bims-meglyc Biomed News
on Metabolic disorders affecting glycosylation
Issue of 2025–10–19
eleven papers selected by
Silvia Radenkovic, UMC Utrecht
  1. Insights into ALG3-CDG: A case study combining glycan profiling and genetic analysis.
  2. Protein glycosylation and synaptic transmission: brain glycogen keeps them separated.
  3. Exploring a Circulating miRNA Signature for PMM2-CDG: Initial Insights Toward Diagnosis, Stratification, and Monitoring.
  4. Treatment of Single Patient With PMM2-Congenital Disorder of Glycosylation With Govorestat (AT-007), an Aldose Reductase Inhibitor.
  5. Phosphoglucomutase 1 deficiency misdiagnosed as Laron syndrome.
  6. Suspected Central Adrenal Insufficiency in a Patient with Phosphomannomutase 2-Congenital Disorder of Glycosylation.
  7. Decoding GNE Myopathy: From Molecular Basis to Therapeutic Advances.
  8. NGLY1 as an Emerging Critical Modulator for Neurodevelopment and Pathogenesis in the Brain.
  9. Structural characterization and insights into the formation of N-acetylglucosaminylasparagine and its derivatives in NGLY1-deficient models and patients.
  10. The emerging landscape of brain glycosylation: from molecular complexity to therapeutic potential.
  11. A 2-year-old girl with merged phenotypes: galactosemia and Coffin-Lowry syndrome.
  1. Mol Genet Metab Rep. 2025 Dec;45 101263
    Insights into ALG3-CDG: A case study combining glycan profiling and genetic analysis.
    Rebeka Kodríková, Zuzana Pakanová, Maroš Krchňák, Veronika Krajčovičová, Anna Šalingová, Katarína Skalická, Miriam Kolníková, Peter Baráth, Marek Nemčovič.
      Congenital disorders of glycosylation (CDG) are a group of rare metabolic disorders caused by the defects in the glycosylation pathways of biomacromolecules leading to altered glycoprofiles in affected individuals. In this case study, we present a 3-year-old Slovak male patient with developmental delay, hearing impairment, epilepsy, microcephaly, facial dysmorphism, corpus callosum dysgenesis, and cardiac abnormalities. To elucidate the underlying cause, we performed LC-ESI-MS analysis of RapiFluor-labelled N-glycans released from blood serum glycoproteins. The results revealed an abnormal N-glycan profile, characterized by an increased relative abundance of truncated mannosylated structures (Hex3HexNAc2 and Hex4HexNAc2) and a decreased presence of higher-order mannose structures (Hex6-8HexNAc2). A molecular analysis was also conducted. Whole exome sequencing confirmed a diagnosis of ALG3-CDG with compound heterozygous variants: c.165C > T (p.Gly55=) and c.1060C > T (p.Arg354Cys) in the ALG3 gene, encoding alpha-1,3-mannosyltransferase in the endoplasmic reticulum. This presented case highlights the importance of glycan profiling and genetic analysis in diagnosing congenital disorders of glycosylation, facilitating early intervention and management.
    Keywords:  ALG3-CDG; Congenital disorders of glycosylation; LC-MS; Mass spectrometry; RapiFluor
    DOI:  https://doi.org/10.1016/j.ymgmr.2025.101263
  2. Brain. 2025 Oct 17. pii: awaf396. [Epub ahead of print]
    Protein glycosylation and synaptic transmission: brain glycogen keeps them separated.
    Gabriele Trentini, Giulia Cazzanelli, Graziano Lolli.
      Brain glycogen has for long been regarded uniquely as a source of energetic support in situations of emergency or heightened activity. Recently, brain glycogen was found to contain a significant amount of glucosamine, which is used to sustain protein glycosylation. In this update, we highlight that glucosamine synthesis through the hexosamine pathway would subtract glutamine, which is instead indispensable for glutamate and GABA recycling. Brain glycogen seems then to serve an additional role. By providing glucosamine and, through it, inhibiting the hexosamine pathway, glycogen avoids glutamine depletion. In neurological glycogen storage diseases, the short-circuit between the hexosamine pathway and neurotransmitters recycling can cause epileptic seizures, which are the most common acute manifestation in these pathologies. We finally discuss the metabolic and symptomatic superposition of glycogen storage diseases with congenital disorders of glycosylation, concluding that treatments ameliorating the clinical symptoms in some of the discussed pathologies could also be beneficial in the others.
