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5. Nonmuscle Myosin Heavy Chain IIA Mutation Predicts Severity and Progression of Sensorineural Hearing Loss in Patients With MYH9-Related Disease

Author

Verver, E.J., Topsakal, V., Kunst, H.P., Huygen, P.L., Heller, P.G., Pujol-Moix, N., Savoia, A., Benazzo, M., Fierro, T., Grolman, W., Gresele, P., Pecci, A., Verver, E.J., Topsakal, V., Kunst, H.P., Huygen, P.L., Heller, P.G., Pujol-Moix, N., Savoia, A., Benazzo, M., Fierro, T., Grolman, W., Gresele, P., and Pecci, A.

Abstract

Item does not contain fulltext, OBJECTIVES: MYH9-related disease (MYH9-RD) is an autosomal- dominant disorder deriving from mutations in MYH9, the gene for the nonmuscle myosin heavy chain (NMMHC)-IIA. MYH9-RD has a complex phenotype including congenital features, such as thrombocytopenia, and noncongenital manifestations, namely sensorineural hearing loss (SNHL), nephropathy, cataract, and liver abnormalities. The disease is caused by a limited number of mutations affecting different regions of the NMMHC-IIA protein. SNHL is the most frequent noncongenital manifestation of MYH9-RD. However, only scarce and anecdotal information is currently available about the clinical and audiometric features of SNHL of MYH9-RD subjects. The objective of this study was to investigate the severity and propensity for progression of SNHL in a large series of MYH9-RD patients in relation to the causative NMMHC-IIA mutations. DESIGN: This study included the consecutive patients diagnosed with MYH9-RD between July 2007 and March 2012 at four participating institutions. A total of 115 audiograms were analyzed from 63 patients belonging to 45 unrelated families with different NMMHC-IIA mutations. Cross-sectional analyses of audiograms were performed. Regression analysis was performed, and age-related typical audiograms (ARTAs) were derived to characterize the type of SNHL associated with different mutations. RESULTS: Severity of SNHL appeared to depend on the specific NMMHC-IIA mutation. Patients carrying substitutions at the residue R702 located in the short functional SH1 helix had the most severe degree of SNHL, whereas patients with the p.E1841K substitution in the coiled-coil region or mutations at the nonhelical tailpiece presented a mild degree of SNHL even at advanced age. The authors also disclosed the effects of different amino acid changes at the same residue: for instance, individuals with the p.R702C mutation had more severe SNHL than those with the p.R702H mutation, and the p.R1165L substitution was associ

Published
2016

6. Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease

Author

Pecci, A., Panza, E., Pujol-Moix, N., Klersy, C., Di, Bari F., Bozzi, V., Gresele, P., Lethagen, S., Fabris, F., Dufour, C., Granata, A., Doubek, M., Pecoraro, C., Koivisto, P.A., Heller, P.G., Iolascon, A., Alvisi, P., Schwabe, D., De, Candia E., Rocca, B., Russo, U., Ramenghi, U., Noris, P., Seri, M., Balduini, C.L., Savoia, A., Pecci, A., Panza, E., Pujol-Moix, N., Klersy, C., Di, Bari F., Bozzi, V., Gresele, P., Lethagen, S., Fabris, F., Dufour, C., Granata, A., Doubek, M., Pecoraro, C., Koivisto, P.A., Heller, P.G., Iolascon, A., Alvisi, P., Schwabe, D., De, Candia E., Rocca, B., Russo, U., Ramenghi, U., Noris, P., Seri, M., Balduini, C.L., and Savoia, A.

