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Manuela Germeshausen - One of the best experts on this subject based on the ideXlab platform.
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Congenital Amegakaryocytic Thrombocytopenia not a single disease
Best Practice & Research Clinical Haematology, 2021Co-Authors: Manuela Germeshausen, Matthias BallmaierAbstract:Congenital Amegakaryocytic Thrombocytopenia (CAMT) is a rare inherited bone marrow failure syndrome (IBMFS) that is characterized by severe Thrombocytopenia at birth due to ineffective megakaryopoiesis and development towards aplastic anemia during the first years of life. CAMT is not a single monogenetic disorder; rather, many descriptions of CAMT include different entities with different etiologies. CAMT in a narrow sense, which is primarily restricted to the hematopoietic system, is caused mainly by mutations in the gene for the thrombopoietin receptor (MPL), sometimes in the gene for its ligand (THPO). CAMT in association with radio-ulnar synostosis, which is not always clinically apparent, is mostly caused by mutations in MECOM, rarely in HOXA11. Patients affected by other IBMFS - especially Fanconi anemia or dyskeratosis congenita - may be misdiagnosed as having CAMT when they lack typical disease features of these syndromes or have only mild symptoms. This article reviews scientific and clinical aspects of the various disorders associated with the term "CAMT" with a main focus on the disease caused by mutations in the MPL gene.
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camt mpl Congenital Amegakaryocytic Thrombocytopenia caused by mpl mutations heterogeneity of a monogenic disorder comprehensive analysis of 56 patients
Haematologica, 2020Co-Authors: Manuela Germeshausen, Matthias BallmaierAbstract:Congenital Amegakaryocytic Thrombocytopenia caused by deleterious homozygous or compound heterozygous mutations in MPL (CAMT-MPL) is a rare inherited bone marrow failure syndrome presenting as an isolated Thrombocytopenia at birth progressing to pancytopenia due to exhaustion of hematopoietic progenitors. The analysis of samples and clinical data from a large cohort of 56 patients with CAMT-MPL resulted in a detailed description of the clinical picture and reliable genotype-phenotype correlations for this rare disease. We extended the spectrum of CAMT causing MPL mutations regarding number (17 novel mutations) and impact. The clinical courses showed a great variability with respect to the severity of Thrombocytopenia, the development of pancytopenia and the consequences from bleedings. The most severe clinical problems were (1) intracranial bleedings pre- and perinatally and the resulting long-term consequences, and (2) the development of aplastic anemia in the later course of the disease. An important and new finding was that Thrombocytopenia was not detected at birth in a quarter of the patients. The rate of non-hematological abnormalities in CAMT-MPL was higher than described so far. Most of the anomalies were related to the head region (brain anomalies, ocular and orbital anomalies) and consequences of intracranial bleedings. The present study demonstrates a higher variability of clinical courses than described so far and has important implications on diagnosis and therapy. The diagnosis CAMT-MPL has to be considered even for those patients who are inconspicuous in the first months of life or show somatic anomalies typical for other inherited bone marrow failure syndromes.
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mecom associated syndrome a heterogeneous inherited bone marrow failure syndrome with Amegakaryocytic Thrombocytopenia
Blood Advances, 2018Co-Authors: Manuela Germeshausen, Phil J Ancliff, Jaime Estrada, Markus Metzler, Eva Ponstingl, Horst Rutschle, Dirk Schwabe, Richard H Scott, Sule Unal, Angela WawerAbstract:Heterozygous mutations in MECOM (MDS1 and EVI1 complex locus) have been reported to be causative of a rare association of Congenital Amegakaryocytic Thrombocytopenia and radioulnar synostosis. Here we report on 12 patients with Congenital hypomegakaryocytic Thrombocytopenia caused by MECOM mutations (including 10 novel mutations). The mutations affected different functional domains of the EVI1 protein. The spectrum of phenotypes was much broader than initially reported for the first 3 patients; we found familial as well as sporadic cases, and the clinical spectrum ranged from isolated radioulnar synostosis with no or mild hematological involvement to severe bone marrow failure without obvious skeletal abnormality. The clinical picture included radioulnar synostosis, bone marrow failure, clinodactyly, cardiac and renal malformations, B-cell deficiency, and presenile hearing loss. No single clinical manifestation was detected in all patients affected by MECOM mutations. Radioulnar synostosis and B-cell deficiency were observed only in patients with mutations affecting a short region in the C-terminal zinc finger domain of EVI1. We propose the term MECOM-associated syndrome for this heterogeneous hereditary disease and inclusion of MECOM sequencing in the diagnostic workup of Congenital bone marrow failure.
