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1. Clinical features and outcome of patients with autoimmune cerebellar ataxia evaluated with the Scale for the Assessment and Rating of Ataxia

Author

Damato, Valentina, Papi, Claudia, Spagni, Gregorio, Evoli Stampanoni-B, Amelia, Silvestri, Gabriella, Masi, Gianvito, Sabatelli, Eleonora, Campetella, Lucia, Mckeon, A., Andreetta, F., Riso, V., Monte, Gabriele, Luigetti, Marco, Primiano, Guido Alessandro, Calabresi, Paolo, Iorio, Raffaele, Damato V., Papi C., Spagni G., Evoli A. (ORCID:0000-0003-0282-8787), Silvestri G. (ORCID:0000-0002-1950-1468), Masi G., Sabatelli E., Campetella L., Monte G., Luigetti M. (ORCID:0000-0001-7539-505X), Primiano G., Calabresi P. (ORCID:0000-0003-0326-5509), Iorio R. (ORCID:0000-0002-6270-0956), Damato, Valentina, Papi, Claudia, Spagni, Gregorio, Evoli Stampanoni-B, Amelia, Silvestri, Gabriella, Masi, Gianvito, Sabatelli, Eleonora, Campetella, Lucia, Mckeon, A., Andreetta, F., Riso, V., Monte, Gabriele, Luigetti, Marco, Primiano, Guido Alessandro, Calabresi, Paolo, Iorio, Raffaele, Damato V., Papi C., Spagni G., Evoli A. (ORCID:0000-0003-0282-8787), Silvestri G. (ORCID:0000-0002-1950-1468), Masi G., Sabatelli E., Campetella L., Monte G., Luigetti M. (ORCID:0000-0001-7539-505X), Primiano G., Calabresi P. (ORCID:0000-0003-0326-5509), and Iorio R. (ORCID:0000-0002-6270-0956)

Abstract

Background and purpose: This study was undertaken to assess the long-term outcome of patients with paraneoplastic and non paraneoplastic autoimmune cerebellar ataxia (ACA) using the Scale for the Assessment and Rating of Ataxia (SARA). Methods: Patients with subacute cerebellar ataxia admitted to our institution between September 2012 and April 2020 were prospectively recruited. Serum and/or cerebrospinal fluid was tested for neural autoantibodies by indirect immunofluorescence on mouse brain, cell-based assays, and radioimmunoassay. SARA and modified Rankin Scale (mRS) score were employed to assess patients’ outcome. Results: Fifty-five patients were recruited, of whom 23 (42%) met the criteria for cerebellar ataxia of autoimmune etiology. Neural autoantibodies were detected in 22 of 23 patients (Yo–immunoglobulin G [IgG], n = 6; glutamic acid decarboxylase 65–IgG, n = 3; metabotropic glutamate receptor 1–IgG, n = 2; voltage-gated calcium channel P/Q type–IgG, n = 2; Hu-IgG, n = 1; glial fibrillary acidic protein–IgG, n = 1; IgG-binding unclassified antigens, n = 7). Thirteen patients were diagnosed with paraneoplastic cerebellar syndrome (PCS) and 10 with idiopathic ACA. All patients received immunotherapy. Median SARA score was higher in the PCS group at all time points (p = 0.0002), while it decreased significantly within the ACA group (p = 0.049) after immunotherapy. Patients with good outcome (mRS ≤ 2) had less neurological disability (SARA < 15) at disease nadir (p = 0.039) and presented less frequently with paraneoplastic neurological syndrome (p = 0.0028). The univariate linear regression model revealed a good correlation between mRS and SARA score both at disease onset (p < 0.0001) and at last follow-up (p < 0.0001). SARA score < 11 identified patients with good outcome. Conclusions: Patients with idiopathic ACA significantly improved after immunotherapy. SARA score

Published
2022

2. Episodic ataxia and severe infantile phenotype in spinocerebellar ataxia type 14: expansion of the phenotype and novel mutations

Author

De Michele, G., Galatolo, D., Galosi, S., Mignarri, A., Silvestri, Gabriella, Casali, C., Leuzzi, V., Ricca, I., Barghigiani, M., Tessa, A., Cioffi, E., Caputi, C., Riso, V., Dotti, M. T., Sacca, F., Cocozza, S., Filla, A., Santorelli, F. M., Silvestri G. (ORCID:0000-0002-1950-1468), De Michele, G., Galatolo, D., Galosi, S., Mignarri, A., Silvestri, Gabriella, Casali, C., Leuzzi, V., Ricca, I., Barghigiani, M., Tessa, A., Cioffi, E., Caputi, C., Riso, V., Dotti, M. T., Sacca, F., Cocozza, S., Filla, A., Santorelli, F. M., and Silvestri G. (ORCID:0000-0002-1950-1468)

Published
2021

3. Ngs in hereditary ataxia: When rare becomes frequent

Author

Galatolo, D., De Michele, G., Silvestri, Gabriella, Leuzzi, V., Casali, C., Musumeci, O., Antenora, A., Astrea, G., Barghigiani, M., Battini, R., Battisti, C., Caputi, C., Cioffi, E., Dotti, M. T., Fico, T., Fiorillo, C., Galosi, S., Lieto, M., Malandrini, A., Melone, M. A. B., Mignarri, A., Natale, G., Pegoraro, E., Petrucci, A., Ricca, I., Riso, V., Rossi, Salvatore, Rubegni, A., Scarlatti, A., Tinelli, F., Trovato, R., Tedeschi, G., Tessa, A., Filla, A., Santorelli, F. M., Silvestri G. (ORCID:0000-0002-1950-1468), Rossi S., Galatolo, D., De Michele, G., Silvestri, Gabriella, Leuzzi, V., Casali, C., Musumeci, O., Antenora, A., Astrea, G., Barghigiani, M., Battini, R., Battisti, C., Caputi, C., Cioffi, E., Dotti, M. T., Fico, T., Fiorillo, C., Galosi, S., Lieto, M., Malandrini, A., Melone, M. A. B., Mignarri, A., Natale, G., Pegoraro, E., Petrucci, A., Ricca, I., Riso, V., Rossi, Salvatore, Rubegni, A., Scarlatti, A., Tinelli, F., Trovato, R., Tedeschi, G., Tessa, A., Filla, A., Santorelli, F. M., Silvestri G. (ORCID:0000-0002-1950-1468), and Rossi S.

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

4. POLR3A variants in hereditary spastic paraparesis and ataxia: clinical, genetic, and neuroradiological findings in a cohort of Italian patients

Author

Di Donato, I., Gallo, A., Ricca, I., Fini, N., Silvestri, Gabriella, Gurrieri, Fiorella, Cirillo, M., Cerase, A., Natale, G., Matrone, F., Riso, V., Melone, M. A. B., Tessa, A., De Michele, G., Federico, A., Filla, A., Dotti, M. T., Santorelli, F. M., Silvestri G. (ORCID:0000-0002-1950-1468), Gurrieri F. (ORCID:0000-0002-6775-5972), Di Donato, I., Gallo, A., Ricca, I., Fini, N., Silvestri, Gabriella, Gurrieri, Fiorella, Cirillo, M., Cerase, A., Natale, G., Matrone, F., Riso, V., Melone, M. A. B., Tessa, A., De Michele, G., Federico, A., Filla, A., Dotti, M. T., Santorelli, F. M., Silvestri G. (ORCID:0000-0002-1950-1468), and Gurrieri F. (ORCID:0000-0002-6775-5972)

Abstract

Mutations in POLR3A are characterized by high phenotypic heterogeneity, with manifestations ranging from severe childhood-onset hypomyelinating leukodystrophic syndromes to milder and later-onset gait disorders with central hypomyelination, with or without additional non-neurological signs. Recently, a milder phenotype consisting of late-onset spastic ataxia without hypomyelinating leukodystrophy has been suggested to be specific to the intronic c.1909 + 22G > A mutation in POLR3A. Here, we present 10 patients from 8 unrelated families with POLR3A-related late-onset spastic ataxia, all harboring the c.1909 + 22G > A variant. Most of them showed an ataxic-spastic picture, two a “pure” cerebellar phenotype, and one a “pure” spastic presentation. The non-neurological findings typically associated with POLR3A mutations were absent in all the patients. The main findings on brain MRI were bilateral hyperintensity along the superior cerebellar peduncles on FLAIR sequences, observed in most of the patients, and cerebellar and/or spinal cord atrophy, found in half of the patients. Only one patient exhibited central hypomyelination. The POLR3A mutations present in this cohort were the c.1909 + 22G > A splice site variant found in compound heterozygosity with six additional variants (three missense, two nonsense, one splice) and, in one patient, with a novel large deletion involving exons 14–18. Interestingly, this patient had the most “complex” presentation among those observed in our cohort; it included some neurological and non-neurological features, such as seizures, neurosensory deafness, and lipomas, that have not previously been reported in association with late-onset POLR3A-related disorders, and therefore further expand the phenotype.

