bims-meglyc 2025-09-07 papers

bims-meglyc

Biomed News

on Metabolic disorders affecting glycosylation

Issue of 2025–09–07
seven papers selected by
Silvia Radenkovic, UMC Utrecht

Genetic disorders of dolichol synthesis and utilization.
Investigation of the Clinical and Genetic Spectrum of PMM2-CDG: Insights from a Family with a Novel Variant and Previous Studies.
Recent insights into the implications of UGDH mutations for human developmental disease.
Mono-allelic p.R37H Dehydrodolichyl Diphosphate Synthase variants lead to protein glycosylation defects, aberrant lipid profiles and interneuron scarcity in a novel mouse model of progressive epileptic encephalopathy.
Molecular genetics and therapeutic development for GNE myopathy.
Galactose treatment rescues neuromuscular junction transmission in glutamine-fructose-6-phosphate transaminase 1 (Gfpt1) deficient mice.
Congenital disorders caused by aberrations in the biosynthesis of chondroitin/dermatan sulfate.

Mol Genet Metab. 2025 Aug 22. pii: S1096-7192(25)00217-3. [Epub ahead of print]146(1-2): 109226

Genetic disorders of dolichol synthesis and utilization.

Eline Pieters, Jaak Jaeken, Matthew P Wilson.

  The polyisoprenoid lipid dolichol is critical for eukaryotic glycosylation. It is used as the membrane anchor for mono- or oligosaccharides transferred during N-glycosylation, O/C-mannosylation and glycosylphosphatidylinositol anchor biosynthesis. Disorders affecting the synthesis or utilization of dolichol cause defective glycosylation and are therefore classified as Congenital Disorders of Glycosylation (CDG). CDG are a group of approximately 200 mostly autosomal recessive inherited metabolic disorders characterized by defective glycosylation of proteins and lipids. Through recently identified defects, we have gained new insights into dolichol synthesis, important to understand the pathological mechanisms in affected patients. This review provides an overview of dolichol synthesis and utilization and an update on CDG caused by disruption of these processes. Finally, we discuss the existing biomarkers for diagnosis of these disorders and the potential for effective therapies.

Keywords:  ALG5; Congenital disorders of glycosylation; DHDDS; DHRSX; DOLK; DPAGT1; DPM1; DPM2; DPM3; Dolichol; Dolichol synthesis defects; Epilepsy; Glycobiology; Intellectual disability; MPDU1; N-linked glycosylation; NUS1; Polyisoprenoids; SRD5A3

DOI:  https://doi.org/10.1016/j.ymgme.2025.109226
Arch Iran Med. 2025 Jul 01. 28(7): 387-397

Investigation of the Clinical and Genetic Spectrum of PMM2-CDG: Insights from a Family with a Novel Variant and Previous Studies.

Parnian Alagha, Tara Akhtarkhavari, Ebrahim Shokouhian, Fatemeh Ghodratpour, Sanaz Arzhangi, Hossein Najmabadi, Kimia Kahrizi.

   BACKGROUND: PMM2-CDG, also known as congenital disorder of glycosylation type 1a, is the most common N-linked glycosylation disorder, characterized by a wide range of neurological and multisystem manifestations. Understanding the genotype-phenotype correlations is essential for accurate diagnosis and patient management. This study aims to identify the genetic cause of PMM2-CDG in an Iranian family with multiple affected members, and to analyze the genetic and clinical spectrum of the disorder through a comprehensive literature review.
METHODS: Exome sequencing re-analysis was performed to detect disease-causing variants in three affected siblings. Additionally, a literature review was conducted, analyzing 91 previously reported cases of PMM2-CDG to determine the most prevalent variants and associated clinical features.
RESULTS: A novel splice site variant (c.640-9T>A) was identified alongside a previously reported missense mutation (c.647A>T; p.N216I) in the affected individuals. The literature review revealed that the most frequent PMM2 variants were p.R141H (28.8%), p.V231M (12.8%), p.N216I (6.4%), and p.V129M (5.8%), with 77.6% of mutations occurring in exons 5 and 8. The most common clinical findings included developmental delay, ocular abnormalities (hypertelorism, strabismus), muscular system defects (hypotonia, muscle weakness), neurological symptoms (abnormal MRI findings), cardiovascular involvement (pericarditis, pericardial effusion), and clotting disorders.
CONCLUSION: We expect that our detailed clinical study will improve the genotype-phenotype interpretation of causal PMM2-CDG variants and the analysis of next-generation sequencing data, leading to clarification of the cause of complicated cases of rare diseases.

