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3. Addressing the impact of SARS-CoV-2 infection in persons with congenital bleeding disorders: The Italian MECCOVID-19 study

Author

Coluccia A., Marchesini E., Giuffrida A. C., Rivolta G. F., Ricca I., Zanon E., Luciani M., De Cristofaro R., Coppola A., Rocino A., Ambaglio C., Borchiellini A., Bonetti E., Caimi T. M., Carulli C., Contino L., Cultrera D., D'Attilio E., Delios G., Feola G., Giordano P., Giuffrida G., Grandone E., Lassandro G., Linari S., Margaglione M., Marino R., Molinari A. C., Napolitano M., Nichele I., Notarangelo L. D., Pasca S., Piscitelli L., Pollio B., Quintavalle G., Radossi P., Santoro C., Santoro R. C., Schiavulli M., Sottilotta G., Speciale V., Tagliaferri A., Valdre L., Coluccia A., Marchesini E., Giuffrida A.C., Rivolta G.F., Ricca I., Zanon E., Luciani M., De Cristofaro R., Coppola A., Rocino A., Ambaglio C., Borchiellini A., Bonetti E., Caimi T.M., Carulli C., Contino L., Cultrera D., D'Attilio E., Delios G., Feola G., Giordano P., Giuffrida G., Grandone E., Lassandro G., Linari S., Margaglione M., Marino R., Molinari A.C., Napolitano M., Nichele I., Notarangelo L.D., Pasca S., Piscitelli L., Pollio B., Quintavalle G., Radossi P., Santoro C., Santoro R.C., Schiavulli M., Sottilotta G., Speciale V., Tagliaferri A., and Valdre L.

Subjects
Adult, Inherited, Male, Pediatrics, medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), congenital bleeding disorders, congenital bleeding disorder, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), haemophilia, Hemorrhage, Haemophilia, Letter to the Editors, SARS‐CoV‐2, Young Adult, Blood Coagulation Disorders, Inherited, COVID‐19, COVID-19, epidemiology, observational study, SARS-CoV-2, Aged, Child, Preschool, Disease Management, Female, Humans, Italy, Middle Aged, Epidemiology, medicine, Young adult, Disease management (health), Child, Preschool, Letter to the Editor, Genetics (clinical), business.industry, Hematology, General Medicine, Blood Coagulation Disorders, medicine.disease, Observational study, business
Abstract

congenital bleeding disorders

Published
2021

4. New data from the italian national register of congenital coagulopathies, 2016 annual survey

Author

Abbonizio F., Hassan H. J., Riccioni R., Santagostino E., Arcieri R., Giampaolo A., Contino L., Accorsi A., Caremani A., Ettorre P. C., Giordano P., Lassandro G., Valdre L., Notarangelo L., Aru A. B., Radossi P., Tagariello G., Cultrera D., Iannaccaro P., Santoro R., Biasoli C., Di Gregorio P., Daniele F., Testa S., Serino M. L., Castaman G., Linari S. S., Morfini M., Molinari A. C., Delios G., Cantori I., Franchini M., Caimi M. T., Mancuso M. E., Peyvandi F., Marietta M., Todisco A., Speciale V., Cerbone A. M., Di Minno G., Schiavulli M., Rocino A., Spiezia M. M., Zanon E., Gagliano F., Mansueto M. F., Siragusa S., Coppola A., Quintavalle G., Rivolta G. F., Tagliaferri A., Ambaglio C., Gamba G., Marchesini E., Oliovecchio E., Dragani A., Arbasi M. C., MacChi S., Vincenzi D., Sottilotta G., Pizzini A. M., Luciani M., De Cristofaro R., Baldacci E., Mazzucconi M. G., Santoro C., Mameli L. A., Coluccia A., Marino P., Borchiellini A., Schinco P. C., Messina M., Pollio B., Ricca I., Agostini P., Cristallo A. F., Barillari G., De Angelis V., Mosanghini M. E., Feola G., Bonetti E., Cesaro S., Gandini G., Giuffrida A., Tosetto A., Abbonizio, F., Hassan, H. J., Riccioni, R., Santagostino, E., Arcieri, R., Giampaolo, A., Contino, L., Accorsi, A., Caremani, A., Ettorre, P. C., Giordano, P., Lassandro, G., Valdre, L., Notarangelo, L., Aru, A. B., Radossi, P., Tagariello, G., Cultrera, D., Iannaccaro, P., Santoro, R., Biasoli, C., Di Gregorio, P., Daniele, F., Testa, S., Serino, M. L., Castaman, G., Linari, S. S., Morfini, M., Molinari, A. C., Delios, G., Cantori, I., Franchini, M., Caimi, M. T., Mancuso, M. E., Peyvandi, F., Marietta, M., Todisco, A., Speciale, V., Cerbone, A. M., Di Minno, G., Schiavulli, M., Rocino, A., Spiezia, M. M., Zanon, E., Gagliano, F., Mansueto, M. F., Siragusa, S., Coppola, A., Quintavalle, G., Rivolta, G. F., Tagliaferri, A., Ambaglio, C., Gamba, G., Marchesini, E., Oliovecchio, E., Dragani, A., Arbasi, M. C., Macchi, S., Vincenzi, D., Sottilotta, G., Pizzini, A. M., Luciani, M., De Cristofaro, R., Baldacci, E., Mazzucconi, M. G., Santoro, C., Mameli, L. A., Coluccia, A., Marino, P., Borchiellini, A., Schinco, P. C., Messina, M., Pollio, B., Ricca, I., Agostini, P., Cristallo, A. F., Barillari, G., De Angelis, V., Mosanghini, M. E., Feola, G., Bonetti, E., Cesaro, S., Gandini, G., Giuffrida, A., and Tosetto, A.

