bims-meglyc Biomed News
on Metabolic disorders affecting glycosylation
Issue of 2025–06–01
six papers selected by
Silvia Radenkovic, UMC Utrecht
  1. A recurrent c.953A>C (p. Gln318Pro) variant in ALG11 causing congenital disorder of glycosylation in Turkish population.
  2. SLC35A2 loss-of-function variants affect glycomic signatures, neuronal fate and network dynamics.
  3. Case Report: De novo variant of the NUS1 gene associated with developmental delay and autism spectrum disorders in a Chinese family.
  4. GDP-fucose transporter SLC35C1: a potential regulatory role in cytosolic GDP-fucose and fucosylated glycan synthesis.
  5. Long term clinical follow-up and natural history in a cohort of Italian patients with GNE myopathy: the experience of a single centre.
  6. Updated Gene Therapy for Renal Inborn Errors of Metabolism.
  1. Neurogenetics. 2025 May 27. 26(1): 46
    A recurrent c.953A>C (p. Gln318Pro) variant in ALG11 causing congenital disorder of glycosylation in Turkish population.
    Pinar Ozkan Kart, Oguzhan Demir, Ayberk Turkyilmaz, Alper Han Cebi, Ali Cansu.
      Congenital disorders of glycosylation type 1p, one of the N-glycosylation defects, Asparagine-dependent glycosylation 11 (ALG11-CDG, #OMIM: 613,666), is a very rare type of autosomal recessive glycosylation defect that causes multisystem involvement and frequently presents with neurological symptoms such as epilepsy and neuromotor developmental delay. In this study, we aimed to present three Turkish patients from three unrelated families with the recurrent variant in the ALG11 gene, along with their clinical and genotypic findings, and to compare them with other cases described in the literature. Three patients from three unrelated families were identified who were comprehensively evaluated with clinical examination, laboratory tests, and imaging studies. The whole exome sequencing (WES) with copy number analysis was performed. The identified variants were confirmed in the proband and parents using Sanger sequencing. Common clinical features of the patients included refractory epileptic seizures, developmental delay, and microcephaly, consistent with the literature. Developmental and Epileptic Encephalopathy starting in the first year of life and burst suppression pattern observed in electroencephalogram are among the important clinical features. WES analysis revealed a homozygous NM_001004127.3: c.953A > C (p. Gln318Pro) missense variant in the ALG11 gene in all three patients. This study presents the clinical and genetic features of three Turkish patients with the ALG11-CDG subtype, which has been previously described in the literature; it reinforces the current knowledge on phenotypic diversity by comparisons with similar cases. In addition, the role of WES in the diagnosis of rare CDG subtypes has been demonstrated once again.
    Keywords:   ALG11 gene; Congenital disorder of glycosylation; Developmental and epileptic encephalopathy; Microcephaly
    DOI:  https://doi.org/10.1007/s10048-025-00826-7
  2. Brain. 2025 May 26. pii: awaf198. [Epub ahead of print]
    SLC35A2 loss-of-function variants affect glycomic signatures, neuronal fate and network dynamics.
    Dulcie Lai, Paulina Sosicka, Damian J Williams, MaryAnn E Bowyer, Andrew K Ressler, Sarah E Kohrt, Savannah J Muron, Peter B Crino, Hudson H Freeze, Michael J Boland, Erin L Heinzen.
      SLC35A2 encodes a UDP-galactose transporter essential for glycosylation of proteins and galactosylation of lipids and glycosaminoglycans. Germline genetic SLC35A2 variants have been identified in congenital disorders of glycosylation and somatic SLC35A2 variants have been linked to intractable epilepsy associated with malformations of cortical development. However, the functional consequences of these pathogenic variants on brain development and network integrity remain unknown. In this study, we use an isogenic human induced pluripotent stem cell-derived neuron model to comprehensively interrogate the functional impact of loss of function variants in SLC35A2 through the integration of cellular and molecular biology, protein glycosylation analysis, neural network dynamics, and single cell electrophysiology. We show that loss of function variants in SLC35A2 result in disrupted glycomic signatures and precocious neurodevelopment, yielding hypoactive, asynchronous neural networks. This aberrant network activity is attributed to an inhibitory/excitatory imbalance as characterization of neural composition revealed preferential differentiation of SLC35A2 loss of function variants towards the GABAergic fate. Furthermore, electrophysiological recordings of synaptic activity and gene expression differences suggest network phenotypes are driven by changes occurring at the synapse. Our study is the first to provide mechanistic insight regarding the early development and functional connectivity of SLC35A2 loss-of-function variant harboring human neurons, providing important groundwork for future exploration of potential therapeutic interventions.
