Academic literature on the topic 'Lysosomal storage disorder (LSD)'
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Journal articles on the topic "Lysosomal storage disorder (LSD)"
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Kuk, Myeong Uk, Yun Haeng Lee, Jae Won Kim, Su Young Hwang, Joon Tae Park, and Sang Chul Park. "Potential Treatment of Lysosomal Storage Disease through Modulation of the Mitochondrial—Lysosomal Axis." Cells 10, no. 2 (February 17, 2021): 420. http://dx.doi.org/10.3390/cells10020420.
Full textAbstract:
Lysosomal storage disease (LSD) is an inherited metabolic disorder caused by enzyme deficiency in lysosomes. Some treatments for LSD can slow progression, but there are no effective treatments to restore the pathological phenotype to normal levels. Lysosomes and mitochondria interact with each other, and this crosstalk plays a role in the maintenance of cellular homeostasis. Deficiency of lysosome enzymes in LSD impairs the turnover of mitochondrial defects, leading to deterioration of the mitochondrial respiratory chain (MRC). Cells with MRC impairment are associated with reduced lysosomal calcium homeostasis, resulting in impaired autophagic and endolysosomal function. This malicious feedback loop between lysosomes and mitochondria exacerbates LSD. In this review, we assess the interactions between mitochondria and lysosomes and propose the mitochondrial–lysosomal axis as a research target to treat LSD. The importance of the mitochondrial–lysosomal axis has been systematically characterized in several studies, suggesting that proper regulation of this axis represents an important investigative guide for the development of therapeutics for LSD. Therefore, studying the mitochondrial–lysosomal axis will not only add knowledge of the essential physiological processes of LSD, but also provide new strategies for treatment of LSD.
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Hayashi, Okamoto, Kawano, and Iwasaki. "Development of Organelle Replacement Therapy Using a Stearyl-Polyhistidine Peptide against Lysosomal Storage Disease Cells." Molecules 24, no. 16 (August 18, 2019): 2995. http://dx.doi.org/10.3390/molecules24162995.
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We previously reported on a polyhistidine peptide, His16 peptide, as a new cell-penetrating peptide. This peptide is anticipated to be a new carrier for drug delivery systems (DDSs) for targeting intracellular lysosomes because it can transport macromolecules (e.g., liposomes) into these organelles. In the present study, we examined the application of His16 peptide as a DDS carrier against lysosomal storage disease (LSD) cells. LSDs are metabolic disorders caused by loss of specific lysosomal enzymes. For the treatment of LSD cells, we devised a system designated organelle replacement therapy (ORT). ORT is a strategy for transporting exogenous lysosomes containing all kinds of lysosomal enzymes from normal cells into endogenous lysosomes in LSD cells using His16 peptide. To develop the ORT system, we prepared His16 peptide-modified healthy lysosomes (His16-Lyso) by insertion of a stearyl-His16 peptide into a hydrophobic region in the lysosomal membrane. His16-Lyso showed cellular uptake and localization to endogenous lysosomes in LSD cells. His16-Lyso also restored the proliferation of LSD cells, which otherwise showed slower proliferation than normal cells. These results suggested that His16-Lyso replenished deficient lysosomal enzymes in LSD cells. The results further suggest that His16-Lyso are promising candidates as a treatment tool for LSD cells and to establish a foundation for ORT.
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Gorbunova, Victoria N. "Congenital metabolic diseases. Lysosomal storage diseases." Pediatrician (St. Petersburg) 12, no. 2 (August 11, 2021): 73–83. http://dx.doi.org/10.17816/ped12273-83.
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The classification and epidemiology of hereditary metabolic disorders are presented. That is a large group consisting from more them 800 monogenic diseases, each of which caused by inherited deficiency of certain metabolic fate. Many of these disorders are extremely rare, but their total incidence in the population is close to 1:10005000. Lysosomal storage diseases (LSD) resulting from inherited deficiency in lysosomal functions occupy a special place among hereditary metabolic disorders. The defects of catabolism cause the accumulation of undigested or partially digested macromolecules in lysosomes (that is, storage), which can result in cellular damage. About 60 diseases take part in this group with total incidence of about 1:70008000. LSDs typically present in infancy and childhood, although adult-onset forms also occur. Most of them have a progressive neurodegenerative clinical course, although symptoms in other organ systems are frequent. The etiology and pathogenetic aspects of their main clinical entities: mucopolysaccharidosis, glycolipidosis, mucolipidosis, glycoproteinosis, etc, are presented. Mucopolysaccharidoses caused by malfunctioning of lysosomal enzymes needed to break down glycosaminoglycans are more frequent among LSD. Sphingolipidoses caused by defects of lipid catabolism are second for frequency group of LSD. The state-of-art in field of newborn screening. clinical, biochemical and molecular diagnostics of these grave diseases are discussed. The main directions of modern lysosomal storage diseases therapy are characterized: transplantation of hematopoietic stem cells; enzyme replacement therapy; therapy with limitation of substrate synthesis (substrate-reducing therapy); pharmacological chaperone therapy. Perspective directions for LSD therapy are gene therapy and genome editing which are at advanced preclinical stages.
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Blumenreich, Shani, Or B. Barav, Bethan J. Jenkins, and Anthony H. Futerman. "Lysosomal Storage Disorders Shed Light on Lysosomal Dysfunction in Parkinson’s Disease." International Journal of Molecular Sciences 21, no. 14 (July 14, 2020): 4966. http://dx.doi.org/10.3390/ijms21144966.
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The lysosome is a central player in the cell, acting as a clearing house for macromolecular degradation, but also plays a critical role in a variety of additional metabolic and regulatory processes. The lysosome has recently attracted the attention of neurobiologists and neurologists since a number of neurological diseases involve a lysosomal component. Among these is Parkinson’s disease (PD). While heterozygous and homozygous mutations in GBA1 are the highest genetic risk factor for PD, studies performed over the past decade have suggested that lysosomal loss of function is likely involved in PD pathology, since a significant percent of PD patients have a mutation in one or more genes that cause a lysosomal storage disease (LSD). Although the mechanistic connection between the lysosome and PD remains somewhat enigmatic, significant evidence is accumulating that lysosomal dysfunction plays a central role in PD pathophysiology. Thus, lysosomal dysfunction, resulting from mutations in lysosomal genes, may enhance the accumulation of α-synuclein in the brain, which may result in the earlier development of PD.
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Onyenwoke, Rob U., Jonathan Z. Sexton, Feng Yan, María Cristina Huertas Díaz, Lawrence J. Forsberg, Michael B. Major, and Jay E. Brenman. "The mucolipidosis IV Ca2+ channel TRPML1 (MCOLN1) is regulated by the TOR kinase." Biochemical Journal 470, no. 3 (September 4, 2015): 331–42. http://dx.doi.org/10.1042/bj20150219.