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Congenital Amegakaryocytic Thrombocytopenia camt presenting as severe pancytopenia in the first month of life
Pediatric Blood & Cancer, 2013Co-Authors: Michael T Stoddart, Manuela Germeshausen, Matthias Ballmaier, Philip Connor, Colin G StewardAbstract:Congenital Amegakaryocytic Thrombocytopenia (CAMT) is characterised by neonatal Thrombocytopenia, with reduced or absent bone marrow megakaryocytes, leading eventually to pancytopenia. The mean age for progression to bone marrow failure is four years, with the earliest reported being six months. We describe a CAMT patient with compound heterozygous mutations of the causative MPL gene (one being a previously unreported splice site mutation in intron 11) who developed pancytopenia within the first month of life. This report emphasises the importance of considering CAMT in the differential diagnosis of Congenital aplastic anaemia or idiopathic aplastic anaemia in babies.
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Congenital Amegakaryocytic Thrombocytopenia clinical presentation diagnosis and treatment
Seminars in Thrombosis and Hemostasis, 2011Co-Authors: Matthias Ballmaier, Manuela GermeshausenAbstract:Congenital Amegakaryocytic Thrombocytopenia (CAMT, MIM #604498) is a rare inherited bone marrow failure syndrome presenting as isolated hypomegakaryocytic Thrombocytopenia at birth without other characteristic physical anomalies. Most of the patients develop a severe aplastic anemia and trilineage cytopenia during the first years of life and hematopoietic stem cell transplantation is the only curative treatment. In most of the cases the disease is caused by homozygous or compound heterozygous mutations in the gene MPL encoding the receptor for the hematopoietic growth factor thrombopoietin. The present review summarizes clinical and laboratory data for 96 patients with CAMT, reported since 1990.
Matthias Ballmaier - One of the best experts on this subject based on the ideXlab platform.
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Congenital Amegakaryocytic Thrombocytopenia not a single disease
Best Practice & Research Clinical Haematology, 2021Co-Authors: Manuela Germeshausen, Matthias BallmaierAbstract:Congenital Amegakaryocytic Thrombocytopenia (CAMT) is a rare inherited bone marrow failure syndrome (IBMFS) that is characterized by severe Thrombocytopenia at birth due to ineffective megakaryopoiesis and development towards aplastic anemia during the first years of life. CAMT is not a single monogenetic disorder; rather, many descriptions of CAMT include different entities with different etiologies. CAMT in a narrow sense, which is primarily restricted to the hematopoietic system, is caused mainly by mutations in the gene for the thrombopoietin receptor (MPL), sometimes in the gene for its ligand (THPO). CAMT in association with radio-ulnar synostosis, which is not always clinically apparent, is mostly caused by mutations in MECOM, rarely in HOXA11. Patients affected by other IBMFS - especially Fanconi anemia or dyskeratosis congenita - may be misdiagnosed as having CAMT when they lack typical disease features of these syndromes or have only mild symptoms. This article reviews scientific and clinical aspects of the various disorders associated with the term "CAMT" with a main focus on the disease caused by mutations in the MPL gene.
