bims-meglyc 2023-02-19 papers

on Metabolic disorders affecting glycosylation

Issue of 2023–02–19
twelve papers selected by
Silvia Radenkovic, Frontiers in Congenital Disorders of Glycosylation Consortium

Diagnosis and management of glycogen storage disease type IV, including adult polyglucosan body disease: A clinical practice resource.
Genetic data protection as an indispensable element of genomic medicine development.
Pompe's Disease Successfully Treated In Utero.
Glycomics-Assisted Glycoproteomics Enables Deep and Unbiased N-Glycoproteome Profiling of Complex Biological Specimens.
Modeling congenital brain malformations with brain organoids: a narrative review.
Engineered cardiac tissue as a novel in vitro human myocardium model for studying cardiac stretch.
Modeling Heart Diseases on a Chip: Advantages and Future Opportunities.
Models of precision medicine for neurodegeneration.
Protocol for Plasma Extracellular Vesicle and Particle Isolation and Mass Spectrometry-Based Proteomic Identification.
Molecular pathways that drive diabetic kidney disease.
Glutathione system enhancement for cardiac protection: pharmacological options against oxidative stress and ferroptosis.
Calcium signaling and genetic rare diseases: An auditory perspective.

Mol Genet Metab. 2023 Jan 25. pii: S1096-7192(23)00155-5. [Epub ahead of print]138(3): 107525

Diagnosis and management of glycogen storage disease type IV, including adult polyglucosan body disease: A clinical practice resource.

Rebecca L Koch, Claudia Soler-Alfonso, Bridget T Kiely, Akihiro Asai, Ariana L Smith, Deeksha S Bali, Peter B Kang, Andrew P Landstrom, H Orhan Akman, T Andrew Burrow, Jennifer L Orthmann-Murphy, Deberah S Goldman, Surekha Pendyal, Areeg H El-Gharbawy, Stephanie L Austin, Laura E Case, Raphael Schiffmann, Michio Hirano, Priya S Kishnani.

  Glycogen storage disease type IV (GSD IV) is an ultra-rare autosomal recessive disorder caused by pathogenic variants in GBE1 which results in reduced or deficient glycogen branching enzyme activity. Consequently, glycogen synthesis is impaired and leads to accumulation of poorly branched glycogen known as polyglucosan. GSD IV is characterized by a remarkable degree of phenotypic heterogeneity with presentations in utero, during infancy, early childhood, adolescence, or middle to late adulthood. The clinical continuum encompasses hepatic, cardiac, muscular, and neurologic manifestations that range in severity. The adult-onset form of GSD IV, referred to as adult polyglucosan body disease (APBD), is a neurodegenerative disease characterized by neurogenic bladder, spastic paraparesis, and peripheral neuropathy. There are currently no consensus guidelines for the diagnosis and management of these patients, resulting in high rates of misdiagnosis, delayed diagnosis, and lack of standardized clinical care. To address this, a group of experts from the United States developed a set of recommendations for the diagnosis and management of all clinical phenotypes of GSD IV, including APBD, to support clinicians and caregivers who provide long-term care for individuals with GSD IV. The educational resource includes practical steps to confirm a GSD IV diagnosis and best practices for medical management, including (a) imaging of the liver, heart, skeletal muscle, brain, and spine, (b) functional and neuromusculoskeletal assessments, (c) laboratory investigations, (d) liver and heart transplantation, and (e) long-term follow-up care. Remaining knowledge gaps are detailed to emphasize areas for improvement and future research.

Keywords:  Adult polyglucosan body disease; Andersen disease; Clinical practice guideline; Diagnosis guideline; Glycogen branching enzyme; Glycogen storage disease type IV; Management guideline

DOI:  https://doi.org/10.1016/j.ymgme.2023.107525
Pol Arch Intern Med. 2023 Feb 10. pii: 16425. [Epub ahead of print]

Genetic data protection as an indispensable element of genomic medicine development.

Małgorzata Madej, Paweł Karpiński, Hayane Akopyan, Michał Witt, Maria M Sąsiadek.

The immense progress in molecular biology observed in the last decades has led to a fundamental change in our understanding of the etiology of human diseases. Whole genome analyses, both DNA sequencing and microarray comparative genomic hybridization, allowed for identification of previously unknown diseases and syndromes. Therefore, in difficult‑to‑diagnose cases, clinical diagnosis is being replaced by molecular diagnosis (molecular dysmorphology, genomic medicine). For both scientific development of human genetics and clinical characteristics of rare genetic diseases, the construction and sharing of internationally available large databases has become crucial. However, genetic data have to be considered on the individual level too; therefore, they have to be treated as sensitive personal information. The context of ethical and legal risks involved in genetic testing has been long analyzed, although recognition of personal data protection issues is a more recent topic. The respective legal acts and protective measures should take into account several different aspects. The present paper explores major benefits and risks associated with international sharing of vast databases of genetic material, and presents legal provisions applied in the European Union, the United States, and China. The latter part is based on the respective acts themselves, as well as on analyses and commentaries by other scholars.

