bims-meglyc 2025-04-13 papers

Issue of 2025–04–13
six papers selected by
Silvia Radenkovic, UMC Utrecht

JIMD Rep. 2025 May;66(3): e70011

Clinical and Molecular Features of Patients With Congenital Disorders of Glycosylation in Japan.

Nobuhiko Okamoto, Machiko Kadoya, Yoshinao Wada.

Congenital disorders of glycosylation (CDG) are a heterogeneous group of diseases caused by defects in various steps of the glycosylation pathway. There are over 200 known human glycosylation-related disorders. Many of these defects lead to multisystemic manifestations, commonly involving the central nervous system, with symptoms ranging from mild to severe. The phenotypic presentation of CDG can vary significantly. Identifying altered protein glycosylation is crucial for accurate diagnosis. Our research institute has contributed to the CDG diagnostic support center in Japan, developing new analytical techniques utilizing mass spectrometry. These techniques allow for the identification of defects in N-glycosylation, O-glycosylation, and combined glycosylation pathways. Advances in genetic analysis, including whole exome sequencing, have revealed that certain types of CDG are more prevalent than previously recognized. We have contributed to the molecular diagnosis of 66 CDG patients in Japan. Although PMM2-CDG is the most common form of CDG, it was only detected in 17% of the patients in the present study, suggesting that its incidence is much lower in Japan compared to European countries. We also conducted a comprehensive review of case reports of CDG in Japan, further describing the clinical and molecular spectrum of the disease in this population.

Keywords: ATP6V0A2‐CDG; NGLY1‐CDDG; PMM2‐CDG; SLC35A2‐CDG

DOI: https://doi.org/10.1002/jmd2.70011

Mol Genet Metab Rep. 2024 Dec;41 101162

Mannose phosphate isomerase-congenital disorder of glycosylation leads to asymptomatic hypoglycemia.

Cheng Luo, Danxia Peng, Yanyan Li, Shuping Liu, Qiong Wu, Xuan Xu, Jie Wen.

Background: Mannose phosphate isomerase deficiency-congenital glycosylation disorders (MPI-CDG) is a rare autosomal recessive disorder caused by pathogenic variants in the MPI gene and characterized by digestive, hepatic, and endocrine-related symptoms. Herein, we reported a case of a 4-month-old baby with MPI-CDG confirmed by genetic testing.
Case summary: Based on the age of the child and the present clinical symptoms (feeding difficulties, intractable diarrhea, vomiting, hepatosplenomegaly, recurrent hypoglycemia, coagulation disorder, and hypoproteinemia under the premise of anti-infection therapy), congenital glycosylation disorder was suspected, which was then confirmed by genetic testing. Her father carried a heterozygous deletion variant of exons 1-2 of the MPI gene, while her mother carried a heterozygous variant of C. 422C > T variant. It was suspected that a biallelic pathogenic variant of the MPI gene caused the CDG.
Conclusion: MPI-CDG should be considered in infancy with unexplained hypoglycemia and recurrent digestive and endocrine system involvement. Also, if evident symptoms are present, a gene examination should be performed, as this could speed up the diagnosis assuring timely treatment.

Keywords: Congenital disorders of glycosylation; Hypoglycemia; MPI gene; Mild diarrhea

DOI: https://doi.org/10.1016/j.ymgmr.2024.101162

J Clin Res Pediatr Endocrinol. 2025 Apr 11.

Diagnostic Utility in Next-Generation Sequencing by Implicating CNV Analysis in Eleven Patients with Peters Plus Syndrome: A Single-Center Experience.

Akçahan Akalın, Enise Avcı Durmuşalioğlu, Şervan Özkalkak, Ruken Yıldırım, Veysel Öz, Edip Ünal, Leyla Hazar, Türkan Turkut Tan, Yusuf Can Doğan, Tahir Atik, Özgür Çoğulu, Esra Işık.

Objective: Peters Plus syndrome (PTRPLS) is an autosomal recessive congenital disorder of glycosylation caused by biallelic pathogenic variants in the ß 1,3-glucosyltransferase gene (B3GLCT). To date, homozygous or compound heterozygous splicing, truncating, missense variants, and whole gene deletions have been reported in the B3GLCT gene. This study aims to emphasize the role of small copy number variations (CNVs) in this condition alongside the clinical features of the patients.
Methods: The study included eleven patients from six consanguineous families originating from the same village. Clinical exome sequencing-based CNV analysis was employed across all probands to ascertain the genetic background.
Results: Using GATK-gCNV, we identified a homozygous deletion on chromosome 13q12.3, encompassing 15th exon of the B3GLCT gene. The mean age at admission was 9.6 ± 13.3 years, ranging from 2 months to 41 years. The mean standart deviation (SD) scores for height and weight at admission were -4.4 ± 0.9 and -3.8 ± 1.8, respectively. Ophthalmological abnormalities included corneal haze, anterior synechiae, unilateral leucoma, corneal-lenticular adhesion, glaucoma, and severe visual loss. Patients under the age of five exhibited global developmental delay, while those older than five years demonstrated varying degrees of intellectual disability, with two exceptions exhibiting normal cognitive function.
Conclusion: Our findings underscore the critical role of NGS-based CNV analysis in improving the diagnostic accuracy of PTRPLS. CNVs represent a significant form of genomic variation and should be systematically considered in genetically unresolved Mendelian disorders. Integrating CNV detection algorithms into routine NGS diagnostic workflows has the potential to enhance the identification of pathogenic variants, ultimately facilitating a more comprehensive molecular diagnosis for affected individuals.