Subjects
Blood coagulation disorder, Haemophilia B, Haemophilia A, Von Willebrand's disease, Register
Abstract

Background - In Italy, the National Register of Congenital Coagulopathies (NRCC) collects epidemiological and therapeutic data from patients affected by haemophilia A (HA), haemophilia B (HB), von Willebrand's disease (vWD) and other rare coagulation disorders. Here we present data from the 2016 annual survey. Materials and methods - Data are provided by the Italian Haemophilia Centres, on a voluntary basis. Information flows from every Centre to a web-based platform of the Italian Association of Haemophilia Centres, shared with the Italian National Institute of Health, in accordance with current privacy laws. Patients are classified by diagnosis, disease severity, age, gender and treatment-related complications. Results - In 2016, the total number of patients with congenital coagulopathies in the NRCC was 10,360: 39.8% of these patients had HA, 31.5% had vWD, 8.5% had HB, and 20.2% had less common factor deficiencies. The overall prevalence of HA and HB was 13.9/100,000 males and 3.0/100,000 males, respectively. The overall prevalence of vWD was 5.4/100,000 inhabitants. During 2016, 126 patients had current alloantibodies to factor VIII (FVIII) or factor IX (FIX) and were under treatment with bypassing agents and/or immune tolerance induction. Overall, 388 patients with a history of alloantibodies were recorded in the NRCC of whom 337 with severe HA and 12 with severe HB. Coagulation factor use, evaluated from treatment plans, was approximately 451,000,000 IU of FVIII for HA patients (7.5 IU/inhabitant), and approximately 53,000,000 IU of FIX for HB patients (0.9 IU/inhabitant). Discussion - The prevalences of HA and HB fall within the ranges reported in more developed countries; the consumption of FVIII and FIX was in line with that of other European countries (France, United Kingdom) and Canada. The NRCC, with its bleeding disorder dataset, is a helpful tool for shaping public health policies, as well as planning clinical and epidemiological research projects.

Published
2020

8. Consensus statements on vaccination in patients with haemophilia—Results from the Italian haemophilia and vaccinations (HEVA) project

Author

Santagostino E., Riva A., Cesaro S., Esposito S., Matino D., Mazzucchelli R. I., Molinari, Angelo Claudio, Mura R., Notarangelo L. D., Tagliaferri A., Di Minno G., Clerici M., Ambaglio C., Brigida Aru A., Baldacci E., Barillari G., Basso M., Bernasconi S., Bertamino M., Bertoni E., Biasoli C., Federica Biguzzi E., Bonetti E., Borchiellini A., Bulgarelli S., Cabibbo S., Cantori I., Castaman G., Castiglia P., Coluccia A., Coppetelli U., Coppola A., Cultrera D., De Candia E., Delios G., Di Gennaro L., Di Gregorio P., Di Minno M., Dragani A., Pietro Ettorre C., Franchini M., Galli M., Gallo G., Giordano P., Giuffrida G., Iannaccaro P., Lassandro G., Lazzareschi I., Linari S., Luciani M., Macchi S., Malcangi G., Malizia R., Marietta M., Marino R., Massoud M., Gabriella Mazzucconi M., Milan M., Morfini M., Napolitano M., Pasca S., Pedrazzi P., Peyvandi F. A., Piscitelli L., Pollio B., Preti P., Quintavalle G., Radossi P., Raso S., Ricca I., Rocino A., Santoro C., Carlotta Santoro R., Sarolo L., Schiavoni M., Schiavulli M., Sciancalepore P., Luisa Serino M., Mario Siragusa S., Sottilotta G., Svahn J., Valdre L., Cristina Vedovati M., Zanon E., Santagostino, E., Riva, A., Cesaro, S., Esposito, S., Matino, D., Mazzucchelli, R. I., Molinari, Angelo Claudio, Mura, R., Notarangelo, L. D., Tagliaferri, A., Di Minno, G., Clerici, M., Ambaglio, C., Brigida Aru, A., Baldacci, E., Barillari, G., Basso, M., Bernasconi, S., Bertamino, M., Bertoni, E., Biasoli, C., Federica Biguzzi, E., Bonetti, E., Borchiellini, A., Bulgarelli, S., Cabibbo, S., Cantori, I., Castaman, G., Castiglia, P., Coluccia, A., Coppetelli, U., Coppola, A., Cultrera, D., De Candia, E., Delios, G., Di Gennaro, L., Di Gregorio, P., Di Minno, M., Dragani, A., Pietro Ettorre, C., Franchini, M., Galli, M., Gallo, G., Giordano, P., Giuffrida, G., Iannaccaro, P., Lassandro, G., Lazzareschi, I., Linari, S., Luciani, M., Macchi, S., Malcangi, G., Malizia, R., Marietta, M., Marino, R., Massoud, M., Gabriella Mazzucconi, M., Milan, M., Morfini, M., Napolitano, M., Pasca, S., Pedrazzi, P., Peyvandi, F. A., Piscitelli, L., Pollio, B., Preti, P., Quintavalle, G., Radossi, P., Raso, S., Ricca, I., Rocino, A., Santoro, C., Carlotta Santoro, R., Sarolo, L., Schiavoni, M., Schiavulli, M., Sciancalepore, P., Luisa Serino, M., Mario Siragusa, S., Sottilotta, G., Svahn, J., Valdre, L., Cristina Vedovati, M., and Zanon, E.

Subjects
Adult, medicine.medical_specialty, Consensus, Delphi Technique, Vaccination schedule, Delphi method, haemophilia, 030204 cardiovascular system & hematology, Hemophilia A, Haemophilia, immunization, Hemophilia B, bleeding disorder, factor VIII inhibitor, vaccination, Child, Evidence-Based Medicine, Humans, Italy, Vaccination, 03 medical and health sciences, 0302 clinical medicine, Vaccine administration, Medicine, In patient, Clinical Haemophilia, Genetics (clinical), business.industry, Original Articles, Hematology, General Medicine, Evidence-based medicine, medicine.disease, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Immunization, Family medicine, Original Article, business, 030215 immunology
Abstract

Vaccination against communicable diseases is crucial for disease prevention, but this practice poses challenges to healthcare professionals in patients with haemophilia. Poor knowledge of the vaccination requirements for these patients and safety concerns often result in vaccination delay or avoidance. In order to address this issue, a panel of 11 Italian haemophilia and immunization experts conducted a Delphi consensus process to identify the main concerns regarding the safe use of vaccines in patients with haemophilia. The consensus was based on a literature search of the available evidence, which was used by the experts to design 27 consensus statements. A group of clinicians then rated these statements using the 5‐point Likert‐type scale (1 = strongly disagree; 5 = strongly agree). The main issues identified by the expert panel included vaccination schedule for haemophilic patients; protocol and optimal route of vaccine administration; vaccination of haemophilic patients with antibodies inhibiting coagulation factor VIII (inhibitors); and vaccination and risk of inhibitor development. This manuscript discusses these controversial areas in detail supported by the available literature evidence and provides evidence‐ and consensus‐based recommendations. Overall, participants agreed on most statements, except those addressing the potential role of vaccination in inhibitor formation. Participants agreed that patients with haemophilia should receive vaccinations according to the institutional schedule for individuals without bleeding disorders; however, vaccination of patients with haemophilia requires comprehensive planning, taking into account disease severity, type and route of vaccination, and bleeding risk. Data also suggest vaccination timing does not need to take into consideration when the patient received factor VIII replacement.

