Clinical phenotype of Gaucher disease in relation to properties of mutant glucocerebrosidase in cultured fibroblasts

Weely, Sonja van; Leeuwen, M.B. van; Jansen, Ineke D. C.; Bruijn, M. A. C. De; Brouwer-Kelder, Elisabeth M.; Schram, A. W.; Miranda, María; Barranger, John A.; Petersen, Evelyn M.; Goldblatt, Jack; Stotz, Harald; Schwarzmann, Günther; Sandhoff, Konrad; Svennerholm, Lars; Erikson, Anders; Tager, J. M.; Aerts, Johannes M. F. G.

doi:10.1016/0925-4439(91)90066-i

Cited by 49 publications

(47 citation statements)

References 19 publications

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“…1,2 In accordance with previous studies, enzyme supplementation therapy was found to improve the nonmetabolic symptoms of the disease. [6][7][8][9][10][11] In addition, we established that hypermetabolism, reflected in increased REE in GD patients improves during enzyme supplementation therapy, although normalization was not achieved.…”

Section: Discussionsupporting

confidence: 73%

“…The clinical manifestations of type 1 GD are highly variable and cannot be predicted from the properties of mutant glucocerebrosidase. 1,2 In general, the altered size, number, and function of macrophages result in a variety of disease manifestations. The presence of lipid-laden macrophages results in a number of clinical signs such as splenomegaly, hepatomegaly, bone lesions, and cytopenia.…”

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confidence: 99%

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Differential Effects of Enzyme Supplementation Therapy on Manifestations of Type 1 Gaucher Disease

Hollak

Corssmit

Aerts

et al. 1997

The American Journal of Medicine

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Differential effects of enzyme supplementation therapy on manifestations of type 1 gaucher disease Hollak, C.E.M.; Corssmit, E.P.M.; Aerts, J.M.F.G.; Endert, E.; Sauerwein, H.P.; Romijn, J.A.; van Oers, M.H.J. Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. ) and hemoglobin and platelet count were obtained before and after 6 months of alglucerase therapy (15 U/kg per month). In 7 of the 12 patients hepatic glucose production was measured by infusing 3-3 H glucose. For comparison, REE and glucose metabolism were studied in 7 weight-and age-matched healthy subjects.RESULTS: REE and glucose production were increased in GD patients as compared with controls (REE: 29.8 kcal/kg/24 h { 3.6 and 23.1 { 2.3 kcal/kg/24 h, respectively, P õ 0.05; glucose production: 14.00 mmol/kg/min { 0.51 and 10.77 mmol/kg/min { 0.26, respectively, P õ 0.03). There were no differences in plasma glucose concentrations. Whereas the elevated REE decreased after 6 months of alglucerase therapy from 129% to 120% of predicted values (P õ 0.01), the increase in hepatic glucose production did not

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Section: Discussionsupporting

confidence: 73%

mentioning

confidence: 99%

Differential Effects of Enzyme Supplementation Therapy on Manifestations of Type 1 Gaucher Disease

Hollak

Corssmit

Aerts

et al. 1997

The American Journal of Medicine

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“…The variability of the clinical spectrum of the disease is intriguing and not explained. Since the clinical symptoms of the disease are not strictly correlated to either properties of mutant glucocerebrosidase or genotype (1,2), epigenetic factors probably influence the disease manifestations. In addition, several clinical phenomena in Gaucher disease are poorly understood, such as hypermetabolism and wasting (3), and an increased incidence of monoclonal gammopathies, multiple myeloma and autantibodies (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Elevated Levels of M-CSF, sCD14 and IL8 in Type 1 Gaucher Disease

Hollak

Evers

Aerts

et al. 1997

Blood Cells, Molecules, and Diseases

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ABSTRACT:In type 1 Gaucher disease, decreased activity of glucocerebrosidase results in accumulation of glucosylceramide in macrophages. Infiltration of liver, spleen and bone marrow by lipid-laden macrophages leads to hepatosplenomegaly, bone lesions and cytopenia. These abnormal macrophages may produce and release macrophage derived factors and cytokines, which could contribute to the pathophysiology of the disease. Whether these cytokines and factors are elevated in Gaucher disease is currently unknown. In 29 type 1 Gaucher disease patients we measured serum levels of the macrophage derived cytokines IL8, IL6, TNFa , M-CSF and the monocyte/macrophage activation marker sCD14. These factors were studied in relation to disease severity and during treatment with enzyme supplementation therapy. Most patients showed remarkably elevated levels of M-CSF (2-8 fold) and sCD14 (2-5 fold) as compared to normal controls. Levels of IL8 were elevated in all patients (2-20 fold), whereas levels of IL6 and TNFa were normal. There was a significant correlation between severity of the disease as determined by the severity score index (SSI), and M-CSF, sCD14 and IL8 levels. M-CSF and sCD14 levels also correlated with the excess liver and spleen volumes. During treatment with alglucerase, levels of M-CSF and sCD14 declined, but IL8 remained unchanged. The relative reduction in excess liver and spleen volume did not correlate with the relative reduction in M-CSF or sCD14 levels. We conclude that serum levels of M-CSF, sCD14 and IL8 are increased in type 1 Gaucher disease. The biological activities of M-CSF and IL8 may add to the pathophysiology of the disease.

