Asta Literature Retrieval: Pathophysiology and clinical mechanisms of MGAT2-congenital disorder of glycosylation. Core disease mechanisms, molec...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Comparison of the Differing Impacts of Lowered N-Acetylglucosaminyltransferase-Ia/b Activity on Motor and Sensory Function in Zebrafish

• Authors: M. Hall, Cody J. Hatchett, Haris A. Khan, H. Lewis, R. A. Schwalbe
• Year: 2025
• Venue: International journal of translational medicine (Basel, Switzerland)
• URL: https://www.semanticscholar.org/paper/6f5308b130201022c7eea2a3e8f4c0d3028ba7af
• DOI: 10.3390/ijtm5030036
• PMID: 41181636
• PMCID: 12573715
• Summary: Investigation of the consequences of substituting complex/hybrid with oligomannose types of N-glycans on nervous and musculature systems, employing mgat1a and mgat1b mutant zebrafish models, revealed that aberrant terminal N-glycan processing impacts brain, spinal and muscle control.
• Evidence snippets:
• Snippet 1 (score: 0.614) > Glycosylation is a process involving complex co-and post-translation protein modifications via the addition of glycans. The three basic types of N-glycans (oligomannose, hybrid, and complex) all share a common pentasaccharide core and are processed sequentially [1]. The various types of N-glycans occur due to the addition of different branch points via the action of N-acetylglucosaminyltransferases (GnTs). These enzymes are encoded by the MGAT genes and are critical to the proper development of organisms at the cellular level. The conversion of oligomannosylated proteins into hybrid type is catalyzed via GnT-I, an enzyme encoded by the MGAT1 gene. GnT-II, encoded by MGAT2, acts to further process hybrid-to complex-type N-glycans [1]. Since most proteins following the secretory pathway undergo N-glycosylation processing and this process can modify the structure and function of a protein, N-glycan processing is vital to the development and maintenance of a multicellular organism. > The magnitude of disruptions in N-glycosylation is highlighted in congenital disorders of glycosylation (CDG). Although CDG's are a rare group of disorders, the number of identified CDGs are rising, and patients face a bleak prognosis as therapeutic options are quite limited, with dietary supplementation as the predominant management technique [2]. The impact of CDGs is multisystemic, with profound neurological complications [3,4]. Neurological symptoms associated with CDG include psychomotor retardation, cognitive disorders, ataxia, epileptic seizures, polyneuropathy, hypotonia, and stroke-like events [5,6]. Further, patients often experience depression and anxiety [7]. Like CDG's, many other diseases have been associated with defective glycosylation, including cancer, neurodegenerative diseases, neurological disorders, and autoimmune diseases [5,8]. As such, additional research is necessary to further advance the field on the relationship between glycans and disease onset, progression, and treatment.

[2] Protease-dependent defects in N-cadherin processing drive PMM2-CDG pathogenesis

• Authors: E. Klaver, Lynn Dukes-Rimsky, B. Kumar, Zhi-Jie Xia, Tammie Dang et al.
• Year: 2021
• Venue: JCI Insight
• URL: https://www.semanticscholar.org/paper/1964b8cddfd573cfd6e04b619109ace9f23d48e8
• DOI: 10.1172/jci.insight.153474
• PMID: 34784297
• PMCID: 8783681
• Citations: 9
• Summary: It is demonstrated in CDG that targeted alterations in protease activity create a pathogenic cascade that affects the maturation of cell adhesion proteins critical for tissue development.
• Evidence snippets:
• Snippet 1 (score: 0.525) > Congenital disorders of glycosylation (CDG) are a heterogeneous group of genetic diseases caused by defects in enzymes, transporters, and trafficking factors needed for protein and lipid glycosylation (1). The most common of the CDG, PMM2-CDG, results from variants in phosphomannomutase 2 (PMM2), encoding an enzyme that converts mannose-6-phospate (M6P) to mannose-1-phosphate (M1P) (2,3). M1P is a precursor for guanosine diphosphate-mannose (GDP-mannose), a nucleotide sugar essential for the synthesis of lipid-linked oligonucleotide precursors needed for N-linked glycosylation (4). Defects in PMM2 limit the production of GDP-mannose, causing reduced glycosylation of serum glycoproteins and numerous clinical manifestations. Common features include failure to thrive, neurological and cognitive impairment, and skeletal dysplasia (5). Despite nearly 4 decades of research on PMM2-CDG, the connection between hypoglycosylation of proteins and phenotypes remains enigmatic. To date no underglycosylated glycoprotein has been mechanistically linked to disease in an affected tissue. This barrier has created a major gap in our understanding of the molecular and cellular mechanisms driving CDG pathogenesis, and thus, has limited the development of therapies. > A major hurdle in defining CDG pathogenesis is the ability to identify sensitive glycoproteins beyond the classic markers, such as transferrin found in serum. Elucidating the pathogenic mechanisms associated with PMM2-CDG is further challenged by the difficulty in generating animal models that faithfully mimic the human disease. Complete loss of many N-glycosylation genes, particularly those involved in lipid-linked oligosaccharide biosynthesis, is lethal. Thus, complete gene knockout is not tenable. Early attempts to either knock out PMM2 or knock in the most common human PMM2-CDG allele, > The genetic bases for the congenital disorders of glycosyla

[3] Predicting disease-overarching therapeutic approaches for Congenital Disorders of Glycosylation using multi-OMICS