Published
2021

5. A next generation sequencing-based analysis of a large cohort of ataxic patients refines the clinical spectrum associated with spinocerebellar ataxia 21

Author

Riso, V., Galatolo, D., Barghigiani, M., Galosi, S., Tessa, A., Ricca, I., Rossi, Salvatore, Caputi, C., Cioffi, E., Leuzzi, V., Casali, C., Santorelli, F. M., Silvestri, Gabriella, Rossi S., Silvestri G. (ORCID:0000-0002-1950-1468), Riso, V., Galatolo, D., Barghigiani, M., Galosi, S., Tessa, A., Ricca, I., Rossi, Salvatore, Caputi, C., Cioffi, E., Leuzzi, V., Casali, C., Santorelli, F. M., Silvestri, Gabriella, Rossi S., and Silvestri G. (ORCID:0000-0002-1950-1468)

Abstract

Background and purpose: Spinocerebellar ataxia 21 (SCA21) is a rare autosomal dominant neurodegenerative disorder caused by TMEM240 gene mutations. To date, SCA21 has been reported only in a limited number of families worldwide. Here, we describe clinical and molecular findings in five additional SCA21 patients from four unrelated families, diagnosed through a multicentre next generation sequencing-based molecular screening project on a large cohort of patients with degenerative and congenital ataxias. Methods: A cohort of 393 patients with ataxia of unknown aetiology was selected. Following the identification of heterozygous pathogenic TMEM240 variants using a target resequencing panel, we carried out an in-depth phenotyping of the novel SCA21 patients. Results: Five patients from four unrelated families, three of Italian and one of Libyan origin, were identified. These patients were carriers of previously reported TMEM240 mutations. Clinically, our SCA21 cohort includes both adult onset, slowly progressive cerebellar ataxias associated with cognitive impairment resembling cerebellar cognitive affective syndrome and early onset forms associated with cognitive delay, neuropsychiatric features, or evidence of hypomyelination on brain magnetic resonance imaging. None of our patients exhibited signs of extrapyramidal involvement. The so-called “recurrent” c.509C>T (p.Pro170Leu) mutation was detected in two of four families, corroborating its role as a hot spot. Conclusions: Our results confirm that SCA21 is present also in Italy, suggesting that it might not be as rare as previously thought. The phenotype of these novel SCA21 patients indicates that slowly progressive cerebellar ataxia, and cognitive and psychiatric symptoms are the most typical clinical features associated with mutations in the TMEM240 gene.

Published
2021

6. Clinical characteristics of metabolic associated fatty liver disease (MAFLD) in subjects with myotonic dystrophy type 1 (DM1)

Author

Miele, Luca, Perna, Alessia, Dajko, M., Zocco, Maria Assunta, De Magistris, A., Nicoletti, Tommaso Filippo, Biolato, Marco, Marrone, Giuseppe, Liguori, Antonio, Maccora, Daria, Valenza, Venanzio, Rossi, Salvatore, Riso, V., Di Natale, Daniele, Gasbarrini, Antonio, Grieco, A., Silvestri, Gabriella, Miele L. (ORCID:0000-0003-3464-0068), Perna A., Zocco M. A. (ORCID:0000-0002-0814-9542), Nicoletti T. F., Biolato M., Marrone G., Liguori A., Maccora D., Valenza V. (ORCID:0000-0002-0023-6625), Rossi S., Di Natale D., Gasbarrini A. (ORCID:0000-0002-7278-4823), Silvestri G. (ORCID:0000-0002-1950-1468), Miele, Luca, Perna, Alessia, Dajko, M., Zocco, Maria Assunta, De Magistris, A., Nicoletti, Tommaso Filippo, Biolato, Marco, Marrone, Giuseppe, Liguori, Antonio, Maccora, Daria, Valenza, Venanzio, Rossi, Salvatore, Riso, V., Di Natale, Daniele, Gasbarrini, Antonio, Grieco, A., Silvestri, Gabriella, Miele L. (ORCID:0000-0003-3464-0068), Perna A., Zocco M. A. (ORCID:0000-0002-0814-9542), Nicoletti T. F., Biolato M., Marrone G., Liguori A., Maccora D., Valenza V. (ORCID:0000-0002-0023-6625), Rossi S., Di Natale D., Gasbarrini A. (ORCID:0000-0002-7278-4823), and Silvestri G. (ORCID:0000-0002-1950-1468)

Abstract

Background: Myotonic dystrophy type 1 (DM1) is a rare inherited neuromuscular disease associated with insulin resistance, and its association with metabolically associated fatty liver disease (MAFLD) has never been explored in prospective studies. The aim of this study was to assess the clinical features of MAFLD in DM1 patients. Methods: We investigated the prevalence and the diagnostic features of MAFLD in a cohort of 29 outpatient fully characterized DM1 patients; afterward, we compared the selected cohort of DM1-MAFLD individuals with a propensity-matched cohort of non-DM1-MAFLD Results: 13/29 (44.83%) DM1 patients received a clinical diagnosis of MAFLD. Compared to DM1 patients with normal liver, DM1-MAFLD individuals showed a higher male prevalence (p = 0.008), BMI (p = 0.014), HOMA score (p = 0.012), and GGT levels (p = 0.050). The statistical comparison showed that the DM1-MAFLD group had a more severe MAFLD according to the FIB4 score than non-DM1-MAFLD patients. This association of a more severe form of liver disease with DM1 remained significant after logistic regression analysis (OR: 6.12, 95% CI 1.44- 26.55).