Published
2019

21. Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study

Author

D'Amore, A. Tessa, A. Casali, C. Dotti, M.T. Filla, A. Silvestri, G. Antenora, A. Astrea, G. Barghigiani, M. Battini, R. Battisti, C. Bruno, I. Cereda, C. Dato, C. Di Iorio, G. Donadio, V. Felicori, M. Fini, N. Fiorillo, C. Gallone, S. Gemignani, F. Gigli, G.L. Graziano, C. Guerrini, R. Gurrieri, F. Kariminejad, A. Lieto, M. Marques LourenḈo, C. Malandrini, A. Mandich, P. Marcotulli, C. Mari, F. Massacesi, L. Melone, M.A.B. Mignarri, A. Milone, R. Musumeci, O. Pegoraro, E. Perna, A. Petrucci, A. Pini, A. Pochiero, F. Pons, M.R. Ricca, I. Rossi, S. Seri, M. Stanzial, F. Tinelli, F. Toscano, A. Valente, M. Federico, A. Rubegni, A. Santorelli, F.M.

Abstract

Hereditary spastic paraplegia (HSP) refers to a group of genetically heterogeneous neurodegenerative motor neuron disorders characterized by progressive age-dependent loss of corticospinal motor tract function, lower limb spasticity, and weakness. Recent clinical use of next generation sequencing (NGS) methodologies suggests that they facilitate the diagnostic approach to HSP, but the power of NGS as a first-tier diagnostic procedure is unclear. The larger-than-expected genetic heterogeneity—there are over 80 potential disease-associated genes—and frequent overlap with other clinical conditions affecting the motor system make a molecular diagnosis in HSP cumbersome and time consuming. In a single-center, cross-sectional study, spanning 4 years, 239 subjects with a clinical diagnosis of HSP underwent molecular screening of a large set of genes, using two different customized NGS panels. The latest version of our targeted sequencing panel (SpastiSure3.0) comprises 118 genes known to be associated with HSP. Using an in-house validated bioinformatics pipeline and several in silico tools to predict mutation pathogenicity, we obtained a positive diagnostic yield of 29% (70/239), whereas variants of unknown significance (VUS) were found in 86 patients (36%), and 83 cases remained unsolved. This study is among the largest screenings of consecutive HSP index cases enrolled in real-life clinical-diagnostic settings. Its results corroborate NGS as a modern, first-step procedure for molecular diagnosis of HSP. It also disclosed a significant number of new mutations in ultra-rare genes, expanding the clinical spectrum, and genetic landscape of HSP, at least in Italy. © Copyright © 2018 D'Amore, Tessa, Casali, Dotti, Filla, Silvestri, Antenora, Astrea, Barghigiani, Battini, Battisti, Bruno, Cereda, Dato, Di Iorio, Donadio, Felicori, Fini, Fiorillo, Gallone, Gemignani, Gigli, Graziano, Guerrini, Gurrieri, Kariminejad, Lieto, Marques LourenḈo, Malandrini, Mandich, Marcotulli, Mari, Massacesi, Melone, Mignarri, Milone, Musumeci, Pegoraro, Perna, Petrucci, Pini, Pochiero, Pons, Ricca, Rossi, Seri, Stanzial, Tinelli, Toscano, Valente, Federico, Rubegni and Santorelli.

Published
2018

22. Italian Frontotemporal Dementia Network (FTD Group-SINDEM): sharing clinical and diagnostic procedures in Frontotemporal Dementia in Italy

Author

Borroni B., Turrone R., Galimberti D., Nacmias B., Alberici A., Benussi A., Caffarra P., Caltagirone C., Cappa S. F., Frisoni G. B., Ghidoni R., Marra C., Padovani A., Rainero I., Scarpini E., Silani V., Sorbi S., Tagliavini F., Tremolizzo L., Bruni A. C., Agosta F., Alberoni M., Appollonio I., Arighi A., Avanzi S., Baglio F., Benussi L., Bianchetti A., Binetti G., Bonanni L., Bottacchi E., Bruno G., Canevelli M., Canu E., Cerami C., Chiari A., Conti M. Z., Costa A., Costa M., Cotelli M., Cotelli M. S., Cupidi C., Daniele A., D'Anna S., de Caro M. F., De Togni L., Dell'Osa M. T., Di Stefano F., Ferrarese C., Ferrari C., Filastro F., Floris G., Franceschi M., Gennuso M., Ghidoni E., Giordana M. T., Gragnaniello D., Grimaldi L., Lanari A., Le Pira F., Lombardi G., Lorusso S., Ludovico L., Luzzi S., Magnani G., Manfredi L. G., Marano P., Marcone A., Marrosu M. G., Martorana A., Mascia M. G., Masullo C., Mauri M., Mazzone A., Mela A., Merlo P., Micheli A., Milia A., Mina C., Montella P., Mura G., Murru M. R., Nemni R., Paci C., Pantieri R., Panza F., Parnetti L., Perini M., Pettenati C., Piccininni M., Piccoli T., Pilia G., Pinessi L., Piras M. R., Realmuto S., Ricca I., Rizzetti M. C., Rozzini L., Rubino E., Sambati L., Seripa D., Siano P., Sinforiani E., Sorrentino G., Specchio L. M., Stracciari A., Susani E., Talarico G., Tartaglione B., Tessitore A., Thomas A., Tiezzi A., Tiraboschi P., Tognoni G., Tondelli M., Trebbastoni A., Turla M., Ursini F., Valluzzi F., Vista M., Zannino G., Zanusso G., Piccoli, T, B. Borroni, R. Turrone, D. Galimberti, B. Nacmia, A. Alberici, A. Benussi, P. Caffarra, C. Caltagirone, S. F. Cappa, G. B. Frisoni, R. Ghidoni, C. Marra, A. Padovani, I. Rainero, E. Scarpini, V. Silani, S. Sorbi, F. Tagliavini, L. Tremolizzo, A. C. Bruni, The FTD Group-SINDEM, Borroni, B, Turrone, R, Galimberti, D, Nacmias, B, Alberici, A, Benussi, A, Caffarra, P, Caltagirone, C, Cappa, Sf, Frisoni, Gb, Ghidoni, R, Marra, C, Padovani, A, Rainero, I, Scarpini, E, Silani, V, Sorbi, S, Tagliavini, F, Tremolizzo, L, Bruni, Ac, The FTD, Group-SINDEM, Agosta, F, Cappa, S, Frisoni, G, Bruni, A, Alberoni, M, Appollonio, I, Arighi, A, Avanzi, S, Baglio, F, Benussi, L, Bianchetti, A, Binetti, G, Bonanni, L, Bottacchi, E, Bruno, G, Canevelli, M, Canu, E, Cerami, C, Chiari, A, Conti, M, Costa, A, Costa, M, Cotelli, M, Cupidi, C, Daniele, A, D'Anna, S, de Caro, M, De Togni, L, Dell'Osa, M, Di Stefano, F, Ferrarese, C, Ferrari, C, Filastro, F, Floris, G, Franceschi, M, Gennuso, M, Ghidoni, E, Giordana, M, Gragnaniello, D, Grimaldi, L, Lanari, A, Le Pira, F, Lombardi, G, Lorusso, S, Ludovico, L, Luzzi, S, Magnani, G, Manfredi, L, Marano, P, Marcone, A, Marrosu, M, Martorana, A, Mascia, M, Masullo, C, Mauri, M, Mazzone, A, Mela, A, Merlo, P, Micheli, A, Milia, A, Mina, C, Montella, P, Mura, G, Murru, M, Nemni, R, Paci, C, Pantieri, R, Panza, F, Parnetti, L, Perini, M, Pettenati, C, Piccininni, M, Pilia, G, Pinessi, L, Piras, M, Realmuto, S, Ricca, I, Rizzetti, M, Rozzini, L, Rubino, E, Sambati, L, Seripa, D, Siano, P, Sinforiani, E, Sorrentino, G, Specchio, L, Stracciari, A, Susani, E, Talarico, G, Tartaglione, B, Tessitore, A, Thomas, A, Tiezzi, A, Tiraboschi, P, Tognoni, G, Tondelli, M, Trebbastoni, A, Turla, M, Ursini, F, Valluzzi, F, Vista, M, Zannino, G, and Zanusso, G

