Platelets and Defective N-Glycosylation

N-glycans are covalently linked to an asparagine residue in a simple acceptor sequence of proteins, called a sequon. This modification is important for protein folding, enhancing thermodynamic stability, and decreasing abnormal protein aggregation within the endoplasmic reticulum (ER), for the lifetime and for the subcellular localization of proteins besides other functions. Hypoglycosylation is the hallmark of a group of rare genetic diseases called congenital disorders of glycosylation (CDG). These diseases are due to defects in glycan synthesis, processing, and attachment to proteins and lipids, thereby modifying signaling functions and metabolic pathways. Defects in N-glycosylation and O-glycosylation constitute the largest CDG groups. Clotting and anticlotting factor defects as well as a tendency to thrombosis or bleeding have been described in CDG patients. However, N-glycosylation of platelet proteins has been poorly investigated in CDG. In this review, we highlight normal and deficient N-glycosylation of platelet-derived molecules and discuss the involvement of platelets in the congenital disorders of N-glycosylation.

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A Novel Homozygous ALG12 Mutation in a Patient with CDG Type Ig: New Report of a Case with a Mild Phenotype

Molecular Syndromology ◽

10.1159/000516606 ◽

2021 ◽

pp. 1-6

Author(s):

Antonio Gennaro Nicotera ◽

Giulia Spoto ◽

Francesco Calì ◽

Giusi Romeo ◽

Antonino Musumeci ◽

...

Keyword(s):

Autosomal Recessive ◽

Autosomal Dominant ◽

Genetic Diseases ◽

Failure To Thrive ◽

Congenital Disorders ◽

Homozygous Mutation ◽

Congenital Disorders Of Glycosylation ◽

Mild Phenotype ◽

Dysmorphic Features ◽

Rare Genetic Diseases

Congenital disorders of glycosylation (CDG) are a group of rare genetic diseases caused by the deficiency of enzymes involved in the biosynthesis or remodeling of the glycan moieties of glycoconjugates. Most of CDG are autosomal recessive; however, few of them show autosomal dominant or X-linked inheritance. ALG12-CDG is an autosomal recessive inherited defect caused by a deficiency in the α-mannosyltransferase, dolichyl-P-mannose: Man7-GlcNAc-2-PP-dolichyl-alpha-6-mannosyltransferase (mannosyltransferase 8), which determines Man7GlcNAc2-PP-dolichol accumulation in tissues including fibroblasts. The clinical features of ALG12-CDG include dysmorphic features, developmental delay, hypotonia, progressive microcephaly, hypogammaglobulinemia, coagulopathies, and failure to thrive. Herein, we describe the case of a Sicilian patient with a milder phenotype bearing an <i>ALG12</i> homozygous mutation. To date, including this patient, only 16 cases have been described with this form of CDG. Furthermore, our study contributes to understanding the milder ALG12-CDG cases and to further expanding the genotype-phenotype spectrum.

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Prevalence of Congenital Disorders of Glycosylation in Childhood Epilepsy and Effects of Anti-Epileptic Drugs on the Transferrin Isoelectric Focusing Test

Genes ◽

10.3390/genes12081227 ◽

2021 ◽

Vol 12 (8) ◽

pp. 1227

Author(s):

Grace Silver ◽

Shalini Bahl ◽

Dawn Cordeiro ◽

Abhinav Thakral ◽

Taryn Athey ◽

...

Keyword(s):

Isoelectric Focusing ◽

Statistical Tests ◽

Genetic Diseases ◽

Cost Effective ◽

Congenital Disorders ◽

Childhood Epilepsy ◽

Congenital Disorders Of Glycosylation ◽

Exact Test ◽

Liver Functions ◽

Effective Diagnosis

Introduction: Childhood epilepsy is one of the most common neurological problems. The transferrin isoelectric focusing (TIEF) test is a screening test for congenital disorders of glycosylation (CDG). We identified abnormal TIEF test in children with epilepsy in our epilepsy genetics clinic. To determine if an abnormal TIEF test is associated with anti-epileptic medications or abnormal liver functions, we performed a retrospective cohort study. Methods: This study was performed between January 2012 and March 2020. Electronic patient charts were reviewed. Standard non-parametric statistical tests were applied using R statistical software. Fischer’s exact test was used for comparisons. Results: There were 206 patients. The TIEF test was abnormal in 11% (23 out of 206) of the patients. Nine patients were diagnosed with CDG: PMM2-CDG (n = 5), ALG3-CDG (n = 1), ALG11-CDG (n = 2), SLC35A2-CDG (n = 1). We report 51 different genetic diseases in 84 patients. Two groups, (1) abnormal TIEF test; (2) normal TIEF test, showed statistically significant differences for abnormal liver functions and for valproic acid treatment. Conclusion: The TIEF test guided CDG diagnosis in 2.9% of the patients. Due to the high prevalence of CDG (4.4%) in childhood epilepsy, the TIEF test might be included into the diagnostic investigations to allow earlier and cost-effective diagnosis.

