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Therapeutic approaches in Congenital Disorders of Glycosylation (CDG) involving N-linked glycosylation: an update.

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.

SUBMITTER: Verheijen J

PROVIDER: S-EPMC8720509 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Nutritional Therapies in Congenital Disorders of Glycosylation (CDG).

Project description: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.

| S-EPMC5707694 | biostudies-literature

Expression data from Congenital disorders of Glycosylation type-1 patients (CDG-I)

2008-07-11 | GSE8440 | GEO

Systematic Review: Drug Repositioning for Congenital Disorders of Glycosylation (CDG).

Project description:Advances in research have boosted therapy development for congenital disorders of glycosylation (CDG), a group of rare genetic disorders affecting protein and lipid glycosylation and glycosylphosphatidylinositol anchor biosynthesis. The (re)use of known drugs for novel medical purposes, known as drug repositioning, is growing for both common and rare disorders. The latest innovation concerns the rational search for repositioned molecules which also benefits from artificial intelligence (AI). Compared to traditional methods, drug repositioning accelerates the overall drug discovery process while saving costs. This is particularly valuable for rare diseases. AI tools have proven their worth in diagnosis, in disease classification and characterization, and ultimately in therapy discovery in rare diseases. The availability of biomarkers and reliable disease models is critical for research and development of new drugs, especially for rare and heterogeneous diseases such as CDG. This work reviews the literature related to repositioned drugs for CDG, discovered by serendipity or through a systemic approach. Recent advances in biomarkers and disease models are also outlined as well as stakeholders' views on AI for therapy discovery in CDG.

| S-EPMC9369176 | biostudies-literature

Transcription profiling of human congenital disorders of Glycosylation type-1 patients (CDG-I)

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

Identification of four novel PMM2 mutations in congenital disorders of glycosylation (CDG) Ia French patients.

Project description:We screened 11 unrelated French patients with congenital disorders of glycosylation (CDG) Ia for PMM2 mutations. Twenty one missense mutations on the 22 chromosomes (95%) including four novel mutations were identified: C9Y (G26A) in exon 1, L32R (TA95GC) in exon 2, and T226S (C677G) and C241S (G722C) in exon 8. We studied the PMM activity of these four novel mutant proteins and of the R141H mutant protein in an E coli expression system. The T226S, C9Y, L32R, and C241S mutant proteins have decreased specific activity (23 to 41% of normal), are all more or less thermolabile, and R141H has no detectable activity. Our results indicate that the new mutations identified here are less severe than the inactive R141H mutant protein, conferring residual PMM activity compatible with life.

| S-EPMC1734666 | biostudies-other

New Insights into Immunological Involvement in Congenital Disorders of Glycosylation (CDG) from a People-Centric Approach.

Project description:Congenital disorders of glycosylation (CDG) are rare diseases with variable phenotypes and severity. Immunological involvement remains a largely uncharted topic in CDG, mainly due to lack of robust data. To better characterize immune-related manifestations' prevalence, relevance, and quality-of-life (QoL) impact, we developed electronic questionnaires targeting (1) CDG patients and (2) the general "healthy" population. Two-hundred and nine CDG patients/caregivers and 349 healthy participants were included in this study. PMM2-CDG was the most represented CDG (n = 122/209). About half of these participants (n = 65/122) described relevant infections with a noteworthy prevalence of those affecting the gastrointestinal tract (GI) (63.1%, n = 41/65). Infection burden and QoL impact were shown as infections correlated with more severe clinical phenotypes and with a set of relevant non-immune PMM2-CDG signs. Autoimmune diseases had only a marginal presence in PMM2-CDG (2.5%, n = 3/122), all being GI-related. Allergy prevalence was also low in PMM2-CDG (33%, n = 41/122) except for food allergies (26.8%, n = 11/41, of PMM2-CDG and 10.8%, n = 17/158, of controls). High vaccination compliance with greater perceived ineffectiveness (28.3%, n = 17/60) and more severe adverse reactions were described in PMM2-CDG. This people-centric approach not only confirmed literature findings, but created new insights into immunological involvement in CDG, namely by highlighting the possible link between the immune and GI systems in PMM2-CDG. Finally, our results emphasized the importance of patient/caregiver knowledge and raised several red flags about immunological management.

| S-EPMC7408855 | biostudies-literature

Translational balancing questioned: Unaltered glycosylation during disulfiram treatment in mannosyl-oligosaccharide alpha-1,2-mannnosidase-congenital disorders of glycosylation (MAN1B1-CDG).

Project description:MAN1B1-CDG is a multisystem disorder caused by mutations in MAN1B1, encoding the endoplasmic reticulum mannosyl-oligosaccharide alpha-1,2-mannnosidase. A defect leads to dysfunction within the degradation of misfolded glycoproteins. We present two additional patients with MAN1B1-CDG and a resulting defect in endoplasmic reticulum-associated protein degradation. One patient (P2) is carrying the previously undescribed p.E663K mutation. A therapeutic trial in patient 1 (P1) using disulfiram with the rationale to generate an attenuation of translation and thus a balanced, restored ER glycoprotein synthesis failed. No improvement of the transferrin glycosylation profile was seen.

| S-EPMC8260486 | biostudies-literature

Congenital disorders of glycosylation.

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.

| S-EPMC6331365 | biostudies-literature

Prepubertal growth in congenital disorder of glycosylation type Ia (CDG-Ia).

Project description:AIMS: To delineate the pattern of growth in prepubertal children with congenital disorder of glycosylation type Ia (CDG-Ia) in order to identify critical period(s) and possible cause(s) of growth failure. METHODS: Longitudinal measurements of weight, length/height, and head circumference from birth to 10 years of age in 25 CDG-Ia patients with the R141H/F119L PMM2 genotype were analysed. The data and derived body mass indices (BMI) were compared with standards and expressed as standard deviation scores (SDS). A linear mixed effects model was fitted to each set of data, and mean curves were estimated. RESULTS: The mean weight SDS decreased from -0.3 at birth to -3.0 at 7 months of age and remained low or increased slightly. The mean length SDS decreased from zero at birth to -2.4 at 7 months of age followed by a slight increase to a maximum of -1.8 SDS at the end of the second year of life. After age 2 the mean length/height SDS decreased again. The mean BMI SDS at birth was -0.7 and declined to a minimum of -2.8 at the end of the second year of life followed by a gradual increase. The mean head circumference SDS declined gradually from 0 at 3 months of age to -1.9 at age 5. CONCLUSION: CDG-Ia patients with the R141H/F119L genotype have normal fetal growth and an immediate postnatal onset of severe growth failure. A notable decline in weight end length SDS takes place during the first seven months of life with no prepubertal catch up.

| S-EPMC1763046 | biostudies-other

A case of fatal Type I congenital disorders of glycosylation (CDG I) associated with low dehydrodolichol diphosphate synthase (DHDDS) activity.

Project description: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.

| S-EPMC4919849 | biostudies-literature

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