Keywords: Copy number variation; Mendelian disorders; Next-generation sequencing; Peters Plus syndrome

DOI: https://doi.org/10.4274/jcrpe.galenos.2025.2025-1-18

Mol Genet Genomic Med. 2025 Apr;13(4): e2442

Sarah Guterman, Agnese Feresin, Lucile Boutaud, Clémence Jacquin, Stanislas Lyonnet, Jean-Pierre Bernard, Claire Colmant, Philippe Roth, Nicolas Bourgon, Pierre Mace, Alice Thoreau, Yves Ville, Joana Bengoa, Zaina Ait Arkoub, Cécile Fourrage, Ferechté Encha-Razavi, Bettina Bessières, Tania Attié-Bitach.

BACKGROUND: CDG2L (MIM#614576) is an autosomal recessive multisystemic disorder due to variants in COG6 gene. Postnatal phenotypes are now well described, while prenatal presentations remain poorly investigated. Only 8 of the 28 published patients have had prenatal ultrasound anomalies reported and no one post-mortem investigation.
METHODS: We used whole-exome sequencing in a consanguineous Turkish family with four siblings presenting with Pierre Robin sequence, arthrogryposis, heart malformation, splenomegaly, hydrocephaly, corpus callosum dysgenesis, brainstem, and cerebellar hypoplasia.
RESULTS: We identified a novel homozygous pathogenic variant in exon 9 of COG6 (NM_020751.2): c.821del, p.(Arg274Lysfs*32). In this family, our post-mortem study led us to describe further the prenatal phenotype of CDG2L. In addition, it permits correlating the most relevant anomalies to a maldevelopmental cascade due to a neurodegenerative process of metabolic origin, affecting the entire central nervous system including the spinal cord.
CONCLUSION: In this context of recurrence of multisystemic disease diagnosed antenatally, exome sequencing is powerful to give a precise diagnosis and allows proposing a molecular prenatal diagnosis at the following pregnancy.

Keywords: arthrogryposis; congenital disorders of glycosylation; corpus callosum; exome sequencing; prenatal ultrasound

DOI: https://doi.org/10.1002/mgg3.2442

J Biol Chem. 2025 Apr 07. pii: S0021-9258(25)00332-1. [Epub ahead of print] 108483

CMP-sialic acid synthetase in Drosophila requires N-glycosylation of a non-canonical site.

Boris Novikov, Devon J Boland, Ilya Mertsalov, Hilary Scott, Saniya Dauletbayeva, Pedro Monagas-Valentin, Vladislav Panin.

Sialylation plays important roles in animals, affecting numerous molecular and cell interactions. In Drosophila, sialylation regulates neural transmission and mediates communication between neurons and glia. Drosophila CMP-sialic acid synthetase (CSAS), a key enzyme of the sialylation pathway, is localized to the Golgi and modified by N-glycosylation, suggesting that this modification can affect CSAS function. Here we tested this hypothesis using in vitro and in vivo approaches. We found that CSAS proteins from divergent Drosophila species have two conserved N-glycosylation sites, including the rarely glycosylated non-canonical N-X-C sequon. We investigated CSAS glycosylation by generating CSAS "glycomutants" lacking glycosylation sites and analyzing them in vivo in transgenic rescue assays. The removal of non-canonical glycosylation significantly decreased CSAS activity, while the canonical site mutation did not affect CSAS function. Although all glycomutants were similarly localized to the Golgi, the non-canonical glycosylation, unlike the canonical one, affected CSAS stability in vivo and in vitro. Our results suggested that CSAS functions as a dimer, which was also supported by protein structure predictions that produced a dimer recapitulating the crystal structures of mammalian and bacterial counterparts, highlighting the evolutionary conservation of the CSAS structure-function relationship. This conclusion was supported by the rescue of CSAS mutants using the human ortholog. The non-canonical CSAS glycosylation was discussed in terms of a potential mechanism of temperature-dependent regulation of sialylation in poikilotherms that modulates neural activity in heat-shock conditions. Taken together, we uncovered an important regulation of sialylation in Drosophila, highlighting a novel interplay between glycosylation pathways in neural regulation.

Keywords: CMP-sialic acid synthetase; Drosophila, non-canonical N-glycosylation; glycosylation; sialylation

DOI: https://doi.org/10.1016/j.jbc.2025.108483