Published
2021

7. Assessment of neurological manifestations in hospitalized patients with COVID-19

Author

Luigetti, M., Iorio, R., Bentivoglio, A. R., Tricoli, L., Riso, V., Marotta, J., Piano, C., Primiano, G., Zileri Del Verme, L., Lo Monaco, M. R., Calabresi, P., Abbate, Valeria, Acampora, Nicola, Addolorato, Giovanni, Agostini, Fabiana, Ainora, Maria Elena, Akacha, Karim, Amato, Elena, Andreani, Francesca, Andriollo, Gloria, Annetta, Maria Giuseppina, Annicchiarico, Brigida Eleonora, Antonelli, Mariangela, Antonucci, Gabriele, Anzellotti, Gian Marco, Armuzzi, Alessandro, Baldi, Fabiana, Barattucci, Ilaria, Barillaro, Christian, Barone, Fabiana, Bellantone, Rocco Domenico Alfonso, Bellieni, Andrea, Bello, Giuseppe, Benicchi, Andrea, Benvenuto, Francesca, Berardini, Ludovica, Berloco, Filippo, Bernabei, Roberto, Bianchi, Antonio, Biasucci, Daniele Guerino, Biasucci, Luigi Marzio, Bibbò, Stefano, Bini, Alessandra, Bisanti, Alessandra, Biscetti, Federico, Bocci, Maria Grazia, Bonadia, Nicola, Bongiovanni, Filippo, Borghetti, Alberto, Bosco, Giulia, Bosello, Silvia, Bove, Vincenzo, Bramato, Giulia, Brandi, Vincenzo, Bruni, Teresa, Bruno, Carmine, Bruno, Dario, Bungaro, Maria Chiara, Buonomo, Alessandro, Burzo, Livia, Calabrese, Angelo, Calvello, Maria Rosaria, Cambieri, Andrea, Cambise, Chiara, Cammà, Giulia, Candelli, Marcello, Canistro, Gennaro, Cantanale, Antonello, Capalbo, Gennaro, Capaldi, Lorenzo, Capone, Emanuele, Capristo, Esmeralda, Carbone, Luigi, Cardone, Silvia, Carelli, Simone, Carfì, Angelo, Carnicelli, Annamaria, Caruso, Cristiano, Casciaro, Francesco Antonio, Catalano, Lucio, Cauda, Roberto, Cecchini, Andrea Leonardo, Cerrito, Lucia, Cesarano, Melania, Chiarito, Annalisa, Cianci, Rossella, Cicchinelli, Sara, Ciccullo, Arturo, Cicetti, Marta, Ciciarello, Francesca, Cingolani, Antonella, Cipriani, Maria Camilla, Consalvo, Maria Ludovica, Coppola, Gaetano, Corbo, Giuseppe Maria, Corsello, Andrea, Costante, Federico, Costanzi, Matteo, Covino, Marcello, Crupi, Davide, Cutuli, Salvatore Lucio, DAddio, Stefano, DAlessandro, Alessia, DAlfonso, Maria Elena, DAngelo, Emanuela, DAversa, Francesca, Damiano, Fernando, De Berardinis, Gian Maria, De Cunzo, Tommaso, De Gaetano, Donati Katleen, De Luca, Giulio, De Matteis, Giuseppe, De Pascale, Gennaro, De Santis, Paolo, De Siena, Martina, De Vito, Francesco, Del Gatto, Valeria, Del Giacomo, Paola, Del Zompo, Fabio, DellAnna, Antonio Maria, Della, Polla Davide, Di Gialleonardo, Luca, Di Giambenedetto, Simona, Di Luca, Roberta, Di Maurizio, Luca, Di Muro, Mariangela, Dusina, Alex, Eleuteri, Davide, Esperide, Alessandra, Fachechi, Daniele, Faliero, Domenico, Falsiroli, Cinzia, Fantoni, Massimo, Fedele, Annalaura, Feliciani, Daniela, Ferrante, Cristina, Ferrone, Giuliano, Festa, Rossano, Fiore, Maria Chiara, Flex, Andrea, Forte, Evelina, Franceschi, Francesco, Francesconi, Alessandra, Franza, Laura, Funaro, Barbara, Fuorlo, Mariella, Fusco, Domenico, Gabrielli, Maurizio, Gaetani, Eleonora, Galletta, Claudia, Gallo, Antonella, Gambassi, Giovanni, Garcovich, Matteo, Gasbarrini, Antonio, Gasparrini, Irene, Gelli, Silvia, Giampietro, Antonella, Gigante, Laura, Giuliano, Gabriele, Giuliano, Giorgia, Giupponi, Bianca, Gremese, Elisa, Grieco, Domenico Luca, Guerrera, Manuel, Guglielmi, Valeria, Guidone, Caterina, Gullì, Antonio, Iaconelli, Amerigo, Iafrati, Aurora, Ianiro, Gianluca, Iaquinta, Angela, Impagnatiello, Michele, Inchingolo, Riccardo, Intini, Enrica, Iorio, Raffaele, Izzi, Immacolata Maria, Jovanovic, Tamara, Kadhim, Cristina, La Macchia, Rosa, La Milia, Daniele Ignazio, Landi, Francesco, Landi, Giovanni, Landi, Rosario, Landolfi, Raffaele, Leo, Massimo, Leone, Paolo Maria, Levantesi, Laura, Liguori, Antonio, Liperoti, Rosa, Lizzio, Marco Maria, Lo Monaco Maria, Rita, Locantore, Pietro, Lombardi, Francesco, Lombardi, Gianmarco, Lopetuso, Loris, Loria, Valentina, Losito, Angela Raffaella, Lucia, Mothanje Barbara Patricia, Macagno, Francesco, Macerola, Noemi, Maggi, Giampaolo, Maiuro, Giuseppe, Mancarella, Francesco, Mangiola, Francesca, Manno, Alberto, Marchesini, Debora, Maresca, Gian Marco, Marrone, Giuseppe, Martis, Ilaria, Martone, Anna Maria, Marzetti, Emanuele, Mattana, Chiara, Matteo, Maria Valeria, Maviglia, Riccardo, Mazzarella, Ada, Memoli, Carmen, Miele, Luca, Migneco, Alessio, Mignini, Irene, Milani, Alessandro, Milardi, Domenico, Montalto, Massimo, Montemurro, Giuliano, Monti, Flavia, Montini, Luca, Morena, Tony Christian, Morra, Vincenzina, Morretta, Chiara, Moschese, Davide, Murace, Celeste Ambra, Murdolo, Martina, Murri, Rita, Napoli, Marco, Nardella, Elisabetta, Natalello, Gerlando, Natalini, Daniele, Navarra, Simone Maria, Nesci, Antonio, Nicoletti, Alberto, Nicoletti, Rocco, Nicoletti, Tommaso Filippo, Nicolò, Rebecca, Nicolotti, Nicola, Nista, Enrico Celestino, Nuzzo, Eugenia, Oggiano, Marco, Ojetti, Veronica, Pagano, Francesco Cosimo, Paiano, Gianfranco, Pais, Cristina, Pallavicini, Federico, Palombo, Andrea, Paolillo, Federico, Papa, Alfredo, Papanice, Domenico, Papparella, Luigi Giovanni, Paratore, Mattia, Parrinello, Giuseppe, Pasciuto, Giuliana, Pasculli, Pierpaolo, Pecorini, Giovanni, Perniola, Simone, Pero, Erika, Petricca, Luca, Petrucci, Martina, Picarelli, Chiara, Piccioni, Andrea, Piccolo, Annalisa, Piervincenzi, Edoardo, Pignataro, Giulia, Pignataro, Raffaele, Pintaudi, Gabriele, Pisapia, Luca, Pizzoferrato, Marco, Pizzolante, Fabrizio, Pola, Roberto, Policola, Caterina, Pompili, Maurizio, Pontecorvi, Flavia, Pontecorvi, Valerio, Ponziani, Francesca, Popolla, Valentina, Porceddu, Enrica, Porfidia, Angelo, Porro, Lucia Maria, Potenza, Annalisa, Pozzana, Francesca, Privitera, Giuseppe, Pugliese, Daniela, Pulcini, Gabriele, Racco, Simona, Raffaelli, Francesca, Ramunno, Vittoria, Rapaccini, Gian Ludovico, Richeldi, Luca, Rinninella, Emanuele, Rocchi, Sara, Romanò, Bruno, Romano, Stefano, Rosa, Federico, Rossi, Laura, Rossi, Raimondo, Rossini, Enrica, Rota, Elisabetta, Rovedi, Fabiana, Rubino, Carlotta, Rumi, Gabriele, Russo, Andrea, Sabia, Luca, Salerno, Andrea, Salini, Sara, Salvatore, Lucia, Samori, Dehara, Sandroni, Claudio, Sanguinetti, Maurizio, Santarelli, Luca, Santini, Paolo, Santolamazza, Danilo, Santoliquido, Angelo, Santopaolo, Francesco, Santoro, Michele Cosimo, Sardeo, Francesco, Sarnari, Caterina, Saviano, Angela, Saviano, Luisa, Scaldaferri, Franco, Scarascia, Roberta, Schepis, Tommaso, Schiavello, Francesca, Scoppettuolo, Giancarlo, Sedda, Davide, Sessa, Flaminio, Sestito, Luisa, Settanni, Carlo, Siciliano, Matteo, Siciliano, Valentina, Sicuranza, Rossella, Simeoni, Benedetta, Simonetti, Jacopo, Smargiassi, Andrea, Soave, Paolo Maurizio, Sonnino, Chiara, Staiti, Domenico, Stella, Claudia, Stella, Leonardo, Stival, Eleonora, Taddei, Eleonora, Talerico, Rossella, Tamburello, Elio, Tamburrini, Enrica, Tanzarella, Eloisa Sofia, Tarascio, Elena, Tarli, Claudia, Tersali, Alessandra, Tilli, Pietro, Timpano, Jacopo, Torelli, Enrico, Torrini, Flavia, Tosato, Matteo, Tosoni, Alberto, Tricoli, Luca, Tritto, Marcello, Tumbarello, Mario, Tummolo, Anita Maria, Vallecoccia, Maria Sole, Valletta, Federico, Varone, Francesco, Vassalli, Francesco, Ventura, Giulio, Verardi, Lucrezia, Vetrone, Lorenzo, Vetrugno, Giuseppe, Visconti, Elena, Visconti, Felicia, Viviani, Andrea, Zaccaria, Raffaella, Zaccone, Carmelina, Zelano, Lorenzo, Zileri Dal Verme, Lorenzo, and Zuccalà, Giuseppe