• Authors: I. Muffels, R. Budhraja, R. Shah, S. Radenkovic, E. Morava et al.
• Year: 2025
• Venue: bioRxiv
• URL: https://www.semanticscholar.org/paper/8f9edb863a2ede55b3a106e304d7bef842ac19b5
• DOI: 10.1101/2025.07.07.663468
• PMID: 40672295
• PMCID: 12265611
• Summary: Most dysregulated pathways were shared across CDG, suggesting the potential for common therapeutic strategies and several candidate drugs targeting these shared abnormalities emerged from integrative analysis and warrant validation in future in vitro studies.
• Evidence snippets:
• Snippet 1 (score: 0.465) > Congenital disorders of glycosylation (CDG) result from impaired glycosylation and are categorized according to their primarily affected glycosylation type: N-glycosylation, O-glycosylation, combined glycosylation defects, glycolipid synthesis, or other related pathway abnormalities (Lefeber et al., 2022) CDG have been associated with pathogenic variants in over 190 different genes. (Ng et al., 2024) Protein glycosylation is highly abundant, with over 50% of proteins being glycosylated. (Apweiler et al., 1999) Glycosylated proteins are involved in a plethora of cellular functions, and contribute to proper protein folding and function, extracellular matrix structure, energy metabolism and cellular signaling. (Gagneux et al., 2022) The clinical phenotype of CDG is highly heterogenous. This might be due to the multitude of dysregulated pathways observed in these diseases. (Ligezka et al., 2023;Zdrazilova et al., 2023) Currently available treatment options for CDG are mostly symptomatic. Dietary supplementation of monosaccharides has been used for many years, although it is only effective for a subset of CDG. (Verheijen et al., 2020) Recently, large-scale drug screenings of FDA-approved drugs have come into play, providing a novel approach to discover therapies for CDG. (Dalton et al., 2024;Iyer et al., 2019;Ligezka et al., 2021;Radenkovic et al., 2023) Drug screening is usually performed by introducing a specific genetic defect in simple disease models (yeast, worm or fly), and verifying which compounds increase overall growth or survival. However, as these models are tailored to a specific genetic defect or variant, the results might not be translatable to other patients or other CDG. Developing novel treatments by modeling each of the 190 known CDG-associated genes individually is a time-intensive endeavor that could take years.

[4] Glycosylation in kidney diseases

• Authors: Yingying Ling, Fei Cai, Tao Su, Y. Zhong, Ling Li et al.
• Year: 2025
• Venue: Precision Clinical Medicine
• URL: https://www.semanticscholar.org/paper/2433e37bf6e26c841c86788356290cf02a7b6ef0
• DOI: 10.1093/pcmedi/pbaf017
• PMID: 40852041
• PMCID: 12368498
• Citations: 7
• Summary: This review provides a comprehensive overview of protein glycosylation mechanisms, its biological roles, molecular pathways, and significant functions in renal physiology and pathology and specifically highlights the dynamic changes and regulatory networks associated with aberrant glycosylation in kidney diseases.
• Evidence snippets:
• Snippet 1 (score: 0.463) > Human glycosylation encompasses 16 distinct pathways, including 14 forms of protein glycosylation and two types of lipid glycosylation. Protein glycosylation is broadly classified into N -glycosylation, O -glycosylation, glycosylphosphatidylinositol (GPI) anchor linkage, tryptophan C -mannosylation, S -glycosylation (e.g. cysteine-S -glycosylation), and P -glycosylation (e.g. phosphorylation-associated glycosylation), with N/O -glycosylation representing the predominant subtypes [ 11 ]. > Protein glycosylation regulates cellular functions through various pathways. Glycans have the capacity to modulate protein structure, subcellular localization, and trafficking, thereby exerting a profound impact on protein folding, activity, and stability. These effects, in turn, underpin fundamental biological processes such as cell-cell recognition, signal transduction, and immune responses [ 12 , 13 ]. Recent advances in high-throughput glycoproteomic technology have enabled systematic analysis of glycoproteins in preclinical and clinical studies, revealing that aberrant glycosylation is closely associated with major diseases, including cancers, kidney disorders, neurodegenerative diseases, and metabolic conditions [ 12 , 14-18 ]. Aberrant alterations in proteins and their attached glycans hold promise as diagnostic and prognostic biomarkers, and as therapeutic targets for managing or slowing disease progression. Therefore, understanding glycosylation modifications is essential for deciphering kidney disease mechanisms. In this review, we first briefly introduce the process of protein glycosylation, including its biological functions and underlying molecular mechanisms.

[5] SLC35A2 Deficiency Promotes an Epithelial-to-Mesenchymal Transition-like Phenotype in Madin–Darby Canine Kidney Cells

• Authors: M. Kot, Ewa Mazurkiewicz, M. Wiktor, Wojciech Wiertelak, A. Mazur et al.
• Year: 2022
• Venue: Cells
• URL: https://www.semanticscholar.org/paper/4e73e40211e8c96bcc3baaaea1db701e0cc53cc5
• DOI: 10.3390/cells11152273
• PMID: 35892570
• PMCID: 9331475
• Citations: 4
• Summary: A novel role for SLC35A2 as a gatekeeper of the epithelial phenotype is pointed to in a non-malignant epithelial cell line that shows several hallmarks of EMT.
• Evidence snippets:
• Snippet 1 (score: 0.439) > Congenital disorders of glycosylation (CDGs) are a large and heterogenous group of rare genetic metabolic diseases caused by defects in glycan synthesis and/or modification pathways [20]. To date, more than 130 CDG subtypes have been characterized. The majority of CDGs are autosomal recessive in inheritance, although autosomal dominant as well as X-linked forms have also been reported [21]. The clinical manifestations of CDGs are very diverse and the most commonly occurring symptoms include developmental retardation, failure to thrive, hypotonia, neurological problems, hepatopathy, and coagulopathy [21]. > For certain CDG subtypes, the relationship between the glycosylation defect and the disease symptoms is well-established. In SLC35C1-CDG, for example, selectin ligands on leukocytes are significantly underfucosylated due to compromised activity of the Golgi GDP-fucose transporter [22]. This prevents tethering and rolling of leukocytes on vascular endothelium which ultimately attenuates inflammatory response. However, for many CDGs, the influence of defective glycosylation on the downstream cellular phenotypes is poorly understood. > Mutations in the SLC35A2 gene are also a cause of a CDG subtype (SLC35A2-CDG; CDG IIm) [e.g., [23][24][25][26][27][28]]. The affected individuals usually experience neurological problems (global developmental delay, epilepsy, encephalopathy), as well as hypotonia. A number of SLC35A2-CDG patients fail to thrive due to gastrointestinal disease and impairment of the growth hormone-insulin-like growth factor axis [29]. They also show dysfunctions of the liver, spleen, kidney, and skeleton. However, it is not clear how an impaired Golgi UDP-galactose transporting activity mechanistically contributes to pathophysiology and clinical manifestation of SLC35A2-CDG.