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The exact mechanisms underlying the lysosomal storage disorder (LSD) mucolipidosis type IV (MLIV) are unclear. In the present study, we provide evidence that mTOR regulates the opening and closing of the lysosomal channel responsible for MLIV through phosphorylation.
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De Filippis, Concetta, Barbara Napoli, Laura Rigon, Giulia Guarato, Reinhard Bauer, Rosella Tomanin, and Genny Orso. "Drosophila D-idua Reduction Mimics Mucopolysaccharidosis Type I Disease-Related Phenotypes." Cells 11, no. 1 (December 31, 2021): 129. http://dx.doi.org/10.3390/cells11010129.
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Deficit of the IDUA (α-L-iduronidase) enzyme causes the lysosomal storage disorder mucopolysaccharidosis type I (MPS I), a rare pediatric neurometabolic disease, due to pathological variants in the IDUA gene and is characterized by the accumulation of the undegraded mucopolysaccharides heparan sulfate and dermatan sulfate into lysosomes, with secondary cellular consequences that are still mostly unclarified. Here, we report a new fruit fly RNAi-mediated knockdown model of a IDUA homolog (D-idua) displaying a phenotype mimicking some typical molecular features of Lysosomal Storage Disorders (LSD). In this study, we showed that D-idua is a vital gene in Drosophila and that ubiquitous reduction of its expression leads to lethality during the pupal stage, when the precise degradation/synthesis of macromolecules, together with a functional autophagic pathway, are indispensable for the correct development to the adult stage. Tissue-specific analysis of the D-idua model showed an increase in the number and size of lysosomes in the brain and muscle. Moreover, the incorrect acidification of lysosomes led to dysfunctional lysosome-autophagosome fusion and the consequent block of autophagy flux. A concomitant metabolic drift of glycolysis and lipogenesis pathways was observed. After starvation, D-idua larvae showed a quite complete rescue of both autophagy/lysosome phenotypes and metabolic alterations. Metabolism and autophagy are strictly interconnected vital processes that contribute to maintain homeostatic control of energy balance, and little is known about this regulation in LSDs. Our results provide new starting points for future investigations on the disease’s pathogenic mechanisms and possible pharmacological manipulations.
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Altarescu, Gheona, Rachel Beeri, Rachel Eiges, Silvina Epsztejn-Litman, Talia Eldar-Geva, Deborah Elstein, Ari Zimran, Ehud J. Margalioth, Ephrat Levy-Lahad, and Paul Renbaum. "Prevention of Lysosomal Storage Diseases and Derivation of Mutant Stem Cell Lines by Preimplantation Genetic Diagnosis." Molecular Biology International 2012 (December 26, 2012): 1–9. http://dx.doi.org/10.1155/2012/797342.
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Preimplantation genetic diagnosis (PGD) allows birth of unaffected children for couples at risk for a genetic disorder. We present the strategy and outcome of PGD for four lysosomal storage disorders (LSD): Tay-Sachs disease (TSD), Gaucher disease (GD), Fabry disease (FD), and Hunter syndrome (HS), and subsequent development of stem cell lines. For each disease, we developed a family-specific fluorescent multiplex single-cell PCR protocol that included the familial mutation and informative markers surrounding the mutation. Embryo biopsy and PGD analysis were performed on either oocytes (polar bodies one and two) or on single blastomeres from a six-cell embryo. We treated twenty families carrying mutations in these lysosomal storage disorders, including 3 couples requiring simultaneous analysis for two disorders (TSD/GD, TSD/balanced Robertsonian translocation 45XYder(21;14), and HS/oculocutaneus albinism). These analyses led to an overall pregnancy rate/embryo transfer of 38% and the birth of 20 unaffected children from 17 families. We have found that PGD for lysosomal disorders is a safe and effective method to prevent birth of affected children. In addition, by using mutant embryos for the derivation of stem cell lines, we have successfully established GD and HS hESC lines for use as valuable models in LSD research.
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Amodio, Federica, Martina Caiazza, Emanuele Monda, Marta Rubino, Laura Capodicasa, Flavia Chiosi, Vincenzo Simonelli, et al. "An Overview of Molecular Mechanisms in Fabry Disease." Biomolecules 12, no. 10 (October 12, 2022): 1460. http://dx.doi.org/10.3390/biom12101460.
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Fabry disease (FD) (OMIM #301500) is a rare genetic lysosomal storage disorder (LSD). LSDs are characterized by inappropriate lipid accumulation in lysosomes due to specific enzyme deficiencies. In FD, the defective enzyme is α-galactosidase A (α-Gal A), which is due to a mutation in the GLA gene on the X chromosome. The enzyme deficiency leads to a continuous deposition of neutral glycosphingolipids (globotriaosylceramide) in the lysosomes of numerous tissues and organs, including endothelial cells, smooth muscle cells, corneal epithelial cells, renal glomeruli and tubules, cardiac muscle and ganglion cells of the nervous system. This condition leads to progressive organ failure and premature death. The increasing understanding of FD, and LSD in general, has led in recent years to the introduction of enzyme replacement therapy (ERT), which aims to slow, if not halt, the progression of the metabolic disorder. In this review, we provide an overview of the main features of FD, focusing on its molecular mechanism and the role of biomarkers.
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Meikle, Peter J., Doug A. Brooks, Elaine M. Ravenscroft, Miao Yan, Ruth E. Williams, Alvis E. Jaunzems, Timothy K. Chataway, et al. "Diagnosis of lysosomal storage disorders: evaluation of lysosome-associated membrane protein LAMP-1 as a diagnostic marker." Clinical Chemistry 43, no. 8 (August 1, 1997): 1325–35. http://dx.doi.org/10.1093/clinchem/43.8.1325.
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Abstract Early diagnosis of lysosomal storage disorders (LSDs), before the onset of irreversible pathologies, will be a key factor in the development of effective therapies for many of these disorders. Newborn screening offers a potential mechanism for the early detection of these disorders. From studies of both normal and LSD-affected human skin fibroblasts we identified the lysosome-associated membrane protein LAMP-1 as a potential diagnostic marker. We have developed a sensitive method for the quantification of this protein with a time-resolved fluorescence immunoassay. A soluble form of LAMP-1 was observed in plasma samples, and determination of 152 unaffected individuals gave a median value of 303 μg/L with the 5th and 95th percentile at 175 and 448 μg/L respectively. Plasma samples from 320 LSD-affected individuals representing 25 different disorders were assayed. We observed that 17 of the 25 disorder groups tested had >88% of individuals above the 95th percentile of the control population, with 12 groups having 100% above the 95th percentile. Overall, 72% of patients had LAMP-1 concentrations above the 95th percentile of the unpartitioned control population. We suggest that LAMP-1 may be a useful marker in newborn screening for LSDs.