Subjects
Male, Hospitalized patients, muscle, Settore M-PSI/02 - PSICOBIOLOGIA E PSICOLOGIA FISIOLOGICA, neurological disorders, 0302 clinical medicine, Hyposmia, 030212 general & internal medicine, Respiratory system, education.field_of_study, Brain Diseases, Headache, virus diseases, Neuromuscular Diseases, Middle Aged, Hospitalization, medicine.anatomical_structure, Neurology, Female, medicine.symptom, Adult, medicine.medical_specialty, SARS‐CoV2, Coronavirus disease 2019 (COVID-19), Patients, Short Communication, Anosmia, precision medicine, Population, Encephalopathy, Short Communications, Clinical Neurology, Settore MED/26, 03 medical and health sciences, COVID‐19, Internal medicine, Throat, Influenza, Human, medicine, Humans, education, Aged, Retrospective Studies, business.industry, SARS-CoV-2, COVID-19, Hypoxia (medical), medicine.disease, respiratory tract diseases, body regions, Neurology (clinical), Nervous System Diseases, business, 030217 neurology & neurosurgery
Abstract

Background and purpose The objective of this study was to assess the neurological manifestations in a series of consecutive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients, comparing their frequency with a population hospitalized in the same period for flu/respiratory symptoms, finally not related to SARS-CoV-2. Methods Patients with flu/respiratory symptoms admitted to Fondazione Policlinico Gemelli hospital from 14 March 2020 to 20 April 2020 were retrospectively enrolled. The frequency of neurological manifestations of patients with SARS-CoV-2 infection was compared with a control group. Results In all, 213 patients were found to be positive for SARS-CoV-2, after reverse transcriptase polymerase chain reaction on nasal or throat swabs, whilst 218 patients were found to be negative and were used as a control group. Regarding central nervous system manifestations, in SARS-CoV-2-positive patients a higher frequency of headache, hyposmia and encephalopathy always related to systemic conditions (fever or hypoxia) was observed. Furthermore, muscular involvement was more frequent in SARS-CoV-2 infection. Conclusions Patients with COVID-19 commonly have neurological manifestations but only hyposmia and muscle involvement seem more frequent compared with other flu diseases.

Published
2020

8. High Prevalence and Gender-Related Differences of Gastrointestinal Manifestations in a Cohort of DM1 Patients: A Perspective, Cross-Sectional Study

Author

Perna, A., Maccora, Daria, Rossi, S., Nicoletti, Tommaso Filippo, Zocco, Maria Assunta, Riso, V., Modoni, Anna, Petrucci, A., Valenza, Venanzio, Grieco, Antonio, Miele, Luca, Silvestri, Gabriella, Maccora D., Nicoletti T. F., Zocco M. A. (ORCID:0000-0002-0814-9542), Modoni A., Valenza V. (ORCID:0000-0002-0023-6625), Grieco A. (ORCID:0000-0002-0544-8993), Miele L. (ORCID:0000-0003-3464-0068), Silvestri G. (ORCID:0000-0002-1950-1468), Perna, A., Maccora, Daria, Rossi, S., Nicoletti, Tommaso Filippo, Zocco, Maria Assunta, Riso, V., Modoni, Anna, Petrucci, A., Valenza, Venanzio, Grieco, Antonio, Miele, Luca, Silvestri, Gabriella, Maccora D., Nicoletti T. F., Zocco M. A. (ORCID:0000-0002-0814-9542), Modoni A., Valenza V. (ORCID:0000-0002-0023-6625), Grieco A. (ORCID:0000-0002-0544-8993), Miele L. (ORCID:0000-0003-3464-0068), and Silvestri G. (ORCID:0000-0002-1950-1468)

Published
2020

10. Compound heterozygosity for an expanded (GAA) and a (GAAGGA) repeat at FXN locus: from a diagnostic pitfall to potential clues to the pathogenesis of Friedreich ataxia

Author

Santoro, M., Perna, A., La Rosa, P., Petrillo, S., Piemonte, F., Rossi, S., Riso, V., Nicoletti, Tommaso Filippo, Modoni, Anna, Pomponi, M. G., Chiurazzi, Pietro, Silvestri, Gabriella, Nicoletti T. F., Modoni A., Chiurazzi P. (ORCID:0000-0001-5104-1521), Silvestri G. (ORCID:0000-0002-1950-1468), Santoro, M., Perna, A., La Rosa, P., Petrillo, S., Piemonte, F., Rossi, S., Riso, V., Nicoletti, Tommaso Filippo, Modoni, Anna, Pomponi, M. G., Chiurazzi, Pietro, Silvestri, Gabriella, Nicoletti T. F., Modoni A., Chiurazzi P. (ORCID:0000-0001-5104-1521), and Silvestri G. (ORCID:0000-0002-1950-1468)

Abstract

Friedreich’s ataxia (FRDA) is usually due to a homozygous GAA expansion in intron 1 of the frataxin (FXN) gene. Rarely, uncommon molecular rearrangements at the FXN locus can cause pitfalls in the molecular diagnosis of FRDA. Here we describe a family whose proband was affected by late-onset Friedreich’s ataxia (LOFA); long-range PCR (LR-PCR) documented two small expanded GAA alleles both in the proband and in her unaffected younger sister, who therefore received a diagnosis of pre-symptomatic LOFA. Later studies, however, revealed that the proband’s unaffected sister, as well as their healthy mother, were both carriers of an expanded GAA allele and an uncommon (GAAGGA)66–67 repeat mimicking a GAA expansion at the LR-PCR that was the cause of the wrong initial diagnosis of pre-symptomatic LOFA. Extensive studies in tissues from all the family members, including LR-PCR, assessment of methylation status of FXN locus, MboII restriction analysis and direct sequencing of LR-PCR products, analysis of FXN mRNA, and frataxin protein expression, support the virtual lack of pathogenicity of the rare (GAAGGA)66–67 repeat, also providing significant data about the modulation of epigenetic modifications at the FXN locus. Overall, this report highlights a rare but possible pitfall in FRDA molecular diagnosis, emphasizing the need of further analysis in case of discrepancy between clinical and molecular data.

