Quantification of globotriaosylsphingosine in plasma and urine of fabry patients by stable isotope ultraperformance liquid chromatography-tandem mass spectrometry.

Background: Biochemical markers that accurately reflect the severity and progression of disease in patients with Fabry disease and their response to treatment are urgently needed. Globotriaosylsphingosine, also called lysoglobotriaosylceramide (lysoGb3), is a promising candidate biomarker.

Methods: We synthesized lysoGb3 and isotope-labeled [5,6,7,8,9] (13)C5-lysoGb3 (internal standard).

Long-term effect of antibodies against infused alpha-galactosidase A in Fabry disease on plasma and urinary (lyso)Gb3 reduction and treatment outcome.

Introduction: Enzyme replacement therapy (ERT) with alpha-Galactosidase A (aGal A) may cause antibody (AB) formation against aGal A in males with Fabry disease (FD). Anti agalsidase ABs negatively influence globotriaosylceramide (Gb3) reduction. We investigated the impact of agalsidase AB on Gb3 and lysoGb3 and clinical outcome in Fabry patients on ERT.

Vascular aspects of Fabry disease in relation to clinical manifestations and elevations in plasma globotriaosylsphingosine.

Fabry disease is an X-linked hereditary lysosomal storage disorder attributed to a deficiency of α-galactosidase A leading to increased plasma levels of globotriaosylsphingosine (lysoGb3). The disease presents as a vascular disease, with cerebral, cardiac, and renal complications. Carotid intima-media thickness (IMT), brachial flow-mediated dilation (FMD), pulse wave velocity, and advanced glycation end products were measured in 57 classically affected patients (22 men and 35 women), 55 healthy matched controls (20 men and 35 women), and 10 atypical Fabry disease patients (5 men and 5 women).

Effects of switching from a reduced dose imiglucerase to velaglucerase in type 1 Gaucher disease: clinical and biochemical outcomes.

This paper describes the effects of a switch to velaglucerase alfa in a group of adult patients with type 1 Gaucher disease, all of whom had previously had their dose reduced as a consequence of the worldwide imiglucerase shortage. Thirty-two patients from two large European Gaucher centers switched to treatment with velaglucerase alfa after 1-8.5 months of dose reduction.

Consequences of a global enzyme shortage of agalsidase beta in adult Dutch Fabry patients.

Background: Enzyme replacement therapy is currently the only approved therapy for Fabry disease. From June 2009 on, viral contamination of Genzyme's production facility resulted in a worldwide shortage of agalsidase beta leading to involuntary dose reductions (approved dose 1 mg/kg/eow, reduced dose 0.5 mg/kg/m), or switch to agalsidase alpha (administered dose 0.

Gaucher disease due to saposin C deficiency, previously described as non-neuronopathic form--no positive effects after 2-years of miglustat therapy.

Gaucher disease occurs mainly as a result of a deficiency of the lysosomal enzyme beta-glucocerebrosidase activity. A rare variant form of Gaucher disease is known in which saposin C required for glucosylceramide degradation is deficient. In an earlier paper we described the first cases of two siblings with the non-neuronopathic form of Gaucher disease caused by saposin C deficiency [Tylki-Szymańska et al.

Elevated plasma glucosylsphingosine in Gaucher disease: relation to phenotype, storage cell markers, and therapeutic response.

Gaucher disease, caused by a deficiency of the lysosomal enzyme glucocerebrosidase, leads to prominent glucosylceramide accumulation in lysosomes of tissue macrophages (Gaucher cells). Here we show glucosylsphingosine, the deacylated form of glucosylceramide, to be markedly increased in plasma of symptomatic nonneuronopathic (type 1) Gaucher patients (n = 64, median = 230.7 nM, range 15.

Biomarkers in the diagnosis of lysosomal storage disorders: proteins, lipids, and inhibodies.

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.

Spontaneous regression of disease manifestations can occur in type 1 Gaucher disease; results of a retrospective cohort study.

Gaucher disease (GD) is a lysosomal storage disorder, caused by deficient activity of the enzyme glucocerebrosidase. GD is classically divided into three major phenotypes. The most prevailing form is type 1, which presents with variable hepatosplenomegaly, cytopenia, and/or bone disease.

Kupffer cells promote hepatic steatosis via interleukin-1beta-dependent suppression of peroxisome proliferator-activated receptor alpha activity.

Unlabelled: Kupffer cells have been implicated in the pathogenesis of various liver diseases. However, their involvement in metabolic disorders of the liver, including fatty liver disease, remains unclear. The present study sought to determine the impact of Kupffer cells on hepatic triglyceride storage and to explore the possible mechanisms involved.

Deficiency in N-acetylgalactosamine-6-sulfate sulfatase results in collagen perturbations in cartilage of Morquio syndrome A patients.

Aim: To investigate extracellular matrix (ECM) characteristics of cortical bone and articular cartilage of patients with Morquio syndrome A, a lysosomal storage disease caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase.

Patients And Methods: Cartilage, bone, and fibroblasts from 2 unrelated patients with Morquio syndrome were used. Histological analysis on bone and cartilage was carried out by means of light and electron microscopy.

Detection of chitinase activity by 2-aminobenzoic acid labeling of chito-oligosaccharides.

