bims-meglyc Biomed News
on Metabolic disorders affecting glycosylation
Issue of 2026–05–31
seven papers selected by
Silvia Radenkovic, UMC Utrecht
  1. The revised three-step detour pathway in dolichol biosynthesis is evolutionarily conserved in budding yeast.
  2. A splice-altering intronic variant in two multiplex families refines autosomal recessive COG4-related congenital disorder of glycosylation.
  3. Genetic rescue of pathogenic O-GlcNAc dyshomeostasis associated with microcephaly and motor deficits.
  4. In Vivo Assessment of dbDNA GNEwt/bi-shRNA-GNEM743T Lipoplex for GNE Myopathy: Improved Potency and Safety.
  5. A mouse model of free sialic acid storage disorder: Hypomyelinating leukodystrophy and Purkinje cell degeneration.
  6. Case Report: Recurrent pathogenic mutation c.110G>A in DHDDS gene.
  7. Clinical and biochemical footprints of inherited cofactor disorders.
  1. Proc Natl Acad Sci U S A. 2026 Jun 02. 123(22): e2613147123
    The revised three-step detour pathway in dolichol biosynthesis is evolutionarily conserved in budding yeast.
    Kazuki Hanaoka, Kuya Matsunaga, Souichirou Shimizu, Soshi Sakai, Harald Pichler, Kouichi Funato.
      The identification of SRD5A3, a causative gene for congenital disorders of glycosylation (CDGs), together with its yeast ortholog DFG10, established the prevailing model that dolichol is synthesized from polyprenol in a single step. Subsequently, a recent discovery of DHRSX in CDG patients revised this view and led to the proposal of a three-step detour pathway for dolichol biosynthesis. However, it remains unclear whether this pathway represents a conserved mechanism or reflects evolutionary diversity in eukaryotes. Here, we identified TDA5 as a yeast ortholog of DHRSX. Deletion of TDA5 caused glycosylation defects, reduced dolichol levels, and accumulated polyprenol. All these phenotypes were rescued by expression of DHRSX, but not by DFG10 or SRD5A3. These findings show that Tda5 serves the same function as DHRSX in yeast, thereby demonstrating conservation of the three-step detour pathway in yeast and supporting a broader eukaryotic framework for dolichol biosynthesis.
    Keywords:  DHRSX; TDA5; congenital disorders of glycosylation (CDGs); dolichol; yeast
    DOI:  https://doi.org/10.1073/pnas.2613147123
  2. Mol Genet Metab. 2026 May 22. pii: S1096-7192(26)00438-5. [Epub ahead of print]148(3): 110155
    A splice-altering intronic variant in two multiplex families refines autosomal recessive COG4-related congenital disorder of glycosylation.
    Lucia Micale, Luisa Sturiale, Federica Russo, Ester Di Muro, Grazia Nardella, Riccardo Pracella, Sonia Lomuscio, Silvia Morlino, Mario Benvenuto, Angela Messina, Angelo Palmigiano, Massimo Carella, Giuseppe d'Orsi, Pietro Palumbo, Orazio Palumbo, Rita Barone, Marco Castori.
      Autosomal recessive COG4-related congenital disorder of glycosylation [COG4-CDG(ar)] is caused by biallelic deleterious variants in COG4, which encodes a component of the conserved oligomeric Golgi complex lobe A. COG4-CDG(ar) has been described in six individuals to date, and its clinical manifestations and disease mechanisms remain poorly understood. Exome sequencing identified the homozygous COG4 c.1647+5G>A variant in four affected individuals from two apparently unrelated Italian families. SNP-array genotyping revealed a common ancestral haplotype extending for 3.36 cM around COG4 and supports a founder effect for the identified variant. Whole transcriptome sequencing and reverse transcriptase PCR from peripheral blood detected an aberrant COG4 transcript which features skipping of exon 12 and results in a frameshift, predicted to introduce a premature termination codon. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry profiling of serum N-glycans showed mildly deficient galactosylation and sialylation, consistent with an impaired Golgi-mediated glycosylation. As a novel finding, N-glycosylation study of serum IgG showed analogous N-glycan anomalies. These findings and literature review define COG4-CDG(ar) as a neurometabolic disorder with a progressive course leading to severe global disability, post-natal microcephaly with brain atrophy, seizures, coagulopathy, liver involvement, recurrent infections, and defective N-glycosylation of serum proteins.
    Keywords:  COG4; Glycosylation; Golgi trafficking; MALDI-TOF MS; Transcriptomics
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110155
  3. eNeuro. 2026 May 28. pii: ENEURO.0453-25.2026. [Epub ahead of print]
    Genetic rescue of pathogenic O-GlcNAc dyshomeostasis associated with microcephaly and motor deficits.
    Florence Authier, Iria Esperon-Abril, Kévin-Sébastien Coquelin, Christian Stald Skoven, Simon Fristed Eskildsen, Nina Ondruskova, Andrew T Ferenbach, Jesper Skovhus Thomsen, Brian Hansen, Daan M F van Aalten.