Subjects
Counseling, Male, medicine.medical_specialty, Neurology, Network, Frontotemporal dementia, Frontotemporal lobar degeneration, Genetics, Survey, Aged, Aged, 80 and over, Caregivers, Female, Frontotemporal Dementia, Humans, Italy, Prevalence, Community Networks, Information Dissemination, Medicine (all), 2708, Neurology (clinical), Psychiatry and Mental Health, Dermatology, ddc:616.89, Caregivers/psychology, Epidemiology, mental disorders, medicine, 80 and over, Dementia, Disease management (health), Psychiatry, MED/26 - NEUROLOGIA, Italian network, FRONTO Temporal dementia, business.industry, Frontotemporal dementia, Frontotemporal lobar degeneration, Network, Survey, Genetics, Counseling, General Medicine, Frontotemporal Dementia/diagnosis/epidemiology, medicine.disease, Clinical trial, Settore MED/26 - Neurologia, Neurosurgery, business
Abstract

In the prospect of improved disease management and future clinical trials in Frontotemporal Dementia, it is desirable to share common diagnostic procedures. To this aim, the Italian FTD Network, under the aegis of the Italian Neurological Society for Dementia, has been established. Currently, 85 Italian Centers involved in dementia care are part of the network. Each Center completed a questionnaire on the local clinical procedures, focused on (1) clinical assessment, (2) use of neuroimaging and genetics; (3) support for patients and caregivers; (4) an opinion about the prevalence of FTD. The analyses of the results documented a comprehensive clinical and instrumental approach to FTD patients and their caregivers in Italy, with about 1,000 newly diagnosed cases per year and 2,500 patients currently followed by the participating Centers. In analogy to other European FTD consortia, future aims will be devoted to collect data on epidemiology of FTD and its subtypes and to provide harmonization of procedures among Centers.

Published
2014

25. A large-scale association study to assess the impact of known variants of the human INHA gene on premature ovarian failure. Italian Network for the study of Ovarian Dysfunctions

Author

Corre, T1, Schuettler, J, Bione, S, Marozzi, A, Persani, L, Rossetti, R, Torricelli, F, Giotti, I, Vogt, P, Toniolo, D, Biondi, M, Bruni, V, Brigante, C, Cisternino, M, Colombo, I, Crosignani, Pg, D'Avanzo, Mg, Dalprà, L, Danesino, C, Di Prospero, F, Donti, E, Falorni, Alberto, Fusi, F, Lanzi, R, Larizza, D, Locatelli, N, Madaschi, S, Maghnie, M, Marzotti, S, Migone, N, Nappi, R, Palli, D, Patricelli, Mg, Pisani, C, Prontera, P, Petraglia, F, Renieri, A, Ricca, I, Ripamonti, A, Russo, G, Russo, S, Tibiletti, Mg, Tonacchera, M, Vegetti, W, Villa, N, Vineis, P, and Zuffardi, O.

Published
2009

26. A large-scale association study to assess the impact of known variants of the human INHA gene on premature ovarian failure

Author

Corre, T., Schuettler, J., Bione, S., Marozzi, A., Persani, L., Rossetti, R., Torricelli, F., Giotti, I., Vogt, P., Toniolo, D., Italian Network for the study of Ovarian Dysfunctions, Biondi, M, Bruni, V, Brigante, C, Cisternino, M, Colombo, I, Crosignani, Pg, D'Avanzo, Mg, Dalprà, L, Danesino, C, Di Prospero, F, Donti, E, Falorni, A, Fusi, F, Lanzi, R, Larizza, D, Locatelli, N, Madaschi, S, Maghnie, M, Marzotti, S, Migone, N, Nappi, R, Palli, D, Patricelli, Mg, Pisani, C, Prontera, P, Petraglia, F, Renieri, Alessandra, Ricca, I, Ripamonti, A, Russo, G, Russo, S, Tibiletti, Mg, Tonacchera, M, Vegetti, W, Villa, N, Vineis, P, and Zuffardi, O.

Subjects
Adult, Adolescent, endocrine system diseases, Genome-wide association study, Primary Ovarian Insufficiency, premature ovarian failure, Biology, Polymorphism, Single Nucleotide, inhibin variants, Cohort Studies, Gene Frequency, Polymorphism (computer science), medicine, Humans, Inhibins, Allele, Risk factor, Child, Allele frequency, Gene, Genetics, INHA, Rehabilitation, genetic risk factor, Obstetrics and Gynecology, Middle Aged, medicine.disease, female genital diseases and pregnancy complications, Premature ovarian failure, infertility, Reproductive Medicine, Female, Genome-Wide Association Study
Abstract

Background Three variants of the human INHA gene have been reported to be associated with premature ovarian failure (POF) in case-control studies involving a small number of patients and controls. Since inhibin has a fundamental role in the control of ovarian function, it is important to establish the relevance of the reported variants for disease risk. Methods Three independent POF cohorts, recruited in Northern and Central Italy and in Germany consisting of a total of 611 patients and 1084 matched controls, were genotyped for the three variants: -16C > T, -124A > G and 769G > A. Results No significant difference was detected between allelic frequencies of the INHA promoter variants between POF patients and controls. The rare allele in the coding variant appeared to be more frequent among the control populations. Conclusions The association between the INHA promoter variants and POF could not be replicated, and our results suggest that this discrepancy is likely to be due to the small sample size of previous studies. The rare allele of the coding variant seems to exert a protective effect against loss of ovarian function, which should be confirmed in additional large and ethnically diverse cohorts.