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camt mpl Congenital Amegakaryocytic Thrombocytopenia caused by mpl mutations heterogeneity of a monogenic disorder comprehensive analysis of 56 patients
Haematologica, 2020Co-Authors: Manuela Germeshausen, Matthias BallmaierAbstract:Congenital Amegakaryocytic Thrombocytopenia caused by deleterious homozygous or compound heterozygous mutations in MPL (CAMT-MPL) is a rare inherited bone marrow failure syndrome presenting as an isolated Thrombocytopenia at birth progressing to pancytopenia due to exhaustion of hematopoietic progenitors. The analysis of samples and clinical data from a large cohort of 56 patients with CAMT-MPL resulted in a detailed description of the clinical picture and reliable genotype-phenotype correlations for this rare disease. We extended the spectrum of CAMT causing MPL mutations regarding number (17 novel mutations) and impact. The clinical courses showed a great variability with respect to the severity of Thrombocytopenia, the development of pancytopenia and the consequences from bleedings. The most severe clinical problems were (1) intracranial bleedings pre- and perinatally and the resulting long-term consequences, and (2) the development of aplastic anemia in the later course of the disease. An important and new finding was that Thrombocytopenia was not detected at birth in a quarter of the patients. The rate of non-hematological abnormalities in CAMT-MPL was higher than described so far. Most of the anomalies were related to the head region (brain anomalies, ocular and orbital anomalies) and consequences of intracranial bleedings. The present study demonstrates a higher variability of clinical courses than described so far and has important implications on diagnosis and therapy. The diagnosis CAMT-MPL has to be considered even for those patients who are inconspicuous in the first months of life or show somatic anomalies typical for other inherited bone marrow failure syndromes.
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Congenital Amegakaryocytic Thrombocytopenia camt presenting as severe pancytopenia in the first month of life
Pediatric Blood & Cancer, 2013Co-Authors: Michael T Stoddart, Manuela Germeshausen, Matthias Ballmaier, Philip Connor, Colin G StewardAbstract:Congenital Amegakaryocytic Thrombocytopenia (CAMT) is characterised by neonatal Thrombocytopenia, with reduced or absent bone marrow megakaryocytes, leading eventually to pancytopenia. The mean age for progression to bone marrow failure is four years, with the earliest reported being six months. We describe a CAMT patient with compound heterozygous mutations of the causative MPL gene (one being a previously unreported splice site mutation in intron 11) who developed pancytopenia within the first month of life. This report emphasises the importance of considering CAMT in the differential diagnosis of Congenital aplastic anaemia or idiopathic aplastic anaemia in babies.
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Congenital Amegakaryocytic Thrombocytopenia clinical presentation diagnosis and treatment
Seminars in Thrombosis and Hemostasis, 2011Co-Authors: Matthias Ballmaier, Manuela GermeshausenAbstract:Congenital Amegakaryocytic Thrombocytopenia (CAMT, MIM #604498) is a rare inherited bone marrow failure syndrome presenting as isolated hypomegakaryocytic Thrombocytopenia at birth without other characteristic physical anomalies. Most of the patients develop a severe aplastic anemia and trilineage cytopenia during the first years of life and hematopoietic stem cell transplantation is the only curative treatment. In most of the cases the disease is caused by homozygous or compound heterozygous mutations in the gene MPL encoding the receptor for the hematopoietic growth factor thrombopoietin. The present review summarizes clinical and laboratory data for 96 patients with CAMT, reported since 1990.
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advances in the understanding of Congenital Amegakaryocytic Thrombocytopenia
British Journal of Haematology, 2009Co-Authors: Matthias Ballmaier, Manuela GermeshausenAbstract:Congenital Amegakaryocytic Thrombocytopenia (MIM #604498) is an extremely rare inherited bone marrow failure syndrome, usually presenting as a severe Thrombocytopenia at birth due to ineffective megakaryocytopoiesis and no characteristic physical anomalies. Usually the isolated Thrombocytopenia progresses to pancytopenia during the first years of life. The only curative therapy to date is haematopoietic stem cell transplantation. Most of the cases of Congenital Amegakaryocytic Thrombocytopenia are caused by defective expression or function of the thrombopoietin receptor due to homozygous or compound heterozygous mutations in the gene MPL. The essential roles of thrombopoietin as a lineage specific regulator of platelet production and as a regulator of haematopoietic stem cell function are reflected in the haematological defects seen in affected individuals.
Franco Locatelli - One of the best experts on this subject based on the ideXlab platform.
