bims-meglyc 2026-03-08 papers

bims-meglyc

Biomed News

on Metabolic disorders affecting glycosylation

Issue of 2026–03–08
eleven papers selected by
Silvia Radenkovic, UMC Utrecht

Neuro-Ophthalmic Presentation of Steroid 5a-Reductase Type 3 Congenital Disorder of Glycosylation: A Case of Monozygotic Twins.
Congenital Disorders of Glycosylation Type I: A Report of Two Cases.
Unilateral Multicystic Dysplastic Kidney in a Fetus Associated With Parental Genetic and Environmental Risk Factors: A Case Report.
Case Report: Novel MAGT1 pathogenic variant with significant atopy, hypogammaglobulinemia and viral skin infections.
Preclinical assessment of GNEwt/bi-shRNA-GNEM743T lipoplex product development for GNE myopathy.
ALG8-Driven Metabolic Reprogramming in Polycystic Kidney Disease: A Systematic Synthesis of Evidence Linking Glycosylation Defects to Metabolic Signaling.
Brain Organoids as Emerging Platforms for Modeling Neurodegenerative Diseases: Progress, Challenges, and Future Directions.
Rodent models with neuraminidase deficiencies.
GalNAc-T13 maintains neurite architecture and memory retention via O-GalNAc glycosylation of seizure protein 6.
Identification of a Homozygous PGM2L1 Variant in a Male Patient With Developmental Delay and Seizures.
Morphological determinants of glycosylation efficiency in Golgi cisternae.

Cureus. 2026 Jan;18(1): e102557

Neuro-Ophthalmic Presentation of Steroid 5a-Reductase Type 3 Congenital Disorder of Glycosylation: A Case of Monozygotic Twins.

Shikha Swaroop, Sudeshna Dasgupta, Preeti Srivastava, Shikhar Deep Jain, Deb Sanjay Nag, Sanjay K Tanti.

  We report a very rare autosomal recessive metabolic disorder in monozygotic twin sisters caused by the steroid 5a-reductase type 3 (SRD5A3) gene defect, a subtype of congenital disorder of glycosylation (CDG). SRD5A3 activity is required for N-glycosylation of proteins. This step is important for the protein to gain its function. The condition is characterized by severe neurodevelopmental delay, cerebellar atrophy or hypoplasia, ocular abnormalities, and ichthyotic skin changes. We describe 20-month-old female monozygotic twins born to non-consanguineous South Asian parents. Notably, both twins exhibited generalized tonic-clonic seizures starting in early infancy - a feature less commonly reported in SRD5A3-CDG. Physical examination of both children showed central hypotonia and bilateral horizontal nystagmus. Fundoscopy of the twins showed optic disc pallor suggestive of optic atrophy. Other features, such as ichthyosis and joint laxity, were absent. Crucially, despite prominent neurological symptoms, brain MRIs at 20 months were entirely normal, showing no evidence of cerebellar hypoplasia or atrophy typically associated with this condition. Whole-exome sequencing identified a homozygous nonsense mutation at exon 1 c.57G>A (p.Trp19Ter), in the SRD5A3 gene, classified as a pathogenic variant as per the American College of Medical Genetics and Genomics (ACMG), helping in establishing the diagnosis. SRD5A3-CDG should be one of the differentials in infants with unexplained seizures, hypotonia, and early ocular signs. This case highlights the phenotypic diversity of SRD5A3-CDG and demonstrates that structural brain anomalies may be absent in the early years of life. It underscores the importance of considering CDG as a differential in infants with unexplained hypotonia and ocular signs, even in the setting of normal neuroimaging.

Keywords:  congenital disorders of glycosylation; hypotonia; nystagmus; optic atrophy; whole exome sequencing

DOI:  https://doi.org/10.7759/cureus.102557
Klin Padiatr. 2026 Mar 02.

Congenital Disorders of Glycosylation Type I: A Report of Two Cases.

Semra Atasoy Yilmaz, Burcu Güven, Ilker Eyüboğlu, Beril Dilber, Aslı Durmus, Basire Nur Yıldız.