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La Cognata, Valentina, Maria Guarnaccia, Agata Polizzi, Martino Ruggieri, and Sebastiano Cavallaro. "Highlights on Genomics Applications for Lysosomal Storage Diseases." Cells 9, no. 8 (August 14, 2020): 1902. http://dx.doi.org/10.3390/cells9081902.
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Lysosomal storage diseases (LSDs) are a heterogeneous group of rare multisystem genetic disorders occurring mostly in infancy and childhood, characterized by a gradual accumulation of non-degraded substrates inside the lysosome. Although the cellular pathogenesis of LSDs is complex and still not fully understood, the approval of disease-specific therapies and the rapid emergence of novel diagnostic methods led to the implementation of extensive national newborn screening (NBS) programs in several countries. In the near future, this will help the development of standardized workflows aimed to more timely diagnose these conditions. Hereby, we report an overview of LSD diagnostic process and treatment strategies, provide an update on the worldwide NBS programs, and discuss the opportunities and challenges arising from genomics applications in screening, diagnosis, and research.
Dissertations / Theses on the topic "Lysosomal storage disorder (LSD)"
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Roy, Elise. "Cell disorders in lysosomal storage diseases." Phd thesis, Université René Descartes - Paris V, 2012. http://tel.archives-ouvertes.fr/tel-00683248.
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Mucopolysaccharidosis type IIIB (MPSIIIB) is a lysosomal storage disease (LSD) characterized by accumulation of heparan sulfate oligosaccharides (HSO), which results in progressive mental retardation, neurodegeneration and premature death in children. The underlying mechanisms are poorly understood. Coming to a better understanding of the pathophysiology of MPSIIIB has become a necessity to assess the efficacy of gene therapy treatment regarding loss of neuronal plasticity, and to define the best conditions for treatment. To address the link between HSO accumulation and downstream pathological events, new cell models of MPSIIIB were created. First, induced pluripotent stem cells (iPSc) were generated from fibroblasts of affected children, followed by differentiation of patient-derived iPSc into a neuronal progeny. Second, a HeLa cell model was created in which expression of shRNAs directed against a-N-acetylglucosaminidase (NAGLU), the deficient enzyme in MPSIIIB, is induced by tetracycline. Success in the isolation of these different models was pointed by the presence of cardinal features of MPSIIIB cell pathology. Studies in these models showed that: I) HSO excreted in the extracellular matrix modifies cell perception of environmental cues, affecting downstream signalling pathways with consequences on the Golgi morphology. II) Accumulation of intracellular storage vesicles, a hallmark of LSDs is due to overexpression of the cis-Golgi protein GM130 and subsequent Golgi alterations. It is likely that these vesicles are abnormal lysosomes formed in the cis- and medial-Golgi which are misrouted at an early step of lysosome biogenesis, giving rise to a dead-end compartment. III) Other cell functions controlled by GM130 are affected, including centrosome morphology and microtubule nucleation. These data point to possible consequences on cell polarization, cell migration and neuritogenesis.
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Mason, Lyndel Ann. "Expression variation in lysosomal storage disorder genes." Thesis, Queensland University of Technology, 2006. https://eprints.qut.edu.au/16240/1/Lyndel_Mason_Thesis.pdf.
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Metachromatic leukodystrophy (MLD) and Gaucher disease (GD) are caused by a deficiency of arylsulphatase A (ASA) and b-glucocerebrosidase (GBA), respectively. They are lysosomal storage disorders with a heterogeneous clinical spectrum encompassing visceral, skeletal and neurologic involvement resulting in high morbidity and mortality. The overall aim of this study is to elucidate the genetic component/s of high ASA and GBA enzyme activity in normal healthy individuals with the ultimate goal of using this information to produce greater protein activity from a recombinant protein. A wide variation in ASA and GBA enzyme activity levels has been observed in the normal population. The first objective of this project was to identify and characterise single nucleotide polymorphisms (SNPs) in the arylsulphatase A (ARSA) and glucocerebrosidase (GBA) genes that are responsible for determining the levels of expressed enzyme activity in the normal population. The second objective was to assess the contribution of transcriptional regulation and TCP80 mediated translational control to normal enzyme variation. TCP80, a translational control protein that interacts with the GBA coding region, is a splice variant of the interleukin binding factor 3 (ILF3) gene. Ten samples from individuals with high ASA activity and twenty samples from individuals with high GBA activity were screened for polymorphisms via denaturing high pressure liquid chromatography (dHPLC) and sequencing. The frequency of these polymorphisms in the normal population was determined using dot-blot hybridisation. Fifteen ARSA polymorphisms (4 promoter, 5 coding, 5 intronic and 1 poly(A) signal) and two GBA polymorphisms (1 intronic and 1 in 3¢-UTR) were identified. Two low frequency ASA polymorphisms (2723A > G, W193C) were found to be correlated with low activity, while another low frequency ASA polymorphism (1101+123C > T) was found to be correlated with high activity in a population of 113 individuals. Real time PCR was used to measure mRNA levels of GBA, ASA and LF3 along with enzyme activity levels of GBA and ASA in two cell types (leucocytes and skin fibroblasts) from four healthy individuals and seven cell lines (HL60, THP1, Huh7, U118, SW1353, Hep G2, and B-cells). Transcriptional control was evident for all three genes with GBA mRNA levels varying over 30 fold, ASA mRNA levels varying over seven fold and ILF3 levels varying more than 24 fold. The 5¢-flanking region of GBA was investigated for the cis-elements responsible for tissue-specific expression. However, it was not possible to demonstrate that the cis-element region was influencing GBA expression. Translational efficiency was measured using the magnitude of the mRNA:enzyme activity ratio as an indicator. GBA translational inefficiency was most pronounced in B cells which require four times more mRNA molecules than hepatocytes (Hep G2) and over 25 times more mRNA molecules than chondrocytes (SW1353) to produce one unit of GBA enzyme activity. Except in B-cells, GBA translational efficiency appears to increase as ILF3 mRNA levels decrease. The tissue-specific variation observed in the protein levels of the ILF3 splice variants, TCP80 and DRBP76, may play a role. The correlation of several low frequency SNPs with low ASA enzyme activity or high ASA activity indicates a role in determining the distribution of enzyme activity levels in the normal population. However, there do not appear to be any common high activity polymorphisms. Knowledge of the exact mechanisms responsible for the observed transcriptional and translational control of these lysosomal genes will greatly enhance the understanding of genotype-phenotype correlation and the contribution of genetic variants to natural variation.
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Mason, Lyndel Ann. "Expression variation in lysosomal storage disorder genes." Queensland University of Technology, 2006. http://eprints.qut.edu.au/16240/.