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Adoptive immunotherapy with antigen-specific T cells during extracorporeal membrane oxygenation (ECMO) for adenovirus-related respiratory failure in a child given haploidentical stem cell transplantation
Pediatric Blood & Cancer, 2013Co-Authors: Matteo Di Nardo, Giuseppina Li Pira, Antonio Amodeo, Corrado Cecchetti, Ezio Giorda, Stefano Ceccarelli, Letizia Pomponia Brescia, Nicola Pirozzi, Sergio Rutella, Franco LocatelliAbstract:We report on the successful infusion of human adenovirus (HAdV)-specific T cells in a child with Congenital Amegakaryocytic Thrombocytopenia, given T-cell-depleted hematopoietic stem cell transplantation (HSCT) from the HLA-haploidentical mother during extracorporeal membrane oxygenation (ECMO) for severe HAdV-related respiratory failure. Donor-derived, interferon (IFN)-γ-secreting HAdV-specific T cells were enriched using the cytokine capture assay, after in vitro stimulation with overlapping peptides from the immunodominant HAdV5 hexon protein. Two weeks after T-cell transfer, viral load decreased and ECMO was discontinued. T-cell responses to HAdV antigens were documented after four weeks and were associated with viral clearance, immune reconstitution and clinical amelioration. Pediatr Blood Cancer 2014;61:376–379. © 2013 Wiley Periodicals, Inc.
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Outcomes after related and unrelated umbilical cord blood transplantation for hereditary bone marrow failure syndromes other than Fanconi anemia.
Haematologica, 2010Co-Authors: Renata Bizzetto, Franco Locatelli, Carmen Bonfim, Vanderson Rocha, Gérard Socié, K. W. Chan, Oscar Ramirez, Joel Stein, Samir Nabhan, Eliana C.m. MirandaAbstract:Background Allogeneic stem cell transplantation is the only curative option for patients with hereditary bone marrow failure syndromes. Umbilical cord blood is an alternative source of stem cells for allogeneic transplantation. Design and Methods This multicenter, retrospective study is based on data reported to the Eurocord Registry about patients with hereditary bone marrow failure syndrome who underwent umbilical cord blood transplantation. Results Sixty-four patients with hereditary bone marrow failure syndromes were transplanted from related (n=20) or unrelated donors (n=44). Diagnoses were Diamond-Blackfan anemia (21 patients), Congenital Amegakaryocytic Thrombocytopenia (16 patients), dyskeratosis congenita (8 patients), Shwachman-Diamond syndrome (2 patients), severe Congenital neutropenia (16 patients) and unclassified (1 patient). In the group of patients who received grafts from related donors, all patients but one received an HLA-matched sibling transplant. The median number of total nucleated cells infused was 5×107/kg. The cumulative incidence of neutrophil recovery at 60 days was 95%. Two patients had grade II–IV acute graft- versus -host disease, while the 2-year cumulative incidence of chronic graft- versus -host disease was 11%. The 3-year overall survival rate was 95%. In the group of patients who received grafts from unrelated donors, 86% had HLA-mismatched grafts and three received two umbilical cord blood units. The median number of total nucleated cells infused was 6.1×107/kg. The cumulative incidence of neutrophil recovery at day 60 in this group was 55%. The 100-day cumulative incidence of grade II–IV acute graft- versus -host disease was 24%, while the 2-year cumulative incidence of chronic graft- versus -host disease was 53%. The 3-year overall survival rate was 61%; better overall survival was associated with age less than 5 years ( P =0.01) and 6.1×107/kg or more total nucleated cells infused ( P =0.05). Conclusions In patients with hereditary bone marrow failure syndromes, related umbilical cord blood transplantation is associated with excellent outcomes while increasing cell dose and better HLA matching might provide better results in unrelated umbilical cord blood transplantation.
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Congenital Amegakaryocytic Thrombocytopenia clinical and biological consequences of five novel mutations
Haematologica, 2007Co-Authors: Anna Savoia, Franco Locatelli, Carlo Dufour, Patrizia Noris, Chiara Ambaglio, Vittorio Rosti, Marco Zecca, Simona Ferrari, Filomena Di Bari, Anna CorcioneAbstract:Background and Objectives Congenital Amegakaryocytic Thrombocytopenia (CAMT) is a rare, autosomal recessive disorder induced by mutations of the gene coding for thrombopoietin (TPO) receptor (c-MPL). Patients initially present with isolated Thrombocytopenia that subsequently progresses into pancytopenia. Although the mechanisms leading to aplasia are unknown, the age of onset has been reported to depend on the severity of the c-MPL functional defect. To improve our knowledge in this field, we studied clinical and biological features of five new patients. Design and Methods We diagnosed five CAMT patients, identified c-MPL mutations, including five novel alterations and investigated relationships between mutations and their clinical-biological consequences. Results In all cases, platelet c-MPL and bone marrow colonies were reduced, while serum TPO levels were elevated. We also documented that the percentage of bone marrow cells expressing tumor necrosis factor-α and interferon-γ was increased during pancytopenia as compared to controls, suggesting that, as in other bone marrow failure diseases, these inhibitory cytokines contributed to the pancytopenia. Contrary to previously published data, we found no evidence of correlations between different types of mutations and the clinical course. Interpretation and Conclusions These results suggest that therapies, such as hematopoietic stem cell transplantation, which are potentially curative although associated with a risk of treatment-related mortality, should not be postponed even in those CAMT patients whose c-MPL mutations might predict residual activity of the TPO receptor.
