bims-meglyc 2024-12-08 papers

Issue of 2024–12–08
three papers selected by
Silvia Radenkovic, UMC Utrecht

Mass Spectrom (Tokyo). 2024 ;13(1): A0159

Quantitative Assessment of Core Fucosylation for Congenital Disorders of Glycosylation.

Congenital disorders of glycosylation (CDG) include a group of diseases characterized by defects of N-glycan fucosylation. The analytical molecule of choice for the diagnosis of CDG affecting N-glycosylation is serum transferrin: approximately 10% of the glycans attached to transferrin are fucosylated via an α1,6 linkage at the innermost N-acetylglucosamine residue, termed "core fucosylation." Isoelectric focusing (IEF) of transferrin is often used for diagnosis, but IEF is ineffective in detecting abnormal fucosylation. Here, we present mass spectrometry (MS) methods for detecting fucosylation disorders. First, the level of core fucosylation of the glycan attached to Asn630 of transferrin can be measured by the signal intensity ratio of tryptic peptide ions containing fucosylated and nonfucosylated biantennary oligosaccharides. The core fucosylation level at this glycosylation site in the 0- to 32-year-old group (n = 68) was 7.9 ± 1.7 (%, mean ± SD), and nearly null for SLC35C1-CDG caused by defects in the GDP-fucose transporter. More simply, fucosylation levels can be measured by quadrupole time-of-flight (QTOF) MS of intact transferrin. The fucosylation levels of intact transferrin measured by MS with a Q-mass analyzer, which is currently used as an instrumental standard for newborn screening for inborn errors of metabolism and has a lower resolution than the QTOF analyzer, correlated well with the values obtained by glycopeptide analysis. These methods, namely the analysis of glycopeptides or intact transferrin by Q MS, can also be used on dried blood spots and are expected to help facilitate the diagnosis of CDG affecting N-glycan fucosylation.

Keywords: CDG; core fucose; diagnosis; fucosylation; transferrin

DOI: https://doi.org/10.5702/massspectrometry.A0159

J Inherit Metab Dis. 2024 Dec 05.

Clinical severity and cardiac phenotype in phosphomannomutase 2-congenital disorders of glycosylation : Insights into genetics and management recommendations.

Cardiac involvement (CI) in phosphomannomutase 2-congenital disorders of glycosylation (PMM2-CDG) is part of the multisystemic presentation contributing to high mortality rates. The most common cardiac manifestations are pericardial effusion, cardiomyopathy, and structural heart defects. A genotype-phenotype correlation with organ involvement has not yet been described. We analyzed clinical, biochemical, and molecular genetic data of 222 patients from eight European centers and characterized the natural course of patients with CI. Fifty-seven patients (45 children) presented with CI, of whom 24 died (median age 21 months, standard deviation 49.8). Pericardial effusion was the most frequent manifestation (55.4%), occurring mostly within the first 6 months of life. The most common pathogenic variants in patients with CI were p.(Arg141His) in 74%, followed by p.(Val231Met) in 36%, which is 3.5 times higher than in PMM2-CDG patients without CI (p < 0.0001). Twenty-one out of 36 patients with p.(Val231Met) had CI; among them, 15 died, compared to 33 out of 166 patients without p.(Val231Met) who had CI (p < 0.0001). Nine out of 33 patients died (p = 0.0015), indicating greater clinical severity. Furthermore, the p.(Val231Met) variant is predominant in Eastern Europe, suggesting a founder effect. Cardiac complications in PMM2-CDG patients are common and serious. The variant p.(Val231Met) profoundly influences the extent of CI and mortality rates. Therefore, we recommend cardiac surveillance be included in the follow-up protocols for PMM2-CDG.

Keywords: CDG; PMM2; cardiac involvement; p.(Val231Met) genotype–phenotype correlations; pericardial effusion

DOI: https://doi.org/10.1002/jimd.12826

Am J Med Genet A. 2024 Dec 06. e63962

CHIME Syndrome in a Child With Homozygous PIGL p.Leu167Pro Variant.

Eszter Sara Arany, David Zocche, Jemima E Mellerio, Muriel Holder-Espinasse, Jan Cobben.

CHIME syndrome is a variable condition characterized by ichthyosiform dermatosis, accompanied by intellectual disability, ocular colobomas, ear anomalies, and heart defects. It is an autosomal recessive condition caused by biallelic pathogenic variants in the PIGL gene. Until now, all reports of individuals affected with CHIME syndrome showed the PIGL c.500T>C p.Leu167Pro DNA variant on one allele of the PIGL gene, in combination with another PIGL DNA variant on the other allele. This has led to the hypothesis that the p.Leu167Pro variant determines to a mild phenotypic effect only and that the core phenotype is determined by the second PIGL DNA variant. We report the first individual with CHIME syndrome, a 6-year-old girl, with homozygous PIGL p.Leu167Pro variants, defusing this hypothesis as she is not mildly affected. As CHIME is a very rare condition, it is expected that a significant proportion of cases will be due to homozygous gene variants, especially of founder DNA variants, and offspring of consanguineous parents. We speculate that the lack of homozygous p.Leu167Pro DNA variants so far has been due to chance and that other homozygous cases will be identified in future reports of affected individuals.

Keywords: CHIME syndrome; PIGL; congenital disorder of glycosylation; ichthyosiform dermatosis; neuroectodermal dysplasia

DOI: https://doi.org/10.1002/ajmg.a.63962