[6] Next-Generation Sequencing Technologies and Neurogenetic Diseases

• Authors: Hui Sun, Xia Shen, Z. Fang, Zong-zhi Jiang, Xiao-jing Wei et al.
• Year: 2021
• Venue: Life
• URL: https://www.semanticscholar.org/paper/610176b2538c442811882df5f33353d4c4fff4d4
• DOI: 10.3390/life11040361
• PMID: 33921670
• PMCID: 8072598
• Citations: 25
• Summary: An overview of the classifications, applications, advantages, and limitations of NGS in research on neurological diseases is provided and examples of N GS-based explorations and insights of the genetic causes of neurogenetic diseases, including Charcot–Marie–Tooth disease, spinocerebellar ataxias, epilepsy, and multiple sclerosis are provided.
• Evidence snippets:
• Snippet 1 (score: 0.437) > In a rare and extreme condition, patients exhibit phenotypes of two congenital diseases. Thus, when confronting diseases that are difficult to diagnose, it is suggested that monism should be used to explain the etiological factors. Congenital myasthenia syndrome (CMS), comprising a group of monogenetic disorders that affect neuromuscular junction, offers a sound explanation for this condition. Among the 32 known genes in CMS, the phenotypes associated with DOK7, MUSK, DPAGT1, CHRNE, and GMPPB can coincide with muscular diseases, such as MD, limb-girdle muscular dystrophy (LMD), and myopathy [116]. Some patients with GMPPB or CHRNE mutations present with MD-like symptoms [117]. The myopathy-like clinical and pathological manifestations of CHRNE, which are involved in slow-channel congenital myasthenic syndrome, are primarily caused by calcium overload due to the delayed closure of slow ion channels [118]. In contrast to the pathway associated with CHRNE, defects in protein glycosylation caused by GMPPB lead to AChR subunits incorrectly settled, and expressed, on the surface of cells [119]. Approximately 40 genes are associated with MD and are primarily involved in extracellular matrix and basement membrane proteins [120]. GMPPB is also involved in N-glycation and O-mannose glycation pathways [121]. In the case of GMPPB, pathological changes of muscular and neuromuscular junctions can be present simultaneously, with the clinical manifestations of LMD and CMS overlapping, or concealing, each other. Therefore, in the complex background of neurogenetic diseases, the pathological mechanisms of different diseases may intersect. Hence, NGS is extremely important for diseases with more than one congenital disease phenotype, with the genes screened by WGS potentially providing insights into new mechanisms. A similar example is that of GARS, which causes distal upper limb dyspraxia and was not only found in CMT, but also in autism spectrum disorder, mitochondrial disease, and motoneuron disease [122][123][124].

[7] Glycomic and Glycoproteomic Techniques in Neurodegenerative Disorders and Neurotrauma: Towards Personalized Markers

• Authors: F. Kobeissy, Abir Kobaisi, Wenjing Peng, Chloe Barsa, Mona Goli et al.
• Year: 2022
• Venue: Cells
• URL: https://www.semanticscholar.org/paper/5dc0275df40f0f5fb80ee75a6b454e8725d5170e
• DOI: 10.3390/cells11030581
• PMID: 35159390
• PMCID: 8834236
• Citations: 21
• Influential citations: 1
• Summary: The role of glycomics in the area of traumatic brain injury (TBI) is reviewed and perspectives on the clinical application of glycoproteomics as potential diagnostic tools and their application in personalized medicine are provided.
• Evidence snippets:
• Snippet 1 (score: 0.434) > Glycosylation is crucial in allowing genes and pathways to function properly. Any mutation present in glycosylation-related genes may lead to the formation of neurologically impaired individuals. These mutations, specifically the congenital disorders of glycosylation (CDG), have been proven to participate in the occurrence of over 80% of neurological abnormalities [41]. Glycans can present irregularities on either proteins or lipids, leading to various genetic defects. Within a mammalian cell, the glycome is highly complex, even more so than the proteome or the genome [42]. This complexity provides a fine-tuning mechanism for several cellular processes, where different proteins are expressing the same sugar chain and present diverse functional consequences. The outcome of glycosylation is mostly context-dependent [43]; several factors influence the formation of the final glycosylation product. These include the supply of the activated sugars, the identity of the proteins or lipids attached, and the enzymes involved in the biosynthesis [44]. Glycosylated proteins can be connected to several different glycan types, making each form a unique one employed in specific pathways [45]. Consequently, any hindrance preventing their formation or delivery can affect the related glycosylation pathways. > Proper glycosylation necessitates the correct functioning of the Golgi system. Flaws in the trafficking of proteins and their composition along with unstable Golgi homeostasis may directly impact glycosylation. Trafficking defects may be due to the mislocalization of several glycosyltransferases and nucleotide-sugar transporters, impacting single or multiple glycosylation pathways. These defects mainly transpire in cytoplasmic proteins transiently associated with the Golgi system, hence affecting the guidance of vesicles holding glycosylation machinery to their location [46]. > Other glycosylation defects may be seen during aging, which is related to the onset of several diseases [47]. Glycosylation can endure age-related modifications, subsequently increasing molecular heterogeneity and impaired protein function, such as in the case of age-related pathologies including sarcopenia and cataracts [48].