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compound heterozygosity for two different amino acid substitution mutations in the thrombopoietin receptor c mpl gene in Congenital Amegakaryocytic Thrombocytopenia camt
Human Genetics, 2000Co-Authors: Roberto Tonelli, Franco Locatelli, Anna Lisa Scardovi, Andrea Pession, Pierluigi Strippoli, Laura Bonsi, Lorenza Vitale, Arcangelo Prete, Gian Paolo Bagnara, G PaolucciAbstract:Congenital Amegakaryocytic Thrombocytopenia (CAMT) without physical anomalies is a rare disease, presenting isolated Thrombocytopenia and megakaryocytopenia in infancy, which can evolve into aplastic anemia and leukemia. Recently, two heterozygous truncating mutations of the thrombopoietin (TPO) receptor MPL, coded by the c-mpl gene, were identified in a 10-year-old Japanese patient with CAMT transmitted in an autosomal recessive manner. Here, we report for the first time two different MPL amino-acid substitutions in a 2-year-old Italian boy with CAMT and compound heterozygosis for two c-mpl point mutations. C-to-T transitions were detected on exons 5 and 12 at the 769 and 1904 cDNA nucleotide positions, respectively. The mutation in exon 5 substitutes an arginine with a cysteine (R257C) in the extracellular domain, 11 amino acids distant from the WSXWS motif conserved in the cytokine-receptor superfamily. The mutation in exon 12 substitutes a proline with a leucine (P635L) in the last amino acid of the C-terminal intracellular domain, responsible for signal transduction. As in the Japanese family, the mutations were both transmitted from the parents. TPO plasma levels were highly increased in the patient. The patient's 7-year-old brother, who was a candidate donor for allografting, turned out to be an asymptomatic heterozygous carrier of P635L and showed defective megakaryocyte colony formation from bone-marrow progenitor cells. The present study provides important confirmation that CAMT can be associated with c-mpl mutations.
Eliana C.m. Miranda - One of the best experts on this subject based on the ideXlab platform.
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Outcomes after related and unrelated umbilical cord blood transplantation for hereditary bone marrow failure syndromes other than Fanconi anemia.
Haematologica, 2010Co-Authors: Renata Bizzetto, Franco Locatelli, Carmen Bonfim, Vanderson Rocha, Gérard Socié, K. W. Chan, Oscar Ramirez, Joel Stein, Samir Nabhan, Eliana C.m. MirandaAbstract:Background Allogeneic stem cell transplantation is the only curative option for patients with hereditary bone marrow failure syndromes. Umbilical cord blood is an alternative source of stem cells for allogeneic transplantation. Design and Methods This multicenter, retrospective study is based on data reported to the Eurocord Registry about patients with hereditary bone marrow failure syndrome who underwent umbilical cord blood transplantation. Results Sixty-four patients with hereditary bone marrow failure syndromes were transplanted from related (n=20) or unrelated donors (n=44). Diagnoses were Diamond-Blackfan anemia (21 patients), Congenital Amegakaryocytic Thrombocytopenia (16 patients), dyskeratosis congenita (8 patients), Shwachman-Diamond syndrome (2 patients), severe Congenital neutropenia (16 patients) and unclassified (1 patient). In the group of patients who received grafts from related donors, all patients but one received an HLA-matched sibling transplant. The median number of total nucleated cells infused was 5×107/kg. The cumulative incidence of neutrophil recovery at 60 days was 95%. Two patients had grade II–IV acute graft- versus -host disease, while the 2-year cumulative incidence of chronic graft- versus -host disease was 11%. The 3-year overall survival rate was 95%. In the group of patients who received grafts from unrelated donors, 86% had HLA-mismatched grafts and three received two umbilical cord blood units. The median number of total nucleated cells infused was 6.1×107/kg. The cumulative incidence of neutrophil recovery at day 60 in this group was 55%. The 100-day cumulative incidence of grade II–IV acute graft- versus -host disease was 24%, while the 2-year cumulative incidence of chronic graft- versus -host disease was 53%. The 3-year overall survival rate was 61%; better overall survival was associated with age less than 5 years ( P =0.01) and 6.1×107/kg or more total nucleated cells infused ( P =0.05). Conclusions In patients with hereditary bone marrow failure syndromes, related umbilical cord blood transplantation is associated with excellent outcomes while increasing cell dose and better HLA matching might provide better results in unrelated umbilical cord blood transplantation.