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“…This was confirmed by biochemical analysis in situ ( Figure 5, lane A), in which [14C]hexanoyl-GlcCer was degraded to ['4C]hexanoyl-Cer, which was subsequently metabolized in the endoplasmic reticulum/Golgi-apparatus complex (Futerman and Pagano, 1991;Futerman et al, 1990;Koval and Pagano, 1989) Similar to [u4C]hexanoyl-GlcCer hydrolysis in vitro, clear differences in residual enzyme activity were observed in situ between fibroblasts obtained from different Gaucher types. Activity in type 1 fibroblasts varied from 2.9 to 4.5 nmol/mg of protein with a mean value of 3.5 + 0.6 (n = 9), and for type 2 and 3 varied from 0.9 to 2.4 nmol/mg of protein with a mean value of 1.8 +0.5 (n = 10) ( (Pagano and Sleight, 1985;Futerman et al, 1990;Futerman and Pagano, 1992 (Hultberg and Ockerman, 1972;Van Weely et al, 1991). In such mixtures, the physical state under which the enzymic reaction proceeds is far removed from conditions existing in situ, inasmuch as both substrate and enzyme are present in aqueous solutions as complexes with detergents.…”

Section: In Vitro Assay Of Glccerase Using [14c]hexanoyl-glccermentioning

confidence: 99%

Analysis of glucocerebrosidase activity using N-(1-[14C]hexanoyl)-d-erythro-glucosylsphingosine demonstrates a correlation between levels of residual enzyme activity and the type of Gaucher disease

Meivar‐Levy

Horowitz

Futerman

1994

Biochemical Journal

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Glucosylceramide, a degradation product of complex glycosphingolipids, is hydrolysed in lysosomes by glucocerebrosidase (GlcCerase). Mutations in the human GlcCerase gene cause a reduction in GlcCerase activity and accumulation of glucosylceramide, which results in the onset of Gaucher disease, the most common lysosomal storage disease. Significant clinical heterogeneity is observed in Gaucher disease, with three main types known, but no clear correlation has been reported between the different types and levels of residual GlcCerase activity. We now demonstrate that a correlation exists by using a radioactive, short-acyl chain substrate, N-(1-[14C]hexanoyl)-D-erythro-glucosylsphingosine ([14C]hexanoyl-GlcCer). This substrate rapidly transferred into biological membranes in the absence of detergent [Futerman and Pagano (1991) Biochem. J. 280, 295-302] and was hydrolyzed to N-(1-[14C]hexanoyl)-D-erythro-sphingosine ([14C]hexanoyl-Cer) both in vitro and in situ, with an acid pH optimum. A strict correlation was observed between levels of [14C]hexanoyl-GlcCer hydrolysis and Gaucher type in human skin fibroblasts. The mean residual activity measured in vitro for 3 h incubation in type 1 Gaucher fibroblasts (the mild form of the disease) was 46.3 +/- 4.6 nmol of [14C]hexanoyl-Cer formed per mg protein (n = 9), and in type 2 and 3 fibroblasts (the neuronopathic forms of the disease) was 19.6 +/- 6.5 (n = 9). A similar correlation was observed when activity was measured in situ, suggesting that the clinical severity of a lysosomal storage disease is related to levels of residual enzyme activity.

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Clinical phenotype of Gaucher disease in relation to properties of mutant glucocerebrosidase in cultured fibroblasts

Cited by 49 publications

References 19 publications

Differential Effects of Enzyme Supplementation Therapy on Manifestations of Type 1 Gaucher Disease

Differential Effects of Enzyme Supplementation Therapy on Manifestations of Type 1 Gaucher Disease

Elevated Levels of M-CSF, sCD14 and IL8 in Type 1 Gaucher Disease

Analysis of glucocerebrosidase activity using N-(1-[14C]hexanoyl)-d-erythro-glucosylsphingosine demonstrates a correlation between levels of residual enzyme activity and the type of Gaucher disease

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