Materiały źródłowe

• #1 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5343975/

  Gaucher disease (GD, ORPHA355) is a rare, autosomal recessive genetic disorder. It is caused by a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of its substrate, glucosylceramide, in macrophages. […] The main cause of the cytopenia, splenomegaly, hepatomegaly, and bone lesions associated with the disease is considered to be the infiltration of the bone marrow, spleen, and liver by Gaucher cells. […] Mutations in the GBA1 gene lead to a marked decrease in GCase activity. The consequences of this deficiency are generally attributed to the accumulation of the GCase substrate, GlcCer, in macrophages, inducing their transformation into Gaucher cells. […] Gaucher cells mainly infiltrate bone marrow, the spleen, and liver, but they also infiltrate other organs and are considered the main protagonists factors in the diseases symptoms.

• #2 Pathophysiology | Know Gaucher Disease

  https://www.knowgaucherdisease.com/hcp/pathophysiology

  Gaucher disease (GD) is a rare, autosomal recessive disorder. Patients with GD have a deficiency of the enzyme glucocerebrosidase, the enzyme responsible for catalyzing glucocerebroside. The progressive accumulation of glucocerebroside throughout the body leads to a variety of symptoms that present in various organs. […] Gaucher disease (GD) is a rare, autosomal recessive lysosomal storage disorder, in which deficiency of the enzyme glucocerebrosidase leads to the accumulation of its substrate glucocerebroside throughout the body, primarily in the spleen, liver, and bone marrow. The accumulation of glucocerebroside in the different areas of the body leads to the progressive, multi-systemic, and heterogeneous nature of the disease. […] GD1 is a lysosomal storage disorder characterized by a deficiency of the enzyme glucocerebrosidase. This is caused by mutations of the gene that controls production of this enzyme. Without sufficient glucocerebrosidase, its substrate glucocerebroside accumulates within the lysosomes of macrophages, leading to the formation of Gaucher cells.

• #3 Mechanisms of Gaucher disease pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4437956/

  Gaucher disease is caused by mutations in the Gba1 gene encoding an acid -glucocerebrosidase (GBA1), the lysosomal hydrolase which breaks down glucosylceramide (GlcCer). In Gaucher type 1 disease the accumulation of this simple glycolipid is mainly restricted to tissue phagocyte lysosomes resulting ultimately in hepatomegaly, splenomegaly and osteopenia. Lower residual GBA1 levels leads to neuronal storage, in types 2 and 3 neurological symptoms are characterised by acute (death at age 2) or sub-acute onset, respectively. […] The links between cellular changes and clinical manifestations are largely unknown but are the key to the development and monitoring of new therapies. […] GlcCer is unusual amongst glycolipids with intracellular trafficking connecting both lysosomal and non-lysosomal pools on both sides of the bilayer membrane.

• #4 Orphanet: Gaucher disease

  https://www.orpha.net/en/disease/detail/355

  Gaucher disease (GD) is a lysosomal storage disorder encompassing three main forms (types 1, 2 and 3), a fetal form and a variant with cardiac involvement (Gaucher disease – ophthalmoplegia – cardiovascular calcification or Gaucher-like disease). […] GD is due to mutations in the GBA gene (1q21) that codes for a lysosomal enzyme, glucocerebrosidase, or in very rare cases the PSAP gene that codes for its activator protein (saposin C). The deficiency in glucocerebrosidase leads to the accumulation of glucosylceramide (or beta-glucocerebrosidase) deposits in the cells of the reticuloendothelial system of the liver, the spleen and the bone marrow (Gaucher cells).

• #5 Gaucher Disease: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/944157-overview

  Gaucher disease is a rare genetic disorder characterized by the deposition of glucocerebroside in cells of the macrophage-monocyte system. The disorder results from the deficiency of the enzyme glucocerebrosidase. […] Glucosylceramide, the accumulated glycolipid, is primarily derived from the phagocytosis and degradation of senescent leukocytes and erythrocyte membranes. The glycolipid storage gives rise to the characteristic Gaucher cells, macrophages engorged with lipid with a crumpledtissue-paper appearance and displaced nuclei. The factors that contribute to neurologic involvement in patients with types 2 and 3 disease are still unknown but may be related to the accumulation of a cytotoxic glycolipid, glucosylsphingosine, in the brain due to the severe deficiency of glucocerebrosidase activity or to neuroinflammation.

• #6 Gaucher Disease – Pediatrics – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/pediatrics/inherited-disorders-of-metabolism/gaucher-disease

  Gaucher disease is a sphingolipidosis, an inherited disorder of metabolism, resulting from glucocerebrosidase deficiency, causing deposition of glucocerebroside and related compounds. […] Glucocerebrosidase normally hydrolyzes glucocerebroside to glucose and ceramide. Genetic defects of the enzyme cause glucocerebroside accumulation in tissue macrophages through phagocytosis, forming Gaucher cells. Accumulation of Gaucher cells in the perivascular spaces in the brain causes gliosis in the neuronopathic forms. […] Diagnosis of Gaucher disease is by DNA analysis and/or enzyme analysis of white blood cells; carriers are detected, and types are distinguished by mutation analysis. […] Treatment for types I and III includes enzyme replacement with glucocerebrosidase, and sometimes miglustat, eliglustat, splenectomy, or stem cell or bone marrow transplantation; there is no treatment for type II.

• #7 Gaucher Disease: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/944157-overview

  Gaucher disease is a rare genetic disorder characterized by the deposition of glucocerebroside in cells of the macrophage-monocyte system. The disorder results from the deficiency of the enzyme glucocerebrosidase. […] Glucosylceramide, the accumulated glycolipid, is primarily derived from the phagocytosis and degradation of senescent leukocytes and erythrocyte membranes. The glycolipid storage gives rise to the characteristic Gaucher cells, macrophages engorged with lipid with a crumpledtissue-paper appearance and displaced nuclei. The factors that contribute to neurologic involvement in patients with types 2 and 3 disease are still unknown but may be related to the accumulation of a cytotoxic glycolipid, glucosylsphingosine, in the brain due to the severe deficiency of glucocerebrosidase activity or to neuroinflammation.

• #8 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://www.mdpi.com/1422-0067/18/2/441

  Due to the accumulation of GlcCer, Mistry et al. identified another metabolic pathway in a mouse model. […] GlcCer is also the substrate of an alternative pathway in which a ceramidase transforms it into glucosylsphingosine (or Lyso-glucosylceramide), which then diffuses into fluids due to its reduced hydrophobicity. […] The enzymatic deficit of GCase is not only due to the intrinsic enzymatic dysfunction but is also the consequence of abnormalities occurring during the transport and delivery of the enzyme to the lysosomes. […] The transport and delivery of GCase to the lysosome does not depend on the mannose 6-phosphate system, like other proteins, but also involves Lysosomal Integral Membrane Protein 2 (LIMP-2). […] It has been observed that patients with the same GCase mutations may vary significantly in disease presentation, from life-threatening to almost asymptomatic, because of molecular co-abnormalities.