    Keywords:  congenital disorders of glycosylation; epilepsy; glucosamine; glutamine; glycogen; glycogen storage diseases
    DOI:  https://doi.org/10.1093/brain/awaf396
  3. J Inherit Metab Dis. 2025 Nov;48(6): e70104
    Exploring a Circulating miRNA Signature for PMM2-CDG: Initial Insights Toward Diagnosis, Stratification, and Monitoring.
    Florencia Epifani, Lluc Cabus, Gregorio A Nolasco, Mercè Bolasell, Jennifer Pérez, Adrián Alcalá, Patricia Fernández, Esther Lizano, Gisela Márquez, Sonia Belmonte, Sílvia Carbonell-Sala, Julien Lagarde, Joao Curado, Cristina Hernando-Davalillo, Mercedes Serrano.
      Phosphomannomutase deficiency (PMM2-CDG) is the most common congenital disorder of glycosylation, characterized by variable early-onset neurological (hypotonia, cerebellar syndrome, developmental delay) and multi-organ manifestations. Although several clinical trials are ongoing, current biomarkers lack prognostic or monitoring utility. Emerging transcriptomic studies suggest dysregulated pathways in PMM2-CDG, but miRNAs, key gene expression regulators, remain unexplored. This cross-sectional study aims to investigate a circulating miRNA signature that may distinguish PMM2-CDG patients from unaffected controls, providing an initial framework for future studies on potential predictive and monitoring tools. Differential gene expression analysis was used to identify significant differentially expressed (DE) miRNAs, while machine learning models (LASSO, XGBoost) were applied to create an miRNA predictive signature. Dysregulated miRNA pathways analysis provided insights into affected tissues and cellular mechanisms. An optimized protocol addressing challenges in pediatric blood samples was implemented. miRNA profiles from blood samples of 28 PMM2-CDG patients and 67 unaffected controls were analyzed, identifying six DE miRNAs. Regarding machine learning models, XGBoost achieved the best performance (AUC 0.917). Biological analysis revealed that DE miRNAs influence neurological, endocrinological, immunological, and cellular pathways related to the PMM2-CDG phenotype. Notably, miR-122-5p emerged as a highly predictive marker, indicating liver and neurological involvement. Circulating miRNAs represent a promising, minimally invasive avenue for further investigation. While preliminary evidence of their potential diagnostic utility is provided, additional validation in larger and more diverse populations is required to determine their relevance for clinical stratification or monitoring in PMM2-CDG, contributing to future biomarker-driven personalized medicine efforts in this disease.
    Keywords:   PMM2‐CDG ; biomarkers; machine learning; miRNA; pathway dysregulation; transcriptomic
    DOI:  https://doi.org/10.1002/jimd.70104
  4. JIMD Rep. 2025 Nov;66(6): e70043
    Treatment of Single Patient With PMM2-Congenital Disorder of Glycosylation With Govorestat (AT-007), an Aldose Reductase Inhibitor.
    Elizabeth R Jalazo, Leigh Anne Weisenfeld, Anna Ligezka, Riccardo Perfetti, Joseph Muenzer.
      Aldose reductase inhibitors (ARI) have been identified as a potential treatment for phosphomannomutase-2 congenital disorder of glycosylation (PMM2-CDG), a serious condition for which no treatments are approved. We treated a single patient for 36 months 30 months of age at enrollment, under a single-patient investigational new drug expanded access request, with govorestat (AT-007), a novel, highly selective, once daily, brain penetrant ARI at a starting dose of 1 mg/kg oral suspension, which was escalated to 30 mg/kg. The primary endpoint was safety. Secondary assessments included liver transaminases, factor XI, antithrombin III, and whole blood and urine sorbitol. Clinical outcomes were also assessed, including Nijmegen Pediatric CDG Rating Scale (NPCRS), Bayley Scales of Infant Development, and Vineland Adaptive Behavioral Scale. Govorestat was well tolerated; no adverse effects were noted. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels improved from a pre-treatment 12-month average of 205 and 268 U/L to 63 and 68 U/L, respectively, averaged over 36 months of govorestat treatment at 30 mg/kg. Antithrombin III and factor XI fluctuated with illness throughout the study period but overall increased by 60%-100%, approaching the normal range (> 83% activity) at the 5 mg/kg dose. Whole blood sorbitol decreased in a dose-dependent fashion, normalizing at the 30 mg/kg dose. The NPCRS improved by 9 points (46%) over the course of treatment. In conclusion, our patient tolerated govorestat without safety concerns. Improvements in liver transaminases, clotting factors, and whole blood sorbitol were observed along with improvements in clinical measures. These findings support further study of govorestat as a potential treatment for PMM2-CDG.
