The Experts below are selected from a list of 327 Experts worldwide ranked by ideXlab platform
Marco Seri - One of the best experts on this subject based on the ideXlab platform.
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MYH9-Related Disease: May-Hegglin Anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome Are not Distinct Entities but Represent a Variable Expression of a Single Illness
Medicine, 2003Co-Authors: Marco Seri, Patrizia Noris, Alessandro Pecci, Roberto Cusano, S Gangarossa, Maria Savino, Filomena Di Bari, Emanuele Panza, Alessandra Nigro, Bianca RoccaAbstract:May-Hegglin anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome are autosomal dominant macrothrombocytopenias distinguished by different combinations of clinical and laboratory signs, such as sensorineural hearing loss, cataract, nephritis, and polymorphonuclear Dohle-like bodies. Mutations in the MYH9 gene encoding for the nonmuscle myosin heavy chain IIA (NMMHC-IIA) have been identified in all these Syndromes. To understand the role of the MYH9 mutations, we report the molecular defects in 12 new cases, which together with our previous works represent a cohort of 19 families. Since no genotype-phenotype correlation was established, we performed an accurate clinical and biochemical re-evaluation of patients. In addition to macrothrombocytopenia, an abnormal distribution of NMMHC-IIA within leukocytes was observed in all individuals, including those without Dohle-like bodies. Selective, high-tone hearing deficiency and cataract was diagnosed in 83% and 23%, respectively, of patients initially referred as having May-Hegglin anomaly or Sebastian Syndrome. Kidney abnormalities, such as hematuria and proteinuria, affected not only patients referred as Fechtner Syndrome and Epstein Syndrome but also those referred as May-Hegglin anomaly and Sebastian Syndrome. These findings allowed us to conclude that May-Hegglin anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome are not distinct entities but rather a single disorder with a continuous clinical spectrum varying from mild macrothrombocytopenia with leukocyte inclusions to a severe form complicated by hearing loss, cataracts, and renal failure. For this new nosologic entity, we propose the term "MHY9-related disease," which better interprets the recent knowledge in this field and identifies all patients at risk of developing renal, hearing, or visual defects.
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myh9 related disease may hegglin anomaly sebastian Syndrome Fechtner Syndrome and epstein Syndrome are not distinct entities but represent a variable expression of a single illness
Medicine, 2003Co-Authors: Marco Seri, Patrizia Noris, Alessandro Pecci, Roberto Cusano, S Gangarossa, Maria Savino, Filomena Di Bari, Emanuele Panza, Alessandra Nigro, Bianca RoccaAbstract:Abstract:May-Hegglin anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome are autosomal dominant macrothrombocytopenias distinguished by different combinations of clinical and laboratory signs, such as sensorineural hearing loss, cataract, nephritis, and polymorphonuclear Dohle-like
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genetics clinical and pathological features of glomerulonephrites associated with mutations of nonmuscle myosin iia Fechtner Syndrome
American Journal of Kidney Diseases, 2003Co-Authors: Gian Marco Ghiggeri, Alessandro Pecci, Gianluca Caridi, Marco Seri, S Gangarossa, Anna Savoia, Umberto Magrini, A Sessa, Roberta Romagnoli, Patrizia NorisAbstract:Abstract Background: Fechtner Syndrome (FTNS), also known as Alport-like Syndrome, is a rare inherited condition characterized by progressive nephritis, macrothrombocytopenia, Dohle-like leukocyte inclusions, deafness, and cataract. Although it recently was shown that FTNS derives from mutation of MYH9 , the gene for the heavy chain of nonmuscle myosin IIA (NMMHC-IIA), its pathophysiological characteristics remain unknown. Methods: We studied a large FTNS family in which 10 components carried a missense mutation of MYH9 determining the D1424H substitution. Results: All affected subjects presented with macrothrombocytopenia and leukocyte Dohle-like bodies consisting of macroaggregates of NMMHC-IIA, but only two subjects had major renal problems characterized by proteinuria and renal failure. Electron microscopy showed focal and segmental effacement of podocytes and loss of the interpodocyte slit diaphragm. Immunohistochemistry showed apical localization of NMMHC-IIA in tubular epithelia and less podocyte staining in the two patients, whereas it was diffuse in normal epithelia. Three patients presented with stable microhematuria, and another five patients had no renal lesions, although they carried the same mutation of MYH9 . Therefore, MYH9 mutation per se was responsible for platelet and leukocyte abnormalities, whereas additional predisposing conditions and/or environmental factors are necessary for nephropathy, cataract, and deafness. Looking at podocyte components conferring permselectivity properties to the kidney, we characterized the haplotype of podocin and found cosegregation of one specific allele in the two patients with nephrotic Syndrome, suggesting a relationship between podocin features and proteinuria. Conclusion: Our study indicates a major role for the NMMHC-IIA abnormality in the pathogenesis of leukocyte, platelet, and kidney defects in FTNS. The basic feature in all cases is aggregation and compartmentation of NMMHC-IIA. However, proteinuria and podocyte lesions are the hallmark of nephropathy in patients who develop renal failure, and podocin may have some function in this setting. Am J Kidney Dis 41:95-104. © 2003 by the National Kidney Foundation, Inc.
