Dominick Amato

Mount Sinai Hospital, Toronto, Toronto, Ontario, Canada

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Publications (25)94.95 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Gaucher disease is an autosomal recessive lysosomal storage disorder resulting from deficient glucocerebrosidase activity. There have been nearly 300 mutations described to date. Novel mutations can potentially provide insight into the biochemical basis of the disease. Two novel mutations are described in two Type 1 Gaucher patients with N370S compound heterozygosity; a point mutation that causes an amino acid substitution at cysteine residue 23 for tryptophan, and a second point mutation within the splicing element at the 3' end of intron 7. Both mutations were identified by PCR amplification and sequence analysis of patient glucocerebrosidase genomic DNA. Restriction fragment length polymorphism analysis was established for both novel mutations for efficient identification in future patients. Past literature suggests that mutations affecting cysteine residues involved in disulfide bridges, as well as mutations affecting splicing patterns of the glucocerebrosidase transcript, are detrimental to enzyme activity. However, compound heterozygosity with N370S, a mild mutation, will lead to a mild phenotype. The cases reported here support these past findings.
    Gene 01/2014; · 2.20 Impact Factor
  • Molecular Genetics and Metabolism 01/2014; 111(2):S30. · 2.83 Impact Factor
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    ABSTRACT: Taliglucerase alfa is a β-glucosidase enzyme replacement therapy (ERT) approved in the US and other countries for the treatment of Gaucher disease (GD) in adults and is approved in pediatric and adult patients in Australia and Canada. It is the first approved plant cell-expressed recombinant human protein. A Phase 3, multicenter, open-label, 9-month study assessed safety and efficacy of switching to taliglucerase alfa in adult and pediatric patients with GD treated with imiglucerase for at least the previous 2 years. Patients with stable disease were offered taliglucerase alfa treatment using the same dose (9–60 U/kg body weight) and regimen of administration (every 2 weeks) as imiglucerase. This report summarizes results from 26 adult and 5 pediatric patients who participated in the trial. Disease parameters (spleen and liver volumes, hemoglobin concentration, platelet count, and biomarker levels) remained stable through 9 months of treatment in adults and children following the switch from imiglucerase. All treatment-related adverse events were mild or moderate in severity and transient in nature. Exploratory parameters of linear growth and development showed positive outcomes in pediatric patients. These findings provide evidence of the efficacy and safety profile of taliglucerase alfa as an ERT for GD in patients previously treated with imiglucerase. This trial was registered at as # NCT00712348.
    Blood Cells Molecules and Diseases 01/2014; · 2.26 Impact Factor
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    ABSTRACT: BACKGROUND: Previous studies have provided equivocal data on the use of miglustat as maintenance therapy in Gaucher disease type 1. We report findings from a clinical trial evaluating the effects of miglustat treatment in patients with stable type 1 Gaucher disease after enzyme therapy. METHODS: Adult type 1 Gaucher disease patients stabilized during at least 3 years of previous enzyme therapy were included in this 2-year, prospective, open-label non-inferiority study. The primary endpoint was percent change from baseline in liver volume. Secondary endpoints included changes in spleen volume, hemoglobin concentration and platelet count. RESULTS: Forty-two patients were enrolled (mean+/-SD age, 45.1+/-12.7 years; previous enzyme therapy duration 9.5+/-4.0 years). Median (range) exposure to miglustat 100 mg t.i.d. was 658 (3--765) days. Twenty-one patients discontinued treatment prematurely; 13 due to adverse events, principally gastrointestinal. The upper 95% confidence limit of mean percent change in liver volume from baseline to end of treatment was below the non-inferiority margin of 10% (-1.1%; 95%CI -6.0, 3.9%). Mean (95%CI) changes in spleen volume, hemoglobin concentration and platelet count were 102 (24,180) mL, --0.95 (-1.38, --0.53) g/dL and -44.1 (-57.6, --30.7) x109/L, respectively. CONCLUSIONS: The primary efficacy endpoint was met; overall there was no change in liver volume during 24 months of miglustat therapy. Several patients showed a gradual deterioration in some disease manifestations, suggesting that miglustat could maintain clinical stability, but not in all patients. Miglustat demonstrated a predictable profile of safety and tolerability that was consistent with that reported in previous clinical trials and experience in clinical practice.Trial registration: identifier NCT00319046.