    Keywords:  PMM2‐CDG; aldose reductase inhibitors; govorestat
    DOI:  https://doi.org/10.1002/jmd2.70043
  5. J Pediatr Endocrinol Metab. 2025 Oct 17.
    Phosphoglucomutase 1 deficiency misdiagnosed as Laron syndrome.
    Seyit Ahmet Uçaktürk, Emre Özer, Ahmet Cevdet Ceylan, Eda Mengen.
       OBJECTIVES: Protein glycosylation is a crucial process involving the addition of oligosaccharides to proteins, which plays a significant role in stabilizing proteins and mediating protein-protein interactions. Mutations in genes associated with glycosylation can lead to congenital disorders of glycosylation (CDG), resulting in multisystem disorders. One such example is phosphoglucomutase 1 (PGM1) -CDG, caused by a deficiency of the PGM1 enzyme. In this report, we describe a patient with PGM1-CDG who was initially misdiagnosed with growth hormone insensitivity and benefited from recombinant human insulin-like growth factor-1 (rhIGF-1) therapy.
    CASE PRESENTATION: A 2-year-11-month-old female patient, born to first-degree cousin parents, presented with hypoglycemia and short stature. Her physical examination revealed frontal bossing, infantile facial appearance, and short stature. Laboratory investigations revealed that basal and stimulated growth hormone levels were very high, IGF-1 was low, and the inadequate response to the IGF generation test was consistent with growth hormone insensitivity (GHI). The patient was started on rhIGF-1 therapy, resulting in significant height gain. Subsequently, the patient showed improvement in height with rhIGF-1 therapy. The patient, who had additional findings such as elevated creatine kinase (CK) and transaminase levels and cardiomyopathy, was diagnosed with PGM1-CDG.
    CONCLUSIONS: This case highlights that PGM1-CDG can mimic clinical and laboratory findings of GHI. CDG diagnosis should be considered in cases with clinical and laboratory findings of GHI accompanied by multisystem disorders such as hepatopathy, elevated CK, and cardiomyopathy. This patient's successful response to rhIGF-1 therapy highlights the potential benefits of targeted therapies in treating growth hormone-related disorders in patients.
    Keywords:  IGF-1; growth hormone insensitivity; phosphoglucomutase 1 deficiency
    DOI:  https://doi.org/10.1515/jpem-2025-0447
  6. JCEM Case Rep. 2025 Nov;3(11): luaf237
    Suspected Central Adrenal Insufficiency in a Patient with Phosphomannomutase 2-Congenital Disorder of Glycosylation.
    Sofie-Louise Feentved Ødum, Sabine W Grønborg, Katharina M Main, Marianne Klose.
      Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is a hereditary defect causing hypoglycosylation of N-linked glycoproteins. It was recently suggested that patients with PMM2-CDG may have central adrenal insufficiency. We present an 18-year-old male with PMM2-CDG, whose initial screening suggested adrenal insufficiency. The patient displayed a morning plasma cortisol of 57 nmol/L (2.07 μg/dL) (reference range, 133-537 nmol/L [4.82-19.46 μg/dL]), a 30-minute ACTH-stimulated cortisol of 165 nmol/L (5.98 μg/dL), and a low-normal ACTH. The patient never experienced obvious symptoms of adrenal insufficiency nor clinical improvement after transient introduction of hydrocortisone. Additional assessment was therefore conducted, including cortisol binding globulin, which was markedly low (253 mmol/L (14.7 mg/L) (reference range, 750-2500 mmol/L [43.7-93.1 mg/L])). Subsequently, 8 Am salivary cortisol measured 24 hours after last hydrocortisone ingestion was normal-to-slightly elevated (38 nmol/L (1.38 μg/dL) (reference range, 2.48-29 nmol/L [0.09-1.05 μg/dL])). In conclusion, we present a patient with PMM2-CDG who, upon measurement of plasma cortisol, displayed "biochemical" adrenal insufficiency, although with low cortisol binding globulin and normal morning salivary free cortisol levels. This case illustrates the caveats of total cortisol for the diagnosis of adrenal insufficiency in patients with PMM2-CDG and highlights the potential impact of N-linked hypoglycosylation on endocrine evaluation.