• #9 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://www.mdpi.com/1422-0067/18/2/441

  Due to the accumulation of GlcCer, Mistry et al. identified another metabolic pathway in a mouse model. […] GlcCer is also the substrate of an alternative pathway in which a ceramidase transforms it into glucosylsphingosine (or Lyso-glucosylceramide), which then diffuses into fluids due to its reduced hydrophobicity. […] The enzymatic deficit of GCase is not only due to the intrinsic enzymatic dysfunction but is also the consequence of abnormalities occurring during the transport and delivery of the enzyme to the lysosomes. […] The transport and delivery of GCase to the lysosome does not depend on the mannose 6-phosphate system, like other proteins, but also involves Lysosomal Integral Membrane Protein 2 (LIMP-2). […] It has been observed that patients with the same GCase mutations may vary significantly in disease presentation, from life-threatening to almost asymptomatic, because of molecular co-abnormalities.

• #10 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5343975/

  The effect of GBA1 gene mutations could be modulated by the co-activator of GCase, saposin C, which may partly explain the limited penetrance of neurological impairment in patients with GD. […] The frequency of hypergammaglobulinemia and the presence of monoclonal Ig in GD are two factors which promote the emergence of multiple myeloma; the incidence of myeloma appears to be increased in GD, with a relative risk of at least 5.9. […] The pathophysiology of cancer development in GD is not well understood. At least two types of mechanisms may be operating, both of them relating to the GCase deficiency and the ensuing catabolic defect, i.e., the accumulation of GlcCer and/or its deacylated product, glucosylsphingosine or Lyso-glucosylceramide. […] Significant new insights into GDs pathophysiology show that GCase deficiency has a much broader impact than the simple macrophage load that transforms them into Gaucher cells.

• #11 Gaucher Disease: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/944157-overview

  Gaucher disease is a rare genetic disorder characterized by the deposition of glucocerebroside in cells of the macrophage-monocyte system. The disorder results from the deficiency of the enzyme glucocerebrosidase. […] Glucosylceramide, the accumulated glycolipid, is primarily derived from the phagocytosis and degradation of senescent leukocytes and erythrocyte membranes. The glycolipid storage gives rise to the characteristic Gaucher cells, macrophages engorged with lipid with a crumpledtissue-paper appearance and displaced nuclei. The factors that contribute to neurologic involvement in patients with types 2 and 3 disease are still unknown but may be related to the accumulation of a cytotoxic glycolipid, glucosylsphingosine, in the brain due to the severe deficiency of glucocerebrosidase activity or to neuroinflammation.

• #12 Pathophysiology | Know Gaucher Disease

  https://www.knowgaucherdisease.com/hcp/pathophysiology

  Gaucher cells are engorged macrophages, visually characterized by a displaced nucleus and a lysosomal architecture that is distorted from its normally spherical shape. […] Gaucher cells infiltrate organs and tissues enriched in cells of the mononuclear phagocyte system, e.g., the spleen, liver, and bone marrow. Over time, they displace normal cells resulting in progressive impairment; the liver and spleen may become enlarged, which can interfere with normal functioning and cause a painful and swollen abdomen. Displacement of hematopoiesis by Gaucher cell accumulation within the bone marrow can lead to anemia and thrombocytopenia, which in turn result in bleeding problems and can compromise the strength of the skeletal system.

• #13 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5343975/

  Gaucher disease (GD, ORPHA355) is a rare, autosomal recessive genetic disorder. It is caused by a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of its substrate, glucosylceramide, in macrophages. […] The main cause of the cytopenia, splenomegaly, hepatomegaly, and bone lesions associated with the disease is considered to be the infiltration of the bone marrow, spleen, and liver by Gaucher cells. […] Mutations in the GBA1 gene lead to a marked decrease in GCase activity. The consequences of this deficiency are generally attributed to the accumulation of the GCase substrate, GlcCer, in macrophages, inducing their transformation into Gaucher cells. […] Gaucher cells mainly infiltrate bone marrow, the spleen, and liver, but they also infiltrate other organs and are considered the main protagonists factors in the diseases symptoms.

• #14 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5343975/

  GlcCer accumulation in Gaucher cells is considered the first step towards bone involvement, leading to the vascular compression which is the source of necrotic complications. […] The pathophysiological mechanisms of neurological involvement remain poorly explained; GlcCer turnover in neurons is low and its accumulation is only significant when residual GCase activity is drastically decreased, i.e., only with some types of GBA1 mutations. […] Recent observations indicate that Gaucher cells do not only result from the transformation of macrophage cells, but correspond to a distinct M2 subpopulation from an alternative differentiation pathway. […] Due to the accumulation of GlcCer, Mistry et al. identified another metabolic pathway in a mouse model. […] The enzymatic deficit of GCase is not only due to the intrinsic enzymatic dysfunction but is also the consequence of abnormalities occurring during the transport and delivery of the enzyme to the lysosomes.

• #15 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://www.mdpi.com/1422-0067/18/2/441

  GlcCer accumulation in Gaucher cells is considered the first step towards bone involvement, leading to the vascular compression which is the source of necrotic complications. […] The pathophysiological mechanisms of neurological involvement remain poorly explained; GlcCer turnover in neurons is low and its accumulation is only significant when residual GCase activity is drastically decreased, i.e., only with some types of GBA1 mutations. […] Recent observations indicate that Gaucher cells do not only result from the transformation of macrophage cells, but correspond to a distinct M2 subpopulation from an alternative differentiation pathway. […] The M2 subpopulation has been described as cells with anti-inflammatory, immunomodulatory and tissue repair properties, and includes macrophages that remove abnormal hematopoietic cells or phagocytose erythroblast nuclei.

• #16 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://www.mdpi.com/1422-0067/18/2/441

  GlcCer accumulation in Gaucher cells is considered the first step towards bone involvement, leading to the vascular compression which is the source of necrotic complications. […] The pathophysiological mechanisms of neurological involvement remain poorly explained; GlcCer turnover in neurons is low and its accumulation is only significant when residual GCase activity is drastically decreased, i.e., only with some types of GBA1 mutations. […] Recent observations indicate that Gaucher cells do not only result from the transformation of macrophage cells, but correspond to a distinct M2 subpopulation from an alternative differentiation pathway. […] The M2 subpopulation has been described as cells with anti-inflammatory, immunomodulatory and tissue repair properties, and includes macrophages that remove abnormal hematopoietic cells or phagocytose erythroblast nuclei.

• #17 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5343975/

  GlcCer accumulation in Gaucher cells is considered the first step towards bone involvement, leading to the vascular compression which is the source of necrotic complications. […] The pathophysiological mechanisms of neurological involvement remain poorly explained; GlcCer turnover in neurons is low and its accumulation is only significant when residual GCase activity is drastically decreased, i.e., only with some types of GBA1 mutations. […] Recent observations indicate that Gaucher cells do not only result from the transformation of macrophage cells, but correspond to a distinct M2 subpopulation from an alternative differentiation pathway. […] Due to the accumulation of GlcCer, Mistry et al. identified another metabolic pathway in a mouse model. […] The enzymatic deficit of GCase is not only due to the intrinsic enzymatic dysfunction but is also the consequence of abnormalities occurring during the transport and delivery of the enzyme to the lysosomes.

• #18 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://www.mdpi.com/1422-0067/18/2/441

  Due to the accumulation of GlcCer, Mistry et al. identified another metabolic pathway in a mouse model. […] GlcCer is also the substrate of an alternative pathway in which a ceramidase transforms it into glucosylsphingosine (or Lyso-glucosylceramide), which then diffuses into fluids due to its reduced hydrophobicity. […] The enzymatic deficit of GCase is not only due to the intrinsic enzymatic dysfunction but is also the consequence of abnormalities occurring during the transport and delivery of the enzyme to the lysosomes. […] The transport and delivery of GCase to the lysosome does not depend on the mannose 6-phosphate system, like other proteins, but also involves Lysosomal Integral Membrane Protein 2 (LIMP-2). […] It has been observed that patients with the same GCase mutations may vary significantly in disease presentation, from life-threatening to almost asymptomatic, because of molecular co-abnormalities.