Published
2009

28. Novel CLN3 mutation causing autophagic vacuolar myopathy

Author

Cortese, A., primary, Tucci, A., additional, Piccolo, G., additional, Galimberti, C. A., additional, Fratta, P., additional, Marchioni, E., additional, Grampa, G., additional, Cereda, C., additional, Grieco, G., additional, Ricca, I., additional, Pittman, A., additional, Ciscato, P., additional, Napoli, L., additional, Lucchini, V., additional, Ripolone, M., additional, Violano, R., additional, Fagiolari, G., additional, Mole, S. E., additional, Hardy, J., additional, Moglia, A., additional, and Moggio, M., additional

Published
2014
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31. Multicenter Prospective Randomized GITMO Trial Comparing High Dose Sequential Chemotherapy with Autografting and CHOP Both Supplemented with Rituximab as Frontline Therapy for High-Risk Follicular Lymphoma (FL) Patients: An Interim Analysis

Author

Ladetto, M., Ricca, I., Benedetti, F., Vitolo, U., Liberati, M., Musso, M., Callea, V., Gallamini, A., Patti, C., Pavone, V., Almici, C., DI RAIMONDO, Francesco, Fioritoni, G., Olivieri, A., Pogliani, E. M., DE SOUZA, C. A., Majolino, I., Boccadoro, M., Gianni, A. M., Pileri, A., Corradini, P., and Tarella, C.

Published
2002

32. The GITMO experience with high-dose chemotherapy and autografting in advanced follicle centre lymphoma (FCL): A multicenter trial showing good feasibility and frequent achievement of clinical and molecular remissions

Author

Ladetto, M., Corradini, P., Sametti, S., Vallet, S., Astolfi, M., Ricca, I., Benedetti, F., Boccomini, C., Brugiatelli, M., Chisesi, T., Coser, P., De Crescenzo, A., Di Renzo, N., Fioritoni, G., Gallamini, A., Levis, A., Majolino, I., Martelli, Maurizio, Morandi, S., Musso, M., Perrotti, A., Santini, G., Vitolo, U., Vivaldi, P., Zambello, R., Pizzolo, G., Gallo, E., Pileri, A., and Tarella, C.

Published
2001

45. Clinical-Genetic Features Influencing Disability in Spastic Paraplegia Type 4: A Cross-sectional Study by the Italian DAISY Network

Author

Salvatore Rossi, Anna Rubegni, Vittorio Riso, Melissa Barghigiani, Maria Teresa Bassi, Roberta Battini, Enrico Bertini, Cristina Cereda, Ettore Cioffi, Chiara Criscuolo, Beatrice Dal Fabbro, Clemente Dato, Maria Grazia D'Angelo, Antonio Di Muzio, Luca Diamanti, Maria Teresa Dotti, Alessandro Filla, Valeria Gioiosa, Rocco Liguori, Andrea Martinuzzi, Roberto Massa, Andrea Mignarri, Rossana Moroni, Olimpia Musumeci, Francesco Nicita, Ilaria Orologio, Laura Orsi, Elena Pegoraro, Antonio Petrucci, Massimo Plumari, Ivana Ricca, Giovanni Rizzo, Silvia Romano, Roberto Rumore, Simone Sampaolo, Marina Scarlato, Marco Seri, Cristina Stefan, Giulia Straccia, Alessandra Tessa, Lorena Travaglini, Rosanna Trovato, Lucia Ulgheri, Giovanni Vazza, Antonio Orlacchio, Gabriella Silvestri, Filippo Maria Santorelli, Mariarosa Anna Beatrice Melone, Carlo Casali, Rossi, S, Rubegni, A, Riso, V, Barghigiani, M, Bassi, Mt, Battini, R, Bertini, E, Cereda, C, Cioffi, E, Criscuolo, C, Dal Fabbro, B, Dato, C, D'Angelo, Mg, Di Muzio, A, Diamanti, L, Dotti, Mt, Filla, A, Gioiosa, V, Liguori, R, Martinuzzi, A, Massa, R, Mignarri, A, Moroni, R, Musumeci, O, Nicita, F, Orologio, I, Orsi, L, Pegoraro, E, Petrucci, A, Plumari, M, Ricca, I, Rizzo, G, Romano, S, Rumore, R, Sampaolo, S, Scarlato, M, Seri, M, Stefan, C, Straccia, G, Tessa, A, Travaglini, L, Trovato, R, Ulgheri, L, Vazza, G, Orlacchio, A, Silvestri, G, Santorelli, Fm, Melone, Mab, Casali, C., and Rossi S, Rubegni A, Riso V, Barghigiani M, Bassi MT, Battini R, Bertini E, Cereda C, Cioffi E, Criscuolo C, Dal Fabbro B, Dato C, D'Angelo MG, Di Muzio A, Diamanti L, Dotti MT, Filla A, Gioiosa V, Liguori R, Martinuzzi A, Massa R, Mignarri A, Moroni R, Musumeci O, Nicita F, Orologio I, Orsi L, Pegoraro E, Petrucci A, Plumari M, Ricca I, Rizzo G, Romano S, Rumore R, Sampaolo S, Scarlato M, Seri M, Stefan C, Straccia G, Tessa A, Travaglini L, Trovato R, Ulgheri L, Vazza G, Orlacchio A, Silvestri G, Santorelli FM, Melone MAB, Casali C.