Published
2020

11. An Italian Neurology Outpatient Clinic Facing SARS-CoV-2 Pandemic: Data From 2,167 Patients

Author

Piano, Carla, Di Stasio, Enrico, Primiano, Guido Alessandro, Janiri, D., Luigetti, Marco, Frisullo, Giovanni, Vollono, Catello, Lucchini, Matteo, Brunetti, V., Monforte, Mauro, Guglielmi, Valeria, Della Marca, Giacomo, Evoli Stampanoni-B, Amelia, Marra, Camillo, Mirabella, Massimiliano, Quaranta, Davide, Ricci, Enzo, Servidei, Serenella, Silvestri, Gabriella, Bellavia, Simone, Bortolani, S., Bove, Francesco, Di Iorio, Riccardo, Di Paolantonio, Andrea, Genovese, Danilo, Ialongo, Tamara, Lo Monaco, Maria Rita, Marotta, Jessica, Patanella, Ak., Perna, Alessia, Petracca, Martina, Presicce, Giorgia, Riso, Vittorio, Rollo, Eleonora, Romano, Angela, Romozzi, Marina, Sancricca, Cristina, Scala, Irene, Spagni, Gregorio, Solito, Marcella, Tricoli, Luca, Zinzi, P., Calabresi, Paolo, Bentivoglio, Anna Rita, Piano C., Di Stasio E. (ORCID:0000-0003-1047-4261), Primiano G., Luigetti M. (ORCID:0000-0001-7539-505X), Frisullo G., Vollono C., Lucchini M. (ORCID:0000-0002-0447-2297), Monforte M., Guglielmi V., Della Marca G. (ORCID:0000-0001-6914-799X), Evoli A. (ORCID:0000-0003-0282-8787), Marra C. (ORCID:0000-0003-3994-4044), Mirabella M. (ORCID:0000-0002-7783-114X), Quaranta D., Ricci E. (ORCID:0000-0003-3092-3597), Servidei S. (ORCID:0000-0001-8478-2799), Silvestri G. (ORCID:0000-0002-1950-1468), Bellavia S., Bove F., Di Iorio R., Di Paolantonio A., Genovese D., Ialongo T., Lo Monaco M. R. (ORCID:0000-0002-1457-7981), Marotta J., Perna A., Petracca M., Presicce G., Riso V., Rollo E., Romano A., Romozzi M., Sancricca C., Scala I., Spagni G., Solito M., Tricoli L., Calabresi P. (ORCID:0000-0003-0326-5509), Bentivoglio A. R. (ORCID:0000-0002-9663-095X), Piano, Carla, Di Stasio, Enrico, Primiano, Guido Alessandro, Janiri, D., Luigetti, Marco, Frisullo, Giovanni, Vollono, Catello, Lucchini, Matteo, Brunetti, V., Monforte, Mauro, Guglielmi, Valeria, Della Marca, Giacomo, Evoli Stampanoni-B, Amelia, Marra, Camillo, Mirabella, Massimiliano, Quaranta, Davide, Ricci, Enzo, Servidei, Serenella, Silvestri, Gabriella, Bellavia, Simone, Bortolani, S., Bove, Francesco, Di Iorio, Riccardo, Di Paolantonio, Andrea, Genovese, Danilo, Ialongo, Tamara, Lo Monaco, Maria Rita, Marotta, Jessica, Patanella, Ak., Perna, Alessia, Petracca, Martina, Presicce, Giorgia, Riso, Vittorio, Rollo, Eleonora, Romano, Angela, Romozzi, Marina, Sancricca, Cristina, Scala, Irene, Spagni, Gregorio, Solito, Marcella, Tricoli, Luca, Zinzi, P., Calabresi, Paolo, Bentivoglio, Anna Rita, Piano C., Di Stasio E. (ORCID:0000-0003-1047-4261), Primiano G., Luigetti M. (ORCID:0000-0001-7539-505X), Frisullo G., Vollono C., Lucchini M. (ORCID:0000-0002-0447-2297), Monforte M., Guglielmi V., Della Marca G. (ORCID:0000-0001-6914-799X), Evoli A. (ORCID:0000-0003-0282-8787), Marra C. (ORCID:0000-0003-3994-4044), Mirabella M. (ORCID:0000-0002-7783-114X), Quaranta D., Ricci E. (ORCID:0000-0003-3092-3597), Servidei S. (ORCID:0000-0001-8478-2799), Silvestri G. (ORCID:0000-0002-1950-1468), Bellavia S., Bove F., Di Iorio R., Di Paolantonio A., Genovese D., Ialongo T., Lo Monaco M. R. (ORCID:0000-0002-1457-7981), Marotta J., Perna A., Petracca M., Presicce G., Riso V., Rollo E., Romano A., Romozzi M., Sancricca C., Scala I., Spagni G., Solito M., Tricoli L., Calabresi P. (ORCID:0000-0003-0326-5509), and Bentivoglio A. R. (ORCID:0000-0002-9663-095X)

Abstract

Objective: Neurological sequelae of SARS-CoV-2 infection have already been reported, but there is insufficient data about the impact of the pandemic on the management of the patients with chronic neurological diseases. We aim to analyze the effect of COVID-19 pandemic and social restriction rules on these fragile patients. Methods: Patients with chronic neurologic diseases routinely followed at the outpatient clinic of Gemelli University Hospital, Rome, were assessed for symptoms suggestive of SARS-CoV-2 infection in the pandemic period, consequences of social restrictions, and neurological disease features, concomitant medical conditions, current medical and disease-specific treatments. Data source: a dedicated telephone survey designed to encompass questions on COVID-19 symptoms and on pandemic effects in chronic neurologic conditions. Results: Overall, 2,167 individuals were analyzed: 63 patients reported contact with COVID-19 positive cases, 41 performed the swab, and 2 symptomatic patients tested positive for COVID-19 (0.09%). One hundred fifty-eight individuals (7%) needed urgent neurological care, deferred due to the pandemic; 641 patients (30%) suspended hospital treatments, physiotherapy or other support interventions; 405 individuals (19%) reported a subjective worsening of neurological symptoms. Conclusions: In our population, the presence of neurological chronic diseases did not increase the prevalence of COVID-19 infection. Nevertheless, the burden of neurological disorders has been worsened by the lockdown.

