Elevated LysoGb3 Concentration in the Neuronopathic Forms of Mucopolysaccharidoses

Baydakova, Galina; Ilyushkina, Alexandra; Gaffke, Lidia; Pierzynowska, Karolina; Bychkov, Igor; Ługowska, Agnieszka; Węgrzyn, Grzegorz; Tylki‐Szymańska, Anna; Zakharova, Ekaterina

doi:10.3390/diagnostics10030155

Cited by 9 publications

(6 citation statements)

References 23 publications

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“…Further longitudinal monitoring studies need to be performed in the future to ascertain whether the normal levels of lyso-Gb3 in some of these patients could be related to treatment response. This corroborates the findings of Baydakova et al (2020), who observed increased DBS lyso-Gb3 in neuronopathic forms of MPS (including MPS III) [ 26 ].…”

Section: Discussionsupporting

confidence: 91%

New Perspectives in Dried Blood Spot Biomarkers for Lysosomal Storage Diseases

Śpiewak

Doykov

Papandreou

et al. 2023

IJMS

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Dried blood spots (DBSs) biomarkers are convenient for monitoring for specific lysosomal storage diseases (LSDs), but they could have relevance for other LSDs. To determine the specificity and utility of glycosphingolipidoses biomarkers against other LSDs, we applied a multiplexed lipid liquid chromatography tandem mass spectrometry assay to a DBS cohort of healthy controls (n = 10) and Gaucher (n = 4), Fabry (n = 10), Pompe (n = 2), mucopolysaccharidosis types I–VI (n = 52), and Niemann–Pick disease type C (NPC) (n = 5) patients. We observed no complete disease specificity for any of the markers tested. However, comparison among the different LSDs highlighted new applications and perspectives of the existing biomarkers. We observed elevations in glucosylceramide isoforms in the NPC and Gaucher patients relative to the controls. In NPC, there was a greater proportion of C24 isoforms, giving a specificity of 96–97% for NPC, higher than 92% for the NPC biomarker N-palmitoyl-O-phosphocholineserine ratio to lyso-sphingomyelin. We also observed significantly elevated levels of lyso-dihexosylceramide in Gaucher and Fabry disease as well as elevated lyso-globotriaosylceramide (Lyso-Gb3) in Gaucher disease and the neuronopathic forms of Mucopolysaccharidoses. In conclusion, DBS glucosylceramide isoform profiling has increased the specificity for the detection of NPC, thereby improving diagnostic accuracy. Low levels of lyso-lipids can be observed in other LSDs, which may have implications in their disease pathogenesis.

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Section: Discussionsupporting

confidence: 91%

New Perspectives in Dried Blood Spot Biomarkers for Lysosomal Storage Diseases

Śpiewak

Doykov

Papandreou

et al. 2023

IJMS

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“…Neurofibrillary light chain is significantly elevated in cerebrospinal fluid (CSF) and serum of MPS II patients with neurological involvement, and they are positively correlated with CSF HS, which can be used to assess neuronal health and damage in treated MPS II patients [ 8 ]. Lysozyme B3 has been found to be a potential secondary biomarker of nervous system involvement in MPS patients [ 6 , 72 ]. Elevated expression of three candidate biomarkers, matrix metalloproteinase 19, α-trypsin interinhibitor heavy chain 3, and α-1-microglobulin, was demonstrated in MPS I cartilage, and serum abundance of these molecules was found to correlate with MRI and histologic degeneration grading [ 92 ].…”

Section: Biomarkersmentioning

confidence: 99%

Application of tandem mass spectrometry in the screening and diagnosis of mucopolysaccharidoses

Li,

Mao,

Chao

et al. 2024

Orphanet J Rare Dis

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Mucopolysaccharidoses (MPSs) are caused by a deficiency in the enzymes needed to degrade glycosaminoglycans (GAGs) in the lysosome. The storage of GAGs leads to the involvement of several systems and even to the death of the patient. In recent years, an increasing number of therapies have increased the treatment options available to patients. Early treatment is beneficial in improving the prognosis, but children with MPSs are often delayed in their diagnosis. Therefore, there is an urgent need to develop a method for early screening and diagnosis of the disease. Tandem mass spectrometry (MS/MS) is an analytical method that can detect multiple substrates or enzymes simultaneously. GAGs are reliable markers of MPSs. MS/MS can be used to screen children at an early stage of the disease, to improve prognosis by treating them before symptoms appear, to evaluate the effectiveness of treatment, and for metabolomic analysis or to find suitable biomarkers. In the future, MS/MS could be used to further identify suitable biomarkers for MPSs for early diagnosis and to detect efficacy.

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“…The principal biochemical abnormality caused by the NAGLU gene or activity deficiency in MPS IIIB is the accumulation of lysosomal HS (the mechanism of HS storage has not yet been fully understood) and the elimination of this polysaccharide, or fragments derived from it, in body fluids [63]. Additionally, secondary storage products, such as: GM 2 and GM 3 gangliosides that play a role in central nervous systems pathology [63,77], inflammatory cytokines, reactive oxygen species [78] and globotriaosylsphingosine (LysoGb3) [79] have also been described. There are hypotheses concerning secondary storage product accumulation.…”

Section: Mucopolysaccharidosis Type Iiibmentioning

confidence: 99%

“…There are hypotheses concerning secondary storage product accumulation. Some have argued that this phenomenon may be due to the inhibition of relevant lysosomal enzymes by HS/GAGs, which when accumulating can selectively bind various hydrolases causing a decrease in their activity [79]. Others claim that they can cause critical disruption of the internal environment of the lysosome (for example, by changes in pH) and thus lead to reduced degradation of additional substrates [80].…”

Section: Mucopolysaccharidosis Type Iiibmentioning

confidence: 99%

Heparan Sulfate, Mucopolysaccharidosis IIIB and Sulfur Metabolism Disorders

2022

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Mucopolysaccharidosis, type IIIB (MPS IIIB) is a rare disease caused by mutations in the N-alpha-acetylglucosaminidase (NAGLU) gene resulting in decreased or absent enzyme activity. On the cellular level, the disorder is characterized by the massive lysosomal storage of heparan sulfate (HS)—one species of glycosaminoglycans. HS is a sulfur-rich macromolecule, and its accumulation should affect the turnover of total sulfur in cells; according to the studies presented here, it, indeed, does. The lysosomal degradation of HS in cells produces monosaccharides and inorganic sulfate (SO42−). Sulfate is a product of L-cysteine metabolism, and any disruption of its levels affects the entire L-cysteine catabolism pathway, which was first reported in 2019. It is known that L-cysteine level is elevated in cells with the Naglu−/− gene mutation and in selected tissues of individuals with MPS IIIB. The level of glutathione and the Naglu−/− cells’ antioxidant potential are significantly reduced, as well as the activity of 3-mercaptopyruvate sulfurtransferase (MPST, EC 2.8.1.2) and the level of sulfane sulfur-containing compounds. The direct reason is not yet known. This paper attempts to identify some of cause-and-effect correlations that may lead to this condition and identifies research directions that should be explored.

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Elevated LysoGb3 Concentration in the Neuronopathic Forms of Mucopolysaccharidoses

Cited by 9 publications

References 23 publications

New Perspectives in Dried Blood Spot Biomarkers for Lysosomal Storage Diseases

New Perspectives in Dried Blood Spot Biomarkers for Lysosomal Storage Diseases

Application of tandem mass spectrometry in the screening and diagnosis of mucopolysaccharidoses

Heparan Sulfate, Mucopolysaccharidosis IIIB and Sulfur Metabolism Disorders

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