• #19 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://www.mdpi.com/1422-0067/18/2/441

  Due to the accumulation of GlcCer, Mistry et al. identified another metabolic pathway in a mouse model. […] GlcCer is also the substrate of an alternative pathway in which a ceramidase transforms it into glucosylsphingosine (or Lyso-glucosylceramide), which then diffuses into fluids due to its reduced hydrophobicity. […] The enzymatic deficit of GCase is not only due to the intrinsic enzymatic dysfunction but is also the consequence of abnormalities occurring during the transport and delivery of the enzyme to the lysosomes. […] The transport and delivery of GCase to the lysosome does not depend on the mannose 6-phosphate system, like other proteins, but also involves Lysosomal Integral Membrane Protein 2 (LIMP-2). […] It has been observed that patients with the same GCase mutations may vary significantly in disease presentation, from life-threatening to almost asymptomatic, because of molecular co-abnormalities.

• #20 Glucosylsphingosine (Lyso-Gb1) as a reliable biomarker in Gaucher disease: a narrative review | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-023-02623-7

  Gaucher disease (GD) is a rare, inherited, autosomal recessive disorder caused by a deficiency of the lysosomal enzyme, acid -glucosidase. […] In GD, a deficiency of GBA functioning leads to the accumulation of glucosylceramide in the lysosomes of macrophages that undergo Gaucher cell transformation. […] The need for a more reliable biomarker of GD activity and disease progression led to identifying the deacylated form of accumulated glucosylceramide, lyso-Gb1. Lyso-Gb1 is a direct metabolite of GBA and may play an essential role in disease-related pathology. […] Elevation of lyso-Gb1 was first reported in the grey matter of the brain and cerebellum of neuronopathic GD (type 2 and 3) patients, giving rise to the debate of its potential neurotoxic role. […] Mistry and colleagues first assessed a lyso-Gb1-based mechanism of skeletal disease in GD1 patients in a murine model with GBA1 gene deletion, which showed the development of severe osteoporosis due to the accumulation of both lyso-Gb1 and glucosylceramide in osteoblasts, inhibiting protein kinase C and bone formation.

• #21 Glucosylsphingosine (Lyso-Gb1) as a reliable biomarker in Gaucher disease: a narrative review | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-023-02623-7

  Gaucher disease (GD) is a rare, inherited, autosomal recessive disorder caused by a deficiency of the lysosomal enzyme, acid -glucosidase. […] In GD, a deficiency of GBA functioning leads to the accumulation of glucosylceramide in the lysosomes of macrophages that undergo Gaucher cell transformation. […] The need for a more reliable biomarker of GD activity and disease progression led to identifying the deacylated form of accumulated glucosylceramide, lyso-Gb1. Lyso-Gb1 is a direct metabolite of GBA and may play an essential role in disease-related pathology. […] Elevation of lyso-Gb1 was first reported in the grey matter of the brain and cerebellum of neuronopathic GD (type 2 and 3) patients, giving rise to the debate of its potential neurotoxic role. […] Mistry and colleagues first assessed a lyso-Gb1-based mechanism of skeletal disease in GD1 patients in a murine model with GBA1 gene deletion, which showed the development of severe osteoporosis due to the accumulation of both lyso-Gb1 and glucosylceramide in osteoblasts, inhibiting protein kinase C and bone formation.

• #22 Pathophysiology | Know Gaucher Disease

  https://www.knowgaucherdisease.com/hcp/pathophysiology

  Gaucher disease (GD) is a rare, autosomal recessive disorder. Patients with GD have a deficiency of the enzyme glucocerebrosidase, the enzyme responsible for catalyzing glucocerebroside. The progressive accumulation of glucocerebroside throughout the body leads to a variety of symptoms that present in various organs. […] Gaucher disease (GD) is a rare, autosomal recessive lysosomal storage disorder, in which deficiency of the enzyme glucocerebrosidase leads to the accumulation of its substrate glucocerebroside throughout the body, primarily in the spleen, liver, and bone marrow. The accumulation of glucocerebroside in the different areas of the body leads to the progressive, multi-systemic, and heterogeneous nature of the disease. […] GD1 is a lysosomal storage disorder characterized by a deficiency of the enzyme glucocerebrosidase. This is caused by mutations of the gene that controls production of this enzyme. Without sufficient glucocerebrosidase, its substrate glucocerebroside accumulates within the lysosomes of macrophages, leading to the formation of Gaucher cells.

• #23 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5343975/

  Gaucher disease (GD, ORPHA355) is a rare, autosomal recessive genetic disorder. It is caused by a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of its substrate, glucosylceramide, in macrophages. […] The main cause of the cytopenia, splenomegaly, hepatomegaly, and bone lesions associated with the disease is considered to be the infiltration of the bone marrow, spleen, and liver by Gaucher cells. […] Mutations in the GBA1 gene lead to a marked decrease in GCase activity. The consequences of this deficiency are generally attributed to the accumulation of the GCase substrate, GlcCer, in macrophages, inducing their transformation into Gaucher cells. […] Gaucher cells mainly infiltrate bone marrow, the spleen, and liver, but they also infiltrate other organs and are considered the main protagonists factors in the diseases symptoms.

• #24 Pathophysiology | Know Gaucher Disease

  https://www.knowgaucherdisease.com/hcp/pathophysiology

  Gaucher cells are engorged macrophages, visually characterized by a displaced nucleus and a lysosomal architecture that is distorted from its normally spherical shape. […] Gaucher cells infiltrate organs and tissues enriched in cells of the mononuclear phagocyte system, e.g., the spleen, liver, and bone marrow. Over time, they displace normal cells resulting in progressive impairment; the liver and spleen may become enlarged, which can interfere with normal functioning and cause a painful and swollen abdomen. Displacement of hematopoiesis by Gaucher cell accumulation within the bone marrow can lead to anemia and thrombocytopenia, which in turn result in bleeding problems and can compromise the strength of the skeletal system.

• #25 Pathophysiology | Know Gaucher Disease

  https://www.knowgaucherdisease.com/hcp/pathophysiology

  Gaucher cells are engorged macrophages, visually characterized by a displaced nucleus and a lysosomal architecture that is distorted from its normally spherical shape. […] Gaucher cells infiltrate organs and tissues enriched in cells of the mononuclear phagocyte system, e.g., the spleen, liver, and bone marrow. Over time, they displace normal cells resulting in progressive impairment; the liver and spleen may become enlarged, which can interfere with normal functioning and cause a painful and swollen abdomen. Displacement of hematopoiesis by Gaucher cell accumulation within the bone marrow can lead to anemia and thrombocytopenia, which in turn result in bleeding problems and can compromise the strength of the skeletal system.