DOI: https://doi.org/10.20452/pamw.16425
Am J Med Genet A. 2023 Mar;191(3): 654-655

Pompe's Disease Successfully Treated In Utero.

DOI: https://doi.org/10.1002/ajmg.a.62795
Methods Mol Biol. 2023 ;2628 235-263

Glycomics-Assisted Glycoproteomics Enables Deep and Unbiased N-Glycoproteome Profiling of Complex Biological Specimens.

The Huong Chau, Anastasia Chernykh, Julian Ugonotti, Benjamin L Parker, Rebeca Kawahara, Morten Thaysen-Andersen.

  Mass spectrometry-driven glycomics and glycoproteomics, the system-wide profiling of detached glycans and intact glycopeptides from biological samples, respectively, are powerful approaches to interrogate the heterogenous glycoproteome. Efforts to develop integrated workflows employing both glycomics and glycoproteomics have been invested since the concerted application of these complementary approaches enables a deeper exploration of the glycoproteome. This protocol paper outlines, step-by-step, an integrated -omics technology, the "glycomics-assisted glycoproteomics" method, that first establishes the N-glycan fine structures and their quantitative distribution pattern of protein extracts via porous graphitized carbon-LC-MS/MS. The N-glycome information is then used to augment and guide the challenging reversed-phase LC-MS/MS-based profiling of intact N-glycopeptides from the same protein samples. Experimental details and considerations relating to the sample preparation and the N-glycomics and N-glycoproteomics data collection, analysis, and integration are discussed. Benefits of the glycomics-assisted glycoproteomics method, which can be readily applied to both simple and complex biological specimens such as protein extracts from cells, tissues, and bodily fluids (e.g., serum), include quantitative information of the protein carriers and site(s) of glycosylation, site occupancy, and the site-specific glycan structures directly from biological samples. The glycomics-assisted glycoproteomics method therefore facilitates a comprehensive view of the complexity and dynamics of the heterogenous glycoproteome.

Keywords:  Glycomics; Glycomics-assisted glycoproteomics; Glycopeptide; Glycoproteome; Glycoproteomics; Mass spectrometry; N-Glycan

DOI:  https://doi.org/10.1007/978-1-0716-2978-9_16
Transl Pediatr. 2023 Jan 31. 12(1): 68-78

Modeling congenital brain malformations with brain organoids: a narrative review.

Xiao-Shan Ji, Xiao-Li Ji, Man Xiong, Wen-Hao Zhou.

   Background and Objective: During embryonic development, the dysregulation of the proliferation and differentiation of neuronal progenitors triggers congenital brain malformations. These malformations are common causes of morbidity and mortality in patients younger than 2 years old. Animal models have provided considerable insights into the etiology of diseases that cause congenital brain malformations. However, the interspecies differences in brain structure limit the ability to transfer these insights directly to studies of humans. In recent years, brain organoids generated from human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs) using a 3-dimensional (3D) culture system have been used to resemble the structure and function of a developing human brain. Therefore, we aimed to summarize the different congenital brain malformations that have been modeled by organoids and discuss the ability of this model to reveal the cellular and molecular mechanisms of congenital brain malformations.
Methods: A comprehensive search was performed using PubMed and Web of Science's Core Collection for literature published from July 1, 2000 to July 1, 2022. Keywords included terms related to brain organoids and congenital brain malformations, as well as names of individual malformations.
Key Content and Findings: The self-assembled 3D aggregates have been used to recapitulate structural malformations of human brains, such as microcephaly, macrocephaly, lissencephaly (LIS), and periventricular nodular heterotopia (PH). The use of disease-specific brain organoids has revealed unprecedented details of mechanisms that cause congenital brain malformations.
Conclusions: This review summarizes the establishment and development of brain organoid technologies and provides an overview of their applications in modeling congenital brain malformations. Although several hurdles still need to be overcome, using brain organoids has greatly expanded our ability to reveal the pathogenesis of congenital brain malformations. Compared with existing methods, the combination with cutting-edge technologies enables a more accurate diagnosis and development of increasingly personalized targeted therapy for patients with congenital brain diseases.