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immunocytochemistry for the heavy chain of the non muscle myosin iia as a diagnostic tool for myh9 related disorders
British Journal of Haematology, 2002Co-Authors: Alessandro Pecci, Saverio Sartore, Patrizia Noris, Gian Marco Ghiggeri, Marco Seri, S Gangarossa, Nicola Bizzaro, Anna Savoia, Rosangela Invernizzi, Carlo L. BalduiniAbstract:Summary. May–Hegglin anomaly (MHA), Sebastian Syndrome (SBS) and Fechtner Syndrome (FTNS) are autosomal-dominant macrothrombocytopenias with Dohle-like leucocyte inclusions. These diseases are due to mutations of the MHY9 gene, encoding the heavy chain of non-muscle myosin IIA (NMMHC-A). We investigated the NMMHC-A localization in blood cells from eight MHA, SBS or FTNS patients with known MYH9 mutations. All the patients showed an altered localization of NMMHC-A in granulocytes and platelets, suggesting that Dohle-like bodies are due to the aggregation of NMMHC-A in the cytoplasm. Therefore, immunocytochemistry for NMMHC-A is a simple and sensitive method to detect pathological phenotypes of granulocytes and platelets in the diagnosis of MYH9-related disorders.
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Epstein Syndrome: another renal disorder with mutations in the nonmuscle myosin heavy chain 9 gene
Human Genetics, 2002Co-Authors: Marco Seri, Roberto Cusano, Maria Savino, Domenico Bordo, Filomena Di Bari, Bianca Rocca, Ilaria Meloni, Pasi A. Koivisto, Martino Bolognesi, Gian Marco GhiggeriAbstract:Epstein Syndrome (EPTS) is an autosomal dominant disease characterized by nephritis, mild hearing loss, and thrombocytopenia with giant platelets. Renal and hearing abnormalities are indistinguishable from those observed in Fechtner Syndrome (FTNS), an Alport-like variant. EPTS macrothrombocytopenia is similar to that described in FTNS, May-Hegglin anomaly (MHA), and Sebastian Syndrome (SBS), three disorders caused by mutations in the nonmuscle heavy chain myosin IIA ( MYH9 ). Unlike FTNS, MHA, and SBS, EPTS does not show inclusion bodies in the leukocytes. The clinical features of EPTS and the chromosomal localization of the respective gene in the same region as MYH9 suggest that this disorder is allelic with the other giant platelet disorders. We identified a MYH9 missense mutation in two EPTS familial cases. In both families, an R702H substitution was found, probably inducing conformational changes to the myosin head. A different amino acid substitution at the same codon (R702C) has been previously identified in FTNS. On the basis of predictions from molecular modeling of the X-ray crystallographic structure of chick smooth muscle myosin, the mutated thiol reactive group of R702C may lead to intermolecular disulfide bridges, with the consequent formation of the inclusions typical of FTNS. On the contrary, the R702H mutation does not allow the protein to aggregate and thus to generate "Döhle-like" bodies, which are indeed absent in EPTS. In conclusion, our results extend the allelic heterogeneity of MYH9 mutations to another clinical Syndrome and contribute to the clarification of the pathogenesis of the various inherited giant platelet disorders.
Gian Marco Ghiggeri - One of the best experts on this subject based on the ideXlab platform.
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genetics clinical and pathological features of glomerulonephrites associated with mutations of nonmuscle myosin iia Fechtner Syndrome
American Journal of Kidney Diseases, 2003Co-Authors: Gian Marco Ghiggeri, Alessandro Pecci, Gianluca Caridi, Marco Seri, S Gangarossa, Anna Savoia, Umberto Magrini, A Sessa, Roberta Romagnoli, Patrizia NorisAbstract:Abstract Background: Fechtner Syndrome (FTNS), also known as Alport-like Syndrome, is a rare inherited condition characterized by progressive nephritis, macrothrombocytopenia, Dohle-like leukocyte inclusions, deafness, and cataract. Although it recently was shown that FTNS derives from mutation of MYH9 , the gene for the heavy chain of nonmuscle myosin IIA (NMMHC-IIA), its pathophysiological characteristics remain unknown. Methods: We studied a large FTNS family in which 10 components carried a missense mutation of MYH9 determining the D1424H substitution. Results: All affected subjects presented with macrothrombocytopenia and leukocyte Dohle-like bodies consisting of macroaggregates of NMMHC-IIA, but only two subjects had major renal problems characterized by proteinuria and renal failure. Electron microscopy showed focal and segmental effacement of podocytes and loss of the interpodocyte slit diaphragm. Immunohistochemistry showed apical localization of NMMHC-IIA in tubular epithelia and less podocyte staining in the two patients, whereas it was diffuse in normal epithelia. Three patients presented with stable microhematuria, and another five patients had no renal lesions, although they carried the same mutation of MYH9 . Therefore, MYH9 mutation per se was responsible for platelet and leukocyte abnormalities, whereas additional predisposing conditions and/or environmental factors are necessary for nephropathy, cataract, and deafness. Looking at podocyte components conferring permselectivity properties to the kidney, we characterized the haplotype of podocin and found cosegregation of one specific allele in the two patients with nephrotic Syndrome, suggesting a relationship between podocin features and proteinuria. Conclusion: Our study indicates a major role for the NMMHC-IIA abnormality in the pathogenesis of leukocyte, platelet, and kidney defects in FTNS. The basic feature in all cases is aggregation and compartmentation of NMMHC-IIA. However, proteinuria and podocyte lesions are the hallmark of nephropathy in patients who develop renal failure, and podocin may have some function in this setting. Am J Kidney Dis 41:95-104. © 2003 by the National Kidney Foundation, Inc.