Full textAbstract:
Metachromatic leukodystrophy (MLD) and Gaucher disease (GD) are caused by a deficiency of arylsulphatase A (ASA) and b-glucocerebrosidase (GBA), respectively. They are lysosomal storage disorders with a heterogeneous clinical spectrum encompassing visceral, skeletal and neurologic involvement resulting in high morbidity and mortality. The overall aim of this study is to elucidate the genetic component/s of high ASA and GBA enzyme activity in normal healthy individuals with the ultimate goal of using this information to produce greater protein activity from a recombinant protein. A wide variation in ASA and GBA enzyme activity levels has been observed in the normal population. The first objective of this project was to identify and characterise single nucleotide polymorphisms (SNPs) in the arylsulphatase A (ARSA) and glucocerebrosidase (GBA) genes that are responsible for determining the levels of expressed enzyme activity in the normal population. The second objective was to assess the contribution of transcriptional regulation and TCP80 mediated translational control to normal enzyme variation. TCP80, a translational control protein that interacts with the GBA coding region, is a splice variant of the interleukin binding factor 3 (ILF3) gene. Ten samples from individuals with high ASA activity and twenty samples from individuals with high GBA activity were screened for polymorphisms via denaturing high pressure liquid chromatography (dHPLC) and sequencing. The frequency of these polymorphisms in the normal population was determined using dot-blot hybridisation. Fifteen ARSA polymorphisms (4 promoter, 5 coding, 5 intronic and 1 poly(A) signal) and two GBA polymorphisms (1 intronic and 1 in 3¢-UTR) were identified. Two low frequency ASA polymorphisms (2723A > G, W193C) were found to be correlated with low activity, while another low frequency ASA polymorphism (1101+123C > T) was found to be correlated with high activity in a population of 113 individuals. Real time PCR was used to measure mRNA levels of GBA, ASA and LF3 along with enzyme activity levels of GBA and ASA in two cell types (leucocytes and skin fibroblasts) from four healthy individuals and seven cell lines (HL60, THP1, Huh7, U118, SW1353, Hep G2, and B-cells). Transcriptional control was evident for all three genes with GBA mRNA levels varying over 30 fold, ASA mRNA levels varying over seven fold and ILF3 levels varying more than 24 fold. The 5¢-flanking region of GBA was investigated for the cis-elements responsible for tissue-specific expression. However, it was not possible to demonstrate that the cis-element region was influencing GBA expression. Translational efficiency was measured using the magnitude of the mRNA:enzyme activity ratio as an indicator. GBA translational inefficiency was most pronounced in B cells which require four times more mRNA molecules than hepatocytes (Hep G2) and over 25 times more mRNA molecules than chondrocytes (SW1353) to produce one unit of GBA enzyme activity. Except in B-cells, GBA translational efficiency appears to increase as ILF3 mRNA levels decrease. The tissue-specific variation observed in the protein levels of the ILF3 splice variants, TCP80 and DRBP76, may play a role. The correlation of several low frequency SNPs with low ASA enzyme activity or high ASA activity indicates a role in determining the distribution of enzyme activity levels in the normal population. However, there do not appear to be any common high activity polymorphisms. Knowledge of the exact mechanisms responsible for the observed transcriptional and translational control of these lysosomal genes will greatly enhance the understanding of genotype-phenotype correlation and the contribution of genetic variants to natural variation.
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Langford-Smith, Alexander William Walker. "Lentiviral vector mediated haematopoietic stem cell gene therapy for mucopolysaccharidosis type IIIA." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/lentiviral-vector-mediated-haematopoietic-stem-cell-gene-therapy-for-mucopolysaccharidosis-type-iiia(89f8e108-58f3-42bb-8b80-0e0a1fe45fd7).html.
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Mucopolysaccharidosis type III (Sanfilippo) is comprised of four phenotypically similar lysosomal storage disorders (MPS IIIA-D) caused by the deficiency of enzymes that catabolise heparan sulphate (HS). Progressive accumulation of HS results in abnormal behaviour, progressive cognitive and motor impairment and death in mid-teens. There are currently no treatments for MPS III. To assess the effect of novel therapeutics in the mouse models of MPS III it is necessary to examine the effect on primary storage of HS, secondary storage and behaviour. The reported behaviour of MPS IIIA and B mice is conflicting therefore we developed a one-hour open field test, performed at the same time of day during a period of hyperactivity observed in a previous circadian rhythm study of MPS IIIB mice. At 8 months of age MPS IIIB mice were hyperactive, with increased rapid exploratory behaviour and a reduction in immobility time. The MPS IIIA mice presented with the same behavioural phenotype as the MPS IIIB mice and were significantly hyperactive at 4 and 6 months of age and also displayed a reduced sense of danger. The hyperactivity and reduced sense of danger observed in the mice is consistent with the patient phenotype. Whilst haematopoietic stem cell transplant (HSCT) is the standard therapy used to treat the similar HS storage disorder MPS I Hurler, it is ineffectual in MPS IIIA. We hypothesise that HSCT failure in MPS IIIA is due to insufficient enzyme production in the brain by donor-derived microglial cells. By increasing expression of N-sulphoglucosamine sulphohydrolase (SGSH) we may be able to treat MPS IIIA. Therefore we compared the effect of HSCT using normal haematopoietic stem cells (WT-HSCT) to lentiviral overexpression of SGSH in normal cells (LV-WT-HSCT) or MPS IIIA cells (LV-IIIA-HSCT) in MPS IIIA mice, using the behavioural tests developed.SGSH activity in the brain of MPS IIIA recipients was not significantly increased by WT-HSCT, but was significantly increased by LV-IIIA-HSCT and LV-WT-HSCT. HS was significantly reduced by all transplants but the best treatment was LV-WT-HSCT. Neuroinflammation, indicated by the number of microglia in the brain, was significantly reduced by all treatments but remains significantly elevated. GM2 gangliosides were significantly reduced by WT-HSCT and LV-WT-HSCT and were no longer significantly elevated, but LV-IIIA-HSCT had no significant effect. Critically LV-WT-HSCT corrected the behaviour at 4 and 6 months of age whilst the other treatments had no significant effect. LV-WT-HSCT and WT-HSCT reduced GM2 gangliosides and neuroinflammation equally but only LV-WT-HSCT corrected behaviour and primary HS storage, suggesting they are the important factors in MPS IIIA pathology. LV-WT-HSCT corrects the neurological phenotype in MPS IIIA mice and is a clinically viable approach to treat MPS IIIA and other neuropathic lysosomal storage disorders.
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Mauri, Victor [Verfasser]. "Trehalose mediated enhancement of glycosaminoglycan degradation in the lysosomal storage disorder Mucopolysaccharidosis III / Victor Mauri." Köln : Deutsche Zentralbibliothek für Medizin, 2014. http://d-nb.info/1047324342/34.
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Huynh, Julie. "ESCRT-Dependent Cell Death in a Caenorhabditis elegans Model of the Lysosomal Storage Disorder Mucolipidosis Type IV." Thesis, The University of Arizona, 2015. http://hdl.handle.net/10150/595811.