Keywords:  Brain organoid; congenital brain malformations; human pluripotent stem cells; neurodevelopment

DOI:  https://doi.org/10.21037/tp-22-239
Biophys J. 2023 Feb 10. pii: S0006-3495(22)03161-7. [Epub ahead of print]122(3S1): 413a

Engineered cardiac tissue as a novel in vitro human myocardium model for studying cardiac stretch.

Daniel G P Turner, Willem J De Lange, Di Lang, Gina Kim, Yanlong Zhu, Ying Ge, Timothy J Kamp, John C Ralphe, Alexey V Glukhov.

DOI: https://doi.org/10.1016/j.bpj.2022.11.2245
Circ Res. 2023 Feb 17. 132(4): 483-497

Modeling Heart Diseases on a Chip: Advantages and Future Opportunities.

Omar Mourad, Ryan Yee, Mengyuan Li, Sara S Nunes.

Heart disease is a significant burden on global health care systems and is a leading cause of death each year. To improve our understanding of heart disease, high quality disease models are needed. These will facilitate the discovery and development of new treatments for heart disease. Traditionally, researchers have relied on 2D monolayer systems or animal models of heart disease to elucidate pathophysiology and drug responses. Heart-on-a-chip (HOC) technology is an emerging field where cardiomyocytes among other cell types in the heart can be used to generate functional, beating cardiac microtissues that recapitulate many features of the human heart. HOC models are showing great promise as disease modeling platforms and are poised to serve as important tools in the drug development pipeline. By leveraging advances in human pluripotent stem cell-derived cardiomyocyte biology and microfabrication technology, diseased HOCs are highly tuneable and can be generated via different approaches such as: using cells with defined genetic backgrounds (patient-derived cells), adding small molecules, modifying the cells' environment, altering cell ratio/composition of microtissues, among others. HOCs have been used to faithfully model aspects of arrhythmia, fibrosis, infection, cardiomyopathies, and ischemia, to name a few. In this review, we highlight recent advances in disease modeling using HOC systems, describing instances where these models outperformed other models in terms of reproducing disease phenotypes and/or led to drug development.

DOI: https://doi.org/10.1161/CIRCRESAHA.122.321670
Handb Clin Neurol. 2023 ;pii: B978-0-323-85538-9.00009-2. [Epub ahead of print]192 21-34

Models of precision medicine for neurodegeneration.

Alberto J Espay.

  The clinicopathologic model that defines neurodegenerative disorders has remained unchanged for over a century. According to it, clinical manifestations are defined and explained by a given pathology, that is, by the burden and distribution of selected proteins aggregated into insoluble amyloids. There are two logical consequences from this model: (1) a measurement of the disease-defining pathology represents a biomarker of that disease in everyone affected, and (2) the targeted elimination of that pathology should end that disease. But success in disease modification guided by this model has remained elusive. New technologies to probe living biology have been used to validate rather than question the clinicopathologic model, despite three important observations: (1) a disease-defining pathology in isolation (without other pathologies) is an exceptional autopsy finding; (2) many genetic and molecular pathways converge on the same pathology; (3) the presence of pathology without neurological disease is more common than expected by chance. We here discuss the rationale for abandoning the clinicopathologic model, review the competing biological model of neurodegeneration, and propose developmental pathways for biomarker development and disease-modifying efforts. Further, in justifying future disease-modifying trials testing putative neuroprotective molecules, a key inclusion criterion must be the deployment of a bioassay of the mechanism corrected by the therapy of interest. No improvements in trial design or execution can overcome the fundamental deficit created by testing experimental therapies in clinically defined recipients unselected for their biologically suitability. Biological subtyping is the key developmental milestone needed to launch precision medicine for patients living with neurodegenerative disorders.

Keywords:  Alzheimer's disease; Amyloid; Disease modification; Parkinson's disease; α-Synuclein

DOI:  https://doi.org/10.1016/B978-0-323-85538-9.00009-2
Methods Mol Biol. 2023 ;2628 291-300

Protocol for Plasma Extracellular Vesicle and Particle Isolation and Mass Spectrometry-Based Proteomic Identification.

Amirmohammad Nasiri Kenari, Linda Bojmar, Søren Heissel, Henrik Molina, David Lyden, Ayuko Hoshino.

  Plasma extracellular vesicles and particles (EVPs) are enriched in biomolecules that reflect individuals' physiological and pathological states. Several studies have demonstrated the potential of human plasma EVPs as a novel liquid biopsy. Here we describe a protocol for human plasma EVPs isolation and proteomic characterization. We isolated human plasma EVPs by the classical ultracentrifugation method and performed mass spectrometry-based proteomic profiling. Using this protocol, researchers can reveal the plasma EVPs proteome and explore the clinical application of plasma EVPs proteins for developing disease biomarkers.

