Lysosomal storage disease overview

Sun, Angela

doi:10.21037/atm.2018.11.39

Cited by 185 publications

(165 citation statements)

References 96 publications

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“…Behavioral changes are common in neuronopathic forms of MPS (MPS I, MPS II, MPS III, and MPS VII), however, their molecular mechanisms remain unclear [1][2][3][4][5][6][7][8][9][10][11]. It is generally accepted that the storage of heparan sulfate (HS) is responsible for these changes, as this GAG accumulates, between others, in neurons, contrary to other major GAGs stored in MPS cells [1,2,12]. On the other hand, among MPS types in which HS storage occurs, behavioral changes are very different [2][3][4][5][6][7][8][9][10].…”

Section: Discussionmentioning

confidence: 99%

“…The group of lysosomal storage diseases (LSD) [1] in which glycosaminoglycans (GAGs) are accumulated due to mutations in genes coding for enzymes involved in degradation of these complex carbohydrates is called mucopolysaccharidosis (MPS) [2]. There are 11 types and subtypes of MPS that are classified according to the kinds of stored GAGs and dysfunctions of specific enzymes [2].…”

Section: Introductionmentioning

confidence: 99%

“…There are 11 types and subtypes of MPS that are classified according to the kinds of stored GAGs and dysfunctions of specific enzymes [2]. In MPS types I and II, heparan sulfate and dermatan sulfate accumulate, but their degradation is inhibited at various stages due to dysfunctions of different enzymes [1]. Heparan sulfate is the primary GAG stored in MPS III, however, there are four subtypes of this disease (named A, B, C and D) which correspond to various defective enzymes responsible for degradation of this GAG; in addition, less efficient secondary storage of dermatan sulfate has also been reported in MPS III [3].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Genetic Base of Behavioral Disorders in Mucopolysaccharidoses: Transcriptomic Studies

Pierzynowska

Gaffke

Podlacha

et al. 2020

IJMS

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Mucopolysaccharidoses (MPS) are a group of inherited metabolic diseases caused by mutations leading to defective degradation of glycosaminoglycans (GAGs) and their accumulation in cells. Among 11 known types and subtypes of MPS, neuronopathy occurs in seven (MPS I, II, IIIA, IIIB, IIIC, IIID, VII). Brain dysfunctions, occurring in these seven types/subtypes include various behavioral disorders. Intriguingly, behavioral symptoms are significantly different between patients suffering from various MPS types. Molecular base of such differences remains unknown. Here, we asked if expression of genes considered as connected to behavior (based on Gene Ontology, GO terms) is changed in MPS. Using cell lines of all MPS types, we have performed transcriptomic (RNA-seq) studies and assessed expression of genes involved in behavior. We found significant differences between MPS types in this regard, with the most severe changes in MPS IIIA (the type considered as the behaviorally most severely affected), while the lowest changes in MPS IVA and MPS VI (types in which little or no behavioral disorders are known). Intriguingly, relatively severe changes were found also in MPS IVB (in which, despite no behavioral disorder noted, the same gene is mutated as in GM1 gangliosidosis, a severe neurodegenerative disease) and MPS IX (in which only a few patients were described to date, thus, behavioral problems are not well recognized). More detailed analyses of expression of certain genes allowed us to propose an association of specific changes in the levels of transcripts in specific MPS types to certain behavioral disorders observed in patients. Therefore, this work provides a principle for further studies on the molecular mechanism of behavioral changes occurring in MPS patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genetic Base of Behavioral Disorders in Mucopolysaccharidoses: Transcriptomic Studies

Pierzynowska

Gaffke

Podlacha

et al. 2020

IJMS

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“…Lysosomal storage diseases (LSD) are often considered model genetic disorders due to the level of understanding of their molecular mechanisms and the stage of development of therapies [3]. Mucopolysaccharidoses (MPS) is a group of intensively investigated LSD caused by deficiency of lysosomal enzymes involved in degradation of glycosaminoglycans (GAG) [4].…”

