bims-meglyc 2024-11-03 papers

Issue of 2024–11–03
three papers selected by
Silvia Radenkovic, UMC Utrecht

Orphanet J Rare Dis. 2024 Nov 01. 19(1): 407

Mapping the diagnostic odyssey of congenital disorders of glycosylation (CDG): insights from the community.

Pedro Granjo, Carlota Pascoal, Diana Gallego, Rita Francisco, Jaak Jaeken, Tristen Moors, Andrew C Edmondson, Kristin A Kantautas, Mercedes Serrano, Paula A Videira, Vanessa Dos Reis Ferreira.

BACKGROUND: Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases with heterogeneous presentations, leading to substantial diagnostic challenges, which are poorly understood. Therefore, this study aims to elucidate this diagnostic journey by examining families' and professionals' experiences.
RESULTS AND DISCUSSION: A questionnaire was designed for CDG families and professionals, garnering 160 and 35 responses, respectively. Analysis revealed the lack of seizures as a distinctive feature between PMM2-CDG (11.2%) with Other CDG (57.7%) at symptom onset. Hypotonia and developmental disability were prevalent symptoms across all studied CDG. Feeding problems were identified as an early onset symptom in PMM2-CDG (Cramer's V (V) = 0.30, False Discovery Rate (FDR) = 3.8 × 10- 9), and hypotonia in all studied CDG (V = 0.34, FDR = 7.0 × 10- 3). The average time to diagnosis has decreased in recent years (now ~ 3.9 years), due to advancements namely the increased use of whole genome and exome sequencing. However, misdiagnoses remain prevalent (PMM2-CDG - 44.9%, non-PMM2-CDG - 64.8%). To address these challenges, we propose adapting medical training to increase awareness of CDG and other rare diseases, ongoing education for physicians, the development of educational resources for relevant medical units, and empowerment of families through patient organizations and support networks.
CONCLUSION: This study emphasizes the crucial role of community-centered research, and the insights families can offer to enhance CDG management. By pinpointing existing gaps and needs, our findings can inform targeted interventions and support systems to improve the lives of those impacted by CDG.

Keywords: Community-centered research; Congenital disorders of glycosylation (CDG); Diagnostic odyssey journey; Patient journey; Rare diseases

DOI: https://doi.org/10.1186/s13023-024-03389-2

PLoS Genet. 2024 Oct 28. 20(10): e1011458

A drug repurposing screen reveals dopamine signaling as a critical pathway underlying potential therapeutics for the rare disease DPAGT1-CDG.

Hans M Dalton, Naomi J Young, Alexys R Berman, Heather D Evans, Sydney J Peterson, Kaylee A Patterson, Clement Y Chow.

DPAGT1-CDG is a Congenital Disorder of Glycosylation (CDG) that lacks effective therapies. It is caused by mutations in the gene DPAGT1 which encodes the first enzyme in N-linked glycosylation. We used a Drosophila rough eye model of DPAGT1-CDG with an improperly developed, small eye phenotype. We performed a drug repurposing screen on this model using 1,520 small molecules that are 98% FDA/EMA-approved to find drugs that improved its eye. We identified 42 candidate drugs that improved the DPAGT1-CDG model. Notably from this screen, we found that pharmacological and genetic inhibition of the dopamine D2 receptor partially rescued the DPAGT1-CDG model. Loss of both dopamine synthesis and recycling partially rescued the model, suggesting that dopaminergic flux and subsequent binding to D2 receptors is detrimental under DPAGT1 deficiency. This links dopamine signaling to N-glycosylation and represents a new potential therapeutic target for treating DPAGT1-CDG. We also genetically validate other top drug categories including acetylcholine-related drugs, COX inhibitors, and an inhibitor of NKCC1. These drugs and subsequent analyses reveal novel biology in DPAGT1 mechanisms, and they may represent new therapeutic options for DPAGT1-CDG.

DOI: https://doi.org/10.1371/journal.pgen.1011458

Biochemistry. 2024 Oct 30.

Sugar Highs: Recent Notable Breakthroughs in Glycobiology.

Jimin Hu, Duc T Huynh, Michael Boyce.

Glycosylation is biochemically complex and functionally critical to a wide range of processes and disease states, making it a vibrant area of contemporary research. Here, we highlight a selection of notable recent advances in the glycobiology of SARS-CoV-2 infection and immunity, cancer biology and immunotherapy, and newly discovered glycosylated RNAs. Together, these studies illustrate the significance of glycosylation in normal biology and the great promise of manipulating glycosylation for therapeutic benefit in disease.

DOI: https://doi.org/10.1021/acs.biochem.4c00418