    Keywords:  CBG; PMM2-CDG; adrenal insufficiency; glycosylation
    DOI:  https://doi.org/10.1210/jcemcr/luaf237
  7. Ann Indian Acad Neurol. 2025 Oct 13.
    Decoding GNE Myopathy: From Molecular Basis to Therapeutic Advances.
    Wakako Yoshioka, Satoru Noguchi, Ichizo Nishino.
       ABSTRACT: GNE myopathy is a rare, adult-onset, autosomal recessive muscle disorder caused by biallelic pathogenic variants in the GNE gene, which encodes a key enzyme in the biosynthesis of sialic acid. Deficient GNE enzyme activity results in decreased production of sialic acid and subsequent hyposialylation of muscle glycoproteins, ultimately leading to progressive muscle degeneration and characteristic histopathological changes. The disease typically presents with progressive distal muscle weakness while sparing the quadriceps until advanced stages. Advances in molecular biology have significantly clarified the underlying disease mechanisms and revealed genotype-phenotype correlations. Natural history studies, supported by patient registries, have detailed the disease course and identified extra-muscular manifestations such as thrombocytopenia and sleep apnea. Multiple therapeutic strategies are under active investigation, including sialic acid supplementation, antioxidant therapy, and gene therapy. Several clinical trials targeting sialic acid biosynthetic pathways, such as oral N-acetylneuraminic acid, ManNAc, and 6'- sialyllactose, have advanced to late-stage development, culminating in the approval of the N-acetyl-neuraminic acid extended-release tablet in Japan in 2024. Other emerging therapeutic approaches, including antioxidant- and gene-based interventions, are also currently being explored. This review synthesizes the current understanding of the molecular pathogenesis of GNE myopathy and highlights recent advances and future prospects in targeted molecular and therapeutic approaches. The ultimate aim is to foster international collaboration toward the development of innovative and effective treatments for GNE myopathy.
    Keywords:  GNE myopathy; founder mutation; genotype–phenotype correlation; sialic acid; therapeutic development
    DOI:  https://doi.org/10.4103/aian.aian_837_25
  8. Int J Mol Sci. 2025 Oct 06. pii: 9705. [Epub ahead of print]26(19):
    NGLY1 as an Emerging Critical Modulator for Neurodevelopment and Pathogenesis in the Brain.
    Haiwei Zhang, Haipeng Xue, Yu-Chieh Wang, Ying Liu.
      N-glycanase 1 (NGLY1) is a cytoplasmic glycoenzyme that removes N-linked glycans from misfolded glycoproteins. It plays an important role in the endoplasmic reticulum-associated degradation (ERAD) pathway in mammalian cells. NGLY1 dysfunction in humans causes NGLY1 deficiency as a rare autosomal recessive disorder that is characterized by neurodevelopmental delay, hypotonia, movement disorders, seizures, and multi-system involvement. In this review, we summarize recent advances in understanding the neural functions of NGLY1 and the neuropathological phenotypes associated with its deficiency. We discuss the molecular basis of NGLY1 deficiency in the central nervous system (CNS) and pathophysiological insights from animal and human induced pluripotent stem cell (iPSC)-based models. We also highlight emerging gene therapy approaches aimed at restoring NGLY1 activity and alleviating neurological symptoms.
    Keywords:  NGLY1 deficiency; disease modeling; iPSCs; proteostasis; rare genetic disorders
    DOI:  https://doi.org/10.3390/ijms26199705
  9. Glycobiology. 2025 Oct 13. pii: cwaf065. [Epub ahead of print]
    Structural characterization and insights into the formation of N-acetylglucosaminylasparagine and its derivatives in NGLY1-deficient models and patients.
    Hiroto Hirayama, Yuriko Tachida, Reiko Fujinawa, Makoto Asahina, Megumi Hirayama, Tomohiro Andou, Masaya Usui, Tadashi Suzuki.
      Cytosolic peptide:N-glycanase (PNGase/NGLY1 in mammals), a widely conserved amidase in eukaryotes, catalyzes the removal of N-glycans from glycoproteins and contributes to the quality control system for nascent glycoproteins. Since the first report of a patient with an autosomal recessive genetic disorder caused by NGLY1 deficiency in 2012, over 150 cases have been identified globally. Among the potential biomarkers for NGLY1 deficiency, Asn-linked mono/oligosaccharides-Asn-GlcNAc and Asn-HexNAc-Hex-NeuAc-have emerged as the most consistently and markedly elevated molecules in the plasma or urine of affected patients. This study examined the Asn-GlcNAc biosynthetic pathway, demonstrating that cytosolic endo-β-N-acetylglucosaminidase (ENGase), the proteasome, and peptidases are essential for its generation. NGLY1-deficient models and patients exhibited accumulation of novel elongated forms of Asn-GlcNAc, including Asn-GlcNAc-GalNAc, Asn-GlcNAc-Gal, and Asn-GlcNAc-Gal-NeuAc, in cells, culture supernatant, plasma, and urine. Our findings indicate that Asn-GlcNAc and Asn-oligosaccharides (Asn-OSs) may serve as promising diagnostic tools for NGLY1 deficiency.