[8] A comprehensive update of genotype–phenotype correlations in PMM2-CDG: insights from molecular and structural analyses

• Authors: Tiago Oliveira, R. Ferraz, Luis Da Silva Azevedo, D. Quelhas, João Carneiro et al.
• Year: 2025
• Venue: Orphanet Journal of Rare Diseases
• URL: https://www.semanticscholar.org/paper/5c5fbf9aa8f1e32368a68a03ebd50b088c22ad47
• DOI: 10.1186/s13023-025-03669-5
• PMID: 40307862
• PMCID: 12042452
• Citations: 5
• Influential citations: 1
• Summary: This work broadens the understanding of the intricate relationships between genotype and clinical manifestations of PMM2-CDG, evaluating at a structural level 41 missense mutations in PMM2-CDG, examining their phenotypical characteristics and clinical severity, protein properties and interference at the enzymatic level.
• Evidence snippets:
• Snippet 1 (score: 0.432) > PMM2-CDG (phosphomannomutase 2-deficiency) is the most prevalent N-glycosylation disorder and results from impairments of PMM2 activity. This disease presents a large variety of pathogenic variants, which cause a wide phenotypical spectrum. This diversity, together with the low number of affected patients, raises the challenge of determining genotype–phenotype correlations in PMM2-CDG. This type of correlation could be highly significant in determining disease progression, prognosis, severity and in developing genome-personalized therapies. Structural analyses offer a valuable approach for assessing the pathogenic mechanisms within the PMM2 protein structure at a molecular level. Such an approach can reveal novel insights into the consequences of missense variants and their relationship with patients'phenotype. In this comprehensive review, we evaluate at a structural level 41 missense mutations in PMM2-CDG, examining their phenotypical characteristics and clinical severity, protein properties and interference at the enzymatic level. This work broadens the understanding of the intricate relationships between genotype and clinical manifestations of PMM2-CDG.

[9] Neural and Synaptic Defects in slytherin, a Zebrafish Model for Human Congenital Disorders of Glycosylation

• Authors: Yuanquan Song, J. Willer, Paul C. Scherer, J. Panzer, Amy Kugath et al.
• Year: 2010
• Venue: PLoS ONE
• URL: https://www.semanticscholar.org/paper/07df2fc2414fd48dc00cb808704fe9a044b25437
• DOI: 10.1371/journal.pone.0013743
• PMID: 21060795
• PMCID: 2966427
• Citations: 33
• Influential citations: 1
• Summary: It is shown, for the first time in a vertebrate in vivo, that defects in protein fucosylation leads to defects in neuronal differentiation, maintenance, axon branching, and synapse formation.
• Evidence snippets:
• Snippet 1 (score: 0.429) > Over the last decade, a large number of human genetic diseases with aberrant glycoprotein synthesis have been identified and grouped as congenital disorders of glycosylation (CDG). Since glycosylation is essential for the function of many proteins, it is not surprising that disruption of glycosylation can lead to severe, multisystemic phenotypes, including neurodevelopmental and cognitive disorders. In srn mutants, the gmds mutation largely abolishes the synthesis of GDP-fucose, resulting in reduction or elimination of both O-linked and N-linked fucosylation of Notch and many other proteins. Thus it is possible that disruption of O-as well as Nlinked glycosylation of Notch and other proteins contributes to CDG IIc pathogenesis, although this has not been examined extensively in humans. > There are several reports of neural deficits in CDGIIc patients, including severe mental retardation, microcephaly, cortical atrophy, seizures, psychomotor retardation and hypotonia [2,4,51]. These clinical observations are consistent with the CNS and PNS cellular phenotypes observed in srn. Giving the advantage of performing imaging, genetic and pharmacological manipulations in zebrafish, srn will be a useful tool to guide future analyses in human CDG IIc patients and contribute to a better understanding of the mechanisms responsible for this devastating disorder that affects nervous system and other organ development.

[10] Synergistic use of glycomics and single‐molecule molecular inversion probes for identification of congenital disorders of glycosylation type‐1

• Authors: N. A. Bakar, A. Ashikov, J. M. Brum, R. Smeets, Marjan Kersten et al.
• Year: 2022
• Venue: Journal of Inherited Metabolic Disease
• URL: https://www.semanticscholar.org/paper/09b821b1ecfa8a382de9199bd325ef26a3eadac7
• DOI: 10.1002/jimd.12496
• PMID: 35279850
• PMCID: 9545396
• Citations: 19
• Summary: Combined plasma glycomics profiling and targeted smMIPs sequencing of candidate genes is a powerful approach to identify causative mutations in CDG‐I patient cohorts.
• Evidence snippets:
• Snippet 1 (score: 0.426) > Congenital disorders of glycosylation (CDG) form a large group of inherited diseases with extremely broad spectrum of clinical symptoms. Since its first description in 1980, more than 140 types of CDG have been reported of which 70 types with deficient N-linked protein glycosylation. 1 CDG type 1 (CDG-I) are seen as the classical form of CDG and comprise defects in the endoplasmic reticulum N-glycosylation pathway. CDG-I patients generally present with multisystem clinical phenotypes with the majority affected by neurological symptoms. Clinical clues might be useful to diagnose CDG-I defects such as (a) nonneurological involvements in MPI-CDG (gastrointestinal/liver phenotype) and DPM3-CDG (heart and muscle phenotype); (b) ichthyosis in MPDU1-CDG, DOLK-CDG, and SRD5A3-CDG; (c) neurosyndromic cataract and/or coloboma in SRD5A3-CDG and ALG2-CDG; and (d) neurosyndromic sensorineural deafness in ALG11-CDG and RFT1-CDG. 2 Traditionally, plasma transferrin has been used as the diagnostic protein marker to screen for CDGs with deficient N-glycosylation. Defects in CDG-I result in a partial absence of complete glycans on the transferrin protein. Introduction of plasma intact transferrin mass spectrometry (MS) has significantly improved the identification of CDG-I patients due to the sensitive detection of a glycan loss. 3,4 To date, at least 27 different genetic defects are known that result in CDG-I screening profiles. 5 Further confirmation of CDG-I gene defects has long depended on enzymatic assays in blood cells, analysis of dolichol-linked oligosaccharide (DLO) in patient fibroblasts or additional biochemical tests, such as analysis of dolichol metabolites in plasma or urine.