Chitinases are hydrolases capable of hydrolyzing the abundant natural polysaccharide chitin. Next to artificial fluorescent substrates, more physiological chito-oligomers are commonly used in chitinase assays. Analysis of chito-oligosaccharides products is generally accomplished by UV detection.

Treatment of Fabry disease with different dosing regimens of agalsidase: effects on antibody formation and GL-3.

Two different enzyme preparations are used for the treatment of Fabry disease patients, agalsidase alpha (Replagal, Shire) and agalsidase beta (Fabrazyme, Genzyme). Therapeutic efficacy of both products has been variable probably due to differences in gender, severity, age and other patient characteristics. We studied the occurrence of alpha-Gal A antibodies and their effect on urinary and plasma globotriaosylceramide (GL-3), plasma chitotriosidase and clinical outcome in 52 patients after 12 months of treatment with either 0.

Prominent increase in plasma ganglioside GM3 is associated with clinical manifestations of type I Gaucher disease.

Background: Patients with Gaucher disease show signs of insulin resistance. The ganglioside GM3 has recently shown to be a negative regulator of insulin sensitivity. In fibroblasts of Gaucher patients, deficient in degradation of glucosylceramide, an increased anabolism of this lipid to gangliosides occurs.

Type I Gaucher disease, a glycosphingolipid storage disorder, is associated with insulin resistance.

Context: Complex glycosphingolipids, in majority the ganglioside GM3, surround the insulin receptor in a special membrane compartment (raft) and modulate signaling through this receptor. Increased levels of GM3 in rafts impair insulin signaling, resulting in insulin resistance. Gaucher disease is a lysosomal storage disorder in which impaired breakdown of glucosylceramide leads to its accumulation in macrophages.

HPLC for simultaneous quantification of total ceramide, glucosylceramide, and ceramide trihexoside concentrations in plasma.

Background: Simple, reproducible assays are needed for the quantification of sphingolipids, ceramide (Cer), and sphingoid bases. We developed an HPLC method for simultaneous quantification of total plasma concentrations of Cer, glucosylceramide (GlcCer), and ceramide trihexoside (CTH).

Methods: After addition of sphinganine as internal calibrator, we extracted lipids from 50 microL plasma.

Low frequency maintenance therapy with imiglucerase in adult type I Gaucher disease: a prospective randomized controlled trial.

Background And Objectives: Gaucher disease type I can be successfully treated with enzyme replacement therapy (ERT). In order to reduce the burden of the intravenously administered enzyme, a low frequency of administration was prospectively studied in patients with stable and minor disease following ERT.

Design And Methods: Eleven patients were randomly assigned either to continue their original regimen of a dose of ERT once every week or fortnight (five patients) or to lower the frequency of administration to once every 4 weeks, at the same cumulative dose (six patients).

Substrate reduction therapy of glycosphingolipid storage disorders.

In the last 15 years enormous progress has been made regarding therapy of type I Gaucher disease, a severely disabling disorder characterized by intralysosomal storage of glucosylceramide in tissue macrophages. Effective enzyme replacement therapy of type I Gaucher disease, based on chronic intravenous administration of mannose-terminated recombinant human glucocerebrosidase, has been available since 1990 and has been applied in several thousand patients without serious adverse effects. An alternative therapeutic approach, so-called substrate reduction therapy, is based on partial reduction of the synthesis of glucosylceramide and hence of subsequent metabolites.

Superior effects of high-dose enzyme replacement therapy in type 1 Gaucher disease on bone marrow involvement and chitotriosidase levels: a 2-center retrospective analysis.

Dosing of enzyme replacement therapy (ERT) for Gaucher disease type 1 is still a subject of debate and varies from 15 to 130 U/kg/mo, making a huge economic difference of 70,000 US dollars to 380,000 US dollars(euro55,000-300,000) per patient per year. To investigate whether this difference in dosing ultimately translates into a different response, we retrospectively compared long-term outcome of ERT at 2 large European treatment centers, Academic Medical Center, Amsterdam, The Netherlands (n = 49, median dose, 15-30 U/kg/4 wks) and Heinrich-Heine University, Duesseldorf, Germany (n = 57, median dose, 80 U/kg/4 wks). These adult cohorts had a similar genetic background.

Transglycosidase activity of chitotriosidase: improved enzymatic assay for the human macrophage chitinase.

Chitotriosidase is a chitinase that is massively expressed by lipid-laden tissue macrophages in man. Its enzymatic activity is markedly elevated in serum of patients suffering from lysosomal lipid storage disorders, sarcoidosis, thalassemia, and visceral Leishmaniasis. Monitoring of serum chitotriosidase activity in Gaucher disease patients during progression and therapeutic correction of their disease is useful to obtain insight in changes in body burden on pathological macrophages.

Clinical variability in mucolipidosis III (pseudo-Hurler polydystrophy).

Mucolipidosis III (MLIII) is caused by a deficiency of UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine 1-phosphotransferase (phosphotransferase) activity, an enzyme responsible for the formation of the recognition marker on most lysosomal enzymes. The consequences of this defect are impairment of many lysosomal catabolic processes. A deficiency of phosphotransferase activity causes two phenotypically different diseases: mucolipidosis II and a rare form, mucolipidosis III (pseudo-Hurler polydystrophy).