• #26 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5343975/

  GlcCer accumulation in Gaucher cells is considered the first step towards bone involvement, leading to the vascular compression which is the source of necrotic complications. […] The pathophysiological mechanisms of neurological involvement remain poorly explained; GlcCer turnover in neurons is low and its accumulation is only significant when residual GCase activity is drastically decreased, i.e., only with some types of GBA1 mutations. […] Recent observations indicate that Gaucher cells do not only result from the transformation of macrophage cells, but correspond to a distinct M2 subpopulation from an alternative differentiation pathway. […] Due to the accumulation of GlcCer, Mistry et al. identified another metabolic pathway in a mouse model. […] The enzymatic deficit of GCase is not only due to the intrinsic enzymatic dysfunction but is also the consequence of abnormalities occurring during the transport and delivery of the enzyme to the lysosomes.

• #27 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://www.mdpi.com/1422-0067/18/2/441

  GlcCer accumulation in Gaucher cells is considered the first step towards bone involvement, leading to the vascular compression which is the source of necrotic complications. […] The pathophysiological mechanisms of neurological involvement remain poorly explained; GlcCer turnover in neurons is low and its accumulation is only significant when residual GCase activity is drastically decreased, i.e., only with some types of GBA1 mutations. […] Recent observations indicate that Gaucher cells do not only result from the transformation of macrophage cells, but correspond to a distinct M2 subpopulation from an alternative differentiation pathway. […] The M2 subpopulation has been described as cells with anti-inflammatory, immunomodulatory and tissue repair properties, and includes macrophages that remove abnormal hematopoietic cells or phagocytose erythroblast nuclei.

• #28 Gaucher Disease: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/944157-overview

  Glucosylceramide accumulation in the bone marrow, liver, spleen, lungs, and other organs contributes to pancytopenia, massive hepatosplenomegaly, and, at times, diffuse infiltrative pulmonary disease. Progressive infiltration of Gaucher cells in the bone marrow may lead to thinning of the cortex, pathologic fractures, bone pain, bony infarcts, and osteopenia. These bony features may also be related to cytokines produced by macrophages. […] Dramatic changes to the ceramide-to-glucosylceramide ratio can affect the barrier formation in the epidermal layer of the skin, leading to ichthyosis or a collodion skin presentation, seen at times in babies who are severely affected (those with type 2).

• #29 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5343975/

  GlcCer accumulation in Gaucher cells is considered the first step towards bone involvement, leading to the vascular compression which is the source of necrotic complications. […] The pathophysiological mechanisms of neurological involvement remain poorly explained; GlcCer turnover in neurons is low and its accumulation is only significant when residual GCase activity is drastically decreased, i.e., only with some types of GBA1 mutations. […] Recent observations indicate that Gaucher cells do not only result from the transformation of macrophage cells, but correspond to a distinct M2 subpopulation from an alternative differentiation pathway. […] Due to the accumulation of GlcCer, Mistry et al. identified another metabolic pathway in a mouse model. […] The enzymatic deficit of GCase is not only due to the intrinsic enzymatic dysfunction but is also the consequence of abnormalities occurring during the transport and delivery of the enzyme to the lysosomes.

• #30 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://www.mdpi.com/1422-0067/18/2/441

  GlcCer accumulation in Gaucher cells is considered the first step towards bone involvement, leading to the vascular compression which is the source of necrotic complications. […] The pathophysiological mechanisms of neurological involvement remain poorly explained; GlcCer turnover in neurons is low and its accumulation is only significant when residual GCase activity is drastically decreased, i.e., only with some types of GBA1 mutations. […] Recent observations indicate that Gaucher cells do not only result from the transformation of macrophage cells, but correspond to a distinct M2 subpopulation from an alternative differentiation pathway. […] The M2 subpopulation has been described as cells with anti-inflammatory, immunomodulatory and tissue repair properties, and includes macrophages that remove abnormal hematopoietic cells or phagocytose erythroblast nuclei.

• #31 Gaucher Disease: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/944157-overview

  Gaucher disease is a rare genetic disorder characterized by the deposition of glucocerebroside in cells of the macrophage-monocyte system. The disorder results from the deficiency of the enzyme glucocerebrosidase. […] Glucosylceramide, the accumulated glycolipid, is primarily derived from the phagocytosis and degradation of senescent leukocytes and erythrocyte membranes. The glycolipid storage gives rise to the characteristic Gaucher cells, macrophages engorged with lipid with a crumpledtissue-paper appearance and displaced nuclei. The factors that contribute to neurologic involvement in patients with types 2 and 3 disease are still unknown but may be related to the accumulation of a cytotoxic glycolipid, glucosylsphingosine, in the brain due to the severe deficiency of glucocerebrosidase activity or to neuroinflammation.

• #32 Gaucher’s disease – Wikipedia

  https://en.wikipedia.org/wiki/Gaucher%27s_disease

  The exact mechanism of neurotoxicity is not understood, but it is thought to involve a reaction to glucosylsphingosine. […] Different mutations in the GBA (beta-glucosidase) gene determine the remaining activity of the enzyme. In type I, there is some residual activity of the enzyme, accounting for the lack of neuropathology in this type. Although there is some correlation between genotype and phenotype, neither the amount of stored lipids nor the residual enzyme activity correlates well with disease symptoms. This circumstance has called for alternative explanations accounting for disease symptoms including jamming of the endo/lysosomal system, ER stress, altered lipid composition of membranes throughout the cell, including the plasma membrane, and consequent changes in the dynamic and signaling properties of the cell membrane, inflammation caused by cytokine secretion as a result of sphingolipid accumulation, and neurodegeneration caused by the accumulation of glucosylsphingosine, a neurotoxin.

• #33 Gaucher disease provides a unique window into Parkinson disease pathogenesis | Nature Reviews Neurology

  https://www.nature.com/articles/s41582-024-00999-z

  An exciting development in the field of neurodegeneration is the association between the rare monogenic disorder Gaucher disease and the common complex disorder Parkinson disease (PD). […] The observation of parkinsonism in a rare subgroup of individuals with Gaucher disease first directed attention to the role of glucocerebrosidase deficiency in the pathogenesis of PD. […] Insights from this association have emphasized the role of lysosomal pathways in parkinsonism. […] The rare, autosomal recessively inherited disorder Gaucher disease is providing new insights into the pathogenesis of Parkinson disease. […] Variants in GBA1, the gene encoding the lysosomal enzyme glucocerebrosidase, are the most common known genetic risk factor for Parkinson disease and dementia with Lewy bodies.

• #34 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://www.mdpi.com/1422-0067/18/2/441

  Patients with a heterozygous (or homozygous) mutation in the GBA1 gene, especially c.1226A>G (N370S), but also c.1448T>C (L444P), c.84dup, c.115+1G>A (IVS2+1G>A), c.1297G>T (V394L), and c.1604G>A (R496H), are now considered at risk for Parkinson’s disease (PD). […] The most recent studies suggest that neuropathic mutations of the GBA gene (especially c.1448T>C (L444P)) could worsen the progression of PD. […] The frequency of hypergammaglobulinemia and the presence of monoclonal Ig in GD are two factors which promote the emergence of multiple myeloma; the incidence of myeloma appears to be increased in GD, with a relative risk of at least 5.9. […] The pathophysiology of cancer development in GD is not well understood. At least two types of mechanisms may be operating, both of them relating to the GCase deficiency and the ensuing catabolic defect, i.e., the accumulation of GlcCer and/or its deacylated product, glucosylsphingosine or Lyso-glucosylceramide.

