scholarly journals Transcriptomic Changes Related to Cellular Processes with Particular Emphasis on Cell Activation in Lysosomal Storage Diseases from the Group of Mucopolysaccharidoses

2020 ◽  
Vol 21 (9) ◽  
pp. 3194 ◽  
Author(s):  
Estera Rintz ◽  
Lidia Gaffke ◽  
Magdalena Podlacha ◽  
Joanna Brokowska ◽  
Zuzanna Cyske ◽  
...  
Keyword(s):  
Cell Activation ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Lysosomal Storage Diseases ◽  
Lysosomal Storage ◽  
Storage Diseases ◽  
Monogenic Disorders ◽  
Cellular Processes ◽  
Transcriptomic Changes ◽  
Molecular Pathomechanisms

Although mucopolysaccharidoses (MPS), inherited metabolic diseases from the group of lysosomal storage diseases (LSD), are monogenic disorders, recent studies indicated that their molecular mechanisms are complicated. Storage of glycosaminoglycans (GAGs), arising from a deficiency in one of the enzymes involved in the degradation of these compounds, is the primary cause of each MPS type. However, dysfunctions of various cellular organelles and disturbance of cellular processes have been reported which contribute considerably to pathomechanisms of the disease. Here, we present a complex transcriptomic analysis in which all types and subtypes of MPS were investigated, with special emphasis on genes related to cell activation processes. Complex changes in expression of these genes were found in fibroblasts of all MPS types, with number of transcripts revealing higher or lower levels (relative to control fibroblasts) between 19 and over 50, depending on MPS type. Genes in which expression was significantly affected in most MPS types code for proteins involved in following processes, classified according to Gene Ontology knowledge database: cell activation, cell growth, cell recognition, and cell division. Levels of some transcripts (including CD9, CLU, MME and others) were especially significantly changed (over five times relative to controls). Our results are discussed in the light of molecular pathomechanisms of MPS, indicating that secondary and/or tertiary changes, relative to GAG storage, might significantly modulate cellular dysfunctions and contribute to molecular mechanisms of the disease. This may influence the efficacy of various therapies and suggests why various treatments are not fully effective in improving the complex symptoms of MPS.

scholarly journals Lysosomal Leukodystrophies Lysosomal Storage Diseases Associated With White Matter Abnormalities

2019 ◽  
Vol 34 (6) ◽  
pp. 339-358 ◽  
Author(s):  
Gustavo H.B. Maegawa
Keyword(s):  
White Matter ◽  
Metabolic Diseases ◽  
Age Groups ◽  
Clinical Manifestations ◽  
Lysosomal Storage Diseases ◽  
Abnormal Development ◽  
Neurologic Manifestations ◽  
Lysosomal Storage ◽  
Storage Diseases ◽  
Extrapyramidal Signs

The leukodystrophies are a group of genetic metabolic diseases characterized by an abnormal development or progressive degeneration of the myelin sheath. The myelin is a complex sheath composed of several macromolecules covering axons as an insulator. Each of the leukodystrophies is caused by mutations in genes encoding enzymes that are involved in myelin production and maintenance. The lysosomal storage diseases are inborn disorders of compartmentalized cellular organelles with broad clinical manifestations secondary to the progressive accumulation of undegraded macromolecules within lysosomes and related organelles. The more than 60 different lysosomal storage diseases are rare diseases; however, collectively, the incidence of lysosomal storage diseases ranges just over 1 in 2500 live births. The majority of lysosomal storage diseases are associated with neurologic manifestations including developmental delay, seizures, acroparesthesia, motor weakness, and extrapyramidal signs. These inborn organelle disorders show wide clinical variability affecting individuals from all age groups. In addition, several of neurologic, also known as neuronopathic, lysosomal storage diseases are associated with some level of white matter disease, which often triggers the diagnostic investigation. Most lysosomal storage diseases are autosomal recessively inherited and few are X-linked, with females being at risk of presenting with mild, but clinically relevant neurologic manifestations. Biochemical assays are the basis of the diagnosis and are usually confirmed by molecular genetic testing. Novel therapies have emerged. However, most affected patients with lysosomal storage diseases have only supportive management to rely on. A better understanding of the mechanisms resulting in the leukodystrophy will certainly result in innovative and efficacious disease-modifying therapies.