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Faculty Opinions recommendation of Gene identification in the congenital disorders of glycosylation type I by whole-exome sequencing.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717956777.793461365 ◽

2012 ◽

Author(s):

Jane Hewitt

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Gene Identification ◽

Congenital Disorders ◽

Type I ◽

Congenital Disorders Of Glycosylation ◽

Whole Exome

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Considerations for Home-Based Treatment of Fabry Disease in Poland during the COVID-19 Pandemic and Beyond

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18168242 ◽

2021 ◽

Vol 18 (16) ◽

pp. 8242

Author(s):

Michał Nowicki ◽

Stanisława Bazan-Socha ◽

Mariusz Kłopotowski ◽

Beata Błażejewska-Hyżorek ◽

Mariusz Kusztal ◽

...

Keyword(s):

Fabry Disease ◽

Genetic Diseases ◽

Healthcare Providers ◽

Treatment Programs ◽

Current Therapy ◽

Term Care ◽

Pharmacological Chaperone ◽

Enzyme Replacement ◽

Home Based ◽

Rare Genetic Diseases

Current therapy for Anderson–Fabry disease in Poland includes hospital or clinic-based intravenous enzyme replacement therapy with recombinant agalsidase alpha or beta, or oral pharmacological chaperone therapy with migalastat. Some countries around the world offer such treatment to patients in the comfort of their own homes. The 2020–2021 COVID-19 pandemic has pushed global healthcare providers to evolve their services so as to minimize the risk of COVID-19 exposure to both patients and providers; this has led to advances in telemedicine services and the increasing availability of at-home treatment for various procedures including parenteral drug administration. A total of 80% of surveyed Anderson–Fabry disease patients in Poland would prefer home-based treatment, which would be a safe and convenient alternative to clinic-based treatment if patient selection is based on our proposed algorithm. Our recommendations for home-based treatments appear feasible for the long term care of Anderson–Fabry disease patients during the COVID-19 pandemic and beyond. This may also serve as a basis for home-based treatment programs in other rare and ultra-rare genetic diseases.

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Congenital disorders of glycosylation in children - histopathological and ultrastructural changes in the liver

Pediatrics & Neonatology ◽

10.1016/j.pedneo.2021.01.017 ◽

2021 ◽

Author(s):

Patryk Lipiński ◽

Joanna Cielecka-Kuszyk ◽

Elżbieta Czarnowska ◽

Anna Bogdańska ◽

Piotr Socha ◽

...

Keyword(s):

Ultrastructural Changes ◽

Congenital Disorders ◽

Congenital Disorders Of Glycosylation

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Capillary zone electrophoresis of transferrin and EDTA samples in congenital disorders of glycosylation screening: CaNOt do, really?

Clinica Chimica Acta ◽

10.1016/j.cca.2021.04.013 ◽

2021 ◽

Vol 519 ◽

pp. 92-93

Author(s):

Alexandre Raynor ◽

Célia Raulet-Bussian ◽

Léa Verel ◽

Grégory Plouviez ◽

Arnaud Bruneel

Keyword(s):

Capillary Zone Electrophoresis ◽

Congenital Disorders ◽

Congenital Disorders Of Glycosylation ◽

Zone Electrophoresis ◽

Capillary Zone

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TRIM32 and Malin in Neurological and Neuromuscular Rare Diseases

Cells ◽

10.3390/cells10040820 ◽

2021 ◽

Vol 10 (4) ◽

pp. 820

Author(s):

Lorena Kumarasinghe ◽

Lu Xiong ◽

Maria Adelaida Garcia-Gimeno ◽

Elisa Lazzari ◽

Pascual Sanz ◽

...

Keyword(s):

Common Ancestor ◽

Genetic Diseases ◽

Ubiquitin Ligases ◽

E3 Ubiquitin Ligases ◽

Lafora Disease ◽

C Terminus ◽

Rare Genetic Diseases ◽

Tripartite Motif ◽

Trim Proteins ◽

Ring E3

Tripartite motif (TRIM) proteins are RING E3 ubiquitin ligases defined by a shared domain structure. Several of them are implicated in rare genetic diseases, and mutations in TRIM32 and TRIM-like malin are associated with Limb-Girdle Muscular Dystrophy R8 and Lafora disease, respectively. These two proteins are evolutionary related, share a common ancestor, and both display NHL repeats at their C-terminus. Here, we revmniew the function of these two related E3 ubiquitin ligases discussing their intrinsic and possible common pathophysiological pathways.

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