Gaucher Disease

Grabowski, Gregory A.

doi:10.1007/978-1-4615-3010-7_5

Cited by 37 publications

(13 citation statements)

References 227 publications

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“…1 We show that, for an unknown reason, their phenotype and clinical outcome are very different from those described in similar patients in other countries.…”

contrasting

confidence: 62%

“…Gaucher disease is the most common autosomal recessive lysosomal storage disease and is caused by a deficiency of glucocerebrosidase due to pathogenic variants of the GBA1 gene. 1 Gaucher disease type 1, the nonneuronopathic form, has an incidence of about 1 in 40,000-60,000 in the general population and 1 in 500-1,000 among Ashkenazi Jews. 2 Patients with Gaucher disease type 3 (also called chronic neuronopathic Gaucher disease) constitute about 5% of the population of patients with Gaucher disease in the United States and in Europe, with an estimated incidence of about 1:100,000.…”

mentioning

confidence: 99%

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Long-term follow up and sudden unexpected death in Gaucher disease type 3 in Egypt

Abdelwahab

Blankenship

Schiffmann

2016

Molecular Genetics and Metabolism

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“…1 We show that, for an unknown reason, their phenotype and clinical outcome are very different from those described in similar patients in other countries.…”

contrasting

confidence: 62%

mentioning

confidence: 99%

Long-term follow up and sudden unexpected death in Gaucher disease type 3 in Egypt

Abdelwahab

Blankenship

Schiffmann

2016

Molecular Genetics and Metabolism

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“…G aucher disease is a lysosomal storage disorder caused by mutations in acid ␤-glucosidase (GlcCerase; EC 3.2.1.45), the enzyme responsible for the catabolism of glucosylceramide to ceramide and glucose (1,2). Deficiency of GlcCerase activity results in the progressive accumulation of glucosylceramide, primarily within macrophages, and it ultimately leads to clinical manifestations of anemia, hepatosplenomegaly, bone lesions, and, in more severe cases, central nervous system impairment (3).…”

mentioning

confidence: 99%

The iminosugar isofagomine increases the activity of N370S mutant acid β-glucosidase in Gaucher fibroblasts by several mechanisms

Steet

Chung

Wustman

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

203

233

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Gaucher disease is a lysosomal storage disorder caused by deficiency in lysosomal acid ␤-glucosidase (GlcCerase), the enzyme responsible for the catabolism of glucosylceramide. One of the most prevalent disease-causing mutations, N370S, results in an enzyme with lower catalytic activity and impaired exit from the endoplasmic reticulum. Here, we report that the iminosugar isofagomine (IFG), an active-site inhibitor, increases GlcCerase activity 3.0 ؎ 0.6-fold in N370S fibroblasts by several mechanisms. A major effect of IFG is to facilitate the folding and transport of newly synthesized GlcCerase in the endoplasmic reticulum, thereby increasing the lysosomal pool of the enzyme. In addition, N370S GlcCerase synthesized in the presence of IFG exhibits a shift in pH optimum from 6.4 to 5.2 and altered sensitivity to SDS. Although IFG fully inhibits GlcCerase in the lysosome in an in situ assay, washout of the drug leads to partial recovery of GlcCerase activity within 4 h and full recovery by 24 h. These findings provide support for the possible use of active-site inhibitors in the treatment of some forms of Gaucher disease.

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“…9 The GBA1 messenger RNA (mRNA) has approximately 2 kb and produces a mature protein of 497 amino acids with 56 kDa. 10,11 The expression levels of mRNA produced from GBA1 varies considerably between different cell types and has no direct correlation with GCase enzyme activity.…”

Section: Introductionmentioning

confidence: 99%

Hampered Vitamin B12 Metabolism in Gaucher Disease?

Hannibal

Siebert

Basgalupp

et al. 2017

Journal of Inborn Errors of Metabolism and Screening

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Untreated vitamin B 12 deficiency manifests clinically with hematological abnormalities and combined degeneration of the spinal cord and polyneuropathy and biochemically with elevated homocysteine (Hcy) and methylmalonic acid (MMA). Vitamin B 12 metabolism involves various cellular compartments including the lysosome, and a disruption in the lysosomal and endocytic pathways induces functional deficiency of this micronutrient. Gaucher disease (GD) is characterized by dysfunctional lysosomal metabolism brought about by mutations in the enzyme beta-glucocerebrosidase (Online Mendelian Inheritance in Man (OMIM): 606463; Enzyme Commission (EC) 3.2.1.45, gene: GBA1). In this study, we collected and examined available literature on the associations between GD, the second most prevalent lysosomal storage disorder in humans, and hampered vitamin B 12 metabolism. Results from independent cohorts of patients show elevated circulating holotranscobalamin without changes in vitamin B 12 levels in serum. Gaucher disease patients under enzyme replacement therapy present normal levels of Hcy and MMA. Although within the normal range, a significant increase in Hcy and MMA with normal serum vitamin B 12 was documented in treated GD patients with polyneuropathy versus treated GD patients without polyneuropathy. Thus, a functional deficiency of vitamin B 12 caused by disrupted lysosomal metabolism in GD is a plausible mechanism, contributing to the neurological form of the disorder but this awaits confirmation. Observational studies suggest that an assessment of vitamin B 12 status prior to the initiation of enzyme replacement therapy may shed light on the role of vitamin B 12 in the pathogenesis and progression of GD.

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Gaucher Disease

Cited by 37 publications

References 227 publications

Long-term follow up and sudden unexpected death in Gaucher disease type 3 in Egypt

Long-term follow up and sudden unexpected death in Gaucher disease type 3 in Egypt

The iminosugar isofagomine increases the activity of N370S mutant acid β-glucosidase in Gaucher fibroblasts by several mechanisms

Hampered Vitamin B12 Metabolism in Gaucher Disease?

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