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Mutations in MCOLN1, which encodes the cation channel protein TRPML1, result in the neurodegenerative lysosomal storage disorder Mucolipidosis type IV. Mucolipidosis type IV patients show lysosomal dysfunction in many tissues and neuronal cell death. The orthologue of TRPML1 in Caenorhabditis elegans is CUP-5; loss of CUP-5 results in lysosomal dysfunction in many tissues and death of developing intestinal cells that results in embryonic lethality. We previously showed that a null mutation in the ATP-Binding Cassette transporter MRP-4 rescues the lysosomal defect and embryonic lethality of cup-5(null) worms. Here we show that reducing levels of the Endosomal Sorting Complex Required for Transport (ESCRT)-associated proteins DID-2, PHI-33, and ALX-1/EGO-2, which mediate the final de-ubiquitination step of integral membrane proteins being sequestered into late endosomes, also almost fully suppress cup-5(null) mutant lysosomal defects and embryonic lethality. Indeed, we show that MRP-4 protein is hypo-ubiquitinated in the absence of CUP-5 and that reducing levels of ESCRT-associated proteins suppresses this hypo-ubiquitination. Thus, increased ESCRT-associated de-ubiquitinating activity mediates the lysosomal defects and corresponding cell death phenotypes in the absence of CUP-5.
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De, Silva Weerakonda Arachchige Bhagya Nilukshi. "A study of neuronal ceroid lipofuscinosis proteins CLN5 and CLN8." Thesis, Kansas State University, 2015. http://hdl.handle.net/2097/35749.
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Master of ScienceBiochemistry and Molecular Biophysics Interdepartmental Program
Stella Yu-Chien Lee
Neuronal ceroid lipofuscinoses (NCLs) are a group of neurodegenerative lysosomal storage disorders which is the most frequent group of inherited neurodegenerative disorders that affect children leading to severe pathological conditions such as progressive loss of motor neuron functions, loss of vision, mental retardation, epilepsy, ataxia and atrophy in cerebral, cerebella cortex and retina and eventually premature death. Among the many genes that cause NCL, mutations in CLN5 leads to different forms of NCL (infantile, late infantile, juvenile and adult) and mutations in CLN8 leads to progressive epilepsy with mental retardation (EPMR) and a variant late infantile form of NCL. The function(s) of both CLN5 and CLN8 proteins remain elusive. CLN5 is a glycosylated soluble protein that resides in the lysosome. We observed that endogenous CLN5 protein exist in two forms and identified a previously unknown C-terminal proteolytic processing event of CLN5. Using a cycloheximide chase experiment we demonstrated that the proteolytic processing of CLN5 is a post-translational modification. Furthermore treatment with chloroquine showed the processing occurs in low pH cellular compartments. After treatment with different protease inhibitors our results suggested the protease involved in the processing of CLN5 could be a cysteine protease. Using two glycosylation mutants of CLN5, retained in the endoplasmic reticulum (ER) or the Golgi we showed the proteolytic processing occurs in an organelle beyond the ER. This study contributes to understanding the characteristics of the CLN5 protein. CLN8 is an ER resident transmembrane protein that shuttles between the ER and the ER-Golgi intermediate compartment (ERGIC). In our study we identified a potential interaction between CLN8 and a PP2A holoenzyme complex consisting regulatory subunit A α isoform and regulatory subunit B α isoform. Using two CLN8 patient derived fibroblast cell lines we were able to show that the phosphorylated levels of PP2A target kinase Akt was reduced at both of its regulatory sites Ser473 and Thr308 and the activity of PP2A was increased. A delay of ceramide transport from ER to Golgi in CLN8 deficient patient cell lines was observed using BODIPY FL C5-Ceramide staining. Our results provide evidence for CLN8 protein being involved in the regulation of PP2A activity and trafficking of ceramide from ER to Golgi.
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Di, Malta Chiara. "The analysis of a mouse model of Lysosomal Storage Disorder uncovers a role for astrocyte dysfunction in neurodegeneration." Thesis, Open University, 2012. http://oro.open.ac.uk/54503/.
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Astrocytes are the most abundant cellular population in the brain and their role in neurodegenerative processes is becoming increasingly appreciated. In my PhD project, I investigated the contribution of astrocytes to neurodegeneration in Multiple Sulfatase Deficiency (MS D), a severe Lysosomal Storage Disorder (LSD) caused by mutations in the Sulfatase Modifying Factor 1 (SUMF1) gene. Using Cre/Lox mouse models, I found that astrocyte-specific deletion of Sumf1 in vivo induced severe lysosomal storage and autophagy dysfunction with consequential cytoplasmic accumulation of toxic substrates. Lysosomal storage in astrocytes was sufficient to induce degeneration of cortical neurons in vivo, whereas other neuronal populations were spared. Furthermore, in an ex vivo co-culture assay, I observed that Sumf1-/- astrocytes failed to support the survival and function of wild type cortical neurons, suggesting a non-cell autonomous mechanism for neurodegeneration in LSDs. Compared to the astrocyte-specific deletion of Sumf1, the concomitant deletion of Sumf1 in both neurons and glia in vivo induced a widespread neuronal loss and robust neuroinflammation. Finally, behavioural analysis of mice with astrocyte-specific deletion of Sumf1 compared to mice with Sumf1 deletion in both astrocytes and neurons allowed me to link a subset of neurological manifestations of LSDs to astrocyte dysfunction. This study indicates that astrocytes are integral components of the neuropathology in LSDs and that modulation of astrocyte function may impact the disease course.
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Hersh, Bradley Michael 1973. "C. elegans apoptosis : CED-4 translocation and involvement in a model of mucolipidosis type IV human lysosomal storage disorder." Thesis, Massachusetts Institute of Technology, 2001. http://hdl.handle.net/1721.1/8305.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, February 2002.Includes bibliographical references.
The process of programmed cell death is important in the development and homeostasis of multicellular organisms. The conserved morphological events of this process have been termed apoptosis. The molecular mechanisms of apoptosis execution are also conserved. We have investigated the behavior of these shared components during programmed cell death in the nematode Caenorhabditis elegans. We have found that the CED-9 protein, an anti-apoptotic member of the Bcl-2 family of apoptotic regulators, is required for the sequestering of the CED-4 cell-death activator to mitochondria. In the absence of CED-9 in C. elegans embryos, we found that CED-4 protein translocates to the nuclear membrane. In addition, inducing excess programmed cell death by expression of the EGL-1 cell-death activator triggers the translocation of CED-4 from mitochondria to the nuclear membrane. We performed a genetic screen for mutations that trigger programmed cell death in ced-9 gain-of-function animals where cell death is blocked. We identified a mutation in cup-5, the C. elegans homolog of the human mucolipidosis type IV gene, which is mutated in a lysosomal storage disorder. We found that cup-5 is required for viability and that excess lysosomes accumulate in cup-5 mutants. In addition, cup--5 mutants contain excess programmed cell deaths, suggesting that apoptosis may play a role in the pathology of mucolipidosis type IV.
by Bradley Michael Hersh.