Subjects
Settore MED/26 - NEUROLOGIA, spastic paraplegia, HSP, SPAST, SPG4, spastic paraplegia, degeneration of the corticospinal tract, Hereditary spastic paraplegia, HSP, SPAST, inherited rare neurologic disorder, Neurology (clinical), SPG4, Spastic paraplegia type 4, Genetics (clinical)
Abstract

Background and Objectives: Hereditary spastic paraplegias (HSPs) are a group of inherited rare neurologic disorders characterized by length-dependent degeneration of the corticospinal tracts and dorsal columns, whose prominent clinical feature is represented by spastic gait. Spastic paraplegia type 4 (SPG4, SPAST-HSP) is the most common form. We present both clinical and molecular findings of a large cohort of patients, with the aim of (1) defining the clinical spectrum of SPAST-HSP in Italy; (2) describing their molecular features; and (3) assessing genotype-phenotype correlations to identify features associated with worse disability.MethodsA cross-sectional retrospective study with molecular and clinical data collected in an anonymized database was performed.ResultsA total of 723 Italian patients with SPAST-HSP (58% men) from 316 families, with a median age at onset of 35 years, were included. Penetrance was 97.8%, with men showing higher Spastic Paraplegia Rating Scale (SPRS) scores (19.67 ± 12.58 vs 16.15 ± 12.61, p = 0.009). In 26.6% of patients with SPAST-HSP, we observed a complicated phenotype, mainly including intellectual disability (8%), polyneuropathy (6.7%), and cognitive decline (6.5%). Late-onset cases seemed to progress more rapidly, and patients with a longer disease course displayed a more severe neurologic disability, with higher SPATAX (3.61 ± 1.46 vs 2.71 ± 1.20, p < 0.001) and SPRS scores (22.63 ± 11.81 vs 12.40 ± 8.83, p < 0.001). Overall, 186 different variants in the SPAST gene were recorded, of which 48 were novel. Patients with SPAST-HSP harboring missense variants displayed intellectual disability (14.5% vs 4.4%, p < 0.001) more frequently, whereas patients with truncating variants presented more commonly cognitive decline (9.7% vs 2.6%, p = 0.001), cerebral atrophy (11.2% vs 3.4%, p = 0.003), lower limb spasticity (61.5% vs 44.5%), urinary symptoms (50.0% vs 31.3%, p < 0.001), and sensorimotor polyneuropathy (11.1% vs 1.1%, p < 0.001). Increasing disease duration (DD) and abnormal motor evoked potentials (MEPs) were also associated with increased likelihood of worse disability (SPATAX score>3).DiscussionThe SPAST-HSP phenotypic spectrum in Italian patients confirms a predominantly pure form of HSP with mild-to-moderate disability in 75% of cases, and slight prevalence of men, who appeared more severely affected. Early-onset cases with intellectual disability were more frequent among patients carrying missense SPAST variants, whereas patients with truncating variants showed a more complicated disease. Both longer DD and altered MEPs are associated with worse disability. Methods: A cross-sectional retrospective study with molecular and clinical data collected in an anonymized database was performed. Results: A total of 723 Italian patients with SPAST-HSP (58%men) from 316 families, with a median age at onset of 35 years, were included. Penetrance was 97.8%, withmen showing higher Spastic Paraplegia Rating Scale (SPRS) scores (19.67 ± 12.58 vs 16.15 ± 12.61, p = 0.009). In 26.6% of patients with SPAST-HSP, we observed a complicated phenotype, mainly including intellectual disability (8%), polyneuropathy (6.7%), and cognitive decline (6.5%). Late-onset cases seemed to progress more rapidly, and patients with a longer disease course displayed a more severe neurologic disability, with higher SPATAX (3.61 ± 1.46 vs 2.71 ± 1.20, p < 0.001) and SPRS scores (22.63 ± 11.81 vs 12.40 ± 8.83, p < 0.001). Overall, 186 different variants in the SPAST gene were recorded, of which 48 were novel. Patients with SPAST-HSP harboring missense variants displayed intellectual disability (14.5% vs 4.4%, p < 0.001) more frequently,whereas patients with truncating variants presentedmore commonly cognitive decline (9.7%vs 2.6%, p = 0.001), cerebral atrophy (11.2% vs 3.4%, p = 0.003), lower limb spasticity (61.5% vs 44.5%), urinary symptoms (50.0% vs 31.3%, p < 0.001), and sensorimotor polyneuropathy (11.1% vs 1.1%, p < 0.001). Increasing disease duration (DD) and abnormalmotor evoked potentials (MEPs) were also associated with increased likelihood of worse disability (SPATAX score>3). Discussion The SPAST-HSP phenotypic spectrum in Italian patients confirms a predominantly pure form of HSP with mild-to-moderate disability in 75% of cases, and slight prevalence of men, who appeared more severely affected. Early-onset cases with intellectual disability were more frequent among patients carrying missense SPAST variants, whereas patients with truncating variants showed a more complicated disease. Both longer DD and altered MEPs are associated with worse disability.

Published
2022

46. Ngs in hereditary ataxia: When rare becomes frequent

Author

Guja Astrea, Roberta Battini, Alessandro Filla, Salvatore Rossi, Vittorio Riso, Marina Melone, Gioacchino Tedeschi, Antonella Antenora, Carlo Casali, Rosanna Trovato, Elena Pegoraro, Gabriella Silvestri, Filippo M. Santorelli, Melissa Barghigiani, Antonio Petrucci, Serena Galosi, Tommasina Fico, Andrea Mignarri, Caterina Caputi, Chiara Fiorillo, Maria Lieto, Alessandro Malandrini, Arianna Scarlatti, Maria Teresa Dotti, Olimpia Musumeci, Ettore Cioffi, Ivana Ricca, Gemma Natale, Francesca Tinelli, Giovanna De Michele, Alessandra Tessa, Carla Battisti, Anna Rubegni, Daniele Galatolo, Vincenzo Leuzzi, Giuseppe De Michele, Galatolo, D, De Michele, G, Silvestri, G, Leuzzi, V, Casali, C, Musumeci, O, Antenora, A, Astrea, G, Barghigiani, M, Battini, Roberta, Battisti, C, Caputi, C, Cioffi, E, Dotti, Mt, Fico, T, Fiorillo, C, Galosi, S, Lieto, M, Alessandro Malandrini, A, Melone, Mab, Mignarri, A, Natale, G, Pegoraro, E, Petrucci, A, Ricca, I, Riso, V, Rossi, S, Rubegni, A, Scarlatti, A, Tinelli, F, Trovato, R, Tedeschi, G, Tessa, A, and Filla, A and Santorelli FM

Subjects
Male, Exome sequencing, HA, Bioinformatics, TRP, Whole Exome Sequencing, Genesi, 80 and over, Medicine, Biology (General), Variant, Child, Genesis, Spectroscopy, Spinocerebellar Degenerations, Aged, 80 and over, Cohort, High-Throughput Nucleotide Sequencing, General Medicine, Middle Aged, Phenotype, Computer Science Applications, Chemistry, Settore MED/26 - NEUROLOGIA, Child, Preschool, Mutation (genetic algorithm), Female, Adult, Diagnostic yield, Mutation, Next‐generation sequencing, Targeted resequencing panel, Adolescent, Aged, Genetic Testing, Humans, Young Adult, QH301-705.5, Article, Catalysis, DNA sequencing, Inorganic Chemistry, Hereditary ataxia, Physical and Theoretical Chemistry, Preschool, QD1-999, cohort, diagnostic yield, exome sequencing, mutation, next-generation sequencing, targeted resequencing panel, variant, Molecular Biology, Gene, business.industry, Organic Chemistry, Etiology, business
Abstract

