Ari Zimran - Academia.edu (original) (raw)

Papers by Ari Zimran

Research paper thumbnail of Parkinson disease penetrance in patients with Gaucher disease and in glucocerebrosidase mutation carriers

Molecular Genetics and Metabolism, Feb 1, 2014

Research paper thumbnail of Significant and continuous improvement in quantitative chemical shift imaging (QCSI) in patients with Gaucher disease treated with taliglucerase alfa during the early access program

Molecular Genetics and Metabolism, Feb 1, 2016

Research paper thumbnail of The interleukin-6 promoter polymorphism in Gaucher disease: a new modifier gene?

QJM: An International Journal of Medicine, Aug 1, 2003

Research paper thumbnail of 1261 Enzyme Replacement Therapy with Velaglucerase Alfa Improves Key Clinical Parameters in a Pediatric Subgroup with Type 1 Gaucher Disease

Pediatric Research, Nov 1, 2010

Research paper thumbnail of Bone mineral density and lean muscle mass characteristics in children with Gaucher disease treated with enzyme replacement therapy or untreated

Blood Cells Molecules and Diseases, Feb 1, 2018

Research paper thumbnail of Lung involvement and enzyme replacement therapy in Gaucher's disease

QJM: An International Journal of Medicine, Aug 1, 2001

Research paper thumbnail of Glucocerebroside: an evolutionary advantage for patients with Gaucher disease and a new immunomodulatory agent

Immunology and Cell Biology, Jun 16, 2009

Gaucher disease (GD) is caused by the reduced activity of a lysosomal enzyme, glucocerebrosidase,... more Gaucher disease (GD) is caused by the reduced activity of a lysosomal enzyme, glucocerebrosidase, leading to the accumulation of glucocerebroside (GC). The relatively high prevalence of this disease within an ethnic group is believed to reflect a selective advantage. Treatment with enzyme replacement therapy (ERT) is safe and effective in ameliorating the primary symptoms of the disease, yet there have been reports that some patients on ERT have developed type 2 diabetes or metabolic syndrome, malignancies and central nervous system disorders. A series of animal studies suggest that these complications may be related to the reduction of GC levels by the enzyme administered. GC has been shown to have an immunomodulatory effect through the promotion of dendritic cells, natural killer T cells, and regulatory T cells. The break down of GC to ceramide can underline part of these findings. Clinical trials suggested a beneficial effect of GC in type 2 diabetes or nonalcoholic steatohepatitis. This review of the data from animal models and humans proposes that the increased level of GC may provide an evolutionary advantage for patients with GD. Indirectly, these data support treating symptomatic patients with mild/moderate GD with low‐dose ERT and re‐evaluating the use of ERT in asymptomatic patients.

Research paper thumbnail of Gaucher Disease

Research paper thumbnail of Proof-of-principle rapid noninvasive prenatal diagnosis of autosomal recessive founder mutations

Journal of Clinical Investigation, Aug 31, 2015

Research paper thumbnail of Reduction in Intravenous Infusion Duration of Enzyme Replacement Therapy to Ten Minutes with Velaglucerase Alfa in Adult Patients with Type 1 Gaucher Disease

Research paper thumbnail of Gaucher Disease and LGL Proliferations: Provocative Commonality?

