Mucopolysaccharidosis type II (MPS II) is an X-linked lysosomal storage disorder resulting from deficiency of iduronate-2-sulphatase activity. The disease manifests almost exclusively in males; only 16 symptomatic heterozygote girls have been reported so far. We describe the results of X-chromosome inactivation analysis in a 5-year-old girl with clinically severe disease and heterozygous mutation p.Arg468Gln in the IDS gene. X inactivation analysed at three X-chromosome loci showed extreme skewing (96/4 to 99/1) in two patient's cell types. This finding correlated with exclusive expression of the mutated allele. Induced pluripotent stem cells (iPSC) generated from the patient's peripheral blood demonstrated characteristic pluripotency markers, deficiency of enzyme activity, and mutation in the IDS gene. These cells were capable of differentiation into other cell types (cardiomyocytes, neurons). In MPS II iPSC clones, the X inactivation ratio remained highly skewed in culture conditions that led to partial X inactivation reset in Fabry disease iPSC clones. Our data, in accordance with the literature, suggest that extremely skewed X inactivation favouring the mutated allele is a crucial condition for manifestation of MPS II in females. This suggests that the X inactivation status and enzyme activity have a prognostic value and should be used to evaluate MPS II in females. For the first time, we show generation of iPSC from a symptomatic MPS II female patient that can serve as a cellular model for further research of the pathogenesis and treatment of this disease.
- MeSH
- iduronátsulfatasa genetika metabolismus MeSH
- inaktivace chromozomu X * MeSH
- indukované pluripotentní kmenové buňky * MeSH
- kultivované buňky MeSH
- lidé MeSH
- mukopolysacharidóza II diagnóza enzymologie genetika MeSH
- mutace MeSH
- předškolní dítě MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- Názvy látek
- iduronátsulfatasa MeSH
In recent years, mass spectrometry (MS) has become the dominant technology in lipidomic analysis. It is widely used in diagnosis and research of lipid metabolism disorders including those characterized by impairment of lysosomal functions and storage of nondegraded-degraded substrates. These rare diseases, which include sphingolipidoses, have severe and often fatal clinical consequences. Modern MS methods have contributed significantly to achieve a definitive diagnosis, which is essential in clinical practice to begin properly targeted patient care. Here we summarize MS and tandem MS methods used for qualitative and quantitative analysis of sphingolipids (SL) relative to the diagnostic process for sphingolipidoses and studies focusing on alterations in cell functions due to these disorders. This review covers the following topics: Tandem MS is sensitive and robust in determining the composition of sphingolipid classes in various biological materials. Its ability to establish SL metabolomic profiles using MS bench-top analyzers, significantly benefits the first stages of a diagnosis as well as metabolic studies of these disorders. It can thus contribute to a better understanding of the biological significance of SL.
- Klíčová slova
- Deacylated sphingolipids, Electrospray ionization, Enzymology, Lysosomal storage disorders, Sphingolipidoses, Sphingolipids, Tandem mass spectrometry,
- MeSH
- lidé MeSH
- sfingolipidózy diagnóza MeSH
- sfingolipidy analýza chemie fyziologie MeSH
- tandemová hmotnostní spektrometrie metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- sfingolipidy MeSH
- MeSH
- dějiny 19. století MeSH
- komunismus * MeSH
- školy lékařské dějiny MeSH
- studium farmacie vysokoškolské dějiny MeSH
- studium lékařství specializační postgraduální dějiny MeSH
- Check Tag
- dějiny 19. století MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- historické články MeSH
- Geografické názvy
- Československo MeSH
- MeSH
- cysty mediastina diagnóza MeSH
- cysty diagnóza MeSH
- diferenciální diagnóza MeSH
- hydrokéla diagnóza MeSH
- krk MeSH
- lidé středního věku MeSH
- lidé MeSH
- nemoci mužských pohlavních orgánů diagnóza MeSH
- senioři MeSH
- skrotum * MeSH
- struma diagnóza MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- kazuistiky MeSH