DOI: https://doi.org/10.1055/a-2799-8968
Cureus. 2026 Jan;18(1): e102475

Unilateral Multicystic Dysplastic Kidney in a Fetus Associated With Parental Genetic and Environmental Risk Factors: A Case Report.

Zuhayr Khan, Mahsum Jafri, Constantino G Lambroussis.

  Multicystic dysplastic kidney (MCDK) is a congenital renal anomaly identified on prenatal ultrasound. They often arise sporadically and unilaterally. Our case involves an isolated unilateral MCDK in a fetus born to a mother with generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), and gastroesophageal reflux disease (GERD), with the father having chronic occupational lead exposure and a congenital disorder of glycosylation type 1A (PMM2-CDG). Our case highlights the multifactorial etiology of renal dysplasia and its potential role of glycosylation defects and environmental toxicity in abnormal kidney development. Contributions from genetic, environmental, and metabolic influences during nephrogenesis contribute to MCDK.

Keywords:  environmental lead exposure; fetal macrosomia; genetic and environmental risk factors; genetic risk factors; kidney ultrasound; multicystic dysplastic kidney; multifactorial etiology; nephrogenesis; ocd/anxiety disorders; unilateral renal cystic disease

DOI:  https://doi.org/10.7759/cureus.102475
Front Immunol. 2026 ;17 1754394

Case Report: Novel MAGT1 pathogenic variant with significant atopy, hypogammaglobulinemia and viral skin infections.

Lauren Gunderman, Christopher P Ptak, Madeline Schutt, Kento Yahashiri, Elizabeth Lippner, Amer Khojah, Aisha Ahmed, Aaruni Khanolkar.

   Background: X-linked MAGT1 deficiency with increased susceptibility to EBV-infection and N-linked glycosylation (XMEN) disease is an inborn error of immunity (IEI) affecting the Magnesium Transporter 1 (MAGT1) gene. In this report, we present the diagnostic odyssey for a patient harboring a novel MAGT1 variant resulting in XMEN disease.
Case presentation: A 6y old male child of Caucasian ancestry presented at the immunology clinic in our hospital with a history of recurrent upper respiratory tract infections, as well as significant atopy and viral skin lesions. Genetic testing identified a novel, hemizygous pathogenic variant in the magnesium transporter 1 (MAGT1) gene (c.580dup; p.Ser194Phefs*3). Follow-up testing by flow cytometry revealed the canonical disruption in Natural Killer Group 2D (NKG2D) surface expression on CD8 T cells and NK cells, and clinical testing for congenital disorders of glycosylation (CDG) additionally verified the hallmark defect in glycosylation that underpins XMEN disease. Subsequent in silico analyses using AlphaFold provided an in-depth view of the resulting aberrant protein structural variant and its inability to tether itself to the OST-B complex, a pre-requisite for optimal enzymatic activity of the MAGT1 protein. Disease management included infection control and prophylaxis, steroids and immunotherapy for the patient's asthma and atopy, topical antiviral treatment for the warts and molluscum, as well as biannual EBV load monitoring (the patient is EBV negative).
Conclusion: This case illustrates how a synergistic multi-disciplinary team approach established a diagnosis of XMEN disease in a patient with an atypical clinical presentation. This case also highlights a growing trend where established diagnostic tools such as flow-cytometry and genomics can be complemented with newer, sophisticated analytical approaches such as AlphaFold to further elucidate the functionally crippling effects of novel variants described in the setting of IEI.

Keywords:  AlphaFold; MAGT1; NKG2D (Natural killer group 2 member D); Oligosaccharyltransferase-B (OST-B); XMEN disease; atopy; congenital disorders of glycosylation (CDG); inborn error of immunity (IEI)

DOI:  https://doi.org/10.3389/fimmu.2026.1754394
Future Sci OA. 2026 Dec;12(1): 2635722

Preclinical assessment of GNEwt/bi-shRNA-GNEM743T lipoplex product development for GNE myopathy.

Fabienne Kerneis, Christopher M Jay, Donald Rao, Jeremy Winchester, Alexander Nemunaitis, Emily Nemunaitis, Ernest Bognar, Gladice Wallraven, Laura Stanbery, Adam Walter, Sep Sarshar, John Nemunaitis.