Blood, Nov 18, 2011

Abstract 1100 Large granular lymphocytes(LGL)which may be of T or NK phenotype, normally account ... more Abstract 1100 Large granular lymphocytes(LGL)which may be of T or NK phenotype, normally account for 10–15% of peripheral blood(PB)lymphocytes. T-LGL leukemia is a clonal expansion of antigen-primed competent cytotoxic-T-lymphocytes(CTL)which is unique in that these cells retain many phenotypic and functional properties of normal cytotoxic effector T cells. Sphingolipid-mediated signaling has been shown to have a role in long-term survival of CTLs. The diagnosis of T-LGL leukemia requires proof of clonality, yet clonal T-LGL proliferations may occur in normal individuals with autoimmune diseases, viral infections, B cell lymphoproliferations and post bone marrow transplantation rendering the differentiation of malignant (leukemic) from benign LGL expansions at times difficult. It has been suggested that T-LGL proliferations with polyclonal or oligoclonal TCR gene rearrangement may be a response to a stimulus before the emergence of a dominant clone. Gaucher disease (GD)is a lysosomal storage disease caused by mutations in the gene encoding acid β-glucocerebrosidase, leading to the accumulation of glucocerebroside in tissue macrophages (Gaucher cells) and resulting in hepatosplenomegaly, cytopenias and skeletal involvement. GD and T-LGL leukemia share strikingly similar clinical features, including cytopenias, splenomegaly, B cell dyscrasias, arthralgias, pulmonary hypertension (PHT), and increased association with neoplasms and autoimmune disorders. The etiology of PHT, B cell dyscrasias, and the increased frequency of neoplasms in GD remains unclear. Table 1 describes the characteristics of 4 GD patients suffering from severe cytopenias relative to the overall phenotype of their GD in whom LGL were found to comprise the majority of the PB lymphocytes. Patient #1: 31year-old female suffering from severe GD with massive splenomegaly and severe cytopenias but refuses Gaucher-specific therapy; Patient #2: 31year-old female has suffered from severe Gaucher disease since childhood, was splenectomized, has unexplained anemia and known LGL expansion for 7 years but clonality studies continue to be negative; Patient #3: 45 year-old female with severe GD, splenectomized, suffered from AVN, bone crisis autoimmune hemolytic anemia, PHT, and B cell dyscrasia; and Patient #4: 72 year-old male has asymptomatic GD with progressive pancytopenia who was diagnosed with myelodysplastic syndrome(MDS),T-LGL proliferation and monclonal gammopathy of unknown origin(MGUS). LGL cells comprised 70% of PB lymphocytes in addition there was severe trilineage dysplastic changes, TCR rearrangement was positive. Interestingly, 8 months after the start of enzyme replacement therapy(ERT),counts improved and the number of PB LGL was reduced to <10% of lymphocytes. In a cohort of 55 consecutive GD patients, 38% had LGL expansions in the PB smears. Since both conditions may be asymptomatic for many years, their co-existence can easily be missed.Table 1:Patient characteristics1234Age at diagnosis31314572GenderFemaleFemaleFemaleMaleSplenectomyNoYesYesNoBony diseaseAVNBone crisis, AVN, osteomyelitisNo?Pulmonary HypertensionNoNoYesNoAutoimmune phenomenonNoNoAIHANoB cell dyscrasiasYesNoPolyclonal hypergammagloblulinemiaMGUSOther neoplasmsNoNoNoMDSLeucocyte count (×10/ul)2.213.36.62.9LGL percent of lymphocytes52%62%30%70%LGL absolute count (×10/ul)0.55.111.10.532LGL phenotypeCD3+,CD8+, CD56+, CD16−, CD57−, TCR αβ+CD3+, CD8+, CD16−, CD56−, TCR αβ+?CD3+, CD8+, CD16−, CD56−, TCR αβ+2 populationsa) CD3+, CD8+, CD56+, TCR αβ+9.3g/dlb) CD3−,CD56+,CD4−, CD8−Hemoglobin (g/dl)4.911.311.4Platelet count (x10/ul)111779630TCR rearrangementNegativeNegativePositivePositiveBone marrow pattern of involvementMild interstitial infiltrate of small lymphocytes CD8+TMild interstitial infiltrate of small lymphocytes CD8+TERTNoYesYesYesERT: improvement of cytopeniasUntreatedNoNoYes The co-existence of two hematological pathologies in more than one patient and the possibility that therapy for one may impact the other, is provocative. We suggest that LGL expansions in GD may be reactive to glucocereborside accumulation in Gaucher cells, and may play a pathogenic role in the development of some of the features of GD as well as induce/exacerbate some associated disorders. Disclosures: Zimran: Actelion: Honoraria.

Research paper thumbnail of Children with type 1 Gaucher disease: Changing profiles in the 21st century

Molecular Genetics and Metabolism, Feb 1, 2016

Research paper thumbnail of Lyso-Gb1 as a biomarker of the real-world situation in Gaucher disease: Comparative data from the Gaucher Outcome Survey (GOS) in ERT-treated and untreated patients

Molecular Genetics and Metabolism

Research paper thumbnail of Effect of macrophage-targeted glucocerebrosidase(alglucerase) on hypolipidaemia of type 1 Gaucher disease(GD)

Research paper thumbnail of Miglustat Therapy in Type 1 Gaucher Disease: Long-Term Treatment Experience From a Multicenter, Retrospective Cohort Study

