bims-meglyc 2025-02-23 papers

Issue of 2025–02–23
four papers selected by
Silvia Radenkovic, UMC Utrecht

J Clin Res Pediatr Endocrinol. 2025 Feb 20.

Endocrine Implications of Congenital Disorders of Glycosylation.

Glycosylation, attachment of monosaccharides or glycans to select residues of proteins and lipids, is the most common post-translational modification. Defects among glycoprotein synthesis or modification pathways result in genetically and clinically heterogenous group of metabolic disorders, congenital disorders of glycosylation (CDGs) with an estimated prevalence of 1/10,000. They have multisystem involvement where significant neurologic dysfunction is frequent with variable impairment of other organ functions. Most of the proteins responsible for endocrine homeostasis are essentially glycoproteins so disorders of glycosylation have an impact on hormone secretory pathways, changing hormone and carrier protein stability, circulatory half-live and abundance, alternating receptor configuration, activation, hormone-substrate affinity, resetting endocrine control and feedback loops. Endocrine implications of CDGs are extensive and are described in up to 55% of all patients with CDGs during natural course of the disease. This frequency is increased up to 85% in some CDG subgroups. Impact on growth and growth factors, thyroid hormones, hypothalamo-pituitary-adrenal axis, hypothalamo-pituitary-gonadaxis, glucose metabolism, bone health and prolactin have been reported, yet clinical studies are scarce, and data mostly derived from case series. This review aims to describe up to date data on endocrine implications of CDGs focusing on both preclinical and clinical studies underlining broad spectrum of findings. Clinical and laboratory findings of CDGs and the effect of current treatment strategies on endocrine implications will be briefly discussed.

Keywords: Congenital disorders of glycosylation; adrenal; bone; endocrine; growth; hypogonadism; thyroid

DOI: https://doi.org/10.4274/jcrpe.galenos.2025.2024-10-7

Orphanet J Rare Dis. 2025 Feb 21. 20(1): 81

An ALG12-CDG patient with a novel homozygous intronic mutation associated with low ALG12 mRNA.

Sandrine Vuillaumier-Barrot, Thierry Dupré, Tiffany Andriantsihoarana, Vincent Desportes, David Cheillan, Stuart E H Moore, Isabelle Chantret.

BACKGROUND: Type I Congenital Disorders of Glycosylation (CDG-I) are inherited diseases presenting deficits in protein N-glycosylation involving either the biosynthesis of the lipid-linked oligosaccharide Glc3Man9GlcNAc2-PP-dolichol or transfer of its oligosaccharide to protein.
RESULTS: We describe a patient harbouring hypoglycosylated transferrin, a characteristic of CDG-I. NGS revealed a homozygous RFT1 (c.16G > T p.Val6Leu) variant of unknown significance that is predicted to be benign. Metabolic radiolabelling of the patient's fibroblasts did not reveal the accumulation of truncated Man5GlcNAc2-PP-dolichol expected of RFT1-CDG but rather an accumulation of Man7GlcNAc2-PP-dolichol, characteristic of ALG12-CDG. Revaluation of the NGS data revealed a homozygous (22_50311909A_G, c.-79 + 2 T > C) variant that modifies the second nucleotide of the first intron of the ALG12 gene upstream of the first coding exon (exon 2). Sequencing of ALG12 cDNA revealed a 4-base insertion between exon 1 and exon 2 suggesting a shift in mRNA splicing in this intron to a putative new GU donor site. The patient's fibroblasts display 3% of control ALG12 mRNA levels.
CONCLUSION: This is the first description of a pathogenic intronic ALG12 variant upstream of the first coding exon. The modification of the splicing process between intron 1 and exon 2, the very low transcript level and the absence of other mutations in the patient's ALG12 gene lead us to conclude that this ALG12 variant is a predicted Loss of Function (pLOF) variant.

Keywords: ALG12; Congenital Disorders of Glycosylation; Dolichol-linked-oligosaccharide; Intronic variant; N-Glycosylation; RFT1

DOI: https://doi.org/10.1186/s13023-025-03535-4

Int J Biol Macromol. 2025 Feb 12. pii: S0141-8130(25)01414-X. [Epub ahead of print]305(Pt 1): 140865

Cysteine variants in PMM2 lead to protein instability and higher sensitivity to oxidative stress in PMM2-CDG.

Jingmiao Sun, Ying Zhang, Wei Yu, Haidong Fu, Ningqin Lin, Fan Yu, Xiangjun Chen, Jianhua Mao, Lidan Hu.

PMM2-congenital disorder of glycosylation (PMM2-CDG) is caused by genetic defects in PMM2, the gene encoding phosphomannomutase 2. Effective therapies for this disorder remain elusive. Recent studies emphasize cysteine's vulnerability to oxidative modifications that can instigate disease by facilitating inter-protein disulfide bonding, reducing protein mobility, highlighting its potential as a target for therapeutic intervention. Specifically, five cysteine-related pathogenic mutants have been identified in PMM2-CDG, namely Phe11Cys (F11C), Tyr64Cys (Y64C), Tyr76Cys (Y76C), Tyr106Cys (Y106C) and Gly228Cys (G228C), however the fundamental molecular mechanisms are still not fully understood. In this study, compared to wild-type (WT), Cys pathogenic mutants induced structural destruction, augmented hydrophobic exposure, reduced thermal stability, and a propensity to aggregate at physiological temperatures. Meanwhile, Cys mutants were sensitive to oxidative stress, which in the evident formation of aggregation. Molecular dynamics simulation revealed alterations in the core region and subunit binding free energy of homologous PMM2, instigated by the pathophysiogenic variants. Based on previous articles, we found cysteine pathogenic mutants can be partly rescued by celastrol. In summary, our findings provide critical insights into the molecular and functional impacts of specific cysteine variants in the PMM2 enzyme, offering a foundation for exploring novel therapeutic strategies for the prevention and treatment of PMM2-CDG.

Keywords: Celastrol; Congenital disorders of glycosylation; Cysteine; Phosphomannomutase2; Protein aggregation; Structural stability

DOI: https://doi.org/10.1016/j.ijbiomac.2025.140865

J Neuromuscul Dis. 2024 Dec 20. 22143602241296226

Ultra-Orphan drug development for GNE Myopathy: A synthetic literature review and meta-analysis.

Naoki Suzuki, Madoka Mori-Yoshimura, Ichizo Nishino, Masashi Aoki.

GNE myopathy is an autosomal recessive hereditary muscle disorder that has the following clinical characteristics: develops in early adulthood, gradually progresses from the distal muscles, and is relatively sparing of quadriceps until the advanced stages of the disease. With further progression, patients become non-ambulatory and need a wheelchair. There is growing concern about extra-muscular presentations such as thrombocytopenia, respiratory dysfunction, and sleep apnea syndrome. Pathologically, rimmed vacuoles and tubulofilamentous inclusions are observed in affected muscles. The cause of the disease is thought to be a sialic acid deficiency due to mutations of the GNE gene required for in vivo sialic acid biosynthesis. Sialic acid supplementation to a presymptomatic GNE myopathy mouse model was effective in preventing the development of the disease. Several clinical studies have been conducted to evaluate the safety and efficacy of sialic acid supplementation in humans. Based on the favorable results of these studies, an extended-release aceneuramic acid formulation was approved for treatment of GNE myopathy in Japan in March 2024. It is anticipated that it will be a significant step in the development of an effective treatment for GNE myopathy and other ultra-orphan diseases.

Keywords: GNE myopathy; aceneuramic acid; distal myopathy; drug development; ultra-orphan disease

DOI: https://doi.org/10.1177/22143602241296226