3 Gaucher's disease: clinical features and natural history

Cox, Timothy M.; Schofield, J. Paul

doi:10.1016/s0950-3536(97)80033-9

Cited by 222 publications

(157 citation statements)

References 60 publications

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“…This may contribute to the fact that most, but not all, homozygotes for the N370S mutation do not develop significant clinical symptoms. Twin studies and the poor predictive power of phenotype-genotype investigations in Gaucher disease have clearly indicated that epigenetic factors also play a key role in Gaucher disease manifestation (Aerts et al 1993;Cox & Schofield 1997).…”

Section: Gaucher Disease (Glucosylceramidosis)mentioning

confidence: 99%

Biochemistry of glycosphingolipid storage disorders: implications for therapeutic intervention

Aerts

Hollak

Boot

et al. 2003

Phil. Trans. R. Soc. Lond. B

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The physiological importance of the degradative processes in lysosomes is revealed by the existence of at least 40 distinct inherited diseases, the so-called lysosomal storage disorders. Most of these diseases are caused by a deficiency in a single lysosomal enzyme, or essential cofactor, and result in the lysosomal accumulation of one, or sometimes several, natural compounds. The most prevalent subgroup of the lysosomal storage disorders is formed by the sphingolipidoses, inherited disorders that are characterized by excessive accumulation of one or multiple (glyco)sphingolipids. The biology of glycosphingolipids has been extensively discussed in other contributions during this symposium. This review will therefore focus in depth on (type 1) Gaucher disease, a prototypical glycosphingolipidosis. The elucidation of the primary genetic defect, being a deficiency in the lysosomal glucocerebrosidase, is described. Characterization of glucocerebrosidase at protein and gene level has subsequently opened avenues for therapeutic intervention. The development of successful enzyme replacement therapy for type 1 Gaucher disease is discussed. Attention is also paid to the alternative approach of substrate modulation using orally administered inhibitors of glucosylceramide synthesis. Novel developments about the monitoring of age of onset, progression and correction of disease are described. The remaining challenges about pathophysiology of glycosphingolipidoses are discussed in view of further improvements in therapy for these debilitating disorders.

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Section: Gaucher Disease (Glucosylceramidosis)mentioning

confidence: 99%

Biochemistry of glycosphingolipid storage disorders: implications for therapeutic intervention

Aerts

Hollak

Boot

et al. 2003

Phil. Trans. R. Soc. Lond. B

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“…This leads to progressive accumulation of glucocerebroside within macrophages, predominantly in spleen, liver, and bone marrow, leading to hepatosplenomegaly, anemia, thrombocytopenia, and skeletal involvement [2].…”

Section: Introductionmentioning

confidence: 99%

Velaglucerase alfa enzyme replacement therapy compared with imiglucerase in patients with Gaucher disease

et al. 2013

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Enzyme replacement therapy for Gaucher disease (GD) has been available since 1991. This study compared the efficacy and safety of velaglucerase alfa with imiglucerase, the previous standard of care. A 9-month, global, randomized, double-blind, non-inferiority study compared velaglucerase alfa with imiglucerase (60 U/kg every other week) in treatment-na€ ıve patients aged 3-73 years with anemia and either thrombocytopenia or organomegaly. The primary endpoint was the difference between groups in mean change from baseline to 9 months in hemoglobin concentration. 35 patients were randomized: 34 received study drug (intent-to-treat: 17 per arm), 20 were splenectomized. Baseline characteristics were similar in the two groups. The per-protocol population included 15 patients per arm. The mean treatment difference for hemoglobin concentration from baseline to 9 months (velaglucerase alfa minus imiglucerase) was 0.14 and 0.16 g/dL in the intent-to-treat and per-protocol populations, respectively. The lower bound of the 97.5% onesided confidence interval in both populations lay within the pre-defined non-inferiority margin of 21.0 g/dL, confirming that velaglucerase alfa is non-inferior to imiglucerase. There were no statistically significant differences in the secondary endpoints. Most adverse events were mild to moderate. No patient receiving velaglucerase alfa developed antibodies to either drug, whereas four patients (23.5%) receiving imiglucerase developed IgG antibodies to imiglucerase, which were cross-reactive with velaglucerase alfa in one patient. This study demonstrates the efficacy and safety of velaglucerase alfa compared with imiglucerase in adult and pediatric patients with GD clinically characterized as Type 1. Differences in immunogenicity were also observed. Am.

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“…3 Even among monozygotic twins with abnormal glucocerebrosidase genotypes, a remarkable variability in disease manifestations can occur. 4 The availability of an effective but very costly therapy has also urged the identification of surrogate markers for Gaucher cells that can guide decisions on initiation of therapy and dosing regimens. The identification of factors secreted by Gaucher cells is also of fundamental interest because it may lead to better understanding of the unique pathophysiology of the disorder.…”

Section: Introductionmentioning

confidence: 99%

Marked elevation of the chemokine CCL18/PARC in Gaucher disease: a novel surrogate marker for assessing therapeutic intervention

Boot

Verhoek

Fost

et al. 2004

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3 Gaucher's disease: clinical features and natural history

Cited by 222 publications

References 60 publications

Biochemistry of glycosphingolipid storage disorders: implications for therapeutic intervention

Biochemistry of glycosphingolipid storage disorders: implications for therapeutic intervention

Velaglucerase alfa enzyme replacement therapy compared with imiglucerase in patients with Gaucher disease

Marked elevation of the chemokine CCL18/PARC in Gaucher disease: a novel surrogate marker for assessing therapeutic intervention

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