Abstract

MYH9-related disease (MYH9-RD) is a rare autosomal-dominant disorder caused by mutations in MYH9, the gene for the heavy chain of nonmuscle myosin IIA (NMMHC-IIA). All patients present from birth with macrothrombocytopenia, but in infancy or adult life, some of them develop sensorineural deafness, presenile cataracts, and/or progressive nephritis leading to end-stage renal failure. No consistent correlations have been identified between the 27 different MYH9 mutations identified so far and the variable clinical evolution of the disease. We have evaluated 108 consecutive MYH9-RD patients belonging to 50 unrelated pedigrees. The risk of noncongenital manifestations associated with different genotypes was estimated over time by event-free survival analysis. We demonstrated that all subjects with mutations in the motor domain of NMMHC-IIA present with severe thrombocytopenia and develop nephritis and deafness before the age of 40 years, while those with mutations in the tail domain have a much lower risk of noncongenital complications and significantly higher platelet counts. We also evaluated the clinical course of patients with mutations in the four most frequently affected residues of NMMHC-IIA (responsible for 70% of MYH9-RD cases). We concluded that mutations at residue 1933 do not induce kidney damage or cataracts and cause deafness only in the elderly, those in position 702 result in severe thrombocytopenia and produce nephritis and deafness at a juvenile age, while alterations at residue 1424 or 1841 result in intermediate clinical pictures. These findings are relevant not only to patients' clinical management but also to the elucidation of the pathogenesis of the disease Udgivelsesdato: 2008/3

Published
2008

9. The ISTH bleeding assessment tool as predictor of bleeding events in inherited platelet disorders: Communication from the ISTH SSC Subcommittee on Platelet Physiology

Author

Gresele, P., Falcinelli, E., Bury, L., Pecci, A., Alessi, M. -C., Borhany, M., Heller, P. G., Santoro, C., Cid, A. R., Orsini, S., Fontana, P., De Candia, E., Podda, G., Kannan, M., Jurk, K., Castaman, G., Falaise, C., Guglielmini, G., Noris, P., Zaninetti, C., Fiore, M., Tosetto, A., Zuniga, P., Miyazaki, K., Dupuis, A., Hayward, C., Casonato, A., Grandone, E., Mazzucconi, M. G., James, P., Fabris, F., Henskens, Y., Napolitano, M., Curnow, J., Gkalea, V., Fedor, M., Lambert, M. P., Zieger, B., Barcella, L., Cosmi, B., Giordano, P., Porri, C., Melazzini, F., Abid, M., Glembotsky, A. C., Ferrara, G., Russo, A., Deckmyn, H., Frelinger, A. L., Harrison, P., Mezzano, D., Mumford, A. D., Lordkipanidzé, M., BAT-VAL Study Investigators, Università degli Studi di Perugia = University of Perugia (UNIPG), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Unidad de Coagulopatías Congénitas. Hospital Universitario La Fe., Gresele, Paolo, Falcinelli, Emanuela, Bury, Loredana, Pecci, Alessandro, Alessi, Marie-Christine, Borhany, Munira, Heller, Paula G, Santoro, Cristina, Cid, Ana Rosa, Orsini, Sara, Fontana, Pierre, De Candia, Erica, Podda, Gianmarco, Kannan, Meganathan, Jurk, Kerstin, Castaman, Giancarlo, Falaise, Céline, Guglielmini, Giuseppe, Noris, Patrizia, Mariasanta Napolitano, Università degli Studi di Perugia (UNIPG), University of Perugia, Gresele, P., Falcinelli, E., Bury, L., Pecci, A., Alessi, M.-C., Borhany, M., Heller, P.G., Santoro, C., Cid, A.R., Orsini, S., Fontana, P., De Candia, E., Podda, G., Kannan, M., Jurk, K., Castaman, G., Falaise, C., Guglielmini, G., Noris, P., Zaninetti, C., Fiore, M., Tosetto, A., Zuniga, P., Miyazaki, K., Dupuis, A., Hayward, C., Casonato, A., Grandone, E., Mazzucconi, M.G., James, P., Fabris, F., Henskens, Y., Napolitano, M., Curnow, J., Gkalea, V., Fedor, M., Lambert, M.P., Zieger, B., Barcella, L., Cosmi, B., Giordano, P., Porri, C., Melazzini, F., Abid, M., Glembotsky, A.C., Ferrara, G., Russo, A., Deckmyn, H., Frelinger, A.L., Harrison, P., Mezzano, D., Mumford, A.D., Lordkipanidzé, M., and BAT-VAL Study Investigators