Ph.D.
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Budden, Theodore. "CLN5 deficiency results in alterations in the activation of autophagy." Thesis, Kansas State University, 2014. http://hdl.handle.net/2097/20473.
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Master of ScienceDepartment of Biology
Stella Y. Lee
CLN5 is one of several proteins that when mutated result in the lysosomal storage disorder (LSD) Neuronal Ceroid Lipofuscinosis (NCL). CLN5 is a soluble lysosomal protein that has no known function at this time. Previously we showed that eight asparagine residues in CLN5 are N-glycosylated, and that this modification is important for the protein’s transport and function. Now, we have identified a link between the activation of autophagy and CLN5 deficiency. The autophagy-lysosomal protein degradation system is one of the major pathways the cell uses to degrade intracellular material and recycle cellular building blocks. It was recently shown that other CLN proteins affect the relative level of autophagy, indicating a potential link between the autophagy pathway and the NCLs. By knocking down endogenous CLN5 in HeLa we showed that, upon stress induction, cells responded with higher levels of autophagy activation. Consistent with these knockdown experiments, there is a higher level of the autophagy marker protein, LC3-II, in CLN5 patient cells that are naturally deficient for the CLN5 protein. Pharmaceutical induction of autophagy through different means also showed higher LC3-II levels compared to control, though patterns differed in the type of autophagy induced. In summary, we discovered that the autophagy pathway is altered in CLN5 deficient cells, indicating a potential role for CLN5 in autophagy. Further analyses of the autophagy pathway will shed light on where CLN5 is acting and the mechanism by which defective CLN5 causes NCL.
Books on the topic "Lysosomal storage disorder (LSD)"
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Maegawa, Gustavo H. B. Lysosomal Storage Disorders. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199937837.003.0068.
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The lysosomal storage disorders (LSDs) are a group of inborn organelle disorders, clinically heterogeneous, and biochemically characterized by accumulation of nondegraded macromolecules primarily in the lysosomal and other cellular compartments. Given the common and essential cellular function of the lysosomal system in different organs and systems, patients afflicted with these disorders present a broad range of clinical problems, including neurological problems, visceromegaly, and skeletal deformities. Onset of symptoms may range from fetal period to adulthood. The neurological problems include developmental delay, seizures, acroparesthesia, motor weakness, muscle wasting, behavioral/psychiatric disturbances, cerebrovascular ischemic events, and extrapyramidal signs. Patients may present with symptoms later that include psychiatric manifestations, are slowly progressive, and may precede other neurologic or systemic features. Most of LSDs are autosomal recessive; however, a few are X-linked with symptpmatic female carriers (e.g., Fabry disease). In most of them, the diagnosis is established by biochemical and/or molecular assays. In terms of management, disease-modifying therapies include enzyme replacement, hematopoietic stem cell transplantation, and substrate reduction therapy. Patients and their families require genetic counseling regarding reproductive risks, disease prognosis, and therapeutic options. Investigations of disease molecular mechanisms provide insights into potential targets for the development of therapeutic strategies. Supportive care has been the key and essential for most LSDs, resulting in substantial improvement in quality of life of patients and families.
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Hollak, Carla E. M. Cholesteryl Ester Storage Disease. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0058.
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Cholesteryl ester storage disease is a very rare lysosomal storage disorder that may present in an attenuated form in adult patients. This clinical phenotype is clearly distinguished from the aggressive form of cholesteryl ester storage disease known as Wolman disease with rapidly progressive, often fatal disease within the first year of life. Most patients with an attenuated form present with “fatty liver” due to the accumulation of cholesterol esters and triglycerides. Most have splenomegaly as well. Enzyme replacement therapy has been recently developed. The natural course of very mild cases and the risk of developing liver failure are currently unknown.
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Cassiman, David, and Carla E. M. Hollak. Approach to the Patient with Hepato-Gastroenterological or Abdominal Signs and Symptoms. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0074.
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A variety of signs and symptoms related to the gastrointestinal tract, including the liver, can be found as a presenting symptom of an inborn error of metabolism in adults. In particular hepatomegaly, a frequent symptom of lysosomal storage disorders and hyperammonemia not caused by acquired liver disease are manifestations of a late presentation of a metabolic disorder. A wide variety of other symptoms and signs including jaundice, abdominal pain or diarrhea, may be caused by toxic metabolites or storage of undergraded macromolecules as well.
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Waldek, Stephen. Fabry disease. Edited by Neil Turner. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199592548.003.0335_update_001.
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Fabry disease is a rare X-linked disorder of glycosphingolipid metabolism caused by a deficiency of the lysosomal acid hydrolase enzyme, alpha-galactosidase A. The resulting accumulation of substrate, mostly globotriaosylceramide, leads to a progressive, multiorgan disease affecting predominantly the kidneys, skin, heart, and nervous system. It is one of over 50 lysosomal storage diseases. It is typically diagnosed in young men after many years of ‘acral pain’ syndrome, when the diagnosis is made through identification of characteristic abnormalities of skin, kidney or heart, or of other organs. Renal failure has been a common outcome. Females may also develop manifestations, usually later in life. Renal biopsy shows vacuoles/deposits in podocytes and other renal cell types with progressive scarring. The diagnosis can be made by measuring enzyme levels in men, or by genetic testing. This latter is the more reliable test in women. Fabry disease can now be treated where affordable by regular (every 2 weeks) intravenous infusions of recombinant preparations of the deficient enzyme. These are burdensome and expensive, but are transforming the outlook for the condition.
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Sedel, Frédéric. Niemann-Pick Disease Type C. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0053.
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Niemann-Pick disease type C (NPC) is a fatal neurovisceral lipid storage disease of autosomal inheritance resulting from mutations in either the NPC1 (95% of families) or NPC2 gene. The encoded proteins appear to be involved in lysosomal/late endosomal transport of cholesterol, glycolipids, and other molecules, but their exact function is still unknown. The clinical spectrum of the disease ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease characterized prominently by psychiatric disorders, cerebellar ataxia, cognitive decline, and vertical supranuclear gaze palsy. Miglustat is the only treatment approved to date which has been demonstrated to slow or halt disease progression.
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Frawley, Geoff. Mucopolysaccharidoses. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199764495.003.0064.