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immunocytochemistry for the heavy chain of the non muscle myosin iia as a diagnostic tool for myh9 related disorders
British Journal of Haematology, 2002Co-Authors: Alessandro Pecci, Saverio Sartore, Patrizia Noris, Gian Marco Ghiggeri, Marco Seri, S Gangarossa, Nicola Bizzaro, Anna Savoia, Rosangela Invernizzi, Carlo L. BalduiniAbstract:Summary. May–Hegglin anomaly (MHA), Sebastian Syndrome (SBS) and Fechtner Syndrome (FTNS) are autosomal-dominant macrothrombocytopenias with Dohle-like leucocyte inclusions. These diseases are due to mutations of the MHY9 gene, encoding the heavy chain of non-muscle myosin IIA (NMMHC-A). We investigated the NMMHC-A localization in blood cells from eight MHA, SBS or FTNS patients with known MYH9 mutations. All the patients showed an altered localization of NMMHC-A in granulocytes and platelets, suggesting that Dohle-like bodies are due to the aggregation of NMMHC-A in the cytoplasm. Therefore, immunocytochemistry for NMMHC-A is a simple and sensitive method to detect pathological phenotypes of granulocytes and platelets in the diagnosis of MYH9-related disorders.
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Epstein Syndrome: another renal disorder with mutations in the nonmuscle myosin heavy chain 9 gene
Human Genetics, 2002Co-Authors: Marco Seri, Roberto Cusano, Maria Savino, Domenico Bordo, Filomena Di Bari, Bianca Rocca, Ilaria Meloni, Pasi A. Koivisto, Martino Bolognesi, Gian Marco GhiggeriAbstract:Epstein Syndrome (EPTS) is an autosomal dominant disease characterized by nephritis, mild hearing loss, and thrombocytopenia with giant platelets. Renal and hearing abnormalities are indistinguishable from those observed in Fechtner Syndrome (FTNS), an Alport-like variant. EPTS macrothrombocytopenia is similar to that described in FTNS, May-Hegglin anomaly (MHA), and Sebastian Syndrome (SBS), three disorders caused by mutations in the nonmuscle heavy chain myosin IIA ( MYH9 ). Unlike FTNS, MHA, and SBS, EPTS does not show inclusion bodies in the leukocytes. The clinical features of EPTS and the chromosomal localization of the respective gene in the same region as MYH9 suggest that this disorder is allelic with the other giant platelet disorders. We identified a MYH9 missense mutation in two EPTS familial cases. In both families, an R702H substitution was found, probably inducing conformational changes to the myosin head. A different amino acid substitution at the same codon (R702C) has been previously identified in FTNS. On the basis of predictions from molecular modeling of the X-ray crystallographic structure of chick smooth muscle myosin, the mutated thiol reactive group of R702C may lead to intermolecular disulfide bridges, with the consequent formation of the inclusions typical of FTNS. On the contrary, the R702H mutation does not allow the protein to aggregate and thus to generate "Döhle-like" bodies, which are indeed absent in EPTS. In conclusion, our results extend the allelic heterogeneity of MYH9 mutations to another clinical Syndrome and contribute to the clarification of the pathogenesis of the various inherited giant platelet disorders.