[11] Glycosylation in aging and neurodegenerative diseases

• Authors: Weilong Zhang, Tian Chen, Huijuan Zhao, Shifang Ren
• Year: 2024
• Venue: Acta Biochimica et Biophysica Sinica
• URL: https://www.semanticscholar.org/paper/70ccf81681b927b8fab87bc148d9d14f687e58a8
• DOI: 10.3724/abbs.2024136
• PMID: 39225075
• PMCID: 11466714
• Citations: 21
• Summary: The potential of glycosylation research as a tool to enhance the understanding of aging and its related diseases is highlighted and the mechanisms of glycosylation explored.
• Evidence snippets:
• Snippet 1 (score: 0.419) > These disorders share mechanistic pathways with the natural aging process, indicating that alterations in glycosylation may play a role in disease pathogenesis and progression [15]. Among these diseases, neurodegenerative diseases have garnered extensive attention in recent research due to their significant impact on health span and quality of life in aging populations. Accumulating evidence suggests that glycosylation modifications are closely linked to the pathophysiology of these disorders, possibly through mechanisms involving protein misfolding and aggregation, which are hallmark features of neurodegenerative diseases. > The relationship between glycosylation and aging or neurodegenerative diseases is particularly compelling as it offers insights into the molecular underpinnings that bridge chronic disease and aging. Research into the molecular basis of aging and neurodegenerative diseases can significantly enhance our understanding of how these processes are interlinked, potentially leading to novel diagnostic and therapeutic strategies. These strategies could focus on modifying glycosylation pathways to mitigate the adverse effects of aging and disease progression. > Given the established connections between glycosylation and aging or age-related diseases, this review focuses primarily on the characteristics of glycosylation modifications in the context of aging and selected neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. By delving into recent research advancements, we aim to highlight how glycosylation impacts these diseases within the broader spectrum of aging, thereby offering new avenues for intervention that could improve diagnosis, treatment, and ultimately patient outcomes. This focused approach allows for a detailed exploration of potential therapeutic targets within glycosylation pathways that could influence both aging and the pathogenesis of neurodegenerative diseases in the future.

[12] Congenital disorders of glycosylation.

• Authors: I. Chang, M. He, Christina Lam
• Year: 2018
• Venue: Annals of translational medicine
• URL: https://www.semanticscholar.org/paper/51f14003a127b5f886afe9c6ab46082e336843fe
• DOI: 10.21037/atm.2018.10.45
• PMID: 30740408
• Citations: 160
• Influential citations: 12
• Summary: Carohydrate deficient transferrin (CDT) and protein-linked glycan analysis with mass spectrometry can diagnose some subtypes of congenital disorders of glycosylation (CDG), while many currently rely on massively parallel genomic sequencing for diagnosis.
• Evidence snippets:
• Snippet 1 (score: 0.405) > N-glycosylation involves the covalent attachment of carbohydrate structures to the side chain amide group of Asn residues within a consensus Asn-X-Ser/Thr acceptor site, translocation of the substrate polypeptide to the endoplasmic reticulum for remodeling, and further modification of the N-glycan chain within the Golgi (11,12). Defects anywhere along the synthesis, assembly, and processing pathway can lead to clinical disease. > PMM2-CDG is caused by pathogenic variants in the phosphomannomutase 2 (PMM2) gene, leading to deficiency of the PMM2 enzyme that catalyzes the cytosolic conversion of mannose-6-phosphate to mannose-1-phosphate in the second step of guanosine diphosphate (GDP) mannose synthesis. Most patients harbor compound heterozygous pathogenic missense mutations (www.lovd.nl/PMM2). The most common recurrent pathogenic variant p.Arg141His is found in approximately 40% of affected individuals of European ancestry, and p.Phe119Leu is also frequently found in northern Europe (1). Genotype-phenotype correlations have been reported for PMM2-CDG (3,13,14). > MPI-CDG is an autosomal recessive disorder caused by pathogenic variants in the mannose phosphate isomerase (MPI) gene leading to deficient phosphomannose isomerase (MPI). MPI normally catalyzes the first step of GDPmannose synthesis (i.e., the conversion of fructose-6phosphate to mannose-6-phosphate), but fructose-6phosphate does not accumulate intracellularly since it can also be metabolized by the glycolytic pathway. Therefore, although biochemically similar to PMM2-CDG, MPI-CDG does not cause as significant neurologic and multisystemic involvement. CDT is also the screening test of choice for MPI-CDG, which shows a type 1 pattern. The diagnosis can then be confirmed molecularly or

[13] The recurrent missense mutation p.(Arg367Trp) in YARS1 causes a distinct neurodevelopmental phenotype