The term hereditary ataxia (HA) refers to a heterogeneous group of neurological disorders with multiple genetic etiologies and a wide spectrum of ataxia-dominated phenotypes. Massive gene analysis in next-generation sequencing has entered the HA scenario, broadening our genetic and clinical knowledge of these conditions. In this study, we employed a targeted resequencing panel (TRP) in a large and highly heterogeneous cohort of 377 patients with a clinical diagnosis of HA, but no molecular diagnosis on routine genetic tests. We obtained a positive result (genetic diagnosis) in 33.2% of the patients, a rate significantly higher than those reported in similar studies employing TRP (average 19.4%), and in line with those performed using exome sequencing (ES, average 34.6%). Moreover, 15.6% of the patients had an uncertain molecular diagnosis. STUB1, PRKCG, and SPG7 were the most common causative genes. A comparison with published literature data showed that our panel would have identified 97% of the positive cases reported in previous TRP-based studies and 92% of those diagnosed by ES. Proper use of multigene panels, when combined with detailed phenotypic data, seems to be even more efficient than ES in clinical practice.

Published
2021

47. Decreasing ganglioside synthesis delays motor and cognitive symptom onset in Spg11 knockout mice.

Author

Fortier M, Cauhapé M, Buono S, Becker J, Menuet A, Branchu J, Ricca I, Mero S, Dorgham K, El Hachimi KH, Dobrenis K, Colsch B, Samaroo D, Devaux M, Durr A, Stevanin G, Santorelli FM, Colombo S, Cowling B, and Darios F

Subjects
Animals, Humans, Mice, Cognitive Dysfunction metabolism, Cognitive Dysfunction genetics, Glucosyltransferases genetics, Glucosyltransferases metabolism, Mice, Inbred C57BL, Neurofilament Proteins, Neurons metabolism, Proteins genetics, Proteins metabolism, Sialyltransferases genetics, Sialyltransferases deficiency, Gangliosides metabolism, Mice, Knockout, Spastic Paraplegia, Hereditary genetics, Spastic Paraplegia, Hereditary metabolism
Abstract

Biallelic variants in the SPG11 gene account for the most common form of autosomal recessive hereditary spastic paraplegia characterized by motor and cognitive impairment, with currently no therapeutic option. We previously observed in a Spg11 knockout mouse that neurodegeneration is associated with accumulation of gangliosides in lysosomes. To test whether a substrate reduction therapy could be a therapeutic option, we downregulated the key enzyme involved in ganglioside biosynthesis using an AAV-PHP.eB viral vector expressing a miRNA targeting St3gal5. Downregulation of St3gal5 in Spg11 knockout mice prevented the accumulation of gangliosides, delayed the onset of motor and cognitive symptoms, and prevented the upregulation of serum levels of neurofilament light chain, a biomarker widely used in neurodegenerative diseases. Importantly, similar results were observed when Spg11 knockout mice were administrated venglustat, a pharmacological inhibitor of glucosylceramide synthase expected to decrease ganglioside synthesis. Downregulation of St3gal5 or venglustat administration in Spg11 knockout mice strongly decreased the formation of axonal spheroids, previously associated with impaired trafficking. Venglustat had similar effect on cultured human SPG11 neurons. In conclusion, this work identifies the first disease-modifying therapeutic strategy in SPG11, and provides data supporting its relevance for therapeutic testing in SPG11 patients., Competing Interests: Declaration of competing interest G.S. received a grant from the PSL-Biogen program 2019–2023, unrelated to this work. S.B., J.Be., A.M., S.C. and B.Cow. were employees of Dynacure SA. J.Br., G.S. and F.D. are authors of a patent related to this work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2024
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48. Spinocerebellar ataxia 27B: a frequent and slowly progressive autosomal-dominant cerebellar ataxia-experience from an Italian cohort.

Author

Satolli S, Rossi S, Vegezzi E, Pellerin D, Manca ML, Barghigiani M, Battisti C, Bilancieri G, Bruno G, Capacci E, Casali C, Ceravolo R, Cocozza S, Cotti Piccinelli S, Criscuolo C, Danzi MC, De Micco R, De Michele G, Dicaire MJ, Falcone GMI, Fancellu R, Ferchichi Y, Ferrari C, Filla A, Fini N, Govoni A, Lo Vecchio F, Malandrini A, Mignarri A, Musumeci O, Nesti C, Pappatà S, Pellecchia MT, Perna A, Petrucci A, Pomponi MG, Ravenni R, Ricca I, Rufa A, Tabolacci E, Tessa A, Tessitore A, Zuchner S, Silvestri G, Cortese A, Brais B, and Santorelli FM

Subjects
Humans, Middle Aged, Italy epidemiology, Male, Female, Aged, Cohort Studies, Spinocerebellar Ataxias genetics, Spinocerebellar Ataxias diagnostic imaging, Spinocerebellar Ataxias epidemiology, Adult, Cerebellar Ataxia genetics, Cerebellar Ataxia epidemiology, Cerebellar Ataxia diagnostic imaging, Cerebellar Ataxia physiopathology, Age of Onset, Fibroblast Growth Factors, Spinocerebellar Degenerations, Disease Progression
Abstract

Background: Autosomal-dominant spinocerebellar ataxia (ADCA) due to intronic GAA repeat expansion in FGF14 (SCA27B) is a recent, relatively common form of late-onset ataxia., Objective: Here, we aimed to: (1) investigate the relative frequency of SCA27B in different clinically defined disease subgroups with late-onset ataxia collected among 16 tertiary Italian centers; (2) characterize phenotype and diagnostic findings of patients with SCA27B; (3) compare the Italian cohort with other cohorts reported in recent studies., Methods: We screened 396 clinically diagnosed late-onset cerebellar ataxias of unknown cause, subdivided in sporadic cerebellar ataxia, ADCA, and multisystem atrophy cerebellar type. We identified 72 new genetically defined subjects with SCA27B. Then, we analyzed the clinical, neurophysiological, and imaging features of 64 symptomatic cases., Results: In our cohort, the prevalence of SCA27B was 13.4% (53/396) with as high as 38.5% (22/57) in ADCA. The median age of onset of SCA27B patients was 62 years. All symptomatic individuals showed evidence of impaired balance and gait; cerebellar ocular motor signs were also frequent. Episodic manifestations at onset occurred in 31% of patients. Extrapyramidal features (17%) and cognitive impairment (25%) were also reported. Brain magnetic resonance imaging showed cerebellar atrophy in most cases (78%). Pseudo-longitudinal assessments indicated slow progression of ataxia and minimal functional impairment., Conclusion: Patients with SCA27B in Italy present as an adult-onset, slowly progressive cerebellar ataxia with predominant axial involvement and frequent cerebellar ocular motor signs. The high consistency of clinical features in SCA27B cohorts in multiple populations paves the way toward large-scale, multicenter studies., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Published
2024
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49. MRI-ARSACS: An Imaging Index for Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) Identification Based on the Multicenter PROSPAX Study.