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Localisation of the gene responsible for Fechtner Syndrome in a region
European Journal of Human Genetics, 2000Co-Authors: Roberto Cusano, Gianluca Caridi, Gian Marco Ghiggeri, S Gangarossa, Roberto Ravazzolo, P Forabosco, G Russo, A Iolascon, Marco SeriAbstract:Fechtner Syndrome is an autosomal dominant disorder which has been thought to be a variant of Alport Syndrome. It is characterised by nephritis, sensorineural hearing loss and eye abnormalities, as well as by macrothrombocytopenia and polymorphonuclear inclusion bodies. Recently, the Fechtner Syndrome has been mapped in a 5.5 Mb region on the long arm of chromosome 22 by linkage analysis in an extended Israeli family. We describe here the genetic refinement of the Fechtner critical interval to a region less than 600 Kb by linkage analysis performed in a large Italian pedigree. The presence of several recombination events allowed the disease gene to be localised between markers D22S278 and D22S426, in a region containing only two non-recombinant markers, D22S1173 and D22S283. This interval, spanning
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localisation of the gene responsible for Fechtner Syndrome in a region 600 kb on 22q11 q13
European Journal of Human Genetics, 2000Co-Authors: Roberto Cusano, Gianluca Caridi, Gian Marco Ghiggeri, S Gangarossa, Roberto Ravazzolo, P Forabosco, G Russo, A Iolascon, Marco SeriAbstract:Fechtner Syndrome is an autosomal dominant disorder which has been thought to be a variant of Alport Syndrome. It is characterised by nephritis, sensorineural hearing loss and eye abnormalities, as well as by macrothrombocytopenia and polymorphonuclear inclusion bodies. Recently, the Fechtner Syndrome has been mapped in a 5.5 Mb region on the long arm of chromosome 22 by linkage analysis in an extended Israeli family. We describe here the genetic refinement of the Fechtner critical interval to a region less than 600 Kb by linkage analysis performed in a large Italian pedigree. The presence of several recombination events allowed the disease gene to be localised between markers D22S278 and D22S426, in a region containing only two non-recombinant markers, D22S1173 and D22S283. This interval, spanning <600 Kb on genomic DNA, has been entirely sequenced and contains six known and three putative genes.
S Gangarossa - One of the best experts on this subject based on the ideXlab platform.
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MYH9-Related Disease: May-Hegglin Anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome Are not Distinct Entities but Represent a Variable Expression of a Single Illness
Medicine, 2003Co-Authors: Marco Seri, Patrizia Noris, Alessandro Pecci, Roberto Cusano, S Gangarossa, Maria Savino, Filomena Di Bari, Emanuele Panza, Alessandra Nigro, Bianca RoccaAbstract:May-Hegglin anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome are autosomal dominant macrothrombocytopenias distinguished by different combinations of clinical and laboratory signs, such as sensorineural hearing loss, cataract, nephritis, and polymorphonuclear Dohle-like bodies. Mutations in the MYH9 gene encoding for the nonmuscle myosin heavy chain IIA (NMMHC-IIA) have been identified in all these Syndromes. To understand the role of the MYH9 mutations, we report the molecular defects in 12 new cases, which together with our previous works represent a cohort of 19 families. Since no genotype-phenotype correlation was established, we performed an accurate clinical and biochemical re-evaluation of patients. In addition to macrothrombocytopenia, an abnormal distribution of NMMHC-IIA within leukocytes was observed in all individuals, including those without Dohle-like bodies. Selective, high-tone hearing deficiency and cataract was diagnosed in 83% and 23%, respectively, of patients initially referred as having May-Hegglin anomaly or Sebastian Syndrome. Kidney abnormalities, such as hematuria and proteinuria, affected not only patients referred as Fechtner Syndrome and Epstein Syndrome but also those referred as May-Hegglin anomaly and Sebastian Syndrome. These findings allowed us to conclude that May-Hegglin anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome are not distinct entities but rather a single disorder with a continuous clinical spectrum varying from mild macrothrombocytopenia with leukocyte inclusions to a severe form complicated by hearing loss, cataracts, and renal failure. For this new nosologic entity, we propose the term "MHY9-related disease," which better interprets the recent knowledge in this field and identifies all patients at risk of developing renal, hearing, or visual defects.
