bims-meglyc Biomed News
on Metabolic disorders affecting glycosylation
Issue of 2024–02–04
six papers selected by
Silvia Radenkovic
  1. Instrumented assessment of gait disturbance in PMM2-CDG adults: a feasibility analysis.
  2. Split but merge: Golgi fragmentation in physiological and pathological conditions.
  3. Case report: A founder UGDH variant associated with developmental epileptic encephalopathy in Saudi Arabia.
  4. Biomarkers of mitochondrial disorders.
  5. Mannose Supplementation Curbs Liver Steatosis and Fibrosis in Murine MASH by Inhibiting Fructose Metabolism.
  6. Brain energetics and glucose transport in metabolic diseases: role in neurodegeneration.
  1. Orphanet J Rare Dis. 2024 Feb 02. 19(1): 39
    Instrumented assessment of gait disturbance in PMM2-CDG adults: a feasibility analysis.
    Lara Cirnigliaro, Fabio Pettinato, Maria Stella Valle, Antonino Casabona, Agata Fiumara, Michele Vecchio, Valerio Amico, Renata Rizzo, Jaak Jaeken, Rita Barone, Matteo Cioni.
       BACKGROUND: Congenital disorders of glycosylation (CDG) are genetic diseases caused by impaired synthesis of glycan moieties linked to glycoconjugates. Phosphomannomutase 2 deficiency (PMM2-CDG), the most frequent CDG, is characterized by prominent neurological involvement. Gait disturbance is a major cause of functional disability in patients with PMM2-CDG. However, no specific gait assessment for PMM2-CDG is available. This study analyses gait-related parameters in PMM2-CDG patients using a standardized clinical assessment and instrumented gait analysis (IGA).
    RESULTS: Seven adult patients with a molecular diagnosis of PMM2-CDG were followed-up from February 2021 to December 2022 and compared to a group of healthy control (HC) subjects, matched for age and sex. Standardized assessment of disease severity including ataxia and peripheral neuropathy along with isometric muscle strength and echo-biometry measurements at lower limbs were performed. IGA spatiotemporal parameters were obtained by means of a wearable sensor in basal conditions. PMM2-CDG patients displayed lower gait speed, stride length, cadence and symmetry index, compared to HC. Significant correlations were found among the used clinical scales and between disease severity (NCRS) scores and the gait speed measured by IGA. Variable reduction of knee extension strength and a significant decrease of lower limb muscle thickness with conserved echo intensity were found in PMM2-CDG compared to HC.
    CONCLUSIONS: The study elucidates different components of gait disturbance in PMM2-CDG patients and shows advantages of using wearable sensor-based IGA in this frame. IGA parameters may potentially serve as quantitative measures for follow-up or outcome quantification in PMM2-CDG.
    Keywords:  Ataxia; Gait; Instrumented gait analysis; PMM2-CDG
    DOI:  https://doi.org/10.1186/s13023-024-03027-x
  2. Mol Biol Rep. 2024 Jan 27. 51(1): 214
    Split but merge: Golgi fragmentation in physiological and pathological conditions.
    Pelin Zobaroğlu-Özer, Gamze Bora-Akoğlu.
      The Golgi complex is a highly dynamic and tightly regulated cellular organelle with essential roles in the processing as well as the sorting of proteins and lipids. Its structure undergoes rapid disassembly and reassembly during normal physiological processes, including cell division, migration, polarization, differentiation, and cell death. Golgi dispersal or fragmentation also occurs in pathological conditions, such as neurodegenerative diseases, infectious diseases, congenital disorders of glycosylation diseases, and cancer. In this review, current knowledge about both structural organization and morphological alterations in the Golgi in physiological and pathological conditions is summarized together with the methodologies that help to reveal its structure.
    Keywords:  Golgi complex; Golgi fragmentation; Golgi morphology; Golgi structure
    DOI:  https://doi.org/10.1007/s11033-023-09153-2
  3. Front Genet. 2023 ;14 1294214
    Case report: A founder UGDH variant associated with developmental epileptic encephalopathy in Saudi Arabia.
    Manal Alaamery, Salam Massadeh, Manar Aldarwish, Nour Albesher, Nora Aljawini, Othman Alahmed, Amna Kashgari, Christopher A Walsh, Wafaa Eyaid.
      Congenital disorders of glycosylation (CDG) are a group of more than 100 rare genetic disorders characterized by impaired glycosylation of proteins and lipids. The clinical presentation of CDG varies tremendously, from single-organ to multi-organ involvement and from prenatal death to a normal adult phenotype. In this case study, we report a large consanguineous family with multiple children suffering from cerebral palsy, seizure, developmental and epileptic encephalopathy, and global developmental delay. Whole-exome sequencing (WES) analysis revealed a homozygous variant in the UDP-glucose dehydrogenase (UGDH) gene (c.950G>A; p.R317Q) which segregates with the familial phenotype with a plausible autosomal recessive mode of inheritance, indicating a potential disease-causing association. The UGDH gene encodes the UDP-glucose dehydrogenase, a key enzyme in the synthesis of specific extracellular matrix constituents (proteoglycans and glycolipids) involved in neural migration and connectivity during early brain development. Many pathogenic mutations of UGDH have been reported in recent literature works. However, the variant identified in this study has been observed only in the Saudi population (13 families) and not in any other ethnic background, suggesting that it may be an ancient founder mutation.