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The mucopolysaccharidoses (MPS) are a group of seven chronic progressive diseases caused by deficiencies of 11 different lysosomal enzymes required for the catabolism of glycosaminoglycans (GAGs). Hurler syndrome (MPS IH) is an autosomal recessive storage disorder caused by a deficiency of α-L-iduronidase. Hunter syndrome (MPS II) is an X-linked recessive disorder of metabolism involving the enzyme iduronate-2-sulfatase. Many of the MPS clinical manifestations have potential anesthetic implications. Significant airway issues are particularly common due to thickening of the soft tissues, enlarged tongue, short immobile neck, and limited mobility of the cervical spine and temporomandibular joints. Spinal deformities, hepatosplenomegaly, airway granulomatous tissue, and recurrent lung infections may inhibit pulmonary function. Odontoid dysplasia and radiographic subluxation of C1 on C2 is common and may cause anterior dislocation of the atlas and spinal cord compression.
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Waldek, Stephen. Fabry disease. Edited by Neil Turner. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0337.
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Fabry disease is a rare X-linked lysosomal storage disorder in which deficiency of alpha-galactosidase A leads to accumulation of substrate, mostly globotriaosylceramide, which causes a progressive, multiorgan disease affecting predominantly the kidneys, skin, heart, and nervous system. Painful peripheral (‘acral’) neuropathy is characteristic.Key clinical signs are angiokeratoma found by close examination of skin; characteristic eye lesions may be seen; lipid deposits may be seen in urine. Renal biopsy appearances are characteristic and this is commonly where the diagnosis is first made. Increasingly, cardiologists are suspecting the condition in adults with echocardiographic appearances of left ventricular hypertrophy. Diagnosis in men is usually made by measurement of alpha-galactosidase in either white cells or plasma (or using blood spots). Unfortunately, many female patients can have normal enzyme levels so that genetic testing is the only way to confirm a diagnosis. Non-selective screening strategies (e.g. males on renal replacement therapy with uncertain renal diagnoses) have had low yields.
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Servais, Aude. Nephropathic Cystinosis in Adults. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0060.
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Cystinosis is an autosomal recessive lysosomal storage disorder caused by a defect in the carrier-mediated system that normally transports cystine out of lysosomes. As a consequence, tissues accumulate variable amounts of the disulphide amino acid cystine. Three overlapping clinical phenotypes are recognized, varying in severity and age of onset. The most severe, the infantile nephropathic form (MIM 219800), appears in the first year of life. The late-onset form (MIM 219900) is also nephropathic, while ocular, non-nephropathic cystinosis manifests largely with corneal crystal deposition (MIM 219750). Infantile cystinosis is the most common form. Affected children develop renal proximal tubulopathy at 6 to 12 months of age. In the absence of treatment, renal failure occurs, with progression to end-stage renal disease (ESRD). Cystine crystal deposition in the cornea leads to photophobia and continuous widespread cystine accumulation eventually leads to rickets, retinal, endocrinological (hypothyroidism and impaired glucose tolerance), hepatic, gastrointestinal, muscular, and neurological abnormalities.
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Waldek, Stephen. Fabry disease. Edited by Neil Turner. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0336.
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Fabry disease is a rare X-linked lysosomal storage disorder in which deficiency of alpha-galactosidase A leads to accumulation of substrate, mostly globotriaosylceramide, which causes a progressive, multiorgan disease affecting predominantly the kidneys, skin, heart, gut, and nervous system. Painful peripheral (‘acral’) neuropathy is characteristic. The disease is commonly diagnosed in children and young men often after some years of usually neuropathic symptoms, with exacerbations (Fabry crises), that commonly elude diagnosis for a long time. These usually occur years in advance of overt involvement of other organs. Diagnosis may also be suspected from renal biopsy, echocardiographic evidence of cardiomyopathy commonly beginning as left ventricular hypertrophy, or characteristic angiokeratomas typically in ‘bathing trunk’ distribution on skin. Renal manifestations are of proteinuria leading to progressive chronic kidney disease associated with deposits in podocytes. Diarrhoea is common. Disordered sweating is typical. Corneal lesions are also typical and there may be tortuosity of retinal vessels. Strokes are increased in frequency, and sensorineural deafness may occur. Women have fewer and later overt manifestations but some develop severe disease.
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van der Ploeg, Ans T., and Pascal Laforêt. Pompe Disease. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0055.
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Pompe disease, also named acid maltase deficiency and glycogen storage disease type II (GSDII), is a rare autosomal recessive disorder caused by the deficiency of the glycogen-degrading lysosomal enzyme acid α-glucosidase. The clinical spectrum of this disease is broad, varying from a lethal infantile-onset generalized myopathy including cardiomyopathy, to late-onset slowly progressive muscle weakness mimicking limb-girdle muscular dystrophy. Respiratory insufficiency is a frequent complication and the main cause of death. The prognosis of Pompe disease has changed considerably with the use of enzyme replacement therapy using recombinant acid α-glucosidase (alglucosidase alfa), which has been widely available since 2006. Improvements in survival and major motor achievements can be observed in patients with infantile forms, and recent studies demonstrate improvement of walking distance and stabilization of pulmonary function in late-onset forms. A longer-term study of the safety and efficacy of ERT, based on data gathering across the complete spectrum of Pompe disease via national or international patient registries, is needed in order to formulate more precise guidelines for treatment.
Book chapters on the topic "Lysosomal storage disorder (LSD)"
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Patel, Shutish C., Peter G. Pentchev, Howard S. Kruth, Margaret L. Grunnet, and Sundar Suresh. "Abnormal Cholesterol Metabolism in Primary Brain Cultures of the Lysosomal Cholesterol Storage Disorder (LCSD) Murine Mutant." In Lipid Storage Disorders, 193–200. Boston, MA: Springer US, 1988. http://dx.doi.org/10.1007/978-1-4613-1029-7_23.
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Ellsworth, Katarzyna A., Laura M. Pollard, Sara Cathey, and Tim Wood. "Measurement of Elevated Concentrations of Urine Keratan Sulfate by UPLC-MSMS in Lysosomal Storage Disorders (LSDs): Comparison of Urine Keratan Sulfate Levels in MPS IVA Versus Other LSDs." In JIMD Reports, 11–18. Berlin, Heidelberg: Springer Berlin Heidelberg, 2016. http://dx.doi.org/10.1007/8904_2016_1.
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"Lysosomal Storage Disease (LSD)." In Clinical Atlas of Canine and Feline Ophthalmic Disease, 308–9. Chichester, UK: John Wiley & Sons, Inc, 2015. http://dx.doi.org/10.1002/9781118840801.ch145.
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"Lysosomal Lipid Storage Disorder." In Encyclopedia of Autism Spectrum Disorders, 2769. Cham: Springer International Publishing, 2021. http://dx.doi.org/10.1007/978-3-319-91280-6_300973.
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Linhart, Ales. "The heart in inherited metabolic disorders: lysosomal and glycogen storage diseases." In ESC CardioMed, 1540–45. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198784906.003.0372.