Insights Into the COVID-19 Infection Related to Inherited Metabolic Diseases

2022 ◽  
pp. 197-208
Author(s):  
Naima Fdil ◽  
Es-Said Sabir ◽  
Karima Lafhal ◽  
Noureddine Rada ◽  
Redouane El Fezzazi ◽  
...  
Keyword(s):  
Metabolic Diseases ◽  
Lysosomal Storage Diseases ◽  
Risk Of Infection ◽  
Lysosomal Storage ◽  
Storage Diseases ◽  
Inherited Metabolic Diseases ◽  
Respiratory Problems ◽  
The Impact

People with respiratory problems and people prone to decompensations are particularly vulnerable to COVID-19. These characteristics are often present in patients with inherited metabolic diseases (IMDs). It is therefore conceivable that patients with IMDs are at a greater risk of infection and may present a more serious form of COVID-19 disease. Currently available data about the impact of COVID-19 on patients suffering from IMDs are very scarce and no study has been able to confirm this hypothesis. In this chapter, the authors have tried to show that the severity of COVID-19 infection in patients with IMDs is specific to the group that the disease belongs. Indeed, lysosomal storage diseases caused by impaired degradation and accumulation of metabolites in lysosomes leads to dysfunction of lysosomal and possible impairment of the COVID-19 egress process. The fact that COVID-19 disease may be considered itself as an IMD was also discussed to highlight the interference which can exist between COVID-19 disease and IMDs in a patient.

scholarly journals Ferroptosis and Its Modulation by Autophagy in Light of the Pathogenesis of Lysosomal Storage Diseases

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 365
Author(s):  
Karolina Pierzynowska ◽  
Estera Rintz ◽  
Lidia Gaffke ◽  
Grzegorz Węgrzyn
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Lysosomal Storage Diseases ◽  
Review Article ◽  
Lysosomal Storage ◽  
Ferrous Ions ◽  
Autophagy Flux ◽  
Considerable Contribution ◽  
Storage Diseases

Ferroptosis is one of the recently described types of cell death which is dependent on many factors, including the accumulation of iron and lipid peroxidation. Its induction requires various signaling pathways. Recent discovery of ferroptosis induction pathways stimulated by autophagy, so called autophagy-dependent ferroptosis, put our attention on the role of ferroptosis in lysosomal storage diseases (LSD). Lysosome dysfunction, observed in these diseases, may influence ferroptosis efficiency, with as yet unknown consequences for the function of cells, tissues, and organisms, due to the effects of ferroptosis on physiological and pathological metabolic processes. Modulation of levels of ferrous ions and enhanced oxidative stress, which are primary markers of ferroptosis, are often described as processes associated with the pathology of LSD. Inhibition of autophagy flux and resultant accumulation of autophagosomes in neuronopathic LSD may induce autophagy-dependent ferroptosis, indicating a considerable contribution of this process in neurodegeneration. In this review article, we describe molecular mechanisms of ferroptosis in light of LSD, underlining the modulation of levels of ferroptosis markers in these diseases. Furthermore, we propose a hypothesis about the possible involvement of autophagy-dependent ferroptosis in these disorders.

scholarly journals Differential diagnosis of hereditary metabolic diseases using the expert knowledge-based system

2020 ◽  
Vol 35 (4) ◽  
pp. 71-78
Author(s):  
N. A. Blagosklonov ◽  
B. A. Kobrinskii
Keyword(s):  
Metabolic Diseases ◽  
Intelligent System ◽  
Expert Knowledge ◽  
Control Sample ◽  
Lysosomal Storage Diseases ◽  
Hereditary Diseases ◽  
Lysosomal Storage ◽  
Diagnostic Systems ◽  
Storage Diseases ◽  
Hereditary Metabolic Diseases