Blood, 2011

3207 Introduction: Miglustat (Zavesca®) was approved for the treatment of adults with mild-to-mod... more 3207 Introduction: Miglustat (Zavesca®) was approved for the treatment of adults with mild-to-moderate type 1 Gaucher disease (GD1) for whom enzyme replacement therapy (ERT) is either unsuitable or not a therapeutic option in the EU in 2002 and in the USA in 2003. However, data from real-world clinical experience with miglustat remain limited. Methods: Medical chart data were collected from consecutive adult GD1 patients who initiated commercial miglustat therapy at centers in 9 EU countries or the US after 20th November 2002. Both ERT-naïve and ERT-pretreated patients were included. Follow-up data were collected from miglustat initiation to the end of the observation period (i.e. last information/visit before the end of the study on 31st December 2008, death or loss to follow up). Data on patient demographics, medical history and disease characteristics were collected. Outcome assessments included hematological and biochemical parameters, liver/spleen volumes, gastrointestinal sig...

Research paper thumbnail of Bone mineral density and lean muscle mass characteristics in children with Gaucher disease treated with enzyme replacement therapy or untreated

Blood cells, molecules & diseases, Jan 9, 2016

Research paper thumbnail of Pyrimethamine increases �-hexosaminidase A activity in patients with Late Onset Tay Sachs

Research paper thumbnail of Iliopsoas hematoma in a young patient with type I Gaucher disease

The Israel Medical Association journal : IMAJ, 2003

Research paper thumbnail of Huge subcapsular splenic hematoma in a patient with Gaucher disease

The Israel Medical Association journal : IMAJ, 2000

Research paper thumbnail of Children with type I Gaucher disease: growing into adulthood with and without enzyme therapy

The Israel Medical Association journal : IMAJ, 2000

... Ari Zimran MD, Ayala Abrahamov MD and Deborah Elstein PhD ... Ann Intern Med 1995;122:33– 9. ... more ... Ari Zimran MD, Ayala Abrahamov MD and Deborah Elstein PhD ... Ann Intern Med 1995;122:33– 9. 4. Zimran A, Elstein D, Levy Lahad E, Zevin S, Hadas-Halpern I, Bar-Ziv Y, Foldes J, Schwartz AJ, Abrahamov A. Replacement therapy with imiglucerase for type 1 Gaucher disease ...

Research paper thumbnail of Parkinson disease penetrance in patients with Gaucher disease and in glucocerebrosidase mutation carriers

Molecular Genetics and Metabolism, Feb 1, 2014

Research paper thumbnail of Significant and continuous improvement in quantitative chemical shift imaging (QCSI) in patients with Gaucher disease treated with taliglucerase alfa during the early access program

Molecular Genetics and Metabolism, Feb 1, 2016

Research paper thumbnail of The interleukin-6 promoter polymorphism in Gaucher disease: a new modifier gene?

QJM: An International Journal of Medicine, Aug 1, 2003

Research paper thumbnail of 1261 Enzyme Replacement Therapy with Velaglucerase Alfa Improves Key Clinical Parameters in a Pediatric Subgroup with Type 1 Gaucher Disease

Pediatric Research, Nov 1, 2010

Research paper thumbnail of Bone mineral density and lean muscle mass characteristics in children with Gaucher disease treated with enzyme replacement therapy or untreated

Blood Cells Molecules and Diseases, Feb 1, 2018

Research paper thumbnail of Lung involvement and enzyme replacement therapy in Gaucher's disease

QJM: An International Journal of Medicine, Aug 1, 2001

Research paper thumbnail of Glucocerebroside: an evolutionary advantage for patients with Gaucher disease and a new immunomodulatory agent

Immunology and Cell Biology, Jun 16, 2009

Gaucher disease (GD) is caused by the reduced activity of a lysosomal enzyme, glucocerebrosidase,... more Gaucher disease (GD) is caused by the reduced activity of a lysosomal enzyme, glucocerebrosidase, leading to the accumulation of glucocerebroside (GC). The relatively high prevalence of this disease within an ethnic group is believed to reflect a selective advantage. Treatment with enzyme replacement therapy (ERT) is safe and effective in ameliorating the primary symptoms of the disease, yet there have been reports that some patients on ERT have developed type 2 diabetes or metabolic syndrome, malignancies and central nervous system disorders. A series of animal studies suggest that these complications may be related to the reduction of GC levels by the enzyme administered. GC has been shown to have an immunomodulatory effect through the promotion of dendritic cells, natural killer T cells, and regulatory T cells. The break down of GC to ceramide can underline part of these findings. Clinical trials suggested a beneficial effect of GC in type 2 diabetes or nonalcoholic steatohepatitis. This review of the data from animal models and humans proposes that the increased level of GC may provide an evolutionary advantage for patients with GD. Indirectly, these data support treating symptomatic patients with mild/moderate GD with low‐dose ERT and re‐evaluating the use of ERT in asymptomatic patients.