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Lysosomal storage diseases (LSDs) represent a large and heterogeneous group of rare inherited disorders caused by a defective function of one of the lysosomal acid hydrolases, their activator proteins, or proteins necessary for intracellular trafficking. The diseases are characterized by an accumulation of macromolecules representing substrates for defective enzymes. Most diseases affect multiple organs causing neurological, musculoskeletal, gastrointestinal and hepatic involvement, renal, and cardiac damage. Several diseases cause myocardial involvement manifesting as hypertrophic or less frequently dilated cardiomyopathy, arrhythmias (conduction abnormalities, bradycardia, and ventricular arrhythmias), valvular lesions, and coronary involvement. Several lysosomal diseases are now treatable by enzyme replacement therapy or by chaperones. The group of glycogen storage diseases largely overlaps with LSDs. In addition to LSDs causing glycogen storage and myocardial involvement (Pompe and Danon diseases), cytoplasmic glycogen metabolism is disturbed in PRKAG2 autosomal dominant cardiomyopathy. The recognition of specific causes of myocardial involvement may allow a timely treatment by specific therapies preventing irreversible damage.
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Syed Haneef, S. A., and C. George Priya Doss. "Personalized Pharmacoperones for Lysosomal Storage Disorder." In Advances in Protein Chemistry and Structural Biology, 225–65. Elsevier, 2016. http://dx.doi.org/10.1016/bs.apcsb.2015.10.001.
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Hoover, Kevin B. "Lipidoses." In Musculoskeletal Imaging Volume 2, edited by Kevin B. Hoover, 73–78. Oxford University Press, 2019. http://dx.doi.org/10.1093/med/9780190938178.003.0083.
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Chapter 83 discusses lipidoses. The lipidoses are genetic diseases caused by enzyme deficiencies, which result in the cellular accumulation of lipids. These abnormal cells infiltrate tissues, including bone marrow, resulting in their dysfunction. Gaucher disease (GD) is the most common lysosomal storage disease (LSD) and lipidosis. Fabry disease (FD) is an X-linked recessive disease. Together, GD and FD account for 20% of LSDs. Nonspecific bone changes are detected using radiography, however, MRI is the most useful modality to evaluate involvement of the bone and bone marrow. MRI can also be used to detect treatment response. Enzyme replacement therapy (ERT) is the primary treatment for GD.
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Sawaf, Hanny, Angelika L. Erwin, Fang Zhao, Tushar J. Vachharajani, and Xiangling Wang. "Enzyme-Replacement Therapy in Fabry Disease." In Multidisciplinary Experiences in Renal Replacement Therapy [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.103799.
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Fabry disease is a rare X-linked lysosomal storage disorder due to mutations in the GLA gene causing complete or partial deficiency of the lysosomal enzyme alpha-galactosidase A (a-Gal A). This enzyme deficiency results in tissue accumulation of trihexosylceramide causing the diseases’ systemic manifestations, including acroparesthesia, angiokeratomas, cardiac disease, cerebrovascular manifestations, and kidney disease. Kidney manifestations of Fabry disease can include proteinuria, renal tubular dysfunction, hypertension, and cystic formation. With the relatively recent introduction of enzyme-replacement therapy (ERT), this congenital disorder can now be treated providing these patients with much longer life expectancies and less severe systemic manifestations than before. When started in the appropriate population, ERT is generally continued until a reason for stopping therapy arises. Although ERT is expensive, it has drastically changed the clinical outcome of patients with Fabry disease, and timely initiation of ERT and regular assessments of disease progression by a multidisciplinary care team are critical for the long-term management of these patients.
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Trauner, Doris A. "Neurological and Cognitive Consequences of Nephropathic Cystinosis." In Cognitive and Behavioral Abnormalities of Pediatric Diseases. Oxford University Press, 2010. http://dx.doi.org/10.1093/oso/9780195342680.003.0039.
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Nephropathic cystinosis is a rare autosomal recessive disorder caused by a deletion mapped to chromosome 17p13. The gene codes for a protein, cystinosin (CTNS), a lysosomal membrane transporter protein. When the CTNS gene is inactivated, the amino acid cystine cannot cross the lysosomal membrane and accumulates in lysosomes. Thus, cystinosis is a lysosomal storage disease. The accumulated cystine forms crystals that can cause damage to multiple organs. Cystinosis is thought to occur with an incidence of 1 in 100,000 live births, although accurate numbers are difficult to obtain because the disease may remain undiagnosed. Cystinosis was first described as a renal tubular disorder in the early 20th century by Fanconi and others (see Gahl et al. 2002 for a review). In 1967, accumulation of cystine within cells was recognized, and the lysosomal transport defect was identified in 1982. The first signs and symptoms of cystinosis are caused by renal tubular dysfunction, with the Fanconi syndrome developing within the first few months of life. Infants develop polyuria, dehydration, vomiting, poor appetite, and excessive thirst. If not recognized and treated early, these infants have failure to thrive and may develop rickets. The diagnosis can be made by assaying the cystine concentration in white blood cells; a level of greater than 2 nmol half-cystine per milligram of protein is diagnostic. The gene can now be sequenced, but this is conducted primarily in research settings and is not readily available clinically. Once diagnosed, treatment with a cystine-depleting agent, cysteamine, can be introduced immediately. The natural history of untreated nephropathic cystinosis is that of progressive renal failure, with renal dialysis and ultimately kidney transplant typically being necessary by the age of 10 years. Even with successful renal transplantation, life expectancy is greatly shortened, with death typically in the third or fourth decade. The reason for the early mortality is that cystinosis affects multiple other organs besides the kidney, and renal transplantation does not prevent the other systemic complications. Although the most prominent manifestations of the disease are renal, other organs are involved to varying degrees.
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Kåks, Ida, and Peter Magnusson. "Fabry Disease." In Cardiomyopathy - Disease of the Heart Muscle [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.99142.
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Fabry disease (FD) is a lysosomal storage disorder where deficient or completely absent activity of the enzyme α-galactosidas A leads to accumulation of globotriaosylceramide (Gb3) and other glycosphingolipids in lysosomes. The condition is rare, approximately 1:50,000, although underdiagnosis seems frequent. The condition can affect multiple organ systems, including the skin, nervous system, kidneys, and heart. Early manifestations include skin lesions (angiokeratoma), neuropathic pain, and gastrointestinal symptoms. Later on, FD can result in cardiomyopathy, kidney failure, and stroke. Both lifespan and health-related quality of life are affected negatively by FD. Patients are divided into a classical or a non-classical phenotype based on presentation, where the diagnosis of classical FD requires that a set of specific criteria are met. Patients with non-classical FD often have a less severe disease course, sometimes limited to one organ. The hereditary pattern is X-linked. Thus, men are in general more severely affected than women, although there is an overlap in symptomatic burden. Two types of specific treatment options are available: enzyme replacement therapy and pharmacological chaperone therapy. In addition to this, management of each organ manifestation with usual treatment is indicated.