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myh9 related disease may hegglin anomaly sebastian Syndrome Fechtner Syndrome and epstein Syndrome are not distinct entities but represent a variable expression of a single illness
Medicine, 2003Co-Authors: Marco Seri, Patrizia Noris, Alessandro Pecci, Roberto Cusano, S Gangarossa, Maria Savino, Filomena Di Bari, Emanuele Panza, Alessandra Nigro, Bianca RoccaAbstract:Abstract:May-Hegglin anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome are autosomal dominant macrothrombocytopenias distinguished by different combinations of clinical and laboratory signs, such as sensorineural hearing loss, cataract, nephritis, and polymorphonuclear Dohle-like
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genetics clinical and pathological features of glomerulonephrites associated with mutations of nonmuscle myosin iia Fechtner Syndrome
American Journal of Kidney Diseases, 2003Co-Authors: Gian Marco Ghiggeri, Alessandro Pecci, Gianluca Caridi, Marco Seri, S Gangarossa, Anna Savoia, Umberto Magrini, A Sessa, Roberta Romagnoli, Patrizia NorisAbstract:Abstract Background: Fechtner Syndrome (FTNS), also known as Alport-like Syndrome, is a rare inherited condition characterized by progressive nephritis, macrothrombocytopenia, Dohle-like leukocyte inclusions, deafness, and cataract. Although it recently was shown that FTNS derives from mutation of MYH9 , the gene for the heavy chain of nonmuscle myosin IIA (NMMHC-IIA), its pathophysiological characteristics remain unknown. Methods: We studied a large FTNS family in which 10 components carried a missense mutation of MYH9 determining the D1424H substitution. Results: All affected subjects presented with macrothrombocytopenia and leukocyte Dohle-like bodies consisting of macroaggregates of NMMHC-IIA, but only two subjects had major renal problems characterized by proteinuria and renal failure. Electron microscopy showed focal and segmental effacement of podocytes and loss of the interpodocyte slit diaphragm. Immunohistochemistry showed apical localization of NMMHC-IIA in tubular epithelia and less podocyte staining in the two patients, whereas it was diffuse in normal epithelia. Three patients presented with stable microhematuria, and another five patients had no renal lesions, although they carried the same mutation of MYH9 . Therefore, MYH9 mutation per se was responsible for platelet and leukocyte abnormalities, whereas additional predisposing conditions and/or environmental factors are necessary for nephropathy, cataract, and deafness. Looking at podocyte components conferring permselectivity properties to the kidney, we characterized the haplotype of podocin and found cosegregation of one specific allele in the two patients with nephrotic Syndrome, suggesting a relationship between podocin features and proteinuria. Conclusion: Our study indicates a major role for the NMMHC-IIA abnormality in the pathogenesis of leukocyte, platelet, and kidney defects in FTNS. The basic feature in all cases is aggregation and compartmentation of NMMHC-IIA. However, proteinuria and podocyte lesions are the hallmark of nephropathy in patients who develop renal failure, and podocin may have some function in this setting. Am J Kidney Dis 41:95-104. © 2003 by the National Kidney Foundation, Inc.
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immunocytochemistry for the heavy chain of the non muscle myosin iia as a diagnostic tool for myh9 related disorders
British Journal of Haematology, 2002Co-Authors: Alessandro Pecci, Saverio Sartore, Patrizia Noris, Gian Marco Ghiggeri, Marco Seri, S Gangarossa, Nicola Bizzaro, Anna Savoia, Rosangela Invernizzi, Carlo L. BalduiniAbstract:Summary. May–Hegglin anomaly (MHA), Sebastian Syndrome (SBS) and Fechtner Syndrome (FTNS) are autosomal-dominant macrothrombocytopenias with Dohle-like leucocyte inclusions. These diseases are due to mutations of the MHY9 gene, encoding the heavy chain of non-muscle myosin IIA (NMMHC-A). We investigated the NMMHC-A localization in blood cells from eight MHA, SBS or FTNS patients with known MYH9 mutations. All the patients showed an altered localization of NMMHC-A in granulocytes and platelets, suggesting that Dohle-like bodies are due to the aggregation of NMMHC-A in the cytoplasm. Therefore, immunocytochemistry for NMMHC-A is a simple and sensitive method to detect pathological phenotypes of granulocytes and platelets in the diagnosis of MYH9-related disorders.
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Localisation of the gene responsible for Fechtner Syndrome in a region
European Journal of Human Genetics, 2000Co-Authors: Roberto Cusano, Gianluca Caridi, Gian Marco Ghiggeri, S Gangarossa, Roberto Ravazzolo, P Forabosco, G Russo, A Iolascon, Marco SeriAbstract:Fechtner Syndrome is an autosomal dominant disorder which has been thought to be a variant of Alport Syndrome. It is characterised by nephritis, sensorineural hearing loss and eye abnormalities, as well as by macrothrombocytopenia and polymorphonuclear inclusion bodies. Recently, the Fechtner Syndrome has been mapped in a 5.5 Mb region on the long arm of chromosome 22 by linkage analysis in an extended Israeli family. We describe here the genetic refinement of the Fechtner critical interval to a region less than 600 Kb by linkage analysis performed in a large Italian pedigree. The presence of several recombination events allowed the disease gene to be localised between markers D22S278 and D22S426, in a region containing only two non-recombinant markers, D22S1173 and D22S283. This interval, spanning
Bianca Rocca - One of the best experts on this subject based on the ideXlab platform.
