bims-meglyc 2023-09-03 papers

Orphanet J Rare Dis. 2023 Aug 29. 18(1): 247

Congenital disorders of glycosylation: narration of a story through its patents.

Maria Monticelli, Tania D'Onofrio, Jaak Jaeken, Eva Morava, Giuseppina Andreotti, Maria Vittoria Cubellis.

Congenital disorders of glycosylation are a group of more than 160 rare genetic defects in protein and lipid glycosylation. Since the first clinical report in 1980 of PMM2-CDG, the most common CDG worldwide, research made great strides, but nearly all of them are still missing a cure. CDG diagnosis has been at a rapid pace since the introduction of whole-exome/whole-genome sequencing as a diagnostic tool. Here, we retrace the history of CDG by analyzing all the patents associated with the topic. To this end, we explored the Espacenet database, extracted a list of patents, and then divided them into three major groups: (1) Drugs/therapeutic approaches for CDG, (2) Drug delivery tools for CDG, (3) Diagnostic tools for CDG. Despite the enormous scientific progress experienced in the last 30 years, diagnostic tools, drugs, and biomarkers are still urgently needed.

Keywords: CDG; Congenital disorder(s) of glycosylation; Diagnosis; Drug Discovery; Intellectual property; Patent; Rare disease

DOI: https://doi.org/10.1186/s13023-023-02852-w

Mol Genet Metab. 2023 Aug 23. pii: S1096-7192(23)00318-9. [Epub ahead of print]140(3): 107688

Defining the phenotype of PGAP3-congenital disorder of glycosylation; a review of 65 cases.

Ruqaiah Altassan, Michael M Allers, Diederik De Graef, Rameen Shah, Maaike de Vries, Austin Larson, Emma Glamuzina, Eva Morava.

Biallelic pathogenic variants in PGAP3 cause a rare glycosylphosphatidyl-inositol biogenesis disorder, PGAP3-CDG. This multisystem condition presents with a predominantly neurological phenotype, including developmental delay, intellectual disability, seizures, and hyperphosphatemia. Here, we summarized the phenotype of sixty-five individuals including six unreported individuals from our CDG natural history study with a confirmed PGAP3-CDG diagnosis. Common additional features found in this disorder included brain malformations, behavioral abnormalities, cleft palate, and characteristic facial features. This report aims to review the genetic and metabolic findings and characterize the disease's phenotype while highlighting the necessary clinical approach to improve the management of this rare CDG.

Keywords: Alkaline phosphatase; GPI-anchor; Glycophosphatidylinositol anchor biogenesis defects; PGAP3; Psychomotor developmental delay

DOI: https://doi.org/10.1016/j.ymgme.2023.107688

J Neurochem. 2023 Aug 31.

Sialic acid biosynthesis pathway blockade disturbs neuronal network formation in human iPSC-derived excitatory neurons.

Rachel Mijdam, Chantal Bijnagte-Schoenmaker, Emma Dyke, Sam J Moons, Thomas J Boltje, Nael Nadif Kasri, Dirk J Lefeber.

N-acetylneuraminic acid (sialic acid) is present in large quantities in the brain and plays a crucial role in brain development, learning, and memory formation. How sialic acid contributes to brain development is not fully understood. The purpose of this study was to determine the effects of reduced sialylation on network formation in human iPSC-derived neurons (iNeurons). Using targeted mass spectrometry and antibody binding, we observed an increase in free sialic acid and polysialic acid during neuronal development, which was disrupted by treatment of iNeurons with a synthetic inhibitor of sialic acid biosynthesis. Sialic acid inhibition disturbed synapse formation and network formation on microelectrode array (MEA), showing short but frequent (network) bursts and an overall lower firing rate, and higher percentage of random spikes. This study shows that sialic acid is necessary for neuronal network formation during human neuronal development and provides a physiologically relevant model to study the role of sialic acid in patient-derived iNeurons.

Keywords: induced pluripotent stem cells; neuronal networks; sialic acid; synapse

DOI: https://doi.org/10.1111/jnc.15934