• Authors: L. Averdunk, H. Sticht, H. Surowy, H. Lüdecke, M. Koch-Hogrebe et al.
• Year: 2021
• Venue: Journal of Molecular Medicine (Berlin, Germany)
• URL: https://www.semanticscholar.org/paper/bb20022a67ad80532547d5db6abf8062fc2dfefc
• DOI: 10.1007/s00109-021-02124-9
• PMID: 34536092
• PMCID: 8599376
• Citations: 6
• Summary: In silico analyses show that the p.(Arg367Trp) does not affect the catalytic domain responsible of enzymatic coupling, but destabilizes the cytokine-like C-terminal domain, and impaired protein translation is likely not the exclusive disease-causing mechanism of YARS1- and ARS1-associated neurodevelopmental disorders.
• Evidence snippets:
• Snippet 1 (score: 0.401) > endocrine abnormalities and show the greatest clinical overlap with the YARS1 p.(Arg367Trp)-associated phenotype delineated here. > Another example of ARS1-associated disorders, in which an impaired protein synthesis as the causative disease mechanism can be questioned is VARS1 causing developmental delay with microcephaly [38]. Interestingly, in in vitro assays, the authors found a 50% residual aminoacylation activity. Because reductions in enzyme activity of approximately 50% are often well tolerated, it can be speculated that reduced aminoacylation is not the underlying disease mechanism, but that dysregulated secondary functions (for example, dysregulation of VEGF) might be involved. In many ARS1 genes, over 200 "catalytic nulls" natural splice variants have been annotated which primarily ablate or disrupt the catalytic domain but retain the noncatalytic section. This observation underpins the diverse, functions of nonenzymatic domains of ARS1 genes [50]. > CMT is another disease reflecting the significance of secondary protein functions of YARS1. Since the discovery of pathogenic variants in YARS1 causing CMT type C more than 15 years ago, the exact disease mechanism has not been understood, yet. All five CMT-causing mutations in YARS1 reside in the N-terminal catalytic domain (Fig. 1A). Because aminoacylation activity is not a shared property of pathogenic variations, it is unlikely that haploinsufficiency affecting the aminoacylation enzyme activity is the underlying mechanism [7,51]. Currently, gain-of-function pathogenic variants in non-catalytical domains or transcriptional dysregulation are discussed to be the potential underlying disease mechanism [52]. Of note, none of the patients or parents reported here is affected by CMT neuropathy. This is in line with the absence of neuropathy in patients with recessive disorders caused by other ARS1 genes which have been implicated with CMT [8]. > One limitation in the interpretation of the impact of YARS1 variants on protein function is that to date no structural model of the full-length protein is available and that separate structures of mini-TyrRS and C-domains are the basis for functional predictions. Another limitation is

[14] Equilibrative nucleoside transporter 3 supports microglial functions and protects against the progression of Huntington's disease in the mouse model.

• Authors: Ying-Sui Lu, Wei-Chien Hung, Yu‐Ting Hsieh, Pei-Yuan Tsai, Tsai-Hsien Tsai et al.
• Year: 2024
• Venue: Brain, behavior, and immunity
• URL: https://www.semanticscholar.org/paper/24f1acd02b8bffd5e4f7cb0604d1d2c4000640a0
• DOI: 10.1016/j.bbi.2024.06.021
• PMID: 38925413
• Citations: 2
• Summary: It is suggested that the delicate balance between microglial metabolism and function is crucial for maintaining brain homeostasis and that ENT3 has a protective role in ameliorating neurodegenerative processes.
• Evidence snippets:
• Snippet 1 (score: 0.398) > Huntington's disease (HD) is a progressive neurodegenerative disorder that primarily affects the central nervous system (CNS). As an inherited autosomal disease, this debilitating condition is characterized by a range of involuntary movements, cognitive deficits, and psychiatric symptoms. HD is caused by the monogenic disorder of expanded CAG repeats in the huntingtin (Htt) gene (Tabrizi et al., 2020), leading to the accumulation of mutant huntingtin (mHTT). The mHTT protein undergoes abnormal folding, leading to the formation of protein aggregates within the cells. These aggregates interfere with essential cellular processes, impairing neuronal function and survival, and are positively correlated with massive neuronal cell death and degeneration. The striatum, a brain region involved in motor control, is affected particularly severely in HD. Currently, there is no cure for HD, with only limited treatment strategies available to manage the symptoms and slow down disease progression. > Although HD has a well-defined genetic origin, the molecular and cellular mechanisms underlying the pathogenesis of HD are complex. While aggregate formation and toxic fragment production lead to cellular transcriptional deregulation, altered protein homeostasis, and mitochondrial dysfunction, neuroglial disturbance, such as neuroinflammation and impaired glutamate uptake by astrocytes, is another crucial contributor to HD pathophysiology (Jimenez-Sanchez et al., 2017). Interestingly, the neuroinflammation and the protein-degradation-resultant defects such as autophagiclysosomal dysfunction in HD are shared features with other neurological diseases such as Alzheimer's disease (AD) or lysosomal storage diseases (LSDs). The majority of LSDs present different degrees of pathology in the CNS and neurodegeneration in multiple brain regions. Depending on the specific type of metabolite accumulation, the patients vary in affected age or neuronal subtypes (Platt et al., 2012). The commonality between these diseases suggests a potential shared molecular mechanism caused by abnormal protein aggregation, autophagic-lysosomal dysfunction, and neuroinflammation.

[15] FUT11 expression in gastric cancer: its prognostic significance and role in immune regulation