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MYH9-Related Disease: May-Hegglin Anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome Are not Distinct Entities but Represent a Variable Expression of a Single Illness
Medicine, 2003Co-Authors: Marco Seri, Patrizia Noris, Alessandro Pecci, Roberto Cusano, S Gangarossa, Maria Savino, Filomena Di Bari, Emanuele Panza, Alessandra Nigro, Bianca RoccaAbstract:May-Hegglin anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome are autosomal dominant macrothrombocytopenias distinguished by different combinations of clinical and laboratory signs, such as sensorineural hearing loss, cataract, nephritis, and polymorphonuclear Dohle-like bodies. Mutations in the MYH9 gene encoding for the nonmuscle myosin heavy chain IIA (NMMHC-IIA) have been identified in all these Syndromes. To understand the role of the MYH9 mutations, we report the molecular defects in 12 new cases, which together with our previous works represent a cohort of 19 families. Since no genotype-phenotype correlation was established, we performed an accurate clinical and biochemical re-evaluation of patients. In addition to macrothrombocytopenia, an abnormal distribution of NMMHC-IIA within leukocytes was observed in all individuals, including those without Dohle-like bodies. Selective, high-tone hearing deficiency and cataract was diagnosed in 83% and 23%, respectively, of patients initially referred as having May-Hegglin anomaly or Sebastian Syndrome. Kidney abnormalities, such as hematuria and proteinuria, affected not only patients referred as Fechtner Syndrome and Epstein Syndrome but also those referred as May-Hegglin anomaly and Sebastian Syndrome. These findings allowed us to conclude that May-Hegglin anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome are not distinct entities but rather a single disorder with a continuous clinical spectrum varying from mild macrothrombocytopenia with leukocyte inclusions to a severe form complicated by hearing loss, cataracts, and renal failure. For this new nosologic entity, we propose the term "MHY9-related disease," which better interprets the recent knowledge in this field and identifies all patients at risk of developing renal, hearing, or visual defects.
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myh9 related disease may hegglin anomaly sebastian Syndrome Fechtner Syndrome and epstein Syndrome are not distinct entities but represent a variable expression of a single illness
Medicine, 2003Co-Authors: Marco Seri, Patrizia Noris, Alessandro Pecci, Roberto Cusano, S Gangarossa, Maria Savino, Filomena Di Bari, Emanuele Panza, Alessandra Nigro, Bianca RoccaAbstract:Abstract:May-Hegglin anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome are autosomal dominant macrothrombocytopenias distinguished by different combinations of clinical and laboratory signs, such as sensorineural hearing loss, cataract, nephritis, and polymorphonuclear Dohle-like
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Epstein Syndrome: another renal disorder with mutations in the nonmuscle myosin heavy chain 9 gene
Human Genetics, 2002Co-Authors: Marco Seri, Roberto Cusano, Maria Savino, Domenico Bordo, Filomena Di Bari, Bianca Rocca, Ilaria Meloni, Pasi A. Koivisto, Martino Bolognesi, Gian Marco GhiggeriAbstract:Epstein Syndrome (EPTS) is an autosomal dominant disease characterized by nephritis, mild hearing loss, and thrombocytopenia with giant platelets. Renal and hearing abnormalities are indistinguishable from those observed in Fechtner Syndrome (FTNS), an Alport-like variant. EPTS macrothrombocytopenia is similar to that described in FTNS, May-Hegglin anomaly (MHA), and Sebastian Syndrome (SBS), three disorders caused by mutations in the nonmuscle heavy chain myosin IIA ( MYH9 ). Unlike FTNS, MHA, and SBS, EPTS does not show inclusion bodies in the leukocytes. The clinical features of EPTS and the chromosomal localization of the respective gene in the same region as MYH9 suggest that this disorder is allelic with the other giant platelet disorders. We identified a MYH9 missense mutation in two EPTS familial cases. In both families, an R702H substitution was found, probably inducing conformational changes to the myosin head. A different amino acid substitution at the same codon (R702C) has been previously identified in FTNS. On the basis of predictions from molecular modeling of the X-ray crystallographic structure of chick smooth muscle myosin, the mutated thiol reactive group of R702C may lead to intermolecular disulfide bridges, with the consequent formation of the inclusions typical of FTNS. On the contrary, the R702H mutation does not allow the protein to aggregate and thus to generate "Döhle-like" bodies, which are indeed absent in EPTS. In conclusion, our results extend the allelic heterogeneity of MYH9 mutations to another clinical Syndrome and contribute to the clarification of the pathogenesis of the various inherited giant platelet disorders.