   AIMS: GNE myopathy is a heredity disease of unmet medical need associated with progressive skeletal muscle wasting, atrophy and weakness caused by mutations in the GNE gene. GNE plays a pivotal role in sialic acid production. Sialic acid is a critical part of glycoprotein, ganglioside and glycolipid cell-cell interaction which is necessary for normal skeletal muscle function. Previously we demonstrated safety and efficacy of the GNEwt gene lipoplex in one patient.
METHODS: We engineered GNEM743T and dual function GNEwt/bi-shRNA plasmids to evaluate GNEM743T specific knockdown and GNEwt expression. Knockdown efficiency, protein expression, and functional rescue were assessed. A dose range study in mice quantified plasmid delivery and human GNE expression in muscle.
RESULTS: We demonstrate effective plasmid function via knockdown of the GNEM743T gene mutation and concurrent expression of GNEwt gene in a dose dependent manner. Similar in vitro increase in sialic acid production is shown between prior single function plasmid and GNEwt/bi-shRNA-GNEM743T dual function plasmid. Moreover, we demonstrate murine in vivo muscle delivery and expression of GNEwt mRNA from the GNEwt/bi-shRNA-GNEM743T plasmid delivered via DOTAP-Cholesterol lipoplex following intravenous injection.
CONCLUSION: These results encourage future studies, potentially leading toward clinical testing of GNEwt/bi-shRNA-GNEM743T lipoplex for GNE myopathy.

Keywords:  GNE; GNE M743T; Plasmid; bi-shRNA; myopathy

DOI:  https://doi.org/10.1080/20565623.2026.2635722
IUBMB Life. 2026 Mar;78(3): e70091

ALG8-Driven Metabolic Reprogramming in Polycystic Kidney Disease: A Systematic Synthesis of Evidence Linking Glycosylation Defects to Metabolic Signaling.

Xiaoran Wang, Zhili Huang, Wen Zhang.

  Endoplasmic reticulum glycosyltransferase ALG8 controls metabolic fate in autosomal dominant polycystic kidney disease (ADPKD). In this paper, we summarize human genetics, cell-based, and organ-based evidence to investigate whether ALG8 variants affect cyst initiation and metabolic states of ADPKD. Population screening showed ALG8 variant enrichment in ADPKD cohorts (OR = 9.75, P0.001); loss-of-function alleles interact with PKD1 mutations to accelerate cystogenesis. ALG8 deficiency leads to metabolic collapse by several mechanisms. Impaired polycystin-1 glycosylation disrupts ER-to-cilium trafficking, prevents PC1/PC2 complex assembly, and impedes calcium-dependent ATP production. Deficient LRP6 glycosylation activates Wnt/-catenin signaling. This shifts metabolism toward aerobic glycolysis, leading to Warburg-like reprogramming seen in malignancy. Single cell analysis showed ALG8 deficient cystic epithelium has tumor-like metabolic signatures, such as increased glucose uptake, suppressed oxidative phosphorylation, and glutamine dependence. Chemical chaperones that restore folding capacity or glycosylation inhibitors that lower anabolic demand both suppressed cyst formation in ALG8/PKD1-deficient organoids. The connection from ALG8 loss to "oncogenic-like" metabolism remains incomplete. Study-to-study variability in model system, genotype, and endpoint still limits cross-cohort comparison. This dual vulnerability-of protein folding and glycosylation-is due to the fragile metabolic balance in cystogenesis. These results recast ADPKD as a metabolic disorder where glycosylation defects link ciliary dysfunction to oncogenic transformation. We focus on three areas: (i) convergence with multiple lines of evidence, (ii) disagreement, and (iii) testable predictions for future studies and trials. The overlap between cystogenic and tumorigenic metabolic programs suggests cancer metabolic inhibitors may be reused for ADPKD in near-term translation. By defining ALG8 as a metabolic checkpoint in polycystic disease, we uncover targets at the glycosylation-metabolism interface.