Keywords:  Extracellular vesicles and particles; Mass spectrometry; Plasma

DOI:  https://doi.org/10.1007/978-1-0716-2978-9_19
J Clin Invest. 2023 Feb 15. pii: e165654. [Epub ahead of print]133(4):

Molecular pathways that drive diabetic kidney disease.

Samer Mohandes, Tomohito Doke, Hailong Hu, Dhanunjay Mukhi, Poonam Dhillon, Katalin Susztak.

Kidney disease is a major driver of mortality among patients with diabetes and diabetic kidney disease (DKD) is responsible for close to half of all chronic kidney disease cases. DKD usually develops in a genetically susceptible individual as a result of poor metabolic (glycemic) control. Molecular and genetic studies indicate the key role of podocytes and endothelial cells in driving albuminuria and early kidney disease in diabetes. Proximal tubule changes show a strong association with the glomerular filtration rate. Hyperglycemia represents a key cellular stress in the kidney by altering cellular metabolism in endothelial cells and podocytes and by imposing an excess workload requiring energy and oxygen for proximal tubule cells. Changes in metabolism induce early adaptive cellular hypertrophy and reorganization of the actin cytoskeleton. Later, mitochondrial defects contribute to increased oxidative stress and activation of inflammatory pathways, causing progressive kidney function decline and fibrosis. Blockade of the renin-angiotensin system or the sodium-glucose cotransporter is associated with cellular protection and slowing kidney function decline. Newly identified molecular pathways could provide the basis for the development of much-needed novel therapeutics.

DOI: https://doi.org/10.1172/JCI165654
Cell Death Dis. 2023 Feb 16. 14(2): 131

Glutathione system enhancement for cardiac protection: pharmacological options against oxidative stress and ferroptosis.

Mingyue Tan, Yunfei Yin, Xiao Ma, Jun Zhang, Wanqian Pan, Minghao Tan, Yongjian Zhao, Tianke Yang, Tingbo Jiang, Hongxia Li.

The glutathione (GSH) system is considered to be one of the most powerful endogenous antioxidant systems in the cardiovascular system due to its key contribution to detoxifying xenobiotics and scavenging overreactive oxygen species (ROS). Numerous investigations have suggested that disruption of the GSH system is a critical element in the pathogenesis of myocardial injury. Meanwhile, a newly proposed type of cell death, ferroptosis, has been demonstrated to be closely related to the GSH system, which affects the process and outcome of myocardial injury. Moreover, in facing various pathological challenges, the mammalian heart, which possesses high levels of mitochondria and weak antioxidant capacity, is susceptible to oxidant production and oxidative damage. Therefore, targeted enhancement of the GSH system along with prevention of ferroptosis in the myocardium is a promising therapeutic strategy. In this review, we first systematically describe the physiological functions and anabolism of the GSH system, as well as its effects on cardiac injury. Then, we discuss the relationship between the GSH system and ferroptosis in myocardial injury. Moreover, a comprehensive summary of the activation strategies of the GSH system is presented, where we mainly identify several promising herbal monomers, which may provide valuable guidelines for the exploration of new therapeutic approaches.

DOI: https://doi.org/10.1038/s41419-023-05645-y
Cell Calcium. 2023 Feb 05. pii: S0143-4160(23)00014-3. [Epub ahead of print]110 102702

Calcium signaling and genetic rare diseases: An auditory perspective.

Elodie M Richard, Tangui Maurice, Benjamin Delprat.

  Deafness is a highly heterogeneous disorder which stems, for 50%, from genetic origins. Sensory transduction relies mainly on sensory hair cells of the cochlea, in the inner ear. Calcium is key for the function of these cells and acts as a fundamental signal transduction. Its homeostasis depends on three factors: the calcium influx, through the mechanotransduction channel at the apical pole of the hair cell as well as the voltage-gated calcium channel at the base of the cells; the calcium buffering via Ca2+-binding proteins in the cytoplasm, but also in organelles such as mitochondria and the reticulum endoplasmic mitochondria-associated membranes with specialized proteins; and the calcium extrusion through the Ca-ATPase pump, located all over the plasma membrane. In addition, the synaptic transmission to the central nervous system is also controlled by calcium. Genetic studies of inherited deafness have tremendously helped understand the underlying molecular pathways of calcium signaling. In this review, we discuss these different factors in light of the associated genetic diseases (syndromic and non-syndromic deafness) and the causative genes.

Keywords:  Calcium; Deafness; Genetic rare disease; Hair cell; Mitochondria

DOI:  https://doi.org/10.1016/j.ceca.2023.102702