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autosomal dominant giant platelet Syndromes a hint of the same genetic defect as in Fechtner Syndrome owing to a similar genetic linkage to chromosome 22q11 13
Blood, 2000Co-Authors: Amos Toren, Bianca Rocca, Ninette Amariglio, Galit Rozenfeldgranot, Frida Broksimoni, Ferdinando Laghi, Charles J Epstein, R Landolfi, Lena E Carlsson, Gideon RechaviAbstract:Families with 3 different Syndromes characterized by autosomal dominant inheritance of low platelet count and giant platelets were studied. Fechtner Syndrome is an autosomal-dominant variant of Alport Syndrome manifested by nephritis, sensorineural hearing loss, and cataract formation in addition to macrothrombocytopenia and polymorphonuclear inclusion bodies. Sebastian platelet Syndrome is an autosomal-dominant macrothrombocytopenia combined with neutrophil inclusions that differ from those found in May-Hegglin Syndrome or Chediak-Higashi Syndrome or the Dohle bodies described in patients with sepsis. These inclusions are, however, similar to those described in Fechtner Syndrome. Other features of Alport Syndrome, though, including deafness, cataracts, and nephritis, are absent in Sebastian platelet Syndrome. Epstein Syndrome is characterized by macrothrombocytopenia without neutrophil inclusions, in addition to the classical Alport manifestations-deafness, cataracts, and nephritis-and it is also inherited in an autosomal-dominant mode. We mapped the disease-causing gene to the long arm of chromosome 22 in an Italian family with Fechtner Syndrome, 2 German families with the Sebastian platelet Syndrome, and an American family with the Epstein Syndrome. Four markers on chromosome 22q yielded an LOD score greater than 2.76. A maximal 2-point LOD score of 3.41 was obtained with the marker D22S683 at a recombination fraction of 0.00. Recombination analysis placed the disease-causing gene in a 3.37-Mb interval between the markers D22S284 and D22S693. The disease-causing gene interval in these 3 Syndromes is similar to the interval described recently in an Israeli family with a slightly different Fechtner Syndrome than the one described here. Recombination analysis of these 3 Syndromes refines the interval containing the disease-causing gene from 5.5 Mb to 3.37 Mb. The clinical likeness and the similar interval containing the disease-causing gene suggest that the 3 different Syndromes may arise from a similar genetic defect.
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Fechtner Syndrome report of a third family and literature review
British Journal of Haematology, 1993Co-Authors: Bianca Rocca, Ferdinando Laghi, Gina Zini, Nicola Maggiano, Raffaele LandolfiAbstract:Summary We observed macrothrombocytopenia with leucocyte inclusions in 10 out of 14 members of a four-generation family. Morphological features of leucocyte inclusions and the presence of Alport-related symptoms supported the diagnosis of Fechtner Syndrome. Compared to the two previously reported Fechtner families, our kindred showed reduced expression of Alport manifestations. These, in members aged less than 50, were represented by clinically silent ocular abnormalities. Due to the frequent non-recognition of macrothrombocytopenia, Fechtner variants with low penetrance might be difficult to diagnose. In addition, Sebastian Syndrome, recently distinguished from Fechtner disease in lacking Alport manifestations, might be one of these variants.
Patrizia Noris - One of the best experts on this subject based on the ideXlab platform.
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myh9 related disease may hegglin anomaly sebastian Syndrome Fechtner Syndrome and epstein Syndrome are not distinct entities but represent a variable expression of a single illness
Medicine, 2003Co-Authors: Marco Seri, Patrizia Noris, Alessandro Pecci, Roberto Cusano, S Gangarossa, Maria Savino, Filomena Di Bari, Emanuele Panza, Alessandra Nigro, Bianca RoccaAbstract:Abstract:May-Hegglin anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome are autosomal dominant macrothrombocytopenias distinguished by different combinations of clinical and laboratory signs, such as sensorineural hearing loss, cataract, nephritis, and polymorphonuclear Dohle-like
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MYH9-Related Disease: May-Hegglin Anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome Are not Distinct Entities but Represent a Variable Expression of a Single Illness
Medicine, 2003Co-Authors: Marco Seri, Patrizia Noris, Alessandro Pecci, Roberto Cusano, S Gangarossa, Maria Savino, Filomena Di Bari, Emanuele Panza, Alessandra Nigro, Bianca RoccaAbstract:May-Hegglin anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome are autosomal dominant macrothrombocytopenias distinguished by different combinations of clinical and laboratory signs, such as sensorineural hearing loss, cataract, nephritis, and polymorphonuclear Dohle-like bodies. Mutations in the MYH9 gene encoding for the nonmuscle myosin heavy chain IIA (NMMHC-IIA) have been identified in all these Syndromes. To understand the role of the MYH9 mutations, we report the molecular defects in 12 new cases, which together with our previous works represent a cohort of 19 families. Since no genotype-phenotype correlation was established, we performed an accurate clinical and biochemical re-evaluation of patients. In addition to macrothrombocytopenia, an abnormal distribution of NMMHC-IIA within leukocytes was observed in all individuals, including those without Dohle-like bodies. Selective, high-tone hearing deficiency and cataract was diagnosed in 83% and 23%, respectively, of patients initially referred as having May-Hegglin anomaly or Sebastian Syndrome. Kidney abnormalities, such as hematuria and proteinuria, affected not only patients referred as Fechtner Syndrome and Epstein Syndrome but also those referred as May-Hegglin anomaly and Sebastian Syndrome. These findings allowed us to conclude that May-Hegglin anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome are not distinct entities but rather a single disorder with a continuous clinical spectrum varying from mild macrothrombocytopenia with leukocyte inclusions to a severe form complicated by hearing loss, cataracts, and renal failure. For this new nosologic entity, we propose the term "MHY9-related disease," which better interprets the recent knowledge in this field and identifies all patients at risk of developing renal, hearing, or visual defects.