    Keywords:  Saudi; UDP-glucose dehydrogenase; encephalopathy; gene; mutation; whole-exome sequencing
    DOI:  https://doi.org/10.3389/fgene.2023.1294214
  4. Neurotherapeutics. 2024 Jan 30. pii: S1878-7479(24)00011-4. [Epub ahead of print]21(1): e00325
    Biomarkers of mitochondrial disorders.
    Brian J Shayota.
      Mitochondrial diseases encompass a heterogeneous group of disorders with a wide range of clinical manifestations, most classically resulting in neurological, muscular, and metabolic abnormalities, but having the potential to affect any organ system. Over the years, substantial progress has been made in identifying and characterizing various biomarkers associated with mitochondrial diseases. This review summarizes the current knowledge of mitochondrial biomarkers based on a literature review and discusses the evidence behind their use in clinical practice. A total of 13 biomarkers were thoroughly reviewed including lactate, pyruvate, lactate:pyruvate ratio, creatine kinase, creatine, amino acid profiles, glutathione, malondialdehyde, GDF-15, FGF-21, gelsolin, neurofilament light-chain, and circulating cell-free mtDNA. Most biomarkers had mixed findings depending on the study, especially when considering their utility for specific mitochondrial diseases versus mitochondrial conditions in general. However, in large biomarker comparison studies, GDF-15 followed by FGF-21, seem to have the greatest value though they are still not perfect. As such, additional studies are needed, especially in light of newer biomarkers that have not yet been thoroughly investigated. Understanding the landscape of biomarkers in mitochondrial diseases is crucial for advancing early detection, improving patient management, and developing targeted therapies.
    Keywords:  Biomarker; Mitochondrial disease; Mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.neurot.2024.e00325
  5. bioRxiv. 2024 Jan 17. pii: 2024.01.17.576067. [Epub ahead of print]
    Mannose Supplementation Curbs Liver Steatosis and Fibrosis in Murine MASH by Inhibiting Fructose Metabolism.
    John G Hong, Yvette Carbajal, Joshaya Trotman, Mariel Glass, Victoria Sclar, Isaac L Alter, Peng Zhang, Liheng Wang, Li Chen, Matthieu Petitjean, Scott L Friedman, Charles DeRossi, Jaime Chu.
      Metabolic dysfunction-associated steatohepatitis (MASH) can progress to cirrhosis and liver cancer. There are no approved medical therapies to prevent or reverse disease progression. Fructose and its metabolism in the liver play integral roles in MASH pathogenesis and progression. Here we focus on mannose, a simple sugar, which dampens hepatic stellate cell activation and mitigates alcoholic liver disease in vitro and in vivo . In the well-validated FAT-MASH murine model, oral mannose supplementation improved both liver steatosis and fibrosis at low and high doses, whether administered either at the onset of the model ("Prevention") or at week 6 of the 12-week MASH regimen ("Reversal"). The in vivo anti-fibrotic effects of mannose supplementation were validated in a second model of carbon tetrachloride-induced liver fibrosis. In vitro human and mouse primary hepatocytes revealed that the anti-steatotic effects of mannose are dependent on the presence of fructose, which attenuates expression of ketohexokinase (KHK), the main enzyme in fructolysis. KHK is decreased with mannose supplementation in vivo and in vitro, and overexpression of KHK abrogated the anti-steatotic effects of mannose. Our study identifies mannose as a simple, novel therapeutic candidate for MASH that mitigates metabolic dysregulation and exerts anti-fibrotic effects.
    DOI:  https://doi.org/10.1101/2024.01.17.576067
  6. Nutr Neurosci. 2024 Jan 31. 1-12
    Brain energetics and glucose transport in metabolic diseases: role in neurodegeneration.
    Orquídea G Méndez-Flores, Luisa C Hernández-Kelly, Tatiana N Olivares-Bañuelos, Gabriel López-Ramírez, Arturo Ortega.
       OBJECTIVES: Neurons and glial cells are the main functional and structural elements of the brain, and the former depends on the latter for their nutritional, functional and structural organization, as well as for their energy maintenance.
    METHODS: Glucose is the main metabolic source that fulfills energetic demands, either by direct anaplerosis or through its conversion to metabolic intermediates. Development of some neurodegenerative diseases have been related with modifications in the expression and/or function of glial glucose transporters, which might cause physiological and/or pathological disturbances of brain metabolism. In the present contribution, we summarized the experimental findings that describe the exquisite adjustment in expression and function of glial glucose transporters from physiologic to pathologic metabolism, and its relevance to neurodegenerative diseases.
    RESULTS: A exhaustive literature review was done in order to gain insight into the role of brain energetics in neurodegenerative disease. This study made evident a critical involvement of glucose transporters and thus brain energetics in the development of neurodegenerative diseases.
    DISCUSSION: An exquisite adjustment in the expression and function of glial glucose transporters from physiologic to pathologic metabolism is a biochemical signature of neurodegenerative diseases.
    Keywords:  Glia cells; brain energetic; glucose transporters; metabolic coupling; neuropathologies
    DOI:  https://doi.org/10.1080/1028415X.2024.2306427
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