Aim. The aim of the study was to create a computer decision support system using expert knowledge for the diagnosis of rare hereditary diseases due to the difficulty of their identification at the pre-laboratory stage.Material and Methods. Descriptions of the clinical picture of lysosomal storage diseases from literature sources were used as the research material. The methods included knowledge extraction, expert assessments, quantization of age intervals, and applied intelligent services to form a knowledge base.Results. The results of the study include the construction of models for a complex assessment of a sign and an integral assessment of a disease, on the basis of which the comparative analysis algorithm is implemented to assess each of the hypotheses put forward by the system. The results of testing the prototype of the created expert system on a control sample of patients with mucopolysaccharidosis showed the efficiency of 90%. Discussion. In the discussion, several diagnostic systems are considered and their distinction from the system, presented in this work, is shown.Conclusion. The results of the development of intelligent system based on knowledge for the diagnosis of lysosomal storage diseases are summarized and the perspectives for its development are highlighted.

Inherited metabolic diseases

2013 ◽  
pp. 1451-1456
Author(s):  
Bernhard Manger
Keyword(s):  
Metabolic Diseases ◽  
Signs And Symptoms ◽  
Lysosomal Storage Diseases ◽  
Organ Damage ◽  
Lysosomal Storage ◽  
Storage Diseases ◽  
Enzyme Replacement ◽  
Hereditary Disorders ◽  
Enzymatic Pathways

A variety of hereditary disorders can present with structural or functional alterations of the musculoskeletal system. In particular, genetic defects within enzymatic pathways involved in the lysosomal degradation of various substrates can manifest with bone or joint symptoms. Because musculoskeletal complaints are frequently the first reason for the patient to seek medical advice, the rheumatologist may play a crucial role in the early diagnosis of these diseases. Lysosomal storage diseases are a heterogeneous group of individually very rare disorders, but taken together they have a prevalence of more than 1 in 8000 live births. Some of these lysosomal storage diseases can nowadays be treated very effectively by enzyme replacement therapies; however, a timely start of treatment is essential to avoid irreversible organ damage and deterioration of the quality of life. Therefore, the rheumatologist should be able to recognize signs and symptoms of the most frequent treatable lysosomal storage diseases.

scholarly journals Changes in expressions of genes involved in the regulation of cellular processes in mucopolysaccharidoses as assessed by fibroblast culture-based transcriptomic analyses

2020 ◽  
Vol 35 (8) ◽  
pp. 1353-1360
Author(s):  
Lidia Gaffke ◽  
Karolina Pierzynowska ◽  
Karolina Krzelowska ◽  
Ewa Piotrowska ◽  
Grzegorz Węgrzyn
Keyword(s):  
Lysosomal Storage Diseases ◽  
Fibroblast Culture ◽  
Lysosomal Storage ◽  
Storage Diseases ◽  
Transcriptomic Data ◽  
Cellular Processes ◽  
Expression Of Genes ◽  
Specific Symptoms ◽  
In Cells

Abstract Recent studies indicated that apart from lysosomal storage of glycosaminoglycans (GAGs), secondary and tertiary changes in cellular processes may significantly contribute to development of disorders and symptoms occurring in mucopolysaccharidoses (MPS), a group of lysosomal storage diseases in which neurodegeneration is specific for most types and subtypes. In this report, using transcriptomic data, we demonstrate that regulation of hundreds of genes coding for proteins involved in regulations of various cellular processes is changed in cells derived from patients suffering from all types and subtypes of MPS. Among such genes there are 10 which expression is significantly changed in 9 or more (out of 11) MPS types/subtypes; they include IER3IP1, SAR1A, TMEM38B, PLCB4, SIN3B, ABHD5, SH3BP5, CAPG, PCOLCE2, and MN1. Moreover, there are several genes whose expression is changed over log2 > 4 times in some MPS types relative to control cells. The above analysis indicates that significant changes in expression of genes coding for various regulators of cellular processes may considerably contribute to development of cellular dysfunctions, and further appearance of specific symptoms of MPS, including neurodegeneration.