      Missense variants in O-GlcNAc transferase (OGT) result in OGT congenital disorder of glycosylation (OGT-CDG), an intellectual disability syndrome associated with O-GlcNAc dyshomeostasis and a range of neurodevelopmental defects. Inhibition of O-GlcNAcase (OGA), the enzyme responsible for removing protein O-GlcNAcylation, has been explored as a target for modulating brain O-GlcNAc homeostasis in neurodegenerative diseases and may also be a target for OGT-CDG. Here, we describe an OGT-CDG mouse line, studied in male mice, that exhibits microcephaly, motor deficits, and brain O-GlcNAc dyshomeostasis, closely mirroring patient symptoms. We genetically explored OGA as a target for OGT-CDG by crossing these mice with a line carrying catalytically inactive OGA. Encouragingly, this partially restored O-GlcNAc homeostasis in brain and blood as determined by Ogt/Oga mRNA ratio. These findings suggest that OGA inhibition can modulate enzymatic imbalance in OGT-CDG mice possessing microcephaly and motor deficits, and that blood can be used to monitor the effects of interventions targeting O-GlcNAc dyshomeostasis.Significance Statement O-GlcNAc is a chemical modification present on many proteins inside cells and is vital for healthy brain development. Mutations in the OGT enzyme, which adds this modification, lead to a neurodevelopmental disorder involving intellectual disability, microcephaly, and motor difficulties. Although more than 70 individuals with this condition are now known, we still lack a clear understanding of how OGT mutations cause the disease. As a result, there are currently no biomarkers or targeted treatments. Our research addresses these gaps by developing a disease-relevant mouse model and identifying measurable changes in O-GlcNAc homeostasis associated with brain function. This work provides crucial groundwork for future diagnosis and therapy.
    DOI:  https://doi.org/10.1523/ENEURO.0453-25.2026
  4. J Gene Med. 2026 May;28(5): e70098
    In Vivo Assessment of dbDNA GNEwt/bi-shRNA-GNEM743T Lipoplex for GNE Myopathy: Improved Potency and Safety.
    Christopher M Jay, Fabienne Kerneis, Donald Rao, Alexander Nemunaitis, Ernest Bognar, Gladice Wallraven, Laura Stanbery, Rebecca Lutz, Adam Walter, Sep Sarshar, John Nemunaitis.
      GNE myopathy is an autosomal recessive disease, associated with skeletal muscle deterioration, which afflicts young adults. GNE plays a pivotal role in sialic acid production. Sialic acid acts as a buffer against reactive oxygen species generated during muscle contraction. Increased oxidative stress may relate to muscle atrophy involving patients with GNE myopathy. GNEM743T is the most common mutation leading to GNE myopathy. In our previous work, we demonstrated that a bifunctional plasmid that expresses wild type (wt) GNE and knocks down the GNEM743T mutant improves sialic acid production in vitro. Now, we expand evidence of in vivo activity of the bifunctional plasmid using a DOTAP-Cholesterol delivery vehicle and reduced toxic plasmid components using dbDNA conversion. We demonstrate that IV delivery of dbDNA lipoplex (LPX) in murine and rat models shows safety, increased DNA delivery, and improved RNA expression per LPX in skeletal muscle over non db plasmid at equal dose. Sialic acid protein expression was also shown increased in mouse muscle following IV treatment with dbDNA plasmid (pDNA) GNEwt/bi-shRNA-GNEM743T LPX. These results support further preclinical investigation to justify product IND development towards Phase 1 trial involving patients with GNE myopathy.
    Keywords:  GNE; HIBM; bi‐shRNA; dbDNA; doggybone DNA; lipoplex
    DOI:  https://doi.org/10.1002/jgm.70098
  5. Dis Model Mech. 2026 May 26. pii: dmm.052652. [Epub ahead of print]
    A mouse model of free sialic acid storage disorder: Hypomyelinating leukodystrophy and Purkinje cell degeneration.
    Mary E Hackbarth, Mahin S Hossain, Marya S Sabir, Petcharat Leoyklang, Heidi Dorward, John Douglas Burke, Gene Elliot, Lisa Garrett, Patricia Zerfas, Danielle A Springer, Laura Pollard, Stephen Wincovitch, Marjan Huizing, William A Gahl, May Christine V Malicdan.
      Free sialic acid storage disorder (FSASD) is a rare, neurodegenerative, lysosomal storage disease caused by biallelic variants in SLC17A5, which encodes the lysosomal sialic acid exporter, sialin. While clinical severity varies, all affected individuals exhibit progressive neurological decline and characteristic lysosomal and urinary accumulation of free sialic acid. No FDA-approved therapies currently exist, and the molecular underpinnings of central nervous system (CNS) dysfunction remain poorly defined. To model the most prevalent FSASD-associated allele, we generated a Slc17a5R39C mouse model carrying the pathogenic p.Arg39Cys variant using CRISPR/Cpf1. Homozygous Slc17a5R39C/R39C mice recapitulated key features of FSASD, including biochemical accumulation of free sialic acid, ataxia, tremors, seizures, and shortened lifespan. Neuropathological analyses revealed widespread CNS hypomyelination, with relatively preserved peripheral nervous system myelination, while transcriptomic profiling showed broad suppression of myelin-associated genes and a cerebellum-specific inflammatory signature. This was accompanied by pronounced astrogliosis, progressive Purkinje cell degeneration, and elevated neurofilament proteins, including serum NfL. Altogether, the Slc17a5R39C/R39C model of FSASD provides critical insights into disease pathogenesis, highlights region-specific neurodegenerative vulnerabilities, and establishes a robust preclinical platform for mechanistic investigation and therapeutic development.
