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Gaucher disease (GD) and Fabry disease (FD) are two relatively common inherited glycosphingolipidoses caused by deficiencies in the lysosomal glycosidases glucocerebrosidase and alpha-galactosidase A, respectively. For both diseases enzyme supplementation is presently used as therapy. Cells and tissues of GD and FD patients are uniformly deficient in enzyme activity, but the two diseases markedly differ in cell types showing lysosomal accumulation of the glycosphingolipid substrates glucosylceramide and globotriaosylceramide, respectively. The clinical manifestation of Gaucher disease and Fabry disease is consequently entirely different and the response to enzyme therapy is only impressive in the case of GD patients. This review compares both glycosphingolipid storage disorders with respect to similarities and differences. Presented is an update on insights regarding pathophysiological mechanisms as well as recently available biochemical markers and diagnostic tools for both disorders. Special attention is paid to sphingoid bases of the primary storage lipids in both diseases. The value of elevated glucosylsphingosine in Gaucher disease and globotriaosylsphingosine in Fabry disease for diagnosis and monitoring of disease is discussed as well as the possible contribution of the sphingoid bases to (patho)physiology. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Problematic severe childhood asthma includes a subgroup of patients who are resistant to therapy. The specific mechanisms involved are unknown, and novel biomarkers are required to facilitate treatment and diagnosis of therapy-resistant asthma. The chitinase-like protein YKL-40 has been related to asthma and airway remodeling., Objectives: To compare serum YKL-40 levels in children with severe, therapy-resistant asthma (n = 34), children with controlled persistent asthma (n = 39), and healthy controls (n = 27), and to investigate correlations with biomarkers of inflammation and airway remodeling., Methods: The study protocol included questionnaires, measurement of exhaled nitric oxide in exhaled air, blood sampling for inflammatory biomarkers, and high-resolution computed tomography of the lungs to identify bronchial wall thickening (therapy-resistant only). Serum YKL-40 levels were measured by ELISA, and all asthmatic children were genotyped for a CHI3L1 promoter single nucleotide polymorphism (rs4950928)., Results: Serum YKL-40 levels were significantly higher in children with therapy-resistant asthma than in healthy children (19.2 ng/mL vs 13.8 ng/mL, P = .03). Among children with severe, therapy-resistant asthma, YKL-40 levels correlated with fraction of exhaled nitric oxide in exhaled air (r = 0.48, P = .004), blood neutrophils (r = 0.63, P < .001), and bronchial wall thickening on high-resolution computed tomography (r = 0.45, P = .01). Following adjustment for CHI3L1 genotype, significantly greater levels of YKL-40 were found in children with therapy-resistant asthma than in children with controlled asthma., Conclusions: YKL-40 levels are increased in children with severe, therapy-resistant asthma compared to healthy children, and also compared to children with controlled asthma following correction for genotype., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

A biomarker is an analyte indicating the presence of a biological process linked to the clinical manifestations and outcome of a particular disease. In the case of lysosomal storage disorders (LSDs), primary and secondary accumulating metabolites or proteins specifically secreted by storage cells are good candidates for biomarkers. Clinical applications of biomarkers are found in improved diagnosis, monitoring disease progression, and assessing therapeutic correction. These are illustrated by reviewing the discovery and use of biomarkers for Gaucher disease and Fabry disease. In addition, recently developed chemical tools allowing specific visualization of enzymatically active lysosomal glucocerebrosidase are described. Such probes, coined inhibodies, offer entirely new possibilities for more sophisticated molecular diagnosis, enzyme replacement therapy monitoring, and fundamental research.

Background: Accumulation of macrophages in multiple organs is a common feature of sarcoidosis and Gaucher disease. The vast number of storage macrophages in Gaucher patients has facilitated the discovery of suitable plasma markers like chitotriosidase and CCL18., Methods: Plasma specimens of patients with sarcoidosis were examined on chitotriosidase activity and CCL18 protein levels., Results: Chitotriosidase was markedly increased, being on average 13.7-fold elevated (range: 1.1-43.3). The sensitivity of demonstrating sarcoidosis using plasma chitotriosidase values exceeded that using serum angiotensin-converting enzyme values. A 3.5-fold (range: 1-15) increase in CCL18 was also observed. The relative changes in chitotriosidase and CCL18 during the course of disease closely mimicked each other, suggesting an identical cellular source. In situ hybridization analysis confirmed massive production of chitotriosidase by sarcoid macrophages. The increase in plasma chitotriosidase correlated with the stage of disease, being highest in active sarcoidosis with extrapulmonary involvement. Therapy with steroids resulted in clear reduction of plasma chitotriosidase and CCL18 and relapse of disease activity was preceded by increases in these parameters., Conclusions: Sarcoid macrophages secrete high quantities of chitotriosidase and CCL18. Determination of plasma chitotriosidase and CCL18 may be useful to monitor changes in granulomatous macrophages during the course of sarcoidosis.

