bims-meglyc 2025-08-31 papers

Issue of 2025–08–31
three papers selected by
Silvia Radenkovic, UMC Utrecht

Biomedicines. 2025 Aug 13. pii: 1964. [Epub ahead of print]13(8):

Advancement in Clinical Glycomics and Glycoproteomics for Congenital Disorders of Glycosylation: Progress and Challenges Ahead.

Nurulamin Abu Bakar, Nurul Izzati Hamzan.

Congenital disorders of glycosylation (CDG) are a group of rare, multisystemic genetic diseases caused by defects in glycan biosynthesis and protein glycosylation. Their broad clinical and genetic heterogeneity often require advanced diagnostic strategies. Clinical glycomics and glycoproteomics have emerged as powerful tools for understanding and diagnosing CDG by enabling high-resolution analysis of glycan structures and glycoproteins. Advancements in high-throughput mass spectrometry (MS) and site-specific glycoproteomics have led to the identification of disease-relevant biomarkers, providing insight into underlying glycosylation defects. These technologies enable detailed analysis of glycan structures and glycoproteins, improving early diagnosis, supporting biomarker discovery, and facilitating therapy monitoring. Integration with genomic and clinical data, including the use of dried blood spot testing and isotopic tracing, further enhances diagnostic precision and reveals the functional consequences of pathogenic variants. While challenges remain in standardizing methods, ensuring accessibility, and implementing bioinformatics tools, global collaborations and harmonized guidelines are beginning to address these gaps. Future directions include the use of artificial intelligence in data analysis, the development of comprehensive diagnostic frameworks, and international efforts to standardize glycomic methods. Collectively, these advances reinforce the growing clinical value of glycomics and glycoproteomics in the diagnosis and management of CDG.

Keywords: biomarker discovery; clinical glycomics; congenital disorders of glycosylation; glycoproteomics; mass spectrometry; multi-omics integration

DOI: https://doi.org/10.3390/biomedicines13081964

Clin Chim Acta. 2025 Aug 24. pii: S0009-8981(25)00454-1. [Epub ahead of print] 120575

Activity values of the enzyme phosphomanomutase 2 for diagnosing the CDG Ia glycosylation defect.

Lina Marcela Ávila Moreno, Wilson Samuel Agudelo Peñaloza, Adis Ayala Fajardo.

INTRODUCTION: Congenital disorders of glycosylation (CDG) are biochemically characterized by abnormal carbohydrate assembly. These disorders can result from mutations in the genes encoding different enzymes, leading to a partial or complete reduction in catalytic activity. They can be inherited in an autosomal recessive, dominant, or X-linked manner. Approximately 130 congenital disorders are currently known, within a multisystemic clinical spectrum with high heterogeneity between family members and between different types of CDG. Deficiencies of the cytosolic enzyme phosphomannomutase 2 (PMM2, E.C.5.4.2.8) cause a type-Ia glycosylation defect (PMM2-CDG or CDG Ia), which results in neurological damage, coagulation disorders, and gastrointestinal, hepatic, cardiac, and ocular problems, among others. This enzyme catalyzes the isomerization of mannose-6-phosphate to mannose-1-phosphate.
OBJECTIVE: Our aim was to determine PMM2 activity levels using a microspectrophotometric method.
MATERIALS AND METHODS: We collected 50 whole blood samples from healthy volunteer donors, including 24 females and 26 males aged 1.94-26. Leukocytes were extracted using the dextran-heparin method and then lysed. Moreover, protein was quantified via the Folin-Lowry method. We used the Van Schaftingen and Jaeken method, which we modified and standardized.
RESULTS: The study established a reference value of 6.546-48.023 nmol/h*mg protein for PMM2.
CONCLUSION: This study allowed detecting a 24-day-old girl with CDG Ia who showed no residual phosphomannomutase 2 activity.

Keywords: Diagnosis; Glycosylation; Micro spectrophotometry; Neurological manifestations; PMM2-CDG; Phosphotransferases

DOI: https://doi.org/10.1016/j.cca.2025.120575

Int J Mol Sci. 2025 Aug 14. pii: 7820. [Epub ahead of print]26(16):

Bi-Allelic Loss-of-Function Variant in MAN1B1 Cause Rafiq Syndrome and Developmental Delay.

Liyu Zang, Yaoling Han, Qiumeng Zhang, Si Luo, Zhengmao Hu, Kun Xia, Ashfaque Ahmed, Qi Tian.

Rafiq syndrome (RAFQS) is a rare autosomal recessive disorder that is classified as a type II congenital disorder of glycosylation (CDG-II), and caused by MAN1B1 gene mutation. To date, 24 pathogenic MAN1B1 mutations have been reported in association with MAN1B1-CDG. However, the underlying pathogenic mechanisms remain poorly understood. In this study, we recruited a consanguineous family from Pakistan with multiple affected individuals exhibiting mild facial dysmorphism, developmental delay, and intellectual disability. Utilizing exome sequencing and homozygosity mapping, we identified a novel MAN1B1 mutation (c.772_775del) that co-segregated with RAFQS in this family. Analysis of public single-cell transcriptomic data revealed that MAN1B1 is predominantly expressed in dorsal progenitors and intermediate excitatory neurons during human brain development. Knockdown of Man1b1 in primarily cultured mouse excitatory neurons disrupted axon growth, dendrite formation, and spine maturation, and could not be rescued by truncated variants identified in the family. Furthermore, in utero, electroporation experiments revealed that Man1b1 knockdown in the murine cortex impaired neural stem cells' proliferation and differentiation, as well as cortical neuron migration. Collectively, these findings elucidate a critical role for MAN1B1 in the etiology of RAFQS and demonstrate that loss-of-function mutation in MAN1B1 disrupt neuro-developmental processes, providing mechanistic insights into the pathogenesis of this disorder.

Keywords: MAN1B1; Rafiq syndrome; intellectual disability; neuronal development

DOI: https://doi.org/10.3390/ijms26167820