Research paper thumbnail of Gaucher Disease

Research paper thumbnail of Proof-of-principle rapid noninvasive prenatal diagnosis of autosomal recessive founder mutations

Journal of Clinical Investigation, Aug 31, 2015

Research paper thumbnail of Reduction in Intravenous Infusion Duration of Enzyme Replacement Therapy to Ten Minutes with Velaglucerase Alfa in Adult Patients with Type 1 Gaucher Disease

Research paper thumbnail of Gaucher Disease and LGL Proliferations: Provocative Commonality?

Blood, Nov 18, 2011

Abstract 1100 Large granular lymphocytes(LGL)which may be of T or NK phenotype, normally account ... more Abstract 1100 Large granular lymphocytes(LGL)which may be of T or NK phenotype, normally account for 10–15% of peripheral blood(PB)lymphocytes. T-LGL leukemia is a clonal expansion of antigen-primed competent cytotoxic-T-lymphocytes(CTL)which is unique in that these cells retain many phenotypic and functional properties of normal cytotoxic effector T cells. Sphingolipid-mediated signaling has been shown to have a role in long-term survival of CTLs. The diagnosis of T-LGL leukemia requires proof of clonality, yet clonal T-LGL proliferations may occur in normal individuals with autoimmune diseases, viral infections, B cell lymphoproliferations and post bone marrow transplantation rendering the differentiation of malignant (leukemic) from benign LGL expansions at times difficult. It has been suggested that T-LGL proliferations with polyclonal or oligoclonal TCR gene rearrangement may be a response to a stimulus before the emergence of a dominant clone. Gaucher disease (GD)is a lysosomal storage disease caused by mutations in the gene encoding acid β-glucocerebrosidase, leading to the accumulation of glucocerebroside in tissue macrophages (Gaucher cells) and resulting in hepatosplenomegaly, cytopenias and skeletal involvement. GD and T-LGL leukemia share strikingly similar clinical features, including cytopenias, splenomegaly, B cell dyscrasias, arthralgias, pulmonary hypertension (PHT), and increased association with neoplasms and autoimmune disorders. The etiology of PHT, B cell dyscrasias, and the increased frequency of neoplasms in GD remains unclear. Table 1 describes the characteristics of 4 GD patients suffering from severe cytopenias relative to the overall phenotype of their GD in whom LGL were found to comprise the majority of the PB lymphocytes. Patient #1: 31year-old female suffering from severe GD with massive splenomegaly and severe cytopenias but refuses Gaucher-specific therapy; Patient #2: 31year-old female has suffered from severe Gaucher disease since childhood, was splenectomized, has unexplained anemia and known LGL expansion for 7 years but clonality studies continue to be negative; Patient #3: 45 year-old female with severe GD, splenectomized, suffered from AVN, bone crisis autoimmune hemolytic anemia, PHT, and B cell dyscrasia; and Patient #4: 72 year-old male has asymptomatic GD with progressive pancytopenia who was diagnosed with myelodysplastic syndrome(MDS),T-LGL proliferation and monclonal gammopathy of unknown origin(MGUS). LGL cells comprised 70% of PB lymphocytes in addition there was severe trilineage dysplastic changes, TCR rearrangement was positive. Interestingly, 8 months after the start of enzyme replacement therapy(ERT),counts improved and the number of PB LGL was reduced to <10% of lymphocytes. In a cohort of 55 consecutive GD patients, 38% had LGL expansions in the PB smears. Since both conditions may be asymptomatic for many years, their co-existence can easily be missed.Table 1:Patient characteristics1234Age at diagnosis31314572GenderFemaleFemaleFemaleMaleSplenectomyNoYesYesNoBony diseaseAVNBone crisis, AVN, osteomyelitisNo?Pulmonary HypertensionNoNoYesNoAutoimmune phenomenonNoNoAIHANoB cell dyscrasiasYesNoPolyclonal hypergammagloblulinemiaMGUSOther neoplasmsNoNoNoMDSLeucocyte count (×10/ul)2.213.36.62.9LGL percent of lymphocytes52%62%30%70%LGL absolute count (×10/ul)0.55.111.10.532LGL phenotypeCD3+,CD8+, CD56+, CD16−, CD57−, TCR αβ+CD3+, CD8+, CD16−, CD56−, TCR αβ+?CD3+, CD8+, CD16−, CD56−, TCR αβ+2 populationsa) CD3+, CD8+, CD56+, TCR αβ+9.3g/dlb) CD3−,CD56+,CD4−, CD8−Hemoglobin (g/dl)4.911.311.4Platelet count (x10/ul)111779630TCR rearrangementNegativeNegativePositivePositiveBone marrow pattern of involvementMild interstitial infiltrate of small lymphocytes CD8+TMild interstitial infiltrate of small lymphocytes CD8+TERTNoYesYesYesERT: improvement of cytopeniasUntreatedNoNoYes The co-existence of two hematological pathologies in more than one patient and the possibility that therapy for one may impact the other, is provocative. We suggest that LGL expansions in GD may be reactive to glucocereborside accumulation in Gaucher cells, and may play a pathogenic role in the development of some of the features of GD as well as induce/exacerbate some associated disorders. Disclosures: Zimran: Actelion: Honoraria.