Section: Introductionmentioning

confidence: 99%

Underestimated Aspect of Mucopolysaccharidosis Pathogenesis: Global Changes in Cellular Processes Revealed by Transcriptomic Studies

Gaffke

Pierzynowska

Podlacha

et al. 2020

IJMS

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Mucopolysaccharidoses (MPS), a group of inherited metabolic disorders caused by deficiency in enzymes involved in degradation of glycosaminoglycans (GAGs), are examples (and models) of monogenic diseases. Accumulation of undegraded GAGs in lysosomes was supposed to be the major cause of MPS symptoms; however, their complexity and variability between particular types of the disease can be hardly explained by such a simple storage mechanism. Here we show that transcriptomic (RNA-seq) analysis of the material derived from fibroblasts of patients suffering from all types and subtypes of MPS, supported by RT-qPCR results, revealed surprisingly large changes in expression of genes involved in various cellular processes, indicating complex mechanisms of MPS. Although each MPS type and subtype was characterized by specific changes in gene expression profile, there were genes with significantly changed expression relative to wild-type cells that could be classified as common for various MPS types, suggesting similar disturbances in cellular processes. Therefore, both common features of all MPS types, and differences between them, might be potentially explained on the basis of changes in certain cellular processes arising from disturbed regulations of genes’ expression. These results may shed a new light on the mechanisms of genetic diseases, indicating how a single mutation can result in complex pathomechanism, due to perturbations in the network of cellular reactions. Moreover, they should be considered in studies on development of novel therapies, suggesting also why currently available treatment methods fail to correct all/most symptoms of MPS. We propose a hypothesis that disturbances in some cellular processes cannot be corrected by simple reduction of GAG levels; thus, combined therapies are necessary which may require improvement of these processes.

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“…Lysosomal storage disorders (LSD) are a group of inherited metabolic disorders that are mainly caused by enzyme deficiencies within the lysosome resulting in accumulation of undegraded substrate [1]. Mucopolysaccharidoses (MPS) are rare LSD caused by a deficiency of specific lysosomal enzymes that affect degradation of glycosaminoglycans (GAGs).…”

Section: Introductionmentioning

confidence: 99%

Mucopolysaccharidosis-Plus Syndrome

Vasilev

Syromyatnikova

Otomo

2020

IJMS

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Previously, we reported a novel disease of impaired glycosaminoglycans (GAGs) metabolism without deficiency of known lysosomal enzymes—mucopolysaccharidosis-plus syndrome (MPSPS). MPSPS, whose pathophysiology is not elucidated, is an autosomal recessive multisystem disorder caused by a specific mutation p.R498W in the VPS33A gene. VPS33A functions in endocytic and autophagic pathways, but p.R498W mutation did not affect both of these pathways in the patient’s skin fibroblast. Nineteen patients with MPSPS have been identified: seventeen patients were found among the Yakut population (Russia) and two patients from Turkey. Clinical features of MPSPS patients are similar to conventional mucopolysaccharidoses (MPS). In addition to typical symptoms for conventional MPS, MPSPS patients developed other features such as congenital heart defects, renal and hematopoietic disorders. Diagnosis generally requires evidence of clinical picture similar to MPS and molecular genetic testing. Disease is very severe, prognosis is unfavorable and most of patients died at age of 10–20 months. Currently there is no specific therapy for this disease and clinical management is limited to supportive and symptomatic treatment.

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Lysosomal storage disease overview

Cited by 185 publications

References 96 publications

Genetic Base of Behavioral Disorders in Mucopolysaccharidoses: Transcriptomic Studies

Genetic Base of Behavioral Disorders in Mucopolysaccharidoses: Transcriptomic Studies

Underestimated Aspect of Mucopolysaccharidosis Pathogenesis: Global Changes in Cellular Processes Revealed by Transcriptomic Studies

Mucopolysaccharidosis-Plus Syndrome

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