    Orphanet Journal of Rare Diseases 12/2012; 7(1):102. · 4.32 Impact Factor
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    ABSTRACT: Taliglucerase alfa (Protalix Biotherapeutics, Carmiel, Israel) is a novel plant cell-derived recombinant human β-glucocerebrosidase for Gaucher disease. A phase 3, double-blind, randomized, parallel-group, comparison-dose (30 vs 60 U/kg body weight/infusion) multinational clinical trial was undertaken. Institutional review board approvals were received. A 9-month, 20-infusion trial used inclusion/exclusion criteria in treatment-naive adult patients with splenomegaly and thrombocytopenia. Safety end points were drug-related adverse events: Ab formation and hypersensitivity reactions. Primary efficacy end point was reduction in splenic volume measured by magnetic resonance imaging. Secondary end points were: changes in hemoglobin, hepatic volume, and platelet counts. Exploratory parameters included biomarkers and bone imaging. Twenty-nine patients (11 centers) completed the protocol. There were no serious adverse events; drug-related adverse events were mild/moderate and transient. Two patients (6%) developed non-neutralizing IgG Abs; 2 other patients (6%) developed hypersensitivity reactions. Statistically significant spleen reduction was achieved at 9 months: 26.9% (95% confidence interval [CI]: -31.9, -21.8) in the 30-unit dose group and 38.0% (95% CI: -43.4, -32.8) in the 60-unit dose group (both P < .0001); and in all secondary efficacy end point measures, except platelet counts at the lower dose. These results support safety and efficacy of taliglucerase alfa for Gaucher disease.
    Blood 09/2011; 118(22):5767-73. · 9.78 Impact Factor
  • Molecular Genetics and Metabolism - MOL GENET METAB. 01/2011; 102(2).
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    ABSTRACT: Gaucher disease (GD) is characterized by reduced activity of glucocerebrosidase leading to complications in the reticuloendothelial system. N396T, a rarer mutation of the glucocerebrosidase gene, has been encountered in Portuguese populations and has generally been associated with milder phenotypes. This report presents brief histories of two Portuguese sisters, both with homozygous N396T mutations. These patients are phenotypically very different despite the fact that in both patients residual enzyme activity is very low. The case of patient 1 is complicated by comorbid diabetes mellitus and human immunodeficiency virus (HIV) infection. Enzyme replacement therapy (ERT) improved this patient's clinical picture sufficiently to enable antiretroviral treatment to proceed for the HIV. This report demonstrates the poor correlation of clinical GD with genotype as well as with residual enzyme activity. It further illustrates how treatment of the underlying GD with ERT improved symptoms allowing for antiretroviral therapy thereby improving both the GD and HIV.
    International Medical Case Reports Journal 01/2011; 4:17-20.
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    Fenglin Cao, Dominick Amato, Chen Wang
    American Journal of Hematology 12/2010; 86(9):782. · 4.00 Impact Factor
  • Siavash Piran, Dominick Amato
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    ABSTRACT: Type 1 Gaucher disease (GD1) is an inherited lysosomal storage disease, which is often managed by enzyme replacement therapy (ERT). The bone response to ERT is usually slower than visceral and hematological responses. There is uncertainty as to whether an increase in the dosage of ERT has a beneficial effect. The aim of our study was to determine whether or not there is sufficient evidence to make a definitive statement about the effects of ERT and substrate reduction therapy (SRT) on bone marrow infiltration and bone mineral density (BMD) in GD1. We conducted a systematic review of all studies examining the effects of ERT and SRT on bony complications of GD1 published before July 2008. The studies were identified by a computerized search with use of Medline, Embase, The Cochrane Database of Systematic Reviews, The Cochrane Central Register of Controlled Trials (CCTR), and bibliographies of papers subsequently retrieved from the search. Three hundred studies were grouped according to whether they deal with the natural history of GD1 or therapeutic issues, and 17 studies were included in the review. The results from our systematic review suggest that further investigations, such as better analysis of the Gaucher Registry, are needed on the effects of ERT and SRT on bony complications of GD1. Studies on the effects of the newly identified velaglucerase and the plant-derived glucocerebrosidase on bony complications of GD1 are also needed.