Keywords:  ALG8 glycosyltransferase; N‐glycosylation; Warburg effect; autosomal dominant polycystic kidney disease (ADPKD); metabolic reprogramming

DOI:  https://doi.org/10.1002/iub.70091
J Neurochem. 2026 Mar;170(3): e70395

Brain Organoids as Emerging Platforms for Modeling Neurodegenerative Diseases: Progress, Challenges, and Future Directions.

Yesim Kaya, Kevser Kübra Kırboğa.

  Neurodegenerative diseases are a group of disorders (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis) characterized by loss of function and death of neurons in different parts of the nervous system. These pathologies constitute a global burden, especially for aging populations. This circumstance leads to an increasing demand for understanding the fundamental mechanisms and development of therapeutic strategies. Conventional models, including two-dimensional cell culture and animal models, postmortem brain tissue provide an overview about neurodegenerative disorders but do not completely recapitulate cellular and molecular mechanisms of the human brain. Although three-dimensional (3D) brain organoids exhibit similar properties with physiological and pathological conditions of human brain, including interaction of neuronal, glial cells and self-organizing structure, protein aggregation, neuroinflammation, and neuronal degeneration. The integration of reprogrammed human induced pluripotent stem cells (iPSCs) with 3D brain organoid systems provides a clinical platform as a bridge between bench to bedside. Brain organoids have been used to elucidate novel insights into the molecular and genetic mechanisms underlying neurodegenerative diseases. Furthermore, brain organoids serve as a tool for in vitro disease modeling, drug screening and emergence of new treatments. Despite these clinical benefits, there are various limitations such as incomplete tissue maturation, lack of vascularization and incomplete cellular diversity in this 3D culture system. This review describes in detail the advantages and disadvantages of brain organoids usage in modeling neurodegenerative diseases from a contemporary perspective.

Keywords:  3D disease modeling; brain organoids; induced pluripotent stem cells; neurodegenerative diseases

DOI:  https://doi.org/10.1111/jnc.70395
Arch Biochem Biophys. 2026 Feb 27. pii: S0003-9861(26)00049-4. [Epub ahead of print]779 110778

Rodent models with neuraminidase deficiencies.

Melike Can, Hande Basırlı, Volkan Seyrantepe.

  Neuraminidases are crucial enzymes that cleave terminal sialic acid residues from sialylated glycoconjugates. Their presence varies across tissues, cellular locations, and substrate specificities in different mammalian species, assigning each neuraminidase distinct functions. Rodent models have significantly contributed to the field of sialobiology, and the absence of these enzymes allows researchers to investigate their roles in degrading oligosaccharides, glycoproteins, and glycolipids. Additionally, these models aid in understanding diseases associated with neuraminidases, such as lysosomal storage disorders and neurodegenerative diseases, thereby supporting the development of new therapies. This review highlights key discoveries from studies of neuraminidase-deficient animal models. SIGNIFICANCE STATEMENT: Neuraminidases are essential for degrading sialic acid-containing biomolecules, and their absence is associated with the development of various neurodegenerative disorders.

Keywords:  Glycoconjugates; LSD; Neuraminidase; Rodent model; Sialic acid

DOI:  https://doi.org/10.1016/j.abb.2026.110778
Proc Natl Acad Sci U S A. 2026 Mar 10. 123(10): e2508476123

GalNAc-T13 maintains neurite architecture and memory retention via O-GalNAc glycosylation of seizure protein 6.

Yao Deng, Xia Zou, Han Zhang, Xiaoyan Lu, Xingming Zhao, Wenjuan Jia, Yingjiao Xu, Fang Yang, Hisashi Narimatsu, Yan Zhang.