Keywords:  Congenital disorder of glycosylation type 1A; Genotype-phenotype correlation; Novel variant; PMM2 gene

DOI:  https://doi.org/10.34172/aim.34187
Biochem Soc Trans. 2025 Aug 29. 53(4): 1119-1128

Recent insights into the implications of UGDH mutations for human developmental disease.

Hali Harwood, Brenna M Zimmer, Asher R Utz, Joseph J Barycki, Melanie A Simpson.

  Congenital disorders of glycosylation are a significant underlying cause of developmental and epileptic encephalopathy (DEE). A subset of these DEE cases results from biallelic variants in the unique, essential gene encoding UDP-glucose dehydrogenase (UGDH). The UGDH enzyme catalyzes two successive NAD+- dependent oxidation reactions to convert the C6 hydroxyl of UDP-glucose to a carboxylate, generating the UDP-glucuronate product. This product is required for three critical reactions that generate: (1) hyaluronan, (2) secreted and cell surface proteoglycans, and (3) glucuronide conjugates for cellular detoxification. UGDH polymorphisms are not frequently observed as they are largely deleterious. However, a number of UGDH variants have been reported and characterized as causative agents of congenital defects in cardiac valve and brain development, and most recently of dystroglycanopathy. The effects of these mutations, clinically and at the molecular level, are summarized and discussed in this review.

Keywords:  UDP-glucose dehydrogenase; cardiac valve defects; congenital disorders of glycosylation; developmental and epileptic encephalopathy; dystroglycanopathy; epilepsy

DOI:  https://doi.org/10.1042/BST20253083
bioRxiv. 2025 Aug 21. pii: 2025.08.15.670547. [Epub ahead of print]

Mono-allelic p.R37H Dehydrodolichyl Diphosphate Synthase variants lead to protein glycosylation defects, aberrant lipid profiles and interneuron scarcity in a novel mouse model of progressive epileptic encephalopathy.

Afitz Da Silva, Samuel Boris Tene Tadoum, Irena J J Muffels, Rohit Budhraja, Luisa Sturiale, Angela Messina, Moshe Giladi, Mahsa Taherzadeh, Mehrnaz Fazeli, Éric Bonneil, Shaukat Khan, Danielle Te Vruchte, Yojiro Yamanaka, Graziella Di Cristo, Fadi F Hamdan, Frances M Platt, Shunji Tomatsu, Yoni Haitin, Tamas Kozicz, Pierre Thibault, Domenico Garozzo, Akilesh Pandey, Eva Morava, Elsa Rossignol, Alexey V Pshezhetsky.

Developmental delay and seizures with or without movement abnormalities (OMIM 617836) caused by heterozygous pathogenic variants in the DHDDS gene (DHDDS-CDG) is a rare genetic disease that belongs to the progressive encephalopathy spectrum. It results in developmental delay in affected children, accompanied by myoclonus, seizures, ataxia and tremor, which worsens over time. DHDDS encodes a subunit of a DHDDS/NUS1 cis-prenyltransferase ( cis- PTase), a branch point enzyme of the mevalonate pathway essential for N-linked glycosylation. We describe the first mouse model of this disease, Dhdds R37H+/- strain, heterozygous for the human recurrent de novo c.110G>A:p.R37H pathogenic variant. Dhdds R37H+/- mice present with seizures, myoclonus and memory deficits associated with reduced density or/and maturity of inhibitory interneurons in the cortex. Multiomics analyses of mouse CNS tissues, together with the enzymatic/structural characterization of the R37H DHDDS mutant protein, reveal that the variant produces a catalytically inactive enzyme and results in a brain dolichol deficit, aberrant glycosylation of brain glycoproteins, including those involved in synaptic transmission, and major perturbations in the CNS proteome and lipidome. Acetazolamide, a carbonic anhydrase inhibitor clinically approved for treatment of glaucoma, epilepsy, and intracranial hypertension, and successfully used "off-label" to treat genetic movement disorders, drastically reduces seizure susceptibility to pentylenetetrazol in Dhdds R37H+/- mice, suggesting potential therapeutic value of using this drug in human DHDDS-CDG patients. Together, our results define cis- PTase as a master regulator of CNS development and function and establish that its monoallelic debilitating variants cause a novel Congenital Disorder of Glycosylation, associated with aberrant levels of neuronal proteins and lipids.
Graphical abstract:

DOI: https://doi.org/10.1101/2025.08.15.670547
J Hum Genet. 2025 Sep 05.

Molecular genetics and therapeutic development for GNE myopathy.

Wakako Yoshioka, Satoru Noguchi, Ichizo Nishino.