    Journal of Inherited Metabolic Disease 03/2010; 33(3):271-9. · 4.07 Impact Factor
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    ABSTRACT: Gaucher disease (GD) is a lysosomal storage disorder characterized by anemia and thrombocytopenia, hepatosplenomegaly, and skeletal involvement. The management of Gaucher disease was improved by the development of enzyme replacement therapy (ERT). However, the bone response to ERT is generally slower compared to other clinical manifestations. Some have recommended the early use of ERT to prevent the development of severe skeletal complications. Because we have access to over 30 untreated patients in Ontario, we questioned the extent to which complications progress in severity over a long period of time. We examined retrospectively the natural history of GD and the extent of skeletal manifestations in 22 untreated type 1 GD adult patients (mean age, 49+/-3.3; range, 20-81 years). The patients were followed for a median of 9.5 years (range, 3-16 years). Hemoglobin (Hb) concentration did not significantly change over time (mean baseline concentration of 12.8+/-0.27 g/dL vs. mean recent concentration of 12.6+/-0.37 g/dL, p=0.65). Mean platelet count also remained relatively stable over time (mean baseline count of 138+/-13x10(9)/L vs. mean recent count of 138.5+/-18x10(9)/L, p=0.98). Mean ferritin and ACE concentrations were elevated and were stable over time. Liver volumes decreased over time (mean baseline liver volume of 1.2xnormal (N) vs. mean recent volume of 1.06xN, p=0.27) and 6 of 22 (27%) patients had moderate hepatomegaly (liver volume, 1.25-2.5xN). Spleen volumes remained stable over time (mean baseline spleen volume of 6.6xN vs. mean recent volume of 5.2xN, p=0.5). None of the changes was statistically significant. Four of 20 (20%) patients had moderate splenomegaly (spleen volume, 5-15xN), 2 of 20 (10%) had marked splenomegaly (spleen volume, >or=15xN), and 2 of 22 (9%) had had splenectomy. The most common skeletal manifestations were infiltration of the bone marrow in 16 of 22 (73%) patients followed by osteopenia in 15 of 22 (68%), Erlenmeyer flask deformity in 13 of 22 (59%), and infarctions in 6 of 22 (27%) patients. We observed that bone disease remained relatively stable over time in most patients, although three patients developed new infarcts over time, one developed an avascular necrosis (AVN), and four had an increase in the degree of osteopenia. Although GD and its skeletal complications progress in severity in some patients, our results suggest that GD complications, including bony disease, may stabilize over time. Therefore, early use of ERT may not be necessary in all type 1 GD patients.
    Blood Cells Molecules and Diseases 09/2009; 43(3):289-93. · 2.26 Impact Factor
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    ABSTRACT: The principal manifestations of type 1 Gaucher disease (GD) (increased risk of bleeding, anaemia, splenomegaly, hepatomegaly and bone disease) are likely to affect females during reproductive events such as menarche and menstruation; fertility, pregnancy, parity, delivery and lactation; and menopause. In order to determine the optimal management of female Gaucher patients based on available data, we examine reproductive events and GD in untreated and alglucerase and/or imiglucerase-treated females. A panel of international clinicians experienced in the management of GD reviewed and presented evidence from peer-reviewed literature, a pharmacovigilance database on imiglucerase, and their own clinical experience to support discussions and recommendations. Nine panel members completed a 130-item-questionnaire on the outcomes of the management of female patients in their clinical practice. Results, covering menarche (137 females), menstruation (261 reports), fertility (295 females), pregnancy (416 pregnancies in 247 women) and menopause (45 women) were analysed. Data from a recent Canadian survey on 50 patients with 39 pregnancies, the imiglucerase pharmacovigilance database (100 pregnancies), and relevant literature (56 items covering 398 pregnancies in 205 women) were also reviewed. Menarche: May be delayed in girls with GD. Menorrhagia: Appears to be more common in GD than in the non-Gaucher population and may be ameliorated by alglucerase and/or imiglucerase treatment (menorrhagia in 67/133 (50.4%) untreated females compared with 37/128 (28.9%) treated; Mann-Whitney U test: p=0.001). Fertility: There is no evidence of decreased fertility in GD. Pregnancy: Pregnancy in GD may be complicated by haematological disease, organomegaly and bone involvement. GD diagnosis occurs frequently during pregnancy. Questionnaire results demonstrate: a reduced risk of spontaneous abortion in women treated with alglucerase and/or imiglucerase (untreated: 26/189 (13.8%); treated 1/58 (1.7%) chi(2)p=0.010); reduced risk of Gaucher-related complications during delivery (untreated 43/109 (39.4%); treated 3/46 (6.5%) chi(2)p<0.0005): and a reduced risk of Gaucher-related complications during the post partum period (untreated 15/71 (21.1%); treated 3/43 (7%) chi(2)p=0.014). There is no evidence to date of any untoward effect of alglucerase and/or imiglucerase on the fetus, or on infants breast fed by mothers receiving alglucerase and/or imiglucerase. Menopause: The impact of GD on menopause requires further study especially in relation to bone pathology. On the basis of this review, GD may have an impact on reproductive events in affected women. Enzyme therapy may have benefits in reducing menorrhagia, spontaneous abortions and complications associated with delivery and the postpartum period.