Amy E Geddis - One of the best experts on this subject based on the ideXlab platform.
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Congenital Amegakaryocytic Thrombocytopenia
Pediatric Blood & Cancer, 2011Co-Authors: Amy E GeddisAbstract:Congenital Amegakaryocytic Thrombocytopenia (CAMT) is clinically characterized by Thrombocytopenia presenting at birth in a child without Congenital or skeletal malformations, reduced or absent bone marrow megakaryocytes, and eventual progression to bone marrow failure. Molecular studies in most cases confirm homozygous or compound heterozygous mutations in the thrombopoietin receptor c-Mpl. In addition to the clinical importance of recognizing this disorder, characterization of mutations identified in patients with CAMT has led to insights into thrombopoietin receptor structure and function. This review will summarize the diagnosis, pathophysiology, and management of CAMT.
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f104s c mpl responds to a transmembrane domain binding thrombopoietin receptor agonist proof of concept that selected receptor mutations in Congenital Amegakaryocytic Thrombocytopenia can be stimulated with alternative thrombopoietic agents
Experimental Hematology, 2010Co-Authors: Norma E Fox, Rose Chen, Jihyang Lim, Amy E GeddisAbstract:Objective To determine whether specific c-Mpl mutations might respond to thrombopoietin receptor agonists. Materials and Methods We created cell line models of type II c-Mpl mutations identified in Congenital Amegakaryocytic Thrombocytopenia. We selected F104S c-Mpl for further study because it exhibited surface expression of the receptor. We measured proliferation of cell lines expressing wild-type or F104S c-Mpl in response to thrombopoetin receptor agonists targeting the extracellular (m-AMP4) or transmembrane (LGD-4665) domains of the receptor by 1-methyltetrazole-5-thiol assay. We measured thrombopoietin binding to the mutant receptor using an in vitro thrombopoietin uptake assay and identified F104 as a potentially critical residue for the interaction between the receptor and its ligand by aligning thrombopoietin and erythropoietin receptors from multiple species. Results Cells expressing F104S c-Mpl proliferated in response to LGD-4665, but not thrombopoietin or m-AMP4. Compared to thrombopoietin, LGD-4665 stimulates signaling with delayed kinetics in both wild-type and F104S c-Mpl−expressing cells. Although F104S c-Mpl is expressed on the cell surface in our BaF3 cell line model, the mutant receptor does not bind thrombopoietin. Comparison to the erythropoietin receptor suggests that F104 engages in hydrogen-bonding interactions that are critical for binding to thrombopoietin. Conclusions These findings suggest that a small subset of patients with Congenital Amegakaryocytic Thrombocytopenia might respond to treatment with thrombopoietin receptor agonists, but that responsiveness will depend on the type of mutation and agonist used. We postulate that F104 is critical for thrombopoietin binding. The kinetics of signaling in response to a transmembrane domain−binding agonist are delayed in comparison to thrombopoietin.
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Congenital Amegakaryocytic Thrombocytopenia and Thrombocytopenia with absent radii
Hematology-oncology Clinics of North America, 2009Co-Authors: Amy E GeddisAbstract:Thrombocytopenia in the neonate is most commonly acquired but may in rare cases be due to a Congenital disorder. This review will summarize the diagnosis, pathophysiology and management of two Congenital inherited platelet disorders that present in the newborn period, Congenital Amegakaryocytic Thrombocytopenia (CAMT) and Thrombocytopenia with absent radii (TAR).