    Keywords:  epilepsy; glycosylation; human stem cells; neural network; neurodevelopment
    DOI:  https://doi.org/10.1093/brain/awaf198
  3. Front Pediatr. 2025 ;13 1557103
    Case Report: De novo variant of the NUS1 gene associated with developmental delay and autism spectrum disorders in a Chinese family.
    Feng Ding, Junlin Pan, Shuhua Ji, Yan Zhang, Jinwei Hou, Na Shi, Haiping Liu.
       Background: Nuclear undecaprenyl pyrophosphate synthase 1 (NUS1) has been implicated in the pathogenesis of neurodevelopmental disorders, including Parkinson's disease, seizures, intellectual disability, dystonia, and congenital disorder of glycosylation. To this day, there have been limited studies and reports on the NUS1 gene.
    Methods: We described the case of an 8-year-old Chinese boy exhibiting developmental delay, intellectual disability, and autism spectrum disorder (ASD). To elucidate the genetic etiology, whole-exome sequencing was performed on the proband. A candidate variant was subsequently validated by Sanger sequencing in the proband and his unaffected parents.
    Results: Whole-exome sequencing analysis discovered a novel heterozygous variant (c.279del, p.L94Wfs*11) on exon 1 of NUS1 (NM_138459.5), leading to premature termination of protein translation (p.L94Wfs*11). Sanger sequencing failed to identify the candidate variant in his unaffected parents. Following the updated American College of Medical Genetics and Genomics guidelines, the c.279del variant was classified as pathogenic (PVS1+PM6+PM2_Supporting). Based on the clinical phenotype of the proband, he was diagnosed with autosomal dominant intellectual developmental disorder-55 with seizures (MRD55) and ASD.
    Conclusions: This study expands the phenotype and mutation spectrum of the NUS1 gene, which contributes to the diagnosis of related disorders. Furthermore, the identification of the genetic basis of the proband and confirmation of the corresponding loci of his family members will facilitate the genetic counseling of the proband's parents regarding reproduction.
    Keywords:  NUS1; autism spectrum disorders; case report; developmental delay; whole-exome sequencing
    DOI:  https://doi.org/10.3389/fped.2025.1557103
  4. FEBS Open Bio. 2025 May 27.
    GDP-fucose transporter SLC35C1: a potential regulatory role in cytosolic GDP-fucose and fucosylated glycan synthesis.
    Edyta Skurska, Mariusz Olczak.
      Glycosylation occurs mainly in the Golgi apparatus, whereas the synthesis of nucleotide sugars occurs in the cytoplasm or nucleus. GDP-fucose in mammalian cells could be produced via de novo and salvage pathways in the cytoplasm; the first one is responsible for about 90% of GDP-fucose in the total pool of this nucleotide sugar in the cell. SLC35C1 (C1) is the primary transporter of GDP-fucose to the Golgi apparatus. In the absence of this transporter, it was proposed that nucleotide sugar could still reach the Golgi apparatus via a SLC35C2, the homologue of SLC35C1. However, simultaneous inactivation of the two transporters did not influence GDP-fucose transport across the Golgi apparatus membranes after external fucose supplementation. In this study, we combined the inactivation of SLC35C1 and enzymes of the GDP-fucose biosynthesis pathways (FCSK, GMDS and TSTA3) to study the impact of double inactivation on the production of nucleotide sugar and fucosylated glycans. We found that a lack of SLC35C1 changed the level of enzymes of both de novo and salvage pathways. Upon fucose supplementation, stimulation of the salvage pathway was remarkably high in the absence of the TSTA3 protein, and the concentration of GDP-fucose increased to millimolar values. In this work, we discovered that simultaneous deficiency of the SLC35C1 protein and TSTA3 enzyme increased GDP-fucose production via the salvage pathway to an even higher level. Finally, we found that nucleotide sugar still accessed the Golgi apparatus and had differential effects on N- and O-glycans.