• #35 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://www.mdpi.com/1422-0067/18/2/441

  Patients with a heterozygous (or homozygous) mutation in the GBA1 gene, especially c.1226A>G (N370S), but also c.1448T>C (L444P), c.84dup, c.115+1G>A (IVS2+1G>A), c.1297G>T (V394L), and c.1604G>A (R496H), are now considered at risk for Parkinson’s disease (PD). […] The most recent studies suggest that neuropathic mutations of the GBA gene (especially c.1448T>C (L444P)) could worsen the progression of PD. […] The frequency of hypergammaglobulinemia and the presence of monoclonal Ig in GD are two factors which promote the emergence of multiple myeloma; the incidence of myeloma appears to be increased in GD, with a relative risk of at least 5.9. […] The pathophysiology of cancer development in GD is not well understood. At least two types of mechanisms may be operating, both of them relating to the GCase deficiency and the ensuing catabolic defect, i.e., the accumulation of GlcCer and/or its deacylated product, glucosylsphingosine or Lyso-glucosylceramide.

• #36 Mechanisms of Gaucher disease pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4437956/

  Crucially, and in marked contrast to Gaucher fibroblasts, both cell types accumulated GlcCer and glucosylsphingosine. […] The potential medical significance of Gaucher disease does not end with the condition itself. Most attention has been focussed on the unexpected finding that having even one mutant copy of the Gba1 gene is a significant risk factor for Parkinsons disease. […] The most fundamental observation is that poorly functional GBA1 is associated with the accumulation of -synuclein (-syn) leading to neuronal death. […] Thus, by means of a bi-directional loop, even a slight loss of GBA1 function can become magnified. […] Further work is needed to unravel the exact mechanism by which mutant Gba1 gives rise to -syn aggregates. […] Recent research has revealed interdependence of phagosome pH and ROS generation hence decreased generation of ROS might be linked to increased pH of Gaucher lysosomes. […] Increased pH may also explain reduced lysosomal proteolysis, co-storage of cholesterol and disrupted membrane trafficking in Gaucher cells. […] Several workers have reported increased levels of inflammatory markers, including M-CSF, in the serum of patients with Gaucher disease.

• #37 Mechanisms of Gaucher disease pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4437956/

  Crucially, and in marked contrast to Gaucher fibroblasts, both cell types accumulated GlcCer and glucosylsphingosine. […] The potential medical significance of Gaucher disease does not end with the condition itself. Most attention has been focussed on the unexpected finding that having even one mutant copy of the Gba1 gene is a significant risk factor for Parkinsons disease. […] The most fundamental observation is that poorly functional GBA1 is associated with the accumulation of -synuclein (-syn) leading to neuronal death. […] Thus, by means of a bi-directional loop, even a slight loss of GBA1 function can become magnified. […] Further work is needed to unravel the exact mechanism by which mutant Gba1 gives rise to -syn aggregates. […] Recent research has revealed interdependence of phagosome pH and ROS generation hence decreased generation of ROS might be linked to increased pH of Gaucher lysosomes. […] Increased pH may also explain reduced lysosomal proteolysis, co-storage of cholesterol and disrupted membrane trafficking in Gaucher cells. […] Several workers have reported increased levels of inflammatory markers, including M-CSF, in the serum of patients with Gaucher disease.

• #38 Mechanisms of Gaucher disease pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4437956/

  Crucially, and in marked contrast to Gaucher fibroblasts, both cell types accumulated GlcCer and glucosylsphingosine. […] The potential medical significance of Gaucher disease does not end with the condition itself. Most attention has been focussed on the unexpected finding that having even one mutant copy of the Gba1 gene is a significant risk factor for Parkinsons disease. […] The most fundamental observation is that poorly functional GBA1 is associated with the accumulation of -synuclein (-syn) leading to neuronal death. […] Thus, by means of a bi-directional loop, even a slight loss of GBA1 function can become magnified. […] Further work is needed to unravel the exact mechanism by which mutant Gba1 gives rise to -syn aggregates. […] Recent research has revealed interdependence of phagosome pH and ROS generation hence decreased generation of ROS might be linked to increased pH of Gaucher lysosomes. […] Increased pH may also explain reduced lysosomal proteolysis, co-storage of cholesterol and disrupted membrane trafficking in Gaucher cells. […] Several workers have reported increased levels of inflammatory markers, including M-CSF, in the serum of patients with Gaucher disease.

• #39

  https://www.ajol.info/index.php/ejhg/article/view/119461

  Gaucher disease (GD) is the most frequently encountered lysosomal storage disease caused by inborn defects of the membrane-bound lysosomal enzyme, acid b-glucosidase or glucocerebrosidase. This defective activity causes an accumulation of glucocerebroside (glucosylceramide) in the lysosomes of cells derived from the monocyte/macrophage lineage. Glucocerebroside-engorged cells, termed Gaucher cells, infiltrate various organs, leading to multisystemic abnormalities. […] Studies are increasingly recognizing the role of immune dysregulation and inflammation in the pathogenesis of Gaucher disease. Many cytokines have been reported as mediators of tissue damage in Gaucher disease. […] The progress in the understanding of the pathogenesis or relevant mechanism(s) of Gaucher disease is providing insights into additional therapeutic targets, enabling the potential for optimized patient outcomes with the use of adjunctive or supplemental agents.

• #40 Diagnosis and management of patients with Gaucher disease: an Egyptian expert opinion | Egyptian Journal of Medical Human Genetics | Full Text

  https://jmhg.springeropen.com/articles/10.1186/s43042-024-00552-z

  Deficiency in the GBA enzyme causes the accumulation of glucocerebroside and other glycolipids within the lysosomes in the macrophages/monocytes in different tissues, and their levels may increase by 20100 times the normal levels. […] The elevated levels of deacylated glucosylsphingosine and glucosylceramide may have a role in neurodegeneration. […] The macrophages loaded with lipids accumulate in the liver, bone marrow, spleen, bones, and other tissues associated with an inflammatory and hyperplastic cellular response, resulting in the clinical manifestation of GD. […] Gaucher cells and neighboring macrophages overexpress and secrete lysosomal proteases and cytokines, including cathepsins, interleukins 6, 8, and 10, and macrophage inflammatory proteins 1 and 1. […] Gaucher cells correspond to the typical M2 subpopulation of macrophages from an alternate differentiation pathway and are linked to chronic inflammation, healing, and fibrosis.

• #41 Mechanisms of Gaucher disease pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4437956/

  Crucially, and in marked contrast to Gaucher fibroblasts, both cell types accumulated GlcCer and glucosylsphingosine. […] The potential medical significance of Gaucher disease does not end with the condition itself. Most attention has been focussed on the unexpected finding that having even one mutant copy of the Gba1 gene is a significant risk factor for Parkinsons disease. […] The most fundamental observation is that poorly functional GBA1 is associated with the accumulation of -synuclein (-syn) leading to neuronal death. […] Thus, by means of a bi-directional loop, even a slight loss of GBA1 function can become magnified. […] Further work is needed to unravel the exact mechanism by which mutant Gba1 gives rise to -syn aggregates. […] Recent research has revealed interdependence of phagosome pH and ROS generation hence decreased generation of ROS might be linked to increased pH of Gaucher lysosomes. […] Increased pH may also explain reduced lysosomal proteolysis, co-storage of cholesterol and disrupted membrane trafficking in Gaucher cells. […] Several workers have reported increased levels of inflammatory markers, including M-CSF, in the serum of patients with Gaucher disease.

