BackgroundGaucher disease (GD) is the most common lysosomal storage disorder (LSD). Based on a deficient β-glucocerebrosidase it leads to an accumulation of glucosylceramide. Standard diagnostic procedures include measurement of enzyme activity, genetic testing as well as analysis of chitotriosidase and CCL18/PARC as biomarkers. Even though chitotriosidase is the most well-established biomarker in GD, it is not specific for GD. Furthermore, it may be false negative in a significant percentage of GD patients due to mutation. Additionally, chitotriosidase reflects the changes in the course of the disease belatedly. This further enhances the need for a reliable biomarker, especially for the monitoring of the disease and the impact of potential treatments.MethodologyHere, we evaluated the sensitivity and specificity of the previously reported biomarker Glucosylsphingosine with regard to different control groups (healthy control vs. GD carriers vs. other LSDs).FindingsOnly GD patients displayed elevated levels of Glucosylsphingosine higher than 12 ng/ml whereas the comparison controls groups revealed concentrations below the pathological cut-off, verifying the specificity of Glucosylsphingosine as a biomarker for GD. In addition, we evaluated the biomarker before and during enzyme replacement therapy (ERT) in 19 patients, demonstrating a decrease in Glucosylsphingosine over time with the most pronounced reduction within the first 6 months of ERT. Furthermore, our data reveals a correlation between the medical consequence of specific mutations and Glucosylsphingosine.InterpretationIn summary, Glucosylsphingosine is a very promising, reliable and specific biomarker for GD.
The interest in periodic geodesies arose at a very early stage of differential geometry, and has grown rapidly since then. It is a basic general problem to estimate the number of distinct periodic geodesies c: R -• Λί, c(t + 1) = c(t) 9 on a complete riemannian manifold M in terms of topological invariants. Here periodic geodesies are always understood to be non-constant, and two such curves c l9 c 2 will be said to be distinct if they are geometrically different, c x (R) Φ c£R).If M is non-compact, then it is even difficult to find reasonable conditions for the existence of at least one periodic geodesic, see §4. However, in the compact case many results are available. It is classical and rather elementary that any non-trivial conjugacy class of the fundamental group n x {M) gives rise to periodic geodesies, and very often the existence of a larger number of distinct periodic geodesies can be deduced from further properties of π x (M) compare [4, p. 240], [7], and also §4. When M is simply connected* the problem is getting much more delicate. Here the first result was obtained in 1905 by Poincare, who proved that there exists a periodic geodesic on every surface analytically equivalent to the euclidean sphere S2 . Yet rather late, in 1952, Fet and Lusternik established the theorem that on any compact riemannian manifold M at least one geodesic is periodic. Several authors have proved the existence of certain finite numbers of distinct periodic geodesies for special topological types of manifolds, partly under restrictive metric conditions. We mention the work of Lusternik, Schnirelmann, Morse, Fet, Alber, and Klingenberg; for references see [11].In §4 of this paper we shall prove: There always exist infinitely many distinct periodic geodesies on an arbitrary compact manifold, provided some weak topological condition holds. In fact, it seems that our condition will be satisfied except in comparatively few cases. Until now it was not even possible to decide whether there is some compact simply connected differentiable manifold M with infinitely many distinct periodic geodesies for all riemannian structures on M.As yet the mast natural ami successful way of dealing with periodic geodesies
Fabry disease (FD) is an X-linked hereditary defect of glycosphingolipid storage caused by mutations in the gene encoding the lysosomal hydrolase α-galactosidase A (GLA, α-gal A). To date, over 400 mutations causing amino acid substitutions have been described. Most of these mutations are related to the classical Fabry phenotype. Generally in lysosomal storage disorders a reliable genotype/phenotype correlation is difficult to achieve, especially in FD with its X-linked mode of inheritance. In order to predict the metabolic consequence of a given mutation, we combined in vitro enzyme activity with in vivo biomarker data. Furthermore, we used the pharmacological chaperone (PC) 1-deoxygalactonojirimycin (DGJ) as a tool to analyse the influence of individual mutations on subcellular organelle-trafficking and stability. We analysed a significant number of mutations and correlated the obtained properties to the clinical manifestation related to the mutation in order to improve our knowledge of the identity of functional relevant amino acids. Additionally, we illustrate the consequences of different mutations on plasma lyso-globotriaosylsphingosine (lyso-Gb3) accumulation in the patients' plasma, a biomarker proven to reflect the impaired substrate clearance caused by specific mutations. The established system enables us to provide information for the clinical relevance of PC therapy for a given mutant. Finally, in order to generate reliable predictions of mutant GLA defects we compared the different data sets to reveal the most coherent system to reflect the clinical situation.
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