Gaucher disease is an inherited lysosomal storage disorder, characterized by massive accumulation of glucosylceramide-laden macrophages in the spleen, liver and bone marrow as a consequence of deficient activity of glucocerebrosidase. Gaucher disease has been the playground to develop new therapeutic interventions such as enzyme-replacement therapy and substrate-reduction therapy. The availability of these costly therapies has stimulated research regarding suitable biomarkers to monitor onset and progression of disease, as well as the efficacy of therapeutic intervention. Given the important role of storage cells in the pathology, various attempts have been made to identify proteins in plasma or serum reflecting the body burden of these pathological cells. In this review, the existing data regarding biomarkers for Gaucher disease, as well as the current application of biomarkers in clinical management of Gaucher patients are discussed. Moreover, the use of several modern proteomic technologies for the identification of Gaucher biomarkers is reviewed.

Unlabelled: A biomarker is an analyte that indicates the presence of a biological process linked to the clinical manifestations and outcome of a particular disease. An ideal biomarker provides indirect but ongoing determinations of disease activity. In the case of lysosomal storage disorders (LSDs), metabolites or proteins specifically secreted by storage cells are good candidates for biomarkers. Potential clinical applications of biomarkers are found in improved diagnosis, monitoring of disease progression and assessment of therapeutic correction. These applications are illustrated by reviewing the use of plasma chitotriosidase in the clinical management of patients with Gaucher disease, the most common LSD. The ongoing debate on the value of biomarkers in patient management is addressed. Novel analytical methods have revolutionized the identification and measurement of biomarkers at the protein and metabolite level. Recent developments in biomarker discovery by proteomics are described and the future for biomarkers of LSDs is discussed., Conclusion: Besides direct applications for biomarkers in patient management, biomarker searches are likely to render new insights into pathophysiological mechanisms and metabolic adaptations, and may provide new targets for therapeutic intervention.

Gaucher disease (GD) is the most common lysosomal storage disorder and is caused by inherited deficiencies of glucocerebrosidase, the enzyme responsible for the lysosomal breakdown of the lipid glucosylceramide. GD is characterized by the accumulation of pathological, lipid laden macrophages, so-called Gaucher cells. Following the development of enzyme replacement therapy for GD, the search for suitable surrogate disease markers resulted in the identification of a thousand-fold increased chitinase activity in plasma from symptomatic Gaucher patients and that decreases upon successful therapeutic intervention. Biochemical investigations identified a single enzyme, named chitotriosidase, to be responsible for this activity. Chitotriosidase was found to be an excellent marker for lipid laden macrophages in Gaucher patients and is now widely used to assist clinical management of patients. In the wake of the identification of chitotriosidase, the presence of other members of the chitinase family in mammals was discovered. Amongst these is AMCase, an enzyme recently implicated in the pathogenesis of asthma. Chitinases are omnipresent throughout nature and are also produced by vertebrates in which they play important roles in defence against chitin-containing pathogens and in food processing.

The synthesis of three fluorogenic chitobiosyl derivatives, modified at the non-reducing 4′-OH with, either a methyl, an isopropyl or a cyclohexylmethyl substituent, is described. The 4′-capped 4-methylumbelliferyl chitobiosides are hydrolysed by the human chitinase CHIT1 following Michaelis–Menten kinetics and in contrast to unmodified chitobiosyl-4-methylumbelliferone do not undergo transglycosylation. The compounds are also relatively poor hexosaminidase substrates and thus provide useful alternatives to 4′-deoxychitobiosyl-4-methylumbelliferone, previously reported by us as fluorogenic substrate to monitor CHIT1 activity as a marker for Gaucher disease state. [ABSTRACT FROM AUTHOR]