GNE myopathy is an autosomal recessive distal myopathy resulting from biallelic pathogenic variants in the GNE gene, a key enzyme in sialic acid biosynthesis. Although most pathogenic variants are missense variants, recent advances have enabled the identification of copy number variations, deep intronic variants, and regulatory changes in the promoter region, significantly enhancing diagnostic accuracy. Progress in genetic diagnostics now allows detection of rare and complex variants. Studies of founder variants in specific populations have clarified that certain GNE genotypes are associated with distinct clinical features and disease progression, deepening our understanding of genotype-phenotype relationships in GNE myopathy. The development of approved therapies, such as aceneuramic acid extended-release tablets, as well as ongoing multicenter Phase 2 trials of ManNAc and promising pilot studies of 6'-sialyllactose, underscore the importance of timely and comprehensive genetic diagnosis. Additional approaches, including antioxidant and gene therapies, are also under investigation. Since genetic testing is currently the sole definitive diagnostic approach, continued efforts to identify challenging or novel variants are essential to ensure all affected individuals receive an accurate diagnosis and access to emerging therapies. Advances in molecular genetics and diagnostics are paving the way for precision medicine and improved outcomes in GNE myopathy.

DOI: https://doi.org/10.1038/s10038-025-01398-y
Hum Mol Genet. 2025 Aug 29. pii: ddaf140. [Epub ahead of print]

Galactose treatment rescues neuromuscular junction transmission in glutamine-fructose-6-phosphate transaminase 1 (Gfpt1) deficient mice.

Stephen Henry Holland, Ricardo Carmona-Martinez, Daniel O'Neil, Kelly Ho, Kaela O'Connor, Yoshiteru Azuma, Andreas Roos, Sally Spendiff, Hanns Lochmüller.

  Congenital myasthenic syndromes (CMS) arise from mutations to proteins involved in neuromuscular junction (NMJ) development, maintenance, and neurotransmission. To date, mutations in more than 35 genes have been linked to CMS development. Glutamine fructose-6-phosphate transaminase 1 (GFPT1/Gfpt1) serves as the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP), producing the byproduct (UDP-GlcNAc) necessary for protein glycosylation. Gfpt1-deficient models have impaired protein glycosylation, impacting key proteins at the NMJ. The Leloir pathway is a galactose metabolizing pathway which produces UDP-GalNAc as its final product. The enzyme UDP-GalNAc Epimerase (GALE) can also convert excess UDP-GalNAc into UDP-GlcNAc, the byproduct of the HBP. We hypothesized that treatment with galactose both in vitro and in vivo in Gfpt1-deficient models would rescue impaired protein O-GlcNAcylation and reverse the glycosylation status of key NMJ-associated proteins. We show that galactose treatment in vitro activated the Leloir pathway and rescued protein O-GlcNAcylation in Gfpt1-deficient C2C12 myoblasts. In addition, we demonstrated that galactose therapy rescued neuromuscular deficits, improved muscle fatigue and restored NMJ morphology in a skeletal muscle-specific Gfpt1 knockout mouse model. Lastly, we showed that galactose treatment rescued protein O-GlcNAcylation in skeletal muscle, preserving the glycosylation status of the delta (δ) subunit of the acetylcholine receptor (AChRδ). Taken together, we suggest that galactose supplementation can be further explored as a therapy for GFPT1-CMS patients.

Keywords:  Congenital Myasthenic Syndrome; Galactose; Glutamine-Fructose-6-Phosphate Transaminase 1; Glycosylation; Neuromuscular Junction

DOI:  https://doi.org/10.1093/hmg/ddaf140
J Hum Genet. 2025 Sep 02.

Congenital disorders caused by aberrations in the biosynthesis of chondroitin/dermatan sulfate.

Tadahisa Mikami, Shuji Mizumoto, Hiroshi Kitagawa, Shuhei Yamada.

Chondroitin sulfate (CS)/dermatan sulfate (DS) proteoglycans that play indispensable roles in multiple physiological processes, including cell proliferation, cell adhesion, development, neuronal guidance, and cartilage formation. Depletion of CS/DS caused by biosynthetic enzyme loss of function impairs these processes and results in embryonic lethality. However, some individuals with mutant enzymes survive and exhibit severe phenotypes. These rare hereditary diseases have been discovered and characterized in recent decades because of marked advances in next-generation sequencing technology. In this review, CS/DS-related inherited diseases caused by aberrations in both CS/DS backbone synthesis, as well as their sulfation and/or epimerization, are comprehensively summarized and their pathogenesis discussed.

DOI: https://doi.org/10.1038/s10038-025-01396-0