• #42 Mechanisms of Gaucher disease pathogenesis

  https://atm.amegroups.org/article/view/6150/html

  Increased pH may also explain reduced lysosomal proteolysis, co-storage of cholesterol and disrupted membrane trafficking in Gaucher cells. […] Several workers have reported increased levels of inflammatory markers, including M-CSF, in the serum of patients with Gaucher disease. These observations raise the possibility that this could be the cause of the reported proliferation of osteoclasts associated with Gaucher disease and the consequent occurrence of bone symptoms in some patients.

• #43 Mechanisms of Gaucher disease pathogenesis

  https://atm.amegroups.org/article/view/6150/html

  Increased pH may also explain reduced lysosomal proteolysis, co-storage of cholesterol and disrupted membrane trafficking in Gaucher cells. […] Several workers have reported increased levels of inflammatory markers, including M-CSF, in the serum of patients with Gaucher disease. These observations raise the possibility that this could be the cause of the reported proliferation of osteoclasts associated with Gaucher disease and the consequent occurrence of bone symptoms in some patients.

• #44

  https://omim.org/entry/230800

  Pandey et al. (2017) showed that activation of complement C5a (120900) and C5a receptor-1 (C5AR1; 113995) controls glucosylceramide (GC) accumulation and the inflammatory response in experimental and clinical Gaucher disease. […] Marked local and systemic complement activation occurred in glucocerebrosidase (GCase)-deficient mice or after pharmacologic inhibition of GCase and was associated with GC storage, tissue inflammation, and proinflammatory cytokine production. […] In mice and humans, GCase deficiency was associated with strong formation of complement-activating GC-specific IgG autoantibodies, leading to complement activation and C5a generation. […] Thus, extensive GC storage induces complement-activating IgG autoantibodies that drive a pathway of C5a generation and C5aR1 activation that fuels a cycle of cellular GC accumulation and innate and adaptive immune cell recruitment and activation in Gaucher disease. […] Pandey et al. (2017) suggested that targeting C5AR1 may serve as a treatment option for patients with Gaucher disease and possibly other lysosomal storage diseases.

• #45 Endocrine and metabolic disorders in patients with Gaucher disease type 1: a review | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1211-5

  Gaucher disease (GD) is one of the most prevalent lysosomal storage diseases and is associated with hormonal and metabolic abnormalities, including nutritional status disorders, hypermetabolic state with high resting energy expenditures, peripheral insulin resistance, hypoadiponectinaemia, leptin and ghrelin impairments, hypolipidaemia, linear growth deceleration and growth hormone deficiency, delayed puberty, hypocalcaemia and vitamin D deficiency. […] GD1 appears to facilitate the development of disorders of nutrition, glucose metabolism and vitamin D insufficiency. […] Hormonal and metabolic disturbances in GD1 are clinically accompanied by symptoms that influence a patients quality of life (QoL). Hormonal disturbances may substantially affect their general health. […] Insulin resistance constitutes the major etiologic defect that defines metabolic syndrome. Insulin resistance is a metabolic key component of obesity and is a major factor in the aetiology of a number of diseases, including type 2 diabetes (DM II) and cardiovascular diseases.

• #46 Endocrine and metabolic disorders in patients with Gaucher disease type 1: a review | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1211-5

  A review by Fuller et al. discussed the altered sphingolipid metabolism seen in GD that leads to a significant decrease in insulin sensitivity. […] Studies show that the accumulation of GM3 results in a loss of the insulin receptors from lipid rafts. […] The physiological function of AKT in muscle involves glucose uptake and glycogen synthesis. […] The mechanism of GHD and growth retardation in patients with GD1 is a complex issue, which is not fully understood. Further research is needed to explain the problem of GHD and delayed puberty in GD1. […] The existence of a casual relationship and confirmed, reasonable pathophysiological mechanism, is hard to prove because of a low incidence of GD in the population and a relatively high incidence of metabolic and hormonal disorders, such as obesity or insulin resistance, in the general population.

• #47 Endocrine and metabolic disorders in patients with Gaucher disease type 1: a review | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1211-5

  A review by Fuller et al. discussed the altered sphingolipid metabolism seen in GD that leads to a significant decrease in insulin sensitivity. […] Studies show that the accumulation of GM3 results in a loss of the insulin receptors from lipid rafts. […] The physiological function of AKT in muscle involves glucose uptake and glycogen synthesis. […] The mechanism of GHD and growth retardation in patients with GD1 is a complex issue, which is not fully understood. Further research is needed to explain the problem of GHD and delayed puberty in GD1. […] The existence of a casual relationship and confirmed, reasonable pathophysiological mechanism, is hard to prove because of a low incidence of GD in the population and a relatively high incidence of metabolic and hormonal disorders, such as obesity or insulin resistance, in the general population.

• #48 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5343975/

  The effect of GBA1 gene mutations could be modulated by the co-activator of GCase, saposin C, which may partly explain the limited penetrance of neurological impairment in patients with GD. […] The frequency of hypergammaglobulinemia and the presence of monoclonal Ig in GD are two factors which promote the emergence of multiple myeloma; the incidence of myeloma appears to be increased in GD, with a relative risk of at least 5.9. […] The pathophysiology of cancer development in GD is not well understood. At least two types of mechanisms may be operating, both of them relating to the GCase deficiency and the ensuing catabolic defect, i.e., the accumulation of GlcCer and/or its deacylated product, glucosylsphingosine or Lyso-glucosylceramide. […] Significant new insights into GDs pathophysiology show that GCase deficiency has a much broader impact than the simple macrophage load that transforms them into Gaucher cells.

• #49 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://www.mdpi.com/1422-0067/18/2/441

  Patients with a heterozygous (or homozygous) mutation in the GBA1 gene, especially c.1226A>G (N370S), but also c.1448T>C (L444P), c.84dup, c.115+1G>A (IVS2+1G>A), c.1297G>T (V394L), and c.1604G>A (R496H), are now considered at risk for Parkinson’s disease (PD). […] The most recent studies suggest that neuropathic mutations of the GBA gene (especially c.1448T>C (L444P)) could worsen the progression of PD. […] The frequency of hypergammaglobulinemia and the presence of monoclonal Ig in GD are two factors which promote the emergence of multiple myeloma; the incidence of myeloma appears to be increased in GD, with a relative risk of at least 5.9. […] The pathophysiology of cancer development in GD is not well understood. At least two types of mechanisms may be operating, both of them relating to the GCase deficiency and the ensuing catabolic defect, i.e., the accumulation of GlcCer and/or its deacylated product, glucosylsphingosine or Lyso-glucosylceramide.

• #50 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5343975/

  The effect of GBA1 gene mutations could be modulated by the co-activator of GCase, saposin C, which may partly explain the limited penetrance of neurological impairment in patients with GD. […] The frequency of hypergammaglobulinemia and the presence of monoclonal Ig in GD are two factors which promote the emergence of multiple myeloma; the incidence of myeloma appears to be increased in GD, with a relative risk of at least 5.9. […] The pathophysiology of cancer development in GD is not well understood. At least two types of mechanisms may be operating, both of them relating to the GCase deficiency and the ensuing catabolic defect, i.e., the accumulation of GlcCer and/or its deacylated product, glucosylsphingosine or Lyso-glucosylceramide. […] Significant new insights into GDs pathophysiology show that GCase deficiency has a much broader impact than the simple macrophage load that transforms them into Gaucher cells.