    Blood Cells Molecules and Diseases 06/2009; 43(3):264-88. · 2.26 Impact Factor
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    ABSTRACT: The response of bone marrow to erythropoietin (EPO) from five children with the Diamond-Blackfan syndrome, also known as congenital hypoplastic anaemia (CHA), was tested in tissue culture by measurement of haem synthesis. Studies of 13 control marrows indicated that the maximum EPO effect occurred at approximately 70 h incubation using an EPO concentration of 0.2–0.3 units/ml and a nucleated cell concentration of 5 × 106 per culture. Under these conditions, haem synthesis was 121% greater in EPO-stimulated than in unstimulated cultures. Patients with CHA with anaemia and diminished marrow erythroids had reduced or absent haem synthesis. In one patient, haem production became normal after a spontaneous remission, and was not inhibited by autologous plasma drawn at the time of diagnosis. Plasma from three patients did not show inhibitory activity when cultured with control marrow. In contrast, plasma from an adult with acquired pure red cell aplasia produced striking inhibition of haem synthesis when cultured with control marrow. We conclude that, in comparison to some cases of the adult acquired condition, CHA is not due to inhibitors or antibodies. When present, erythroid precursors in children with CHA are capable of responding normally to EPO with increased haem synthesis.
    British Journal of Haematology 03/2008; 31(4):515 - 520. · 4.94 Impact Factor
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    ABSTRACT: The finding of monoclonal B-cell lymphocytosis (MBL) raises questions on the nature of clonal cell expansion and its risk of progression. We identified and characterized 7 cases of clinically benign clonal B-cell lymphocytosis. The clonal lymphocytes were clearly of CD5- and non-chronic lymphocytic leukemia (CLL) phenotype. All cases had mild to moderate absolute lymphocytosis. The clonal population accounted for 95% to 99% of B cells. For a follow-up period of 4 to 16 years, clonal lymphocytosis was persistent but virtually not progressing. Patients' conditions remained clinically stable and asymptomatic. The clonal populations had somatic hypermutations of the VH gene in 6 cases, indicating a germinal center or post-germinal center B-lymphocyte origin. Clonal cytogenetic aberrations were found in 5 of 6 cases, with 2 clones bearing isochromosome 17q that resulted in loss of p53 and 2 other clones with 7q abnormalities. By the presence of absolute lymphocytosis, this series differs from MBL cases identified by sensitive flow cytometry in normal populations. The phenotypic profiles are distinct from that of benign CLL. We suggest these CD5-B-cell lymphocytosis cases may represent an intermediate condition between covert clonal expansions and overt malignancy.
    American Journal of Clinical Pathology 09/2007; 128(2):333-8. · 2.88 Impact Factor
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    Chen Wang, Dominick Amato
    British Journal of Haematology 07/2007; 137(6):489. · 4.94 Impact Factor
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    ABSTRACT: Polycythemia vera (PV), an acquired, chronic, clonal disorder arising in a multipotential hematopoietic progenitor cell, is characterized by hyperplasia of three major myeloid lineages, with a pronounced increase in cells of the erythroid lineage. Erythroid progenitor cells in PV are strikingly hypersensitive to insulin-like growth factor-I (IGF-I); this effect is specific and is mediated through the IGF-I receptor. To investigate the possibility that in PV the increase in number of erythroid progenitors and their hypersensitivity to IGF-I result from a defect in negative regulation of cytokine activity, we examined the expression of members of the SOCS gene family. Circulating mononuclear cells, grown in serum-free methylcellulose medium in the presence of IGF-I, produced BFU-E-derived colonies whose cells revealed a reduction of SOCS-2 and SOCS-3 expression in PV only. Overexpression of these genes in transfected PV cells reduced their erythroid overgrowth and IGF-I hypersensitivity. We hypothesize that a defect in expression of SOCS-2 and SOCS-3 genes may be crucial for the IGF-I hypersensitivity and progressive increase in erythroid cell population size characteristic of PV.