scholarly journals Reconstruction of the Cytokine Signaling in Lysosomal Storage Diseases by Literature Mining and Network Analysis

2021 ◽  
Vol 9 ◽  
Author(s):  
Silvia Parolo ◽  
Danilo Tomasoni ◽  
Pranami Bora ◽  
Alan Ramponi ◽  
Chanchala Kaddi ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Molecular Mechanisms ◽  
Clinical Manifestations ◽  
Lysosomal Storage Diseases ◽  
Acid Sphingomyelinase ◽  
Cytokine Signaling ◽  
Literature Mining ◽  
Lysosomal Storage ◽  
Storage Diseases ◽  
Inflammatory Signals

Lysosomal storage diseases (LSDs) are characterized by the abnormal accumulation of substrates in tissues due to the deficiency of lysosomal proteins. Among the numerous clinical manifestations, chronic inflammation has been consistently reported for several LSDs. However, the molecular mechanisms involved in the inflammatory response are still not completely understood. In this study, we performed text-mining and systems biology analyses to investigate the inflammatory signals in three LSDs characterized by sphingolipid accumulation: Gaucher disease, Acid Sphingomyelinase Deficiency (ASMD), and Fabry Disease. We first identified the cytokines linked to the LSDs, and then built on the extracted knowledge to investigate the inflammatory signals. We found numerous transcription factors that are putative regulators of cytokine expression in a cell-specific context, such as the signaling axes controlled by STAT2, JUN, and NR4A2 as candidate regulators of the monocyte Gaucher disease cytokine network. Overall, our results suggest the presence of a complex inflammatory signaling in LSDs involving many cellular and molecular players that could be further investigated as putative targets of anti-inflammatory therapies.

Electron Microscopy in the diagnosis of lysosomal storage diseases

1989 ◽  
Vol 47 ◽  
pp. 866-867
Author(s):  
Carole Vogler ◽  
Harvey S. Rosenberg
Keyword(s):  
Electron Microscopy ◽  
Lysosomal Enzyme ◽  
Rectal Mucosa ◽  
Lysosomal Storage Diseases ◽  
Cell Types ◽  
Lysosomal Storage ◽  
Storage Material ◽  
Ultrastructural Examination ◽  
Blood Leukocytes ◽  
Storage Diseases

Diagnostic procedures for evaluation of patients with lysosomal storage diseases (LSD) seek to identify a deficiency of a responsible lysosomal enzyme or accumulation of a substance that requires the missing enzyme for degradation. Most patients with LSD have progressive neurological degeneration and may have a variety of musculoskeletal and visceral abnormalities. In the LSD, the abnormally diminished lysosomal enzyme results in accumulation of unmetabolized catabolites in distended lysosomes. Because of the subcellular morphology and size of lysosomes, electron microscopy is an ideal tool to study tissue from patients with suspected LSD. In patients with LSD all cells lack the specific lysosomal enzyme but the distribution of storage material is dependent on the extent of catabolism of the substrate in each cell type under normal circumstances. Lysosmal storages diseases affect many cell types and tissues. Storage material though does not accumulate in all tissues and cell types and may be different biochemically and morphologically in different tissues.Conjunctiva, skin, rectal mucosa and peripheral blood leukocytes may show ultrastructural evidence of lysosomal storage even in the absence of clinical findings and thus any of these tissues can be used for ultrastructural examination in the diagnostic evaluation of patients with suspected LSD. Biopsy of skin and conjunctiva are easily obtained and provide multiple cell types including endothelium, epithelium, fibroblasts and nerves for ultrastructural study. Fibroblasts from skin and conjunctiva can also be utilized for the initiation of tissue cultures for chemical assays. Brain biopsy has been largely replaced by biopsy of more readily obtained tissue and by biochemical assays. Such assays though may give equivical or nondiagnostic results and in some lysosomal storage diseases an enzyme defect has not yet been identified and diagnoses can be made only by ultrastructural examination.

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