Research paper thumbnail of Children with type 1 Gaucher disease: Changing profiles in the 21st century

Molecular Genetics and Metabolism, Feb 1, 2016

Research paper thumbnail of Lyso-Gb1 as a biomarker of the real-world situation in Gaucher disease: Comparative data from the Gaucher Outcome Survey (GOS) in ERT-treated and untreated patients

Molecular Genetics and Metabolism

Research paper thumbnail of Effect of macrophage-targeted glucocerebrosidase(alglucerase) on hypolipidaemia of type 1 Gaucher disease(GD)

Research paper thumbnail of Miglustat Therapy in Type 1 Gaucher Disease: Long-Term Treatment Experience From a Multicenter, Retrospective Cohort Study

Blood, 2011

3207 Introduction: Miglustat (Zavesca®) was approved for the treatment of adults with mild-to-mod... more 3207 Introduction: Miglustat (Zavesca®) was approved for the treatment of adults with mild-to-moderate type 1 Gaucher disease (GD1) for whom enzyme replacement therapy (ERT) is either unsuitable or not a therapeutic option in the EU in 2002 and in the USA in 2003. However, data from real-world clinical experience with miglustat remain limited. Methods: Medical chart data were collected from consecutive adult GD1 patients who initiated commercial miglustat therapy at centers in 9 EU countries or the US after 20th November 2002. Both ERT-naïve and ERT-pretreated patients were included. Follow-up data were collected from miglustat initiation to the end of the observation period (i.e. last information/visit before the end of the study on 31st December 2008, death or loss to follow up). Data on patient demographics, medical history and disease characteristics were collected. Outcome assessments included hematological and biochemical parameters, liver/spleen volumes, gastrointestinal sig...

Research paper thumbnail of Bone mineral density and lean muscle mass characteristics in children with Gaucher disease treated with enzyme replacement therapy or untreated

Blood cells, molecules & diseases, Jan 9, 2016

Research paper thumbnail of Pyrimethamine increases �-hexosaminidase A activity in patients with Late Onset Tay Sachs

Research paper thumbnail of Iliopsoas hematoma in a young patient with type I Gaucher disease

The Israel Medical Association journal : IMAJ, 2003

Research paper thumbnail of Huge subcapsular splenic hematoma in a patient with Gaucher disease

The Israel Medical Association journal : IMAJ, 2000

Research paper thumbnail of Children with type I Gaucher disease: growing into adulthood with and without enzyme therapy

The Israel Medical Association journal : IMAJ, 2000

... Ari Zimran MD, Ayala Abrahamov MD and Deborah Elstein PhD ... Ann Intern Med 1995;122:33– 9. ... more ... Ari Zimran MD, Ayala Abrahamov MD and Deborah Elstein PhD ... Ann Intern Med 1995;122:33– 9. 4. Zimran A, Elstein D, Levy Lahad E, Zevin S, Hadas-Halpern I, Bar-Ziv Y, Foldes J, Schwartz AJ, Abrahamov A. Replacement therapy with imiglucerase for type 1 Gaucher disease ...