Published
2020

12. Assessment of neurological manifestations in hospitalized patients with COVID-19

Author

Luigetti, Marco, Iorio, Raffaele, Bentivoglio, Anna Rita, Tricoli, Luca, Riso, Vittorio, Marotta, Jessica, Piano, Carla, Primiano, Guido Alessandro, Zileri Del Verme, L., Lo Monaco, Maria Rita, Calabresi, Paolo, Abbate, V., Acampora, N., Addolorato, G., Agostini, F., Ainora, M. E., Akacha, K., Amato, E., Andreani, F., Andriollo, G., Annetta, Maria Giuseppina, Annicchiarico, B. E., Antonelli, Massimo, Antonucci, G., Anzellotti, G. M., Armuzzi, A., Baldi, F., Barattucci, I., Barillaro, C., Barone, F., Bellantone, R. D. A., Bellieni, A., Bello, G., Benicchi, A., Benvenuto, F., Berardini, L., Berloco, F., Bernabei, R., Bianchi, A., Biasucci, D. G., Biasucci, L. M., Bibbo, S., Bini, A., Bisanti, A., Biscetti, F., Bocci, M. G., Bonadia, N., Bongiovanni, F., Borghetti, A., Bosco, G., Bosello, Silvia Laura, Bove, V., Bramato, G., Brandi, V., Bruni, T., Bruno, C., Bruno, D., Bungaro, M. C., Buonomo, A., Burzo, L., Calabrese, A., Calvello, M. R., Cambieri, A., Cambise, C., Camma, G., Candelli, M., Canistro, G., Cantanale, A., Capalbo, G., Capaldi, L., Capone, E., Capristo, E., Carbone, L., Cardone, S., Carelli, S., Carfi, A., Carnicelli, A., Caruso, C., Casciaro, F. A., Catalano, L., Cauda, R., Cecchini, A. L., Cerrito, L., Cesarano, M., Chiarito, A., Cianci, Rossella, Cicchinelli, S., Ciccullo, A., Cicetti, M., Ciciarello, F., Cingolani, A., Cipriani, M. C., Consalvo, M. L., Coppola, G., Corbo, G. M., Corsello, A., Costante, F., Costanzi, M., Covino, M., Crupi, D., Cutuli, S. L., D'Addio, S., D'Alessandro, A., D'Alfonso, M. E., D'Angelo, E., D'Aversa, F., Damiano, F., De Berardinis, G. M., De Cunzo, T., De Gaetano, D. K., De Luca, G., De Matteis, G., De Pascale, G., De Santis, P., De Siena, M., De Vito, F., Del Gatto, V., Del Giacomo, P., Del Zompo, F., Dell'Anna, A. M., Della, P. D., Di Gialleonardo, L., Di Giambenedetto, S., Di Luca, R., Di Maurizio, L., Di Muro, M., Dusina, A., Eleuteri, D., Esperide, A., Fachechi, D., Faliero, D., Falsiroli, C., Fantoni, M., Fedele, A., Feliciani, D., Ferrante, C., Ferrone, G., Festa, R., Fiore, M. C., Flex, A., Forte, E., Franceschi, Francesco, Francesconi, A., Franza, L., Funaro, B., Fuorlo, M., Fusco, D., Gabrielli, M., Gaetani, E., Galletta, C., Gallo, A., Gambassi, G., Garcovich, M., Gasbarrini, A., Gasparrini, I., Gelli, S., Giampietro, A., Gigante, L., Giuliano, G., Giupponi, B., Gremese, E., Grieco, Domenico Luca, Guerrera, M., Guglielmi, V., Guidone, C., Gulli, A., Iaconelli, A., Iafrati, A., Ianiro, Gianluca, Iaquinta, A., Impagnatiello, M., Inchingolo, R., Intini, E., Iorio, R., Izzi, I. M., Jovanovic, T., Kadhim, C., La Macchia, R., La Milia, D. I., Landi, F., Landi, G., Landi, R., Landolfi, R., Leo, M., Leone, P. M., Levantesi, L., Liguori, A., Liperoti, R., Lizzio, M. M., Lo Monaco Maria, R., Locantore, P., Lombardi, F., Lombardi, G., Lopetuso, L., Loria, V., Losito, A. R., Lucia, M. B. P., Macagno, F., Macerola, N., Maggi, G., Maiuro, G., Mancarella, F., Mangiola, F., Manno, A., Marchesini, D., Maresca, G. M., Marrone, G., Martis, I., Martone, A. M., Marzetti, Emanuele, Mattana, C., Matteo, M. V., Maviglia, R., Mazzarella, A., Memoli, C., Miele, Luca, Migneco, A., Mignini, I., Milani, A., Milardi, D., Montalto, M., Montemurro, G., Monti, F., Montini, Luca, Morena, T. C., Morra, V., Morretta, C., Moschese, D., Murace, C. A., Murdolo, M., Murri, Rita, Napoli, M., Nardella, E., Natalello, G., Natalini, D., Navarra, S. M., Nesci, A., Nicoletti, A., Nicoletti, R., Nicoletti, T. F., Nicolo, R., Nicolotti, N., Nista, E. C., Nuzzo, E., Oggiano, M., Ojetti, V., Pagano, F. C., Paiano, G., Pais, C., Pallavicini, F., Palombo, A., Paolillo, F., Papa, Alfredo, Papanice, D., Papparella, L. G., Paratore, M., Parrinello, G., Pasciuto, G., Pasculli, P., Pecorini, G., Perniola, S., Pero, E., Petricca, L., Petrucci, M., Picarelli, C., Piccioni, A., Piccolo, A., Piervincenzi, E., Pignataro, G., Pignataro, R., Pintaudi, G., Pisapia, L., Pizzoferrato, M., Pizzolante, F., Pola, R., Policola, C., Pompili, M., Pontecorvi, F., Pontecorvi, V., Ponziani, F., Popolla, V., Porceddu, E., Porfidia, A., Porro, L. M., Potenza, A., Pozzana, F., Privitera, G., Pugliese, D., Pulcini, G., Racco, S., Raffaelli, F., Ramunno, V., Rapaccini, G. L., Richeldi, Luca, Rinninella, Emanuele, Rocchi, S., Romano, B., Romano, S., Rosa, F., Rossi, L., Rossi, R., Rossini, E., Rota, E., Rovedi, F., Rubino, C., Rumi, G., Russo, A., Sabia, L., Salerno, A., Salini, S., Salvatore, L., Samori, D., Sandroni, Claudio, Sanguinetti, M., Santarelli, L., Santini, P., Santolamazza, D., Santoliquido, A., Santopaolo, F., Santoro, M. C., Sardeo, F., Sarnari, C., Saviano, A., Saviano, L., Scaldaferri, Franco, Scarascia, R., Schepis, T., Schiavello, F., Scoppettuolo, G., Sedda, D., Sessa, F., Sestito, L., Settanni, C., Siciliano, M., Siciliano, V., Sicuranza, R., Simeoni, B., Simonetti, J., Smargiassi, A., Soave, P. M., Sonnino, C., Staiti, D., Stella, C., Stella, L., Stival, E., Taddei, E., Talerico, R., Tamburello, E., Tamburrini, E., Tanzarella, E. S., Tarascio, E., Tarli, C., Tersali, A., Tilli, P., Timpano, J., Torelli, E., Torrini, F., Tosato, M., Tosoni, A., Tricoli, L., Tritto, M., Tumbarello, M., Tummolo, A. M., Vallecoccia, M. S., Valletta, F., Varone, F., Vassalli, F., Ventura, G., Verardi, L., Vetrone, L., Vetrugno, G., Visconti, E., Visconti, F., Viviani, A., Zaccaria, R., Zaccone, C., Zelano, L., Zileri Dal Verme, L., Zuccala, G., Luigetti M. (ORCID:0000-0001-7539-505X), Iorio R. (ORCID:0000-0002-6270-0956), Bentivoglio A. R. (ORCID:0000-0002-9663-095X), Tricoli L., Riso V., Marotta J., Piano C., Primiano G., Lo Monaco M. R. (ORCID:0000-0002-1457-7981), Calabresi P. (ORCID:0000-0003-0326-5509), Annetta M. G. (ORCID:0000-0001-7574-1311), Antonelli M. (ORCID:0000-0003-3007-1670), Bosello S. (ORCID:0000-0002-4837-447X), Cianci R. (ORCID:0000-0001-5378-8442), Franceschi F. (ORCID:0000-0001-6266-445X), Grieco D. L. (ORCID:0000-0002-4557-6308), Ianiro G. (ORCID:0000-0002-8318-0515), Marzetti E. (ORCID:0000-0001-9567-6983), Miele L. (ORCID:0000-0003-3464-0068), Montini L. (ORCID:0000-0003-4602-5134), Murri R. (ORCID:0000-0003-4263-7854), Papa A. (ORCID:0000-0002-4186-7298), Richeldi L. (ORCID:0000-0001-8594-1448), Rinninella E. (ORCID:0000-0002-9165-2367), Sandroni C. (ORCID:0000-0002-8878-2611), Scaldaferri