• Authors: Yanqing Huang, XiaoYing Yang, Mengda Wei, Xi Yang, Zhenmin Yuan et al.
• Year: 2024
• Venue: Discover Oncology
• URL: https://www.semanticscholar.org/paper/77b65e1fc209f5f8bf1576a4cac7b81ada3972c4
• DOI: 10.1007/s12672-024-01120-y
• PMID: 38941002
• PMCID: 11213843
• Citations: 6
• Summary: It is revealed that FUT11 expression is significantly increased in GC tissues and is associated with poor prognosis and might affect immune regulation, which might regulate the tumor microenvironment.
• Evidence snippets:
• Snippet 1 (score: 0.397) > Gastric cancer (GC) is the fifth most common cancer worldwide and the third leading cause of cancer death [1].The GC morbidity and mortality rates are among the top five in the world [2].The current standard treatment for GC is radical tumor resection with perioperative chemotherapy, while the standard treatment for metastatic or unresectable GC includes chemotherapy regimens such as platinum-based drugs, docetaxel, paclitaxel, and irinotecan.The 5-year overall survival rate (OS) for patients with early-stage GC who undergo surgery is 90%.However, the lack of specific early clinical manifestations in patients with GC results in many patients only being diagnosed when the disease is relatively advanced and there is no longer an opportunity for radical surgical intervention.Advanced GC grows rapidly, has a high degree of malignancy, is difficult to treat, and has a poor prognosis. > GC occurrence and prognosis are closely related to abnormal gene expression in patients [3,4].However, the molecular mechanism of GC carcinogenesis remains unclear.Therefore, it is necessary to elucidate these mechanisms and search for molecular markers that can aid early diagnosis and prognosis assessment.Glycosylation is a well-regulated cellular and microenvironment-specific post-translational modification [5].Abnormal protein glycosylation regulates the malignant cancer cell phenotype and is crucial in cancer cell interactions and tumor angiogenesis.Additionally, abnormal protein glycosylation is closely related to cancer cell immune evasion [6]. > Fucosylation is key in tumor-associated abnormal glycosylation.Fucosyltransferase (FUT) is one of the most important enzymes that coordinates fucosylation.The abnormal protein modification by FUT is closely related to cancer occurrence and development.FUT is a key enzyme that catalyzes the transfer of l-fucose from the donor substrate β-l-fucose guanosine diphosphate to its respective substrate [7].Glycosylation can be divided into core and terminal fucosylation according to the fucose location.

[16] PROCEEDINGS OF THE XIX CONGRESS OF THE ITALIAN SOCIETY OF MYOLOGY

• Authors: June, C. Minetti, A. Berardinelli, A. Aliverti, A. Ambrosini
• Year: 2019
• Venue: Acta Myologica
• URL: https://www.semanticscholar.org/paper/ef33e60e12f45e3b53f7dca4296ed13355e3b67b
• PMID: 31309183
• PMCID: 6598409
• Citations: 1
• Influential citations: 1
• Summary: European muscle MRI study in Limb Girdle Muscular Dystrophy Type 2A, a progressive myopathy caused by deficiency of calpain 3, a calcium-dependent cysteine protease of skeletal muscle, and it represents the most frequent type of LGMD worldwide.
• Evidence snippets:
• Snippet 1 (score: 0.397) > ated, genomes, nuclear and mitochondrial DNAs. The genetic and biochemical intricacy of mitochondrial bioenergetics explains the extreme heterogeneity of mitochondrial disorders, a group of highly invalidating human conditions, for which no effective treatment is nowadays available. In addition to bioenergetic failure, other mechanisms are probably predominant in the pathogenesis of specific syndromes, such as alterations of cellular redox status, the production of reactive oxygen species, compromised Ca 2+ homeostasis, mitochondrial protein and organelle quality control, and mitochondrial pathways of apoptosis. By investigating selected families and patients, we have identified several new disease genes, each responsible of distinct defects of the respiratory chain, mtDNA metabolism, or both, associated with paediatric or adultonset clinical presentations. Recently published and still unpublished findings will be presented and discussed. Structural analysis and the creation of ad hoc recombinant lines in yeast, flies, and mice have allowed us to dissect out the molecular consequences of the ablation or defects of some of these proteins, and their physical status in normal and disease conditions. These models have also been exploited to implement experimental therapeutic strategies, based on gene and cell replacement, or pharmacological control of mitochondrial biogenesis. Background. Limb Girdle Muscular Dystrophy type 2A (LGMD2A) is a progressive myopathy caused by deficiency of calpain 3, a calcium-dependent cysteine protease of skeletal muscle, and it represents the most frequent type of LGMD worldwide. In the last few years, muscle magnetic resonance imaging (MRI) has been proposed as a tool for identifying patterns of muscular involvement in genetically disorders, and as a biomarker of disease progression in muscle diseases.

[17] New therapeutic targets in rare genetic skeletal diseases

• Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
• Year: 2015
• Venue: Expert Opinion on Orphan Drugs
• URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
• DOI: 10.1517/21678707.2015.1083853
• PMID: 26635999
• PMCID: 4643203
• Citations: 37
• Influential citations: 1
• Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.397) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[18] Microcephaly in Neurometabolic Diseases

• Authors: Wiktoria Kempińska, Karolina Korta, Magdalena Marchaj, J. Paprocka
• Year: 2022
• Venue: Children
• URL: https://www.semanticscholar.org/paper/63d9574ab9178fa1f4b12a48b9c9d350dc6baaa0
• DOI: 10.3390/children9010097
• PMID: 35053723
• PMCID: 8774396
• Citations: 6
• Summary: The authors review the diseases with microcephaly, which may be one of the most visible signs of neurometabolic disorders, and investigates the mechanisms behind the progressive deterioration of mental, motor, and perceptual functions.
• Evidence snippets:
• Snippet 1 (score: 0.396) > Microcephaly is one of the significant clinical manifestations in pediatric neurology, which can be a difficult diagnostic problem due to its different etiology [93]. Microcephaly occurs in various types of metabolic diseases such as inborn glycosylation disorders, mitochondrial diseases, peroxisomal disorders, glucose transporter defects, congenital amino acid metabolism disorders (enzymatic and receptor defects), organic acidosis, or lipid metabolism disorders. Such a wide variety of disorders that lead to the occurrence of microcephaly result in the fact that microcephaly, as a symptom accompanying neurometabolic diseases, is part of a complex clinical picture that requires a complete multidisciplinary approach by neurologists, psychiatrists, cardiologists, orthopedists, or gastroenterologists. Neurometabolic disorders are mostly diagnosed in neonates and infants. Neurological symptoms are very common in this group of diseases. The onset of symptoms of neurometabolic disorders often occurs after initially relatively normal or near-normal growth and development. In addition, affected children may have metabolic crises that have particularly adverse effects on the developing nervous system. During metabolic decompensation, patients with neurometabolic disorders present with severe clinical symptoms, including eating disorders, vomiting, seizures, lethargy, and loss of consciousness. Progression of CNS damage and regression in neurodevelopmental milestones are reported [1]. Therefore, it would be crucial to find a way to effectively restore damaged nerve cells. Medical advances over the past decades have made it possible to diagnose metabolic disorders much earlier than in the past, which contributes to faster treatment. As a result, complications of the disease can be prevented more successfully. The development of molecular medicine and genetics gives hope for a better understanding of the disease mechanism of individual syndromes, which creates a new field for research into new treatment methods. Neurometabolic disorders could be treated at three levels typical of a given disease. First option is enzyme replacement therapy. Second, interventions could be applied at the metabolite level whose aim is to reduce flux through the pathway or to replenish substrates. Third, gene therapy would replace the mutated DNA [94].