    Keywords:  NGLY1 deficiency; endo-β-N-acetylglucosaminidase; free glycan; peptide:N-glycanase
    DOI:  https://doi.org/10.1093/glycob/cwaf065
  10. Exp Mol Med. 2025 Oct 14.
    The emerging landscape of brain glycosylation: from molecular complexity to therapeutic potential.
    Youngsuk Seo, Ji Eun Park, Jae Young Yu, Boyoung Lee, Jong Hyuk Yoon, Hyun Joo An.
      Glycosylation functions as a pivotal posttranslational modification in proteins and as a distinct biosynthetic process in lipids. In the brain, it plays essential roles in development, function and homeostasis by modulating protein folding, receptor trafficking and intercellular communication. Although glycans constitute less than 1% of the brain's mass, their impact is disproportionately profound. Recent technological advances have uncovered the essential contributions of both protein- and lipid-bound glycans, including N-glycans, O-glycans and gangliosides, to brain physiology and disease. Here we explore the emerging landscape of brain glycosylation, highlighting its distinct roles in neurodevelopment, synaptic organization and immune regulation. Aberrant glycosylation has been implicated in neurodegenerative diseases (for example, Alzheimer's and Parkinson's), psychiatric disorders (for example, depression and schizophrenia) and neurodevelopmental conditions (for example, autism spectrum disorders, attention deficit hyperactivity disorder and dystroglycanopathies). We summarize recent breakthroughs in glycomics technologies, including glycan enrichment, liquid chromatography-tandem mass spectrometry, MALDI-based imaging mass spectrometry and high-throughput omics, which enable molecular and spatial mapping of brain glycosylation. Artificial-intelligence-driven bioinformatics and multi-omics integration are rapidly opening new avenues for deciphering glycan-mediated regulation in brain health and disease. Together, these developments position brain glycosylation as a transformative frontier in neuroscience, with the potential to yield novel diagnostic biomarkers and therapeutic strategies for complex brain disorders.
    DOI:  https://doi.org/10.1038/s12276-025-01560-8
  11. J Pediatr Endocrinol Metab. 2025 Oct 13.
    A 2-year-old girl with merged phenotypes: galactosemia and Coffin-Lowry syndrome.
    Esra Sayar, Gizem Gökçe Altaş, Abdullah Sezer, Abdulkerim Kolkıran, Berna Ucan, Asburce Olgac.
       OBJECTIVES: Galactosemia is a congenital disorder of carbohydrate metabolism, in which the body is unable to metabolize galactose properly. Coffin-Lowry syndrome (CLS) is characterized by intellectual disability, developmental delay, dysmorphic features, growth retardation, vision and hearing loss, and skeletal changes, which is an X-linked disorder, with males being more severely affected, whereas the clinical findings in females show variability. This case is presented due to the rare concomitance of galactosemia and CLS.
    CASE PRESENTATION: A 2-year-old female patient, previously diagnosed with galactosemia, who had good dietary adherence was noticed to have developmental delay, dysmorphic features, nephrolithiasis and recurrent pericardial effusions during follow-up. Further research was carried out to diagnose an underlying second disease. Metabolic tests were inconclusive. Clinical exome sequencing (CES) analysis, revealed a heterozygous c.472C>T p. (Arg158Cys) pathogenic variant in RPS6KA3 (OMIM #300075) and CLS (OMIM #303600) was diagnosed.
    CONCLUSIONS: This case report is a unique summary of a patient with galactosemia who further was diagnosed with CLS that emphasizes the possibility of co-occurrence of rare diseases and highlights the importance of conducting further investigations in patients with unexplained findings in the context of existing metabolic diseases.
    Keywords:   GALT ; RPS6KA3 ; Coffin-Lowry syndrome; galactosemia
    DOI:  https://doi.org/10.1515/jpem-2025-0159
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