    Keywords:  FCSK; GMDS; SLC35C1; TSTA3; carbohydrate metabolism; fucosylation
    DOI:  https://doi.org/10.1002/2211-5463.70057
  5. Neurol Sci. 2025 May 31.
    Long term clinical follow-up and natural history in a cohort of Italian patients with GNE myopathy: the experience of a single centre.
    Alessia Pugliese, M Sframeli, P D'Ambrosio, A Barbaccia, F Biasini, A Migliorato, C Terranova, S Messina, A Toscano, C Rodolico.
       BACKGROUND: GNE myopathy is a muscle disease due to mutations in the GNE gene, encoding for the key enzyme of sialic acid biosynthesis. This disorder firstly involves distal lower limb muscles and slowly progresses to scapular girdle and distal upper limb muscles.
    PATIENTS/METHODS: We describe a cohort of 13 patients (9/13 women and 4/13 men) affected by GNE myopathy, followed on average for 15 years. The diagnoses were based on clinical evaluation, EMG, muscle MRI/CT, muscle biopsy and genetic analysis.
    RESULTS: Our patients have a mean age of 44 years old. The onset of symptoms was between the second and third decade of life. In the early stage, every patient complained difficulty in walking caused by foot drop. Ten patients are now wheelchair-bound, and quadriceps is typically spared in each patient, as commonly described for GNE myopathy. Only one patient developed respiratory failure requiring non-invasive ventilation. EMG study revealed a myopathic pattern in quite all patients and muscle biopsy showed atrophic fibres with "rimmed" vacuoles. Finally, all our patients are genetically characterized: 4/13 present a homozygous mutation in GNE gene, 9/13 a compound heterozygous one.
    CONCLUSIONS: GNE myopathy is a very rare muscle disorder, probably under-diagnosed because of the large group of diseases manifesting with foot drop. Although that, it's necessary to suspect it in case of distal and bilateral lower limb muscles weakness with quadriceps sparing. Several aspects of this myopathy are still unclear and there is no approved therapy for, but novel therapeutic strategies continue to be explored.
    Keywords:  Foot drop; GNE myopathy; Hereditary inclusion body myopathy (hIBM); Rimmed vacuoles; Sialic acid
    DOI:  https://doi.org/10.1007/s10072-025-08265-w
  6. Genes (Basel). 2025 Apr 29. pii: 516. [Epub ahead of print]16(5):
    Updated Gene Therapy for Renal Inborn Errors of Metabolism.
    Sean Hergenrother, Mustafa Husein, Cole Thompson, Ethan Kalina, Rupesh Raina.
      Inborn errors of metabolism (IEMs) are a group of disorders resulting from defects in enzymes in metabolic pathways. These disorders impact the processing of metabolites, leading to a wide array of effects on each organ system. Advances in genetic screening have allowed for the early identification and intervention of IEMs, traditionally in the form of enzyme replacement or vitamin supplementation. However, many IEMs disrupt essential metabolic pathways where simple supplementation proves ineffective, resulting in substantial disease burden. In the case of renal IEMs, metabolic pathway disruption leads to the onset of chronic kidney disease (CKD). For these diseases, genetic therapy provides hope. Over the past few decades, the technology for genetic therapy has emerged as a promising solution to these disorders. These therapies aim to correct the source of the defect in the genetic code so that patients may live full, unencumbered lives. In this review, we searched a large database to identify IEMs that affect the kidney and investigated the current landscape and progression of gene therapy technology. Multiple promising genetic therapies were identified for IEMs affecting the kidney, including primary hyperoxaluria, argininemia, glycogen storage diseases Ia and Ib, and Fabry disease. Emerging gene therapy approaches using adeno-associated virus (AAV) vectors, lentiviral vectors, and CRISPR/Cas9 techniques hold promising potential to provide curative treatments for additional single-mutation disorders.
    Keywords:  Fabry disease; adeno-associated virus vectors; argininemia; glycogen storage diseases; inborn errors of metabolism; kidney; primary hyperoxaluria
    DOI:  https://doi.org/10.3390/genes16050516
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