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genetics clinical and pathological features of glomerulonephrites associated with mutations of nonmuscle myosin iia Fechtner Syndrome
American Journal of Kidney Diseases, 2003Co-Authors: Gian Marco Ghiggeri, Alessandro Pecci, Gianluca Caridi, Marco Seri, S Gangarossa, Anna Savoia, Umberto Magrini, A Sessa, Roberta Romagnoli, Patrizia NorisAbstract:Abstract Background: Fechtner Syndrome (FTNS), also known as Alport-like Syndrome, is a rare inherited condition characterized by progressive nephritis, macrothrombocytopenia, Dohle-like leukocyte inclusions, deafness, and cataract. Although it recently was shown that FTNS derives from mutation of MYH9 , the gene for the heavy chain of nonmuscle myosin IIA (NMMHC-IIA), its pathophysiological characteristics remain unknown. Methods: We studied a large FTNS family in which 10 components carried a missense mutation of MYH9 determining the D1424H substitution. Results: All affected subjects presented with macrothrombocytopenia and leukocyte Dohle-like bodies consisting of macroaggregates of NMMHC-IIA, but only two subjects had major renal problems characterized by proteinuria and renal failure. Electron microscopy showed focal and segmental effacement of podocytes and loss of the interpodocyte slit diaphragm. Immunohistochemistry showed apical localization of NMMHC-IIA in tubular epithelia and less podocyte staining in the two patients, whereas it was diffuse in normal epithelia. Three patients presented with stable microhematuria, and another five patients had no renal lesions, although they carried the same mutation of MYH9 . Therefore, MYH9 mutation per se was responsible for platelet and leukocyte abnormalities, whereas additional predisposing conditions and/or environmental factors are necessary for nephropathy, cataract, and deafness. Looking at podocyte components conferring permselectivity properties to the kidney, we characterized the haplotype of podocin and found cosegregation of one specific allele in the two patients with nephrotic Syndrome, suggesting a relationship between podocin features and proteinuria. Conclusion: Our study indicates a major role for the NMMHC-IIA abnormality in the pathogenesis of leukocyte, platelet, and kidney defects in FTNS. The basic feature in all cases is aggregation and compartmentation of NMMHC-IIA. However, proteinuria and podocyte lesions are the hallmark of nephropathy in patients who develop renal failure, and podocin may have some function in this setting. Am J Kidney Dis 41:95-104. © 2003 by the National Kidney Foundation, Inc.
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immunocytochemistry for the heavy chain of the non muscle myosin iia as a diagnostic tool for myh9 related disorders
British Journal of Haematology, 2002Co-Authors: Alessandro Pecci, Saverio Sartore, Patrizia Noris, Gian Marco Ghiggeri, Marco Seri, S Gangarossa, Nicola Bizzaro, Anna Savoia, Rosangela Invernizzi, Carlo L. BalduiniAbstract:Summary. May–Hegglin anomaly (MHA), Sebastian Syndrome (SBS) and Fechtner Syndrome (FTNS) are autosomal-dominant macrothrombocytopenias with Dohle-like leucocyte inclusions. These diseases are due to mutations of the MHY9 gene, encoding the heavy chain of non-muscle myosin IIA (NMMHC-A). We investigated the NMMHC-A localization in blood cells from eight MHA, SBS or FTNS patients with known MYH9 mutations. All the patients showed an altered localization of NMMHC-A in granulocytes and platelets, suggesting that Dohle-like bodies are due to the aggregation of NMMHC-A in the cytoplasm. Therefore, immunocytochemistry for NMMHC-A is a simple and sensitive method to detect pathological phenotypes of granulocytes and platelets in the diagnosis of MYH9-related disorders.
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Background and Objectives. May-Hegglin anomaly
2002Co-Authors: Mha And Sebastian, Patrizia Noris, Alessandro Pecci, Marco Seri, Anna Savoia, Michele Dipumpo, Iride F. Ceresa, Carlo L. BalduiniAbstract:penia. The differentiation of MHA from SBS is based on subtle differences in the ultrastructural features of the Dhle-like bodies. 1,2 The MHA-SBS genetic defect has been recently mapped on the long arm of chromosome 22 3 and then identified in the gene (MYH9) encoding the heavy chain of non-muscle myosin IIA (NMMHCIIA) . MYH9 mutations are associated with two other macrothrombocytopenic Syndromes: Fechtner Syndrome, 7 characterized by nephritis, sensorineural hearing loss, cataract and polymorphonuclear inclusion bodies, and Epstein Syndrome, 8-10 differing from Fechtner Syndrome by the absence of cataract and Dhle-like bodies. Vertebrates possess two isoforms of NMMHC-II, which are widely and differentially expressed in tissues and have overlapping but distinct intracellular localizations. 11 Only NMMHC-IIA is expressed in human platelets and leukocytes. In normal subjects it has a diffuse and homogeneous distribution in leukocyte cytoplasm and platelets, while in p