F. (ORCID:0000-0001-8334-7541), Luigetti, Marco, Iorio, Raffaele, Bentivoglio, Anna Rita, Tricoli, Luca, Riso, Vittorio, Marotta, Jessica, Piano, Carla, Primiano, Guido Alessandro, Zileri Del Verme, L., Lo Monaco, Maria Rita, Calabresi, Paolo, Abbate, V., Acampora, N., Addolorato, G., Agostini, F., Ainora, M. E., Akacha, K., Amato, E., Andreani, F., Andriollo, G., Annetta, Maria Giuseppina, Annicchiarico, B. E., Antonelli, Massimo, Antonucci, G., Anzellotti, G. M., Armuzzi, A., Baldi, F., Barattucci, I., Barillaro, C., Barone, F., Bellantone, R. D. A., Bellieni, A., Bello, G., Benicchi, A., Benvenuto, F., Berardini, L., Berloco, F., Bernabei, R., Bianchi, A., Biasucci, D. G., Biasucci, L. M., Bibbo, S., Bini, A., Bisanti, A., Biscetti, F., Bocci, M. G., Bonadia, N., Bongiovanni, F., Borghetti, A., Bosco, G., Bosello, Silvia Laura, Bove, V., Bramato, G., Brandi, V., Bruni, T., Bruno, C., Bruno, D., Bungaro, M. C., Buonomo, A., Burzo, L., Calabrese, A., Calvello, M. R., Cambieri, A., Cambise, C., Camma, G., Candelli, M., Canistro, G., Cantanale, A., Capalbo, G., Capaldi, L., Capone, E., Capristo, E., Carbone, L., Cardone, S., Carelli, S., Carfi, A., Carnicelli, A., Caruso, C., Casciaro, F. A., Catalano, L., Cauda, R., Cecchini, A. L., Cerrito, L., Cesarano, M., Chiarito, A., Cianci, Rossella, Cicchinelli, S., Ciccullo, A., Cicetti, M., Ciciarello, F., Cingolani, A., Cipriani, M. C., Consalvo, M. L., Coppola, G., Corbo, G. M., Corsello, A., Costante, F., Costanzi, M., Covino, M., Crupi, D., Cutuli, S. L., D'Addio, S., D'Alessandro, A., D'Alfonso, M. E., D'Angelo, E., D'Aversa, F., Damiano, F., De Berardinis, G. M., De Cunzo, T., De Gaetano, D. K., De Luca, G., De Matteis, G., De Pascale, G., De Santis, P., De Siena, M., De Vito, F., Del Gatto, V., Del Giacomo, P., Del Zompo, F., Dell'Anna, A. M., Della, P. D., Di Gialleonardo, L., Di Giambenedetto, S., Di Luca, R., Di Maurizio, L., Di Muro, M., Dusina, A., Eleuteri, D., Esperide, A., Fachechi, D., Faliero, D., Falsiroli, C., Fantoni, M., Fedele, A., Feliciani, D., Ferrante, C., Ferrone, G., Festa, R., Fiore, M. C., Flex, A., Forte, E., Franceschi, Francesco, Francesconi, A., Franza, L., Funaro, B., Fuorlo, M., Fusco, D., Gabrielli, M., Gaetani, E., Galletta, C., Gallo, A., Gambassi, G., Garcovich, M., Gasbarrini, A., Gasparrini, I., Gelli, S., Giampietro, A., Gigante, L., Giuliano, G., Giupponi, B., Gremese, E., Grieco, Domenico Luca, Guerrera, M., Guglielmi, V., Guidone, C., Gulli, A., Iaconelli, A., Iafrati, A., Ianiro, Gianluca, Iaquinta, A., Impagnatiello, M., Inchingolo, R., Intini, E., Iorio, R., Izzi, I. M., Jovanovic, T., Kadhim, C., La Macchia, R., La Milia, D. I., Landi, F., Landi, G., Landi, R., Landolfi, R., Leo, M., Leone, P. M., Levantesi, L., Liguori, A., Liperoti, R., Lizzio, M. M., Lo Monaco Maria, R., Locantore, P., Lombardi, F., Lombardi, G., Lopetuso, L., Loria, V., Losito, A. R., Lucia, M. B. P., Macagno, F., Macerola, N., Maggi, G., Maiuro, G., Mancarella, F., Mangiola, F., Manno, A., Marchesini, D., Maresca, G. M., Marrone, G., Martis, I., Martone, A. M., Marzetti, Emanuele, Mattana, C., Matteo, M. V., Maviglia, R., Mazzarella, A., Memoli, C., Miele, Luca, Migneco, A., Mignini, I., Milani, A., Milardi, D., Montalto, M., Montemurro, G., Monti, F., Montini, Luca, Morena, T. C., Morra, V., Morretta, C., Moschese, D., Murace, C. A., Murdolo, M., Murri, Rita, Napoli, M., Nardella, E., Natalello, G., Natalini, D., Navarra, S. M., Nesci, A., Nicoletti, A., Nicoletti, R., Nicoletti, T. F., Nicolo, R., Nicolotti, N., Nista, E. C., Nuzzo, E., Oggiano, M., Ojetti, V., Pagano, F. C., Paiano, G., Pais, C., Pallavicini, F., Palombo, A., Paolillo, F., Papa, Alfredo, Papanice, D., Papparella, L. G., Paratore, M., Parrinello, G., Pasciuto, G., Pasculli, P., Pecorini, G., Perniola, S., Pero, E., Petricca, L., Petrucci, M., Picarelli, C., Piccioni, A., Piccolo, A., Piervincenzi, E., Pignataro, G., Pignataro, R., Pintaudi, G., Pisapia, L., Pizzoferrato, M., Pizzolante, F., Pola, R., Policola, C., Pompili, M., Pontecorvi, F., Pontecorvi, V., Ponziani, F., Popolla, V., Porceddu, E., Porfidia, A., Porro, L. M., Potenza, A., Pozzana, F., Privitera, G., Pugliese, D., Pulcini, G., Racco, S., Raffaelli, F., Ramunno, V., Rapaccini, G. L., Richeldi, Luca, Rinninella, Emanuele, Rocchi, S., Romano, B., Romano, S., Rosa, F., Rossi, L., Rossi, R., Rossini, E., Rota, E., Rovedi, F., Rubino, C., Rumi, G., Russo, A., Sabia, L., Salerno, A., Salini, S., Salvatore, L., Samori, D., Sandroni, Claudio, Sanguinetti, M., Santarelli, L., Santini, P., Santolamazza, D., Santoliquido, A., Santopaolo, F., Santoro, M. C., Sardeo, F., Sarnari, C., Saviano, A., Saviano, L., Scaldaferri, Franco, Scarascia, R., Schepis, T., Schiavello, F., Scoppettuolo, G., Sedda, D., Sessa, F., Sestito, L., Settanni, C., Siciliano, M., Siciliano, V., Sicuranza, R., Simeoni, B., Simonetti, J., Smargiassi, A., Soave, P. M., Sonnino, C., Staiti, D., Stella, C., Stella, L., Stival, E., Taddei, E., Talerico, R., Tamburello, E., Tamburrini, E., Tanzarella, E. S., Tarascio, E., Tarli, C., Tersali, A., Tilli, P., Timpano, J., Torelli, E., Torrini, F., Tosato, M., Tosoni, A., Tricoli, L., Tritto, M., Tumbarello, M., Tummolo, A. M., Vallecoccia, M. S., Valletta, F., Varone, F., Vassalli, F., Ventura, G., Verardi, L., Vetrone, L., Vetrugno, G., Visconti, E., Visconti, F., Viviani, A., Zaccaria, R., Zaccone, C., Zelano, L., Zileri Dal Verme, L., Zuccala, G., Luigetti M. (ORCID:0000-0001-7539-505X), Iorio R. (ORCID:0000-0002-6270-0956), Bentivoglio A. R. (ORCID:0000-0002-9663-095X), Tricoli L., Riso V., Marotta J., Piano C., Primiano G., Lo Monaco M. R. (ORCID:0000-0002-1457-7981), Calabresi P. (ORCID:0000-0003-0326-5509), Annetta M. G. (ORCID:0000-0001-7574-1311), Antonelli M. (ORCID:0000-0003-3007-1670), Bosello S. (ORCID:0000-0002-4837-447X), Cianci R. (ORCID:0000-0001-5378-8442), Franceschi F. (ORCID:0000-0001-6266-445X), Grieco D. L. (ORCID:0000-0002-4557-6308), Ianiro G. (ORCID:0000-0002-8318-0515), Marzetti E. (ORCID:0000-0001-9567-6983), Miele L. (ORCID:0000-0003-3464-0068), Montini L. (ORCID:0000-0003-4602-5134), Murri R. (ORCID:0000-0003-4263-7854), Papa A. (ORCID:0000-0002-4186-7298), Richeldi L. (ORCID:0000-0001-8594-1448), Rinninella E. (ORCID:0000-0002-9165-2367), Sandroni C. (ORCID:0000-0002-8878-2611), and Scaldaferri F. (ORCID:0000-0001-8334-7541)