Subjects
medicine.medical_specialty, animal structures, mild&#8208, Platelet Function Tests, Platelet disorder, inherited platelet disorder, Hemorrhage, 030204 cardiovascular system & hematology, Hemorrhage/diagnosis, 03 medical and health sciences, 0302 clinical medicine, Von Willebrand factor, hemic and lymphatic diseases, Internal medicine, von Willebrand Factor, Von Willebrand disease, Medicine, Humans, Platelet, Bleeding prediction, Bleeding score, Blood platelet disorders, Child, Communication, Hemorrhage, Humans, Inherited platelet disorders, Mild-moderate bleeding disorders, Platelet Function Tests, von Willebrand diseases, von Willebrand Factor, Child, Blood Platelet Disorders, ddc:616, mild-moderate bleeding disorders, biology, business.industry, mild-moderate bleeding disorder, Incidence (epidemiology), Communication, Settore MED/09 - MEDICINA INTERNA, bleeding prediction, von Willebrand Diseases/diagnosis/genetics, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, medicine.disease, Blood Platelet Disorders/diagnosis/genetics, 3. Good health, bleeding score, Institutional repository, von Willebrand Diseases, moderate bleeding disorders, inherited platelet disorders, Quartile, biology.protein, von Willebrand disease, business
Abstract

Background: The ISTH Bleeding Assessment Tool (ISTH-BAT) has been validated for clinical screening of suspected von Willebrand disease (VWD) and for bleeding prediction. Recently it has been validated for subjects with inherited platelet disorders (IPD) (BAT-VAL study). Objectives: To determine whether the ISTH-BAT bleeding score (BS) predicts subsequent bleeding events requiring treatment in IPD patients. Methods: Patients with IPD, type 1 VWD (VWD-1) and age- and sex-matched healthy controls enrolled in the BAT-VAL study were prospectively followed-up for 2years and bleeding episodes requiring treatment were recorded. Results: Of the 1098 subjects initially enrolled, 955 were followed-up and 124 suffered hemorrhages during follow-up, 60% of whom had inherited platelet function disorders (IPFD). Total number of events was significantly higher in IPFD (n=235) than VWD-1 (n=52) or inherited thrombocytopenia (IT; n=20). Events requiring transfusions were 66% in IPFD, 5.7% in VWD-1, and 3% in IT. Baseline BS was significantly higher in IPFD patients with a bleeding event at follow-up than in those without (p&nbsp

Published
2021
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10. Heavy chain myosin 9-related disease (MYH9 -RD): neutrophil inclusions of myosin-9 as a pathognomonic sign of the disorder

Author

Paula G. Heller, Andrew D Mumford, Fabrizio Fabris, Alessandro Pecci, Silvia Riondino, Marco R. de Groot, Daniela De Rocco, Marisa Giani, Nuria Pujol-Moix, Francesca Scognamiglio, Valeria Bozzi, Marco Seri, Giuseppe Loffredo, Patrizia Noris, Anna Savoia, Raffaella Scandellari, Emanuele Panza, Carlo L. Balduini, Paolo Freddi, Savoia A., De Rocco D., Panza E., Bozzi V., Scandellari R., Loffredo G., Mumford A., Heller P.G., Noris P., De Groot M.R., Giani M., Freddi P., Scognamiglio F., Riondino S., Pujol-Moix N., Fabris F., Seri M., Balduini C.L., Pecci A., Savoia, Anna, DE ROCCO, Daniela, Panza, E, Bozzi, V, Scandellari, R, Loffredo, G, Mumford, A, Heller, Pg, Noris, P, DE GROOT, Mr, Giani, M, Freddi, P, Scognamiglio, F, Riondino, S, PUJOL MOIX, N, Fabris, F, Seri, M, Balduini, Cl, and Pecci, A.