Author

Scaravilli A, Negroni D, Senatore C, Ugga L, Cosottini M, Ricca I, Bender B, Traschütz A, Başak AN, Vural A, van de Warrenburg BP, Durr A, La Piana R, Timmann D, Schüle R, Synofzik M, Santorelli FM, and Cocozza S

Subjects
Humans, Male, Female, Adult, Middle Aged, Young Adult, Aged, Prospective Studies, Brain diagnostic imaging, Brain pathology, Magnetic Resonance Imaging methods, Spinocerebellar Ataxias diagnostic imaging, Spinocerebellar Ataxias genetics, Spinocerebellar Ataxias congenital, Muscle Spasticity diagnostic imaging, Spastic Paraplegia, Hereditary genetics, Spastic Paraplegia, Hereditary diagnostic imaging, Spastic Paraplegia, Hereditary diagnosis
Abstract

Background: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and hereditary spastic paraplegia type 7 (SPG7) represent the most common genotypes of spastic ataxia (SPAX). To date, their magnetic resonance imaging (MRI) features have only been described qualitatively, and a pure neuroradiological differential diagnosis between these two conditions is difficult to achieve., Objectives: To test the performance of MRI measures to discriminate between ARSACS and SPG7 (as an index of common SPAX disease)., Methods: In this prospective multicenter study, 3D-T1-weighted images of 59 ARSACS (35.4 ± 10.3 years, M/F = 33/26) and 78 SPG7 (54.8 ± 10.3 years, M/F = 51/27) patients of the PROSPAX Consortium were analyzed, together with 30 controls (45.9 ± 16.9 years, M/F = 15/15). Different linear and surface measures were evaluated. A receiver operating characteristic analysis was performed, calculating area under the curve (AUC) and corresponding diagnostic accuracy parameters., Results: The pons area proved to be the only metric increased exclusively in ARSACS patients (P = 0.02). Other different measures were reduced in ARSACS and SPG7 compared with controls (all with P ≤ 0.005). A cut-off value equal to 1.67 of the pons-to-superior vermis area ratio proved to have the highest AUC (0.98, diagnostic accuracy 93%, sensitivity 97%) in discriminating between ARSACS and SPG7., Conclusions: Evaluation of the pons-to-superior vermis area ratio can discriminate ARSACS from other SPAX patients, as exemplified here by SPG7. Hence, we hereby propose this ratio as the Magnetic Resonance Index for the Assessment and Recognition of patients harboring SACS mutations (MRI-ARSACS), a novel diagnostic tool able to identify ARSACS patients and useful for discriminating ARSACS from other SPAX patients undergoing MRI. © 2024 International Parkinson and Movement Disorder Society., (© 2024 International Parkinson and Movement Disorder Society.)

Published
2024
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50. Deep phenotyping of the neuroimaging and skeletal features in KBG syndrome: a study of 53 patients and review of the literature.

Author

Peluso F, Caraffi SG, Contrò G, Valeri L, Napoli M, Carboni G, Seth A, Zuntini R, Coccia E, Astrea G, Bisgaard AM, Ivanovski I, Maitz S, Brischoux-Boucher E, Carter MT, Dentici ML, Devriendt K, Bellini M, Digilio MC, Doja A, Dyment DA, Farholt S, Ferreira CR, Wolfe LA, Gahl WA, Gnazzo M, Goel H, Grønborg SW, Hammer T, Iughetti L, Kleefstra T, Koolen DA, Lepri FR, Lemire G, Louro P, McCullagh G, Madeo SF, Milone A, Milone R, Nielsen JEK, Novelli A, Ockeloen CW, Pascarella R, Pippucci T, Ricca I, Robertson SP, Sawyer S, Falkenberg Smeland M, Stegmann S, Stumpel CT, Goel A, Taylor JM, Barbuti D, Soresina A, Bedeschi MF, Battini R, Cavalli A, Fusco C, Iascone M, Van Maldergem L, Venkateswaran S, Zuffardi O, Vergano S, Garavelli L, and Bayat A

Subjects
Humans, Facies, Phenotype, Repressor Proteins genetics, Transcription Factors, Neuroimaging, Intellectual Disability diagnosis, Intellectual Disability genetics, Abnormalities, Multiple diagnosis, Abnormalities, Multiple genetics, Bone Diseases, Developmental diagnostic imaging, Bone Diseases, Developmental genetics, Tooth Abnormalities diagnostic imaging, Tooth Abnormalities genetics
Abstract

Background: KBG syndrome is caused by haploinsufficiency of ANKRD11 and is characterised by macrodontia of upper central incisors, distinctive facial features, short stature, skeletal anomalies, developmental delay, brain malformations and seizures. The central nervous system (CNS) and skeletal features remain poorly defined., Methods: CNS and/or skeletal imaging were collected from molecularly confirmed individuals with KBG syndrome through an international network. We evaluated the original imaging and compared our results with data in the literature., Results: We identified 53 individuals, 44 with CNS and 40 with skeletal imaging. Common CNS findings included incomplete hippocampal inversion and posterior fossa malformations; these were significantly more common than previously reported (63.4% and 65.9% vs 1.1% and 24.7%, respectively). Additional features included patulous internal auditory canal, never described before in KBG syndrome, and the recurrence of ventriculomegaly, encephalic cysts, empty sella and low-lying conus medullaris. We found no correlation between these structural anomalies and epilepsy or intellectual disability. Prevalent skeletal findings comprised abnormalities of the spine including scoliosis, coccygeal anomalies and cervical ribs. Hand X-rays revealed frequent abnormalities of carpal bone morphology and maturation, including a greater delay in ossification compared with metacarpal/phalanx bones., Conclusion: This cohort enabled us to describe the prevalence of very heterogeneous neuroradiological and skeletal anomalies in KBG syndrome. Knowledge of the spectrum of such anomalies will aid diagnostic accuracy, improve patient care and provide a reference for future research on the effects of ANKRD11 variants in skeletal and brain development., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2023
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