Abstract

Background and purpose: The objective of this study was to assess the neurological manifestations in a series of consecutive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients, comparing their frequency with a population hospitalized in the same period for flu/respiratory symptoms, finally not related to SARS-CoV-2. Methods: Patients with flu/respiratory symptoms admitted to Fondazione Policlinico Gemelli hospital from 14 March 2020 to 20 April 2020 were retrospectively enrolled. The frequency of neurological manifestations of patients with SARS-CoV-2 infection was compared with a control group. Results: In all, 213 patients were found to be positive for SARS-CoV-2, after reverse transcriptase polymerase chain reaction on nasal or throat swabs, whilst 218 patients were found to be negative and were used as a control group. Regarding central nervous system manifestations, in SARS-CoV-2-positive patients a higher frequency of headache, hyposmia and encephalopathy always related to systemic conditions (fever or hypoxia) was observed. Furthermore, muscular involvement was more frequent in SARS-CoV-2 infection. Conclusions: Patients with COVID-19 commonly have neurological manifestations but only hyposmia and muscle involvement seem more frequent compared with other flu diseases.

Published
2020

13. Cerebello-Cortical Alterations Linked to Cognitive and Social Problems in Patients With Spastic Paraplegia Type 7: A Preliminary Study

Author

Lupo, M., Olivito, G., Clausi, S., Siciliano, L., Riso, Vittorio, Bozzali, M., Santorelli, F. M., Silvestri, Gabriella, Leggio, M., Riso V., Silvestri G. (ORCID:0000-0002-1950-1468), Lupo, M., Olivito, G., Clausi, S., Siciliano, L., Riso, Vittorio, Bozzali, M., Santorelli, F. M., Silvestri, Gabriella, Leggio, M., Riso V., and Silvestri G. (ORCID:0000-0002-1950-1468)

Abstract

Spastic paraplegia type 7 (SPG7), which represents one of the most common forms of autosomal recessive spastic paraplegia (MIM#607259), often manifests with a complicated phenotype, characterized by progressive spastic ataxia with evidence of cerebellar atrophy on brain MRI. Recent studies have documented the presence of peculiar dentate nucleus hyperintensities on T2-weighted images and frontal executive dysfunction in neuropsychological tests in SPG7 patients. Therefore, we decided to assess whether any particular MRI pattern might be specifically associated with SPG7 mutations and possibly correlated with patients' cognitive profiles. For this purpose, we evaluated six SPG7 patients, studying the cerebello-cortical network by MRI voxel-based morphometry and functional connectivity techniques, compared to 30 healthy control subjects. In parallel, we investigated the cognitive and social functioning of the SPG7 patients. Our results document specific cognitive alterations in language, verbal memory, and executive function in addition to an impairment of social task and emotional functions. The MRI scans showed a diffuse symmetric reduction in the cerebellar gray matter of the right lobule V, right Crus I, and bilateral lobule VI, together with a cerebral gray matter reduction in the lingual gyrus, precuneus, thalamus, and superior frontal gyrus. The evidence of an over-connectivity pattern between both the right and left cerebellar dentate nuclei and specific cerebral regions (the lateral occipital cortex, precuneus, left supramarginal gyrus, and left superior parietal lobule) confirms the presence of cerebello-cortical dysregulation in different networks involved in cognition and social functioning in SPG7 patients.

Published
2020

14. The complex phenotype of spinocerebellar ataxia type 48 in eight unrelated Italian families

Author

Lieto, M., Riso, Vittorio, Galatolo, D., De Michele, G., Rossi, S., Barghigiani, M., Cocozza, S., Pontillo, G., Trovato, R., Sacca, F., Salvatore, E., Tessa, A., Filla, A., Santorelli, F. M., Silvestri, Gabriella, Riso V., Silvestri G. (ORCID:0000-0002-1950-1468), Lieto, M., Riso, Vittorio, Galatolo, D., De Michele, G., Rossi, S., Barghigiani, M., Cocozza, S., Pontillo, G., Trovato, R., Sacca, F., Salvatore, E., Tessa, A., Filla, A., Santorelli, F. M., Silvestri, Gabriella, Riso V., and Silvestri G. (ORCID:0000-0002-1950-1468)

Abstract

Background and purpose: Heterozygous mutations in the STUB1 gene have recently been associated with an autosomal dominant form of spinocerebellar ataxia (SCA) associated with cerebellar cognitive-affective syndrome (CCAS), named SCA48. Methods: Molecular screening was performed in a cohort of 235 unrelated patients with adult-onset, autosomal dominant (17) or sporadic (218) cerebellar ataxia, negative for pathological trinucleotide expansions in the common SCAs, FRDA and FXTAS loci, by using targeted multigene panels or whole-exome sequencing. Bioinformatics analyses, detailed neurological phenotyping and family segregation studies corroborated the pathogenicity of the novel STUB1 mutations. Clinico-diagnostic findings were reviewed to define the phenotypic spectrum. Results: Eight heterozygous STUB1 mutations were identified, six of which were novel in 11 patients from eight index families, giving an estimated overall frequency of 3.4% (8/235) for SCA48 in our study cohort, rising to 23.5% (4/17) when considering only familial cases. All our SCA48 patients had cerebellar ataxia and dysarthria associated with cerebellar atrophy on brain magnetic resonance imaging; of note, many cases were also associated with parkinsonism, chorea and dystonia. CCAS also occurred frequently, whereas definite signs of pyramidal tract dysfunction and peripheral nervous system involvement were absent. One SCA48 patient presented with hypogonadism, associated with other autoimmune endocrine dysfunctions. Conclusions: Our results support SCA48 as a significant cause of adult-onset SCA. Besides CCAS, our SCA48 patients often showed movement disorders and other clinical manifestations previously described in SCAR16, linked to biallelic variants in the same gene, thus suggesting a continuous clinical spectrum and significant overlap amongst recessive and dominantly inherited mutations in STUB1.

Published
2020

16. The complex phenotype of spinocerebellar ataxia type 48 in eight unrelated Italian families

Author

Lieto, M., primary, Riso, V., additional, Galatolo, D., additional, De Michele, G., additional, Rossi, S., additional, Barghigiani, M., additional, Cocozza, S., additional, Pontillo, G., additional, Trovato, R., additional, Saccà, F., additional, Salvatore, E., additional, Tessa, A., additional, Filla, A., additional, Santorelli, F. M., additional, and Silvestri, G., additional

Published
2019
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17. Genetic and epigenetic mutations affect the DNA binding capability of human ZFP57 in transient neonatal diabetes type 1 [*Esposito S, *Baglivo I, co-first authors]

Author

Baglivo I, ESPOSITO, Sabrina, De Cesare L, Sparago A, Anvar Z, Riso V, Cammisa M, FATTORUSSO, Roberto, Grimaldi G, RICCIO, Andrea, PEDONE, Paolo Vincenzo, Baglivo, I, Esposito, Sabrina, De Cesare, L, Sparago, A, Anvar, Z, Riso, V, Cammisa, M, Fattorusso, Roberto, Grimaldi, G, Riccio, Andrea, and Pedone, Paolo Vincenzo

Subjects
Transient neonatal diabete, Hypomethylation, DNA binding, Imprintin g, ZFP57
Abstract

""In the mouse, ZFP57 contains three classical Cys2His2 zinc finger domains (ZF) and recognizes the methylated TGC(met)CGC target sequence using the first and the second ZFs. In this study, we demonstrate that the human ZFP57 (hZFP57) containing six Cys2His2 ZFs, binds the same methylated sequence through the third and the fourth ZFs, and identify the aminoacids critical for DNA interaction. In addition, we present evidences indicating that hZFP57 mutations and hypomethylation of the TNDM1 ICR both associated with Transient Neonatal Diabetes Mellitus type 1 result in loss of hZFP57 binding to the TNDM1 locus, likely causing PLAGL1 activation."" In the mouse, ZFP57 contains three classical Cys2His2 zinc finger domains (ZF) and recognizes the methylated TGCmetCGC target sequence using the first and the second ZFs. In this study, we demonstrate that the human ZFP57 (hZFP57) containing six Cys2His 2 ZFs, binds the same methylated sequence through the third and the fourth ZFs, and identify the