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compound heterozygous c mpl mutations in a child with Congenital Amegakaryocytic Thrombocytopenia functional characterization and a review of the literature
Experimental Hematology, 2009Co-Authors: Norma E Fox, Rose Chen, Ian S Hitchcock, Jennifer Keatesbaleeiro, Haydar Frangoul, Amy E GeddisAbstract:Objective To genetically and functionally characterize mutations of c-Mpl that lead to Thrombocytopenia in a child with Congenital Amegakaryocytic Thrombocytopenia. Materials and Methods We identified two c-Mpl mutations in a child with clinical features of Congenital Amegakaryocytic Thrombocytopenia, one a previously described mutation in the extracellular domain (R102P) and the other a novel mutation leading to truncation of the receptor after the box 1 homology domain (541Stop). Cell line models were created to examine the ability of the mutant receptors to signal in response to thrombopoietin and thrombopoietin-like agonists. Results Data from cell-line models indicate that c-Mpl R102P does not support significant signaling in response to thrombopoietin due to impaired trafficking of the mutant receptor to the cell surface. Alternative thrombopoietic agents do not circumvent this block to signaling, likely due to the inaccessibility of the receptor. In addition, previous data indicate that c-Mpl 541Stop does not support intracellular signaling due to the loss of critical intracellular domains. Conclusions This case demonstrates two different mechanisms by which c-Mpl mutations can impair thrombopoietin signaling, and suggests that mutations in the extracellular domain will not be rescued by c-Mpl agonists if they interfere with normal receptor expression.
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Congenital Amegakaryocytic Thrombocytopenia in a thrombocytopenic child presenting without amegakaryocytosis
Blood, 2006Co-Authors: Amy E Geddis, Norma E Fox, Jennifer Keatesbaleeiro, Hung Nguyen, Haydar FrangoulAbstract:Abstract Congenital Amegakaryocytic Thrombocytopenia (CAMT) is an inherited bone marrow syndrome due mutation of the thrombopoietin receptor c-Mpl. Affected children present with Thrombocytopenia at birth and absence or severe reduction of megakaryocytes in the bone marrow and usually progress to complete bone marrow failure within the first decade of life. Mutations of c-Mpl have been classified as either type I mutations, in which the receptor has lost all activity, or type II mutations, in which the receptor retains some degree of function. Clinically, type II patients have a slightly delayed onset of bone marrow failure (mean age 48 months) compared to type I patients (22 months). Here we describe a girl with CAMT who had a clinical course similar to patients with type I mutations but without marked amegakaryocytosis at onset. The patient was born with intracranial hemorrhage due to severe Thrombocytopenia (platelets 17K), which was initially thought to be due to alloimmune Thrombocytopenia because of consistent platelet antigen typing studies and because the child responded to transfusion with her mother's platelets and not to random donor platelets. However, Thrombocytopenia persisted and she did not respond to immune directed therapies such as IVIG, prednisone or Rituximab, and after 14 months of age she began to develop neutropenia and anemia and by 24 months she had progressed to severe aplastic anemia. Bone marrow evaluation at 3 months showed trileage hematopoiesis with only mildly decreased megakaryocytes although they were noted to be small with hypolobulated nuclei. By 6 months of age, however, megakaryocytes appeared mildly decreased but were morphologically unremarkable and the marrow showed increased hematogones. At 24 months, marrow cellularity had decreased to 5% of normal with frank amegakaryocytosis. Sequencing of c-Mpl revealed two heterozygous mutations, one at Arg102Pro in the extracellular domain and the other one resulting in a stop codon at amino acid 541 in the intracellular domain. Arg102Pro is the most commonly occurring mutation reported in CAMT and is generally associated with type II disease. 541Stop is the first mutation reported in exon 11 and results in truncation of the receptor shortly after the box 1 homology domain. Previous in vitro studies involving the murine homolog of this mutation, which is missing all but the proximal 28 amino acids of the intracellular domain, demonstrated that it does not signal in response to thrombopoietin. This case illustrates the variation in clinical phenotype that can be seen in CAMT and the importance of gene sequencing for accurate diagnosis.