    Leukemia and Lymphoma 02/2007; 48(1):134-46. · 2.61 Impact Factor
  • Chen Wang, Dominick Amato
    American Journal of Hematology 12/2004; 77(3):311-2. · 4.00 Impact Factor
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    ABSTRACT: To report 2 cases of acute tumor lysis syndrome (ATLS) associated with hydroxyurea treatment. A 79-year-old woman diagnosed with chronic lymphocytic leukemia presented with an acute blastic transformation. She was promptly hydrated, started on allopurinol, and treated with hydroxyurea. About 24 hours later, her biochemistry panel showed parameters consistent with ATLS when compared with pretreatment levels. The second case was a 76-year-old man newly diagnosed with acute myeloid leukemia presenting with high blast fraction. He was given appropriate hydration and allopurinol prophylaxis, and was started on high-dose hydroxyurea treatment. He became symptomatic after 12 hours and results of his blood work were consistent with ATLS. ATLS is a well-known metabolic disturbance that occurs after cell destruction of rapidly growing tumors. In standard doses, hydroxyurea leads to cell death in the S phase and is not thought to cause significant cell lysis. However, in large doses, it possibly acts by a different mechanism and had a direct cytolytic effect associated with ATLS in our patients. Although ATLS caused by hydroxyurea appears to be rare, patients at risk should be closely monitored for this complication. An objective causality assessment using the Naranjo probability scale revealed that the adverse drug reaction was probable between ATLS and hydroxyurea therapy in these 2 patients.
    Annals of Pharmacotherapy 06/2003; 37(5):675-8. · 2.57 Impact Factor
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    ABSTRACT: Chronic lymphocytic leukemia (CLL) is recognized as a unique lymphoproliferative disorder of CD5(+) B cells. However, many published series of CLL included a subgroup of CD5(-) cases. CD5(-) B cell CLL is a topic of controversy and its nature and true incidence remain unclear. We in this study performed a retrospective analysis of a total of 128 consecutive patients with a diagnosis of CLL and available immunophenotypic record. Of these, 14 cases were previously considered CD5(-) CLL. From a further analysis of clinical, hematological and immunophenotypic results, we have reclassified seven of the patients as having weak or dim expression of CD5 and four patients as being monoclonal B lymphocytosis of undetermined significance (MLUS). The remaining three cases had clinical and morphological features consistent with prolymphocytic leukemia (PLL) or mixed CLL/PLL. Our results suggest that the CD5(-) phenotype probably does not qualify for CLL. Previous CD5(-) CLL may include false negatives due to heterogeneity of the intensity of CD5 expression, CD5(-) MLUS and variant CLL; the latter likely represents CLL in transformation. All the patients with MLUS were found to have a mild and non-progressing lymphocytosis with CD5(-) phenotype. These features may be used to differentiate them from CLL.
    Leukemia Research 01/2003; 26(12):1125-9. · 2.76 Impact Factor
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    Chen Wang, Dominick Amato, Bernard Fernandes
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    ABSTRACT: Monoclonal B lymphocytosis of undetermined significance (MLUS) is a benign condition of clonal lymphocytosis. Because of its clonal small lymphocytes and indolent clinical course, MLUS resembles and may be indistinguishable from an early stage of chronic lymphocytic leukemia (CLL). In this study we characterized the immunophenotype of MLUS. The clonal B lymphocytes from three patients of typical MLUS were shown to be CD5(-) and CD23(-) phenotype. Their immunophenotypic features remained unchanged during the clinical course. The results indicate a distinct immunophenotype of MLUS that can be useful for its diagnosis and differentiation from CLL.
    American Journal of Hematology 03/2002; 69(2):147-9. · 4.00 Impact Factor
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    C Wang, D Amato, B Fernandes
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    ABSTRACT: Gelatinous marrow transformation is characterized by marrow hypoplasia, fat atrophy, and gelatinous material deposition, and usually develops as a hematologic complication of chronic wasting disorders. Most of the cases associated with severe nutritional deficiency were seen in anorexia nervosa due to a depletion of protein or fat. This report describes a case of gelatinous transformation attributed to a specific restriction of carbohydrates in diet. The hematologic deficiency was eventually recovered after the patient resumed a regular starch-containing diet. This brief report illustrates the potential side effect of the compulsive dietary behavior on the hematologic system.
    American Journal of Hematology 10/2001; 68(1):58-9. · 4.00 Impact Factor

Publication Stats

240 Citations
94.95 Total Impact Points


  • 2007–2014
    • Mount Sinai Hospital, Toronto
      Toronto, Ontario, Canada
  • 2000–2012
    • University of Toronto
      • • Mount Sinai Hospital
      • • Department of Medicine
      • • Faculty of Medicine
      • • Department of Laboratory Medicine and Pathobiology
      • • Division of Anatomy
      Toronto, Ontario, Canada