• #51 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://www.mdpi.com/1422-0067/18/2/441

  Patients with a heterozygous (or homozygous) mutation in the GBA1 gene, especially c.1226A>G (N370S), but also c.1448T>C (L444P), c.84dup, c.115+1G>A (IVS2+1G>A), c.1297G>T (V394L), and c.1604G>A (R496H), are now considered at risk for Parkinson’s disease (PD). […] The most recent studies suggest that neuropathic mutations of the GBA gene (especially c.1448T>C (L444P)) could worsen the progression of PD. […] The frequency of hypergammaglobulinemia and the presence of monoclonal Ig in GD are two factors which promote the emergence of multiple myeloma; the incidence of myeloma appears to be increased in GD, with a relative risk of at least 5.9. […] The pathophysiology of cancer development in GD is not well understood. At least two types of mechanisms may be operating, both of them relating to the GCase deficiency and the ensuing catabolic defect, i.e., the accumulation of GlcCer and/or its deacylated product, glucosylsphingosine or Lyso-glucosylceramide.

• #52 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://www.mdpi.com/1422-0067/18/2/441

  The most common hypothesis is that the (perturbed) cellular and cytokinic microenvironment in GD is responsible for tumorigenesis: perturbations include markedly elevated levels of some cytokines and chemokines, activated (M2) macrophages, abnormal responses by T lymphocytes, and a reduction of NK cells. […] Iron is stored in ferritin to avoid toxicity to cell components. In GD, ferritin levels in Gaucher cells are higher and the synthesis of hepcidin, which inhibits intestinal absorption of iron, is increased.

• #53 What Is Gaucher Disease? | National Gaucher Foundation

  https://www.gaucherdisease.org/about-gaucher-disease/what-is/

  Gaucher disease is caused by low levels of glucocerebrosidase (GCase), an enzyme that breaks down a fatty chemical in the body called glucocerebroside. Gaucher cells are normal scavenger cells called macrophages that become full of unprocessed glucocerebroside. Gaucher cells accumulate primarily in the spleen, liver and bone marrow, causing organ inflammation and dysfunction. […] Available treatments include enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). It is essential to work with a Gaucher specialist who can monitor your health and make adjustments to your medication as necessary. […] Enzyme replacement therapy (ERT) balances low levels of GCase in patients with Gaucher disease so their bodies can break down glucocerebroside. (This compensates for the missing enzyme, which is why the therapy is called enzyme replacement.) ERT involves receiving intravenous (IV) infusions about every 2 weeks, either at an infusion center or at home. […] Substrate reduction therapy (SRT) is a newer treatment that works differently than ERT. SRT is an oral medication that decreases the amount of glucocerebroside that the body makes, reducing excess buildup.

• #54 What Is Gaucher Disease? | National Gaucher Foundation

  https://www.gaucherdisease.org/about-gaucher-disease/what-is/

  Gaucher disease is caused by low levels of glucocerebrosidase (GCase), an enzyme that breaks down a fatty chemical in the body called glucocerebroside. Gaucher cells are normal scavenger cells called macrophages that become full of unprocessed glucocerebroside. Gaucher cells accumulate primarily in the spleen, liver and bone marrow, causing organ inflammation and dysfunction. […] Available treatments include enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). It is essential to work with a Gaucher specialist who can monitor your health and make adjustments to your medication as necessary. […] Enzyme replacement therapy (ERT) balances low levels of GCase in patients with Gaucher disease so their bodies can break down glucocerebroside. (This compensates for the missing enzyme, which is why the therapy is called enzyme replacement.) ERT involves receiving intravenous (IV) infusions about every 2 weeks, either at an infusion center or at home. […] Substrate reduction therapy (SRT) is a newer treatment that works differently than ERT. SRT is an oral medication that decreases the amount of glucocerebroside that the body makes, reducing excess buildup.

• #55 Gaucher Disease: Symptoms, Causes & Treatment

  https://my.clevelandclinic.org/health/diseases/16234-gaucher-disease

  With regular therapy, Gaucher disease type 1 is treatable. Gaucher disease treatment either increases enzyme levels or decreases the fatty substance that builds up in your body. Theres no treatment for the neurological damage from Gaucher disease types 2 and 3. […] People with Gaucher disease need ERT regularly (every two weeks) for treatment to be effective. Your healthcare provider will give you an enzyme infusion intravenously (through a vein in your arm). […] During ERT, the enzyme is delivered directly into your bloodstream from where it can reach your organs and bones. Then it breaks down fatty chemicals so they cant build up. […] This treatment decreases fatty chemicals so they cant build up in your body. You take SRT medication orally (by mouth). You must continue taking the medication regularly to prevent damage to your body. […] Researchers are actively developing several new therapies using genetic engineering and stem cell technologies.

• #56 What Is Gaucher Disease? | National Gaucher Foundation

  https://www.gaucherdisease.org/about-gaucher-disease/what-is/

  Gaucher disease is caused by low levels of glucocerebrosidase (GCase), an enzyme that breaks down a fatty chemical in the body called glucocerebroside. Gaucher cells are normal scavenger cells called macrophages that become full of unprocessed glucocerebroside. Gaucher cells accumulate primarily in the spleen, liver and bone marrow, causing organ inflammation and dysfunction. […] Available treatments include enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). It is essential to work with a Gaucher specialist who can monitor your health and make adjustments to your medication as necessary. […] Enzyme replacement therapy (ERT) balances low levels of GCase in patients with Gaucher disease so their bodies can break down glucocerebroside. (This compensates for the missing enzyme, which is why the therapy is called enzyme replacement.) ERT involves receiving intravenous (IV) infusions about every 2 weeks, either at an infusion center or at home. […] Substrate reduction therapy (SRT) is a newer treatment that works differently than ERT. SRT is an oral medication that decreases the amount of glucocerebroside that the body makes, reducing excess buildup.

• #57 Gaucher Disease: Symptoms, Causes & Treatment

  https://my.clevelandclinic.org/health/diseases/16234-gaucher-disease

  With regular therapy, Gaucher disease type 1 is treatable. Gaucher disease treatment either increases enzyme levels or decreases the fatty substance that builds up in your body. Theres no treatment for the neurological damage from Gaucher disease types 2 and 3. […] People with Gaucher disease need ERT regularly (every two weeks) for treatment to be effective. Your healthcare provider will give you an enzyme infusion intravenously (through a vein in your arm). […] During ERT, the enzyme is delivered directly into your bloodstream from where it can reach your organs and bones. Then it breaks down fatty chemicals so they cant build up. […] This treatment decreases fatty chemicals so they cant build up in your body. You take SRT medication orally (by mouth). You must continue taking the medication regularly to prevent damage to your body. […] Researchers are actively developing several new therapies using genetic engineering and stem cell technologies.

• #58 Gaucher disease provides a unique window into Parkinson disease pathogenesis | Nature Reviews Neurology

  https://www.nature.com/articles/s41582-024-00999-z

  Most individuals with homozygous or heterozygous GBA1 variants do not develop parkinsonism. Identifying the factors that impact penetrance will be crucial to our understanding of disease mechanisms. […] Therapeutic strategies under development for Gaucher disease, such as brain-penetrant enzyme replacement strategies, gene therapy approaches, and small molecule chaperones and activators, might inform new treatment approaches for Parkinson disease.