  Glycosylation, a key and prevalent modification in brain proteins and lipids, is essential for brain development and function. O-GalNAc glycosylation, initiated by the family of polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts, GALNTs), is the most abundant type of O-glycosylation in the brain. Despite growing evidence linking GALNT variations to neuropsychiatric disorders, the molecular roles and underlying mechanisms by which O-GalNAc glycosylation contributes to brain functions remain poorly characterized. Here, we focus on GalNAc-T13, a member of the GalNAc-T family that is highly expressed in the brain. We established a brain-specific Galnt13 conditional knockout mouse model and found that these mice exhibited reduced neurite length, simplified dendritic branching, and decreased dendritic spine density in the cerebral cortex across embryonic and adult stages. Behavioral analyses further revealed impaired spatial memory consolidation following Galnt13 knockout. Mechanistically, we identified seizure protein 6 (SEZ6), a neurodevelopment-related protein, as a key substrate of GalNAc-T13 using a lectin-based mass spectrometry glycoproteomic approach. Our results demonstrated that GalNAc-T13 regulates the O-GalNAc glycosylation levels of SEZ6 with high catalytic efficiency in vitro and in vivo, improving protein stability and its interaction with PRSS12 at the cell surface to promote neurite outgrowth. Collectively, these findings suggest a critical role for GalNAc-T13 in maintaining cortical neurite architecture and memory retention, providing a mechanistic example for understanding the function of O-GalNAc glycosylation in the brain.

Keywords:  GalNAc-T13; O-glycosylation; neuronal development; seizure protein 6 (SEZ6)

DOI:  https://doi.org/10.1073/pnas.2508476123
Mol Genet Genomic Med. 2026 Mar;14(3): e70195

Identification of a Homozygous PGM2L1 Variant in a Male Patient With Developmental Delay and Seizures.

Mengmeng Niu, Dong Wang, Shanshan Jia.

   BACKGROUND: PGM2L1 gene variants are associated with developmental delays, seizures, and various neurological and physical symptoms. This study aims to report the clinical features and genetic findings in a male patient with developmental delay, regression, and seizures.
METHODS: Whole-exome sequencing (WES) was performed on the patient to identify the genetic etiology of the patient. Sanger sequencing was used for variant confirmation. Clinical evaluations were conducted, including cerebrospinal fluid analysis, cranial MRI, EEG, and neurological assessments.
RESULTS: The patient is a 1-year-old male who presented with psychomotor delays and developed seizures and impaired consciousness at 1 year of age. Cranial MRI revealed bilateral frontotemporal subarachnoid widening. Developmental regression was observed shortly after the onset of seizures. The EEG results showed diffuse slow background activity and epileptiform discharges. WES identified a rare homozygous variant in the PGM2L1 gene (OMIM: 611,610, NM_173582.6: c.1673delC, p.Thr558Ilefs*19), which was inherited from both parents. Sanger sequencing confirmed the presence of the variant, and it was evaluated as a likely pathogenic variant according to American College of Medical Genetics and Genomics (ACMG) guidelines.
CONCLUSION: Our study was the second report of a PGM2L1 gene variant associated with early-onset developmental delay and seizures, further expanding the genetic spectrum of this disorder.

Keywords:  PGM2L1 variant; developmental delay; dysmorphic facies; neurodevelopmental disorder with hypotonia; seizures; skin abnormalities; whole‐exome sequencing

DOI:  https://doi.org/10.1002/mgg3.70195
PLoS Comput Biol. 2026 Mar 06. 22(3): e1013993

Morphological determinants of glycosylation efficiency in Golgi cisternae.

Christopher K Revell, Martin Lowe, Nicola L Stevenson, Oliver E Jensen.

The Golgi apparatus has an intricate spatial structure characterized by flattened membrane-bound compartments, known as cisternae. Cisternae house integral membrane enzymes that catalyse glycosylation, the addition of polymeric sugars to protein cargo, which is important for the trafficking and function of the products. The unusual and specific shape of Golgi cisternae is highly conserved across eukaryotic cells, suggesting significant influence in the correct functioning of the Golgi. Motivated by experimental evidence that disruption to Golgi morphology can lead to observable changes in secreted cargo mass distribution, we develop and analyse a mathematical model of polymerisation in a cisterna that combines chemical kinetics, spatial diffusion and adsorption and desorption between lumen and membrane. Exploiting the slender geometry, we derive a non-local non-linear advection-diffusion equation that predicts secreted cargo mass distribution as a function of cisternal shape. The model predicts a maximum cisternal thickness for which successful glycosylation is possible, demonstrates the existence of an optimal thickness for most efficient glycosylation, and suggests how kinetic and geometric factors may combine to promote or disrupt polymer production.

DOI: https://doi.org/10.1371/journal.pcbi.1013993