The diagnosis of CDG is often challenging due to the broad variety of disorders, the variable level of severity, and phenotypic heterogeneity. Most CDGs are multisystem disorders, and neurologic involvement is frequent. Patients with CDG often present coagulation abnormalities characterized by low levels of procoagulant or anticoagulant factors. Antithrombin deficiency is frequently associated with factor XI deficiency and less frequently with a protein C, protein S, or factor IX deficiency. This coagulation profile differs from those observed in liver failure, disseminated intravascular coagulation, and vitamin K deficiency, and so, should prompt the physician to consider a diagnosis of CDG. Coagulopathy can lead to thrombotic and/or hemorrhagic complications. In patients with phosphomannomutase 2 deficiency (the most common CDG), thrombotic events are more frequent than hemorrhagic events. In other types of CDGs, both hemorrhagic and thrombotic events have been described. Overall, the hemostatic balance in these patients is precarious and necessitates close monitoring in a setting of acute illness with greater metabolic needs. Here, we review the most relevant hemostatic defects observed in CDG and their clinical implications. Finally, we summarize relevant new data on this topic presented at the ISTH 2022 congress.
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Project description:Congenital disorders of glycosylation (CDG) are a group of hereditary diseases characterised by deficiency of enzymes involved in proteins glycosylation. We describe the clinical case of a neonate with CDG type 1a, nowadays designated phosphomannomutase 2 (PMM2)-CDG. Physical examination showed an abnormal facies, axial hypotonia, abnormal fat distribution, inverted nipples, non-palpable testicles and arachnodactyly. Progressive multiple system organ involvement and worsening of hypertrophic cardiomyopathy occurred. Metabolic study revealed a CDG disturbance, which was confirmed by genetic study. The following mutations were identified: c.193G>T; p.D65Y and c.470T>C; p.F157S. Clinical deterioration was inevitable with multisystemic failure and death. CDG represents a challenge for physicians due to multiple organ involvement, and heterogeneous clinical manifestations. The neonatal form is usually associated with the worst prognosis.
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