• #59 Gaucher Disease: Symptoms, Causes & Treatment

  https://my.clevelandclinic.org/health/diseases/16234-gaucher-disease

  With regular therapy, Gaucher disease type 1 is treatable. Gaucher disease treatment either increases enzyme levels or decreases the fatty substance that builds up in your body. Theres no treatment for the neurological damage from Gaucher disease types 2 and 3. […] People with Gaucher disease need ERT regularly (every two weeks) for treatment to be effective. Your healthcare provider will give you an enzyme infusion intravenously (through a vein in your arm). […] During ERT, the enzyme is delivered directly into your bloodstream from where it can reach your organs and bones. Then it breaks down fatty chemicals so they cant build up. […] This treatment decreases fatty chemicals so they cant build up in your body. You take SRT medication orally (by mouth). You must continue taking the medication regularly to prevent damage to your body. […] Researchers are actively developing several new therapies using genetic engineering and stem cell technologies.

• #60 Macrophage models of Gaucher disease for evaluating disease pathogenesis and candidate drugs.

  https://www.stemcell.com/macrophage-models-of-gaucher-disease-for-evaluating-disease-pathogenesis-and-candidate-drugs.html

  Gaucher disease is caused by an inherited deficiency of glucocerebrosidase that manifests with storage of glycolipids in lysosomes, particularly in macrophages. […] We used these cellular models both to investigate altered macrophage biology in Gaucher disease and to evaluate candidate drugs for its treatment. […] Macrophages derived from patient monocytes or iPSCs showed reduced glucocerebrosidase activity and increased storage of glucocerebroside and glucosylsphingosine in lysosomes. […] The disease phenotype was reversed with a noninhibitory small-molecule chaperone drug that enhanced glucocerebrosidase activity in the macrophages, reduced glycolipid storage, and normalized chemotaxis and production of reactive oxygen species. […] Macrophages differentiated from patient monocytes or patient-derived iPSCs provide cellular models that can be used to investigate disease pathogenesis and facilitate drug development.

• #61 Glucosylsphingosine (Lyso-Gb1) as a reliable biomarker in Gaucher disease: a narrative review | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-023-02623-7

  The specificity of lyso-Gb1 as a biomarker for GD was established in 2013, with pathological levels identified in GD patients but not in healthy controls, GD carriers, and patients with other lysosomal storage disorders. […] A pathophysiological role of lyso-Gb1 in GD was suggested in a long-term infusion model in genetically normal mice. […] In monoclonal B-cell pathogenesis, lyso-Gb1 influenced antigen-specific type II natural killer T cells that stimulate T-follicular helper phenotype leading to immune dysfunction. […] Given that lyso-Gb1 is directly involved in the pathological pathway of GD, and may therefore more accurately represent residual whole-body GD activity, lyso-Gb1 may be the biomarker of choice to evaluate disease burden and monitor treatment response, compared with chitotriosidase, which is specifically secreted by activated macrophages.

• #62 A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5343975/

  The effect of GBA1 gene mutations could be modulated by the co-activator of GCase, saposin C, which may partly explain the limited penetrance of neurological impairment in patients with GD. […] The frequency of hypergammaglobulinemia and the presence of monoclonal Ig in GD are two factors which promote the emergence of multiple myeloma; the incidence of myeloma appears to be increased in GD, with a relative risk of at least 5.9. […] The pathophysiology of cancer development in GD is not well understood. At least two types of mechanisms may be operating, both of them relating to the GCase deficiency and the ensuing catabolic defect, i.e., the accumulation of GlcCer and/or its deacylated product, glucosylsphingosine or Lyso-glucosylceramide. […] Significant new insights into GDs pathophysiology show that GCase deficiency has a much broader impact than the simple macrophage load that transforms them into Gaucher cells.

• #63

  https://www.ajol.info/index.php/ejhg/article/view/119461

  Gaucher disease (GD) is the most frequently encountered lysosomal storage disease caused by inborn defects of the membrane-bound lysosomal enzyme, acid b-glucosidase or glucocerebrosidase. This defective activity causes an accumulation of glucocerebroside (glucosylceramide) in the lysosomes of cells derived from the monocyte/macrophage lineage. Glucocerebroside-engorged cells, termed Gaucher cells, infiltrate various organs, leading to multisystemic abnormalities. […] Studies are increasingly recognizing the role of immune dysregulation and inflammation in the pathogenesis of Gaucher disease. Many cytokines have been reported as mediators of tissue damage in Gaucher disease. […] The progress in the understanding of the pathogenesis or relevant mechanism(s) of Gaucher disease is providing insights into additional therapeutic targets, enabling the potential for optimized patient outcomes with the use of adjunctive or supplemental agents.

• #64 Gaucher disease provides a unique window into Parkinson disease pathogenesis | Nature Reviews Neurology

  https://www.nature.com/articles/s41582-024-00999-z

  Most individuals with homozygous or heterozygous GBA1 variants do not develop parkinsonism. Identifying the factors that impact penetrance will be crucial to our understanding of disease mechanisms. […] Therapeutic strategies under development for Gaucher disease, such as brain-penetrant enzyme replacement strategies, gene therapy approaches, and small molecule chaperones and activators, might inform new treatment approaches for Parkinson disease.

• #65

  https://atm.amegroups.org/article/view/6150

  Gaucher disease is caused by mutations in the Gba1 gene encoding an acid -glucocerebrosidase (GBA1), the lysosomal hydrolase which breaks down glucosylceramide (GlcCer). […] Lower residual GBA1 levels leads to neuronal storage, in types 2 and 3 neurological symptoms are characterised by acute (death at age 2) or sub-acute onset, respectively. […] The links between cellular changes and clinical manifestations are largely unknown but are the key to the development and monitoring of new therapies. […] However, closer acquaintance reveals not a classic Mendelian disorder sometimes even monozygotic twins have different symptoms and studies at the cellular level have so far failed to reveal clear GlcCer functions.

• #66 Mechanisms of Gaucher disease pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4437956/

  Gaucher disease is caused by mutations in the Gba1 gene encoding an acid -glucocerebrosidase (GBA1), the lysosomal hydrolase which breaks down glucosylceramide (GlcCer). In Gaucher type 1 disease the accumulation of this simple glycolipid is mainly restricted to tissue phagocyte lysosomes resulting ultimately in hepatomegaly, splenomegaly and osteopenia. Lower residual GBA1 levels leads to neuronal storage, in types 2 and 3 neurological symptoms are characterised by acute (death at age 2) or sub-acute onset, respectively. […] The links between cellular changes and clinical manifestations are largely unknown but are the key to the development and monitoring of new therapies. […] GlcCer is unusual amongst glycolipids with intracellular trafficking connecting both lysosomal and non-lysosomal pools on both sides of the bilayer membrane.

• #67 Gaucher Disease: A Rare Disease Sheds Light on More Common Conditions > News > Yale Medicine

  https://www.yalemedicine.org/news/gaucher-disease-interview

  Based on the lab study, that activation of the immune system is believed to eventually cause a sequence of events, he explains, that leads to the development of multiple myeloma. […] Although Gaucher disease is a rare disease, it has immense potential to inform the understanding and treatment of more common diseases. […] After observing an unexpectedly high prevalence of Parkinsons in Gaucher patients21 times greater than in the general populationmyself and other researchers identified key shared biological mechanisms. […] We’ve learned that this lipid, this fatty material that builds up in Gaucher disease, drives the fundamental process that harms neurons in the substantia nigra, the part of the brain that is damaged in Parkinson’s disease. […] But what we have learned from Gaucher disease is that you can arrest the disease process itself with disease-modifying therapies that we are attempting to create.

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