Subjects
Male, Pathology, Cytoplasmic inclusion, Neutrophils, inclusioni in neutrofili, Mutant, DNA Mutational Analysis, piastrinopenia, Fluorescent Antibody Technique, Medicina Clínica, medicine.disease_cause, MYH9-related diseases, malattia MYH9 associata, Immunopathology, Myosin, Prospective Studies, Registries, Child, gene MYH9, Aged, 80 and over, Inclusion Bodies, Mutation, medicine.diagnostic_test, Molecular Motor Proteins, Hematology, Middle Aged, Italy, Child, Preschool, Sensorineural hearing loss, Female, Adult, medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, Adolescent, Giant platelets, MYH9 gene, Biology, Immunofluorescence, Sensitivity and Specificity, Young Adult, Predictive Value of Tests, medicine, Humans, Hematología, Aged, Myosin Heavy Chains, medicine.disease, Thrombocytopenia, Heavy chain disease, Microscopy, Fluorescence, Case-Control Studies, Neutrophil inclusions
Abstract

MYH9 -related disease ( MYH9 -RD) is an autosomal dominant thrombocytopenia with giant platelets variably associated with young-adult onset of progressive sensorineural hearing loss, presenile cataract, and renal damage. MYH9 -RD is caused by mutations of MYH9 , the gene encoding for non-muscle heavy-chain myosin-9. Wild-type and mutant myosin-9 aggregate as cytoplasmic inclusions in patients’ leukocytes, the identification of which by immunofluorescence has been proposed as a suitable tool for the diagnosis of MYH9 -RD. Since the predictive value of this assay, in terms of sensitivity and specificity, is unknown, we investigated 118 consecutive unrelated patients with a clinical presentation strongly consistent with MYH9 -RD. All patients prospectively underwent both the immunofluorescence assay for myosin-9 aggregate detection and molecular genetic analysis of the MYH9 gene. Myosin-9 aggregates were identified in 82 patients, 80 of which (98%) had also a MYH9 mutation. In the remaining 36 patients neither myosin-9 aggregates nor MYH9 mutations were found. Sensitivity and specificity of the immunofluorescence assay was evaluated to be 100% and 95%, respectively. Except for the presence of aggregates, we did not find any other significant difference between patients with or without aggregates, demonstrating that the myosin-9 inclusions in neutrophils are a pathognomonic sign of the disease. However, the identification of the specific MYH9 mutation is still of importance for prognostic aspects of MYH9 -RD. Fil: Savoia, Anna. Universita Degli Studi Di Trieste; Italia. Italian Registry for MYH9-Related Disease; Italia Fil: de Rocco, Daniela. Universita Degli Studi Di Trieste; Italia. Italian Registry for MYH9-Related Disease; Italia Fil: Panza, Emanuele. Italian Registry for MYH9-Related Disease; Italia. Universita Di Bologna; Italia Fil: Bozzi, Valeria. Italian Registry for MYH9-Related Disease; Italia. University of Pavia; Italia Fil: Scandellari, Raffaella. Italian Registry for MYH9-Related Disease; Italia. Universita Di Padova; Italia Fil: Loffredo, Giuseppe. Italian Registry for MYH9-Related Disease; Italia. Pausilipon Hospital; Italia Fil: Mumford, Andrew. University of Bristol; Reino Unido Fil: Heller, Paula Graciela. Italian Registry for MYH9-Related Disease; Italia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Noris, Patrizia. Italian Registry for MYH9-Related Disease; Italia Fil: de Groot, Marco R.. University of Bristol; Reino Unido Fil: Giani, Marisa. Italian Registry for MYH9-Related Disease; Italia. Istituto di Ricovero e Cura a Carattere Scientifico; Italia Fil: Freddi, Paolo. Italian Registry for MYH9-Related Disease; Italia Fil: Scognamiglio, Francesca. Italian Registry for MYH9-Related Disease; Italia Fil: Riondino, Silvia. Italian Registry for MYH9-Related Disease; Italia. Istituto di Ricovero e Cura a Carattere Scientifico; Italia Fil: Pujol Moix, Núria. Universitat Autonoma de Barcelona; España Fil: Fabris, Fabrizio. Italian Registry for MYH9-Related Disease; Italia. Universita Di Padova; Italia Fil: Seri, Marco. Italian Registry for MYH9-Related Disease; Italia. Universita Di Bologna; Italia Fil: Balduini, Carlo L.. Italian Registry for MYH9-Related Disease; Italia. University of Pavia; Italia Fil: Pecci, Alessandro. Italian Registry for MYH9-Related Disease; Italia. University of Pavia; Italia

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