    Keywords:  Myelin development; Purkinje cell loss; Rare disorders; Sialic acid
    DOI:  https://doi.org/10.1242/dmm.052652
  6. Front Neurosci. 2026 ;20 1801725
    Case Report: Recurrent pathogenic mutation c.110G>A in DHDDS gene.
    Ci Liu, Qiaoyu Ye, Jie Li, Siming Bu, Chenlu Ge, Xiangnan Wang, Moyuan Quan, Liang Wang.
      Recent studies have demonstrated the close association of mutations in the dehydrodolichyl diphosphate synthase (DHDDS) gene with neurodevelopmental disorders and the onset of epilepsy. This report describes a female patient harboring a de novo heterozygous variant c.110G>A (p.Arg37His) in the DHDDS gene, characterized by childhood-onset myoclonus-like movement disorder (at age 6) and late-onset epilepsy (at age 17). The movement disorder was remarkably improved through the levetiracetam+ clonazepam+ haloperidol triple therapy, and epileptic seizures were also effectively controlled. A retrospective analysis of 59 epilepsy patients with DHDDS gene variants revealed significant clinical heterogeneity in disease phenotypes caused by DHDDS mutations. Epilepsy was identified as the predominant symptom, commonly accompanied by movement disorders and varying degrees of intellectual disability. Furthermore, while pathogenic mutations in DHDDS tend to be relatively clustered, no definitive genotype-phenotype correlation has been established. This study highlights the clinical manifestations, imaging features, treatment experiences, and genetic testing results through case reports and literature review, thereby providing crucial references for the clinical diagnosis, treatment, and further research of such diseases.
    Keywords:  DHDDS; ataxia; epilepsy; myoclonus; whole exome sequencing (WES)
    DOI:  https://doi.org/10.3389/fnins.2026.1801725
  7. Mol Genet Metab. 2026 May 18. pii: S1096-7192(26)00446-4. [Epub ahead of print]148(3): 110163
    Clinical and biochemical footprints of inherited cofactor disorders.
    Ivano Di Meo, Carlos R Ferreira, Thomas Opladen, Günter Schwarz, Valeria Tiranti, Clara van Karnebeek, Eva van Walree, Nenad Blau.
      Inherited metabolic disorders (IMDs) affecting cofactor biosynthesis, recycling, transport, or utilization cause characteristic combinations of biochemical abnormalities and multi-system clinical signs. Here, we describe footprints of 29 ICIMD-curated cofactor disorders: tetrahydrobiopterin (BH4; n = 6), molybdenum cofactor (MoCo; n = 5), vitamin B6 (pyridoxal-5'-phosphate; n = 6), niacin/nicotinamide adenine dinucleotide (NAD; n = 7), and pantothenate/coenzyme A (n = 5), by integrating disorder-specific biomarker panels with a structured symptom matrix. Across domains, heat map-based profiling highlights recurrent neurologic hot spots (seizures, movement disorders, neurodevelopmental impairment) while also revealing pathway-anchored signatures that can rapidly narrow the differential diagnosis, such as hyperphenylalaninemia with monoamine deficiency in several BH4 disorders, sulfite intoxication markers in classic MoCo deficiency, a B6-responsive neonatal epileptic encephalopathy pattern, an ocular-predominant footprint in nicotinamide mononucleotide adenylyltransferase 1 NMNAT1-related NAD disease, and cardio-metabolic failure in multiple CoA biosynthesis defects. We summarize pathomechanisms and current treatment options, emphasizing time-critical, treatable conditions (e.g., cyclic pyranopterin monophosphate (cPMP; fosdenopterin) replacement in MoCo-A; neurotransmitter and vitamin replacement strategies). This harmonized framework is intended to support early, pathway-informed testing and management in suspected cofactor-related IMDs. By aligning clinical-system patterns with biochemical 'anchors', this framework complements genomic diagnostics, guides surveillance, and prioritizes interventions in neonatal encephalopathy, childhood movement disorders, and recurrent acute metabolic crises. While newborn screening is well established for disorders of BH4 metabolism, screening for several other disorders, such as PDE-ALDH7A1 deficiency, is still in the pilot phase and available only in a few specialized centers. In contrast, genomic screening, with all its benefits and pitfalls, is emerging as a complement to classic newborn screening.
    Keywords:  Biomarkers; Coenzyme a; Cofactor; Inherited metabolic disorders; Molybdenum cofactor; NAD; Phenotype; Tetrahydrobiopterin; Vitamin B(6)
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110163
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