[19] Personalized Medicine: The Future of Health Care

• Authors: A. Meiliana, Nurrani Mustika Dewi, A. Wijaya
• Year: 2016
• Venue: The Indonesian Biomedical Journal
• URL: https://www.semanticscholar.org/paper/02edaa39ecdab3dd64c077e71b14398b94beb742
• DOI: 10.18585/inabj.v8i3.271
• Citations: 8
• Summary: Personalized medicine seeks to use advances in knowledge about genetic factors and biological mechanisms of disease coupled with unique considerations of an individual’s patient care needs to make health care more safe and effective.
• Evidence snippets:
• Snippet 1 (score: 0.396) > (98,170,171) The genetic cardiomyopathies present a window to cardiac pathophysiology when discrete cellular pathways are disrupted. Over the past decades, the role of numerous proteins in triggering cardiomyopathy and hence HF has finally become clear. Despite the genetic complexity, direct application of genetic testing is now a mainstay in managing affected families, and scientifically and clinically useful themes are emerging that should lead to improved treatment.( 95) > Investigations of rare monogenic disorders of heart rhythm has elucidated the fundamental molecular and genetic mechanisms of sickle cell disease. After identification of more than 25 causal genes, there remain many subjects with inherited arrhythmia susceptibility but do not have mutations, this suggests that there is still other genes left unidentified. Newer strategies such as exome and WGS may be valuable to uncover additional molecular etiologies. Efforts to understand mechanisms responsible for incomplete penetrance, including identification of modifier genes, will also contribute to deciphering the complex relationships between genotype and phenotype. (97) In diabetes, personalized medicine refers to utilize the patients specific characters for most effective diagnostic or treatment strategies. These include individual behavioral and phenotypic features, standard clinical laboratory findings, and gene sequences and other molecular markers.( 172) Diabetes mellitus has long been recognized to be a complex, heterogeneous disorder, especially in type 2 diabetes patients with substantial variability in genetic risk factors, underlying pathogenic mechanisms, and clinical features. Therefore it represents a human disease that gains a substantial benefit from personalized approaches to treatment. Nevertheless, patients with type 2 diabetes often are treated similarly, with little consideration of individual characteristics that might affect clinical outcome and therapeutic response.(173) Both type 1 and type 2 diabetes are thought to be complex diseases, which means they need the interplay of numerous susceptibility and protective genes, acting in concert with negative and positive environmental factors to be developed. (174) Type 2 diabetes typically is characterized by a combination of abnormalities in both insulin secretion and responsiveness, plus a more gradual and less extensive loss of β-cell secretory capacity than occurs in type 1 diabetes.

[20] Precision Therapeutics in Lennox–Gastaut Syndrome: Targeting Molecular Pathophysiology in a Developmental and Epileptic Encephalopathy

• Authors: Debopam Samanta
• Year: 2025
• Venue: Children
• URL: https://www.semanticscholar.org/paper/455479c1bfbea7b90b73c109228f67c813d13888
• DOI: 10.3390/children12040481
• PMID: 40310132
• PMCID: 12025602
• Citations: 19
• Influential citations: 1
• Summary: A narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies, receptor and ligand dysfunction, receptor and ligand dysfunction, cell signaling abnormalities, cell signaling abnormalities, synaptopathies, and the repurposing of existing medications with mechanism-specific effects.
• Evidence snippets:
• Snippet 1 (score: 0.395) > Lennox–Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Current treatments primarily focus on symptom management through antiseizure medications (ASMs), dietary therapy, epilepsy surgery, and neuromodulation, but often fail to address the underlying pathophysiology or improve cognitive outcomes. As genetic causes are identified in 30–40% of LGS cases, precision therapeutics targeting specific molecular mechanisms are emerging as promising disease-modifying approaches. This narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies (SCN2A, SCN8A, KCNQ2, KCNA2, KCNT1, CACNA1A), receptor and ligand dysfunction (GABA/glutamate systems), cell signaling abnormalities (mTOR pathway), synaptopathies (STXBP1, IQSEC2, DNM1), epigenetic dysregulation (CHD2), and CDKL5 deficiency disorder. Treatment modalities discussed include traditional ASMs, dietary therapy, targeted pharmacotherapy, antisense oligonucleotides, gene therapy, and the repurposing of existing medications with mechanism-specific effects. Early intervention with precision therapeutics may not only improve seizure control but could also potentially prevent progression to LGS in susceptible populations. Future directions include developing computable phenotypes for accurate diagnosis, refining molecular subgrouping, enhancing drug development, advancing gene-based therapies, personalizing neuromodulation, implementing adaptive clinical trial designs, and ensuring equitable access to precision therapeutic approaches. While significant challenges remain, integrating biological insights with innovative clinical strategies offers new hope for transforming LGS treatment from symptomatic management to targeted disease modification.

Notes

• This provider combines search_papers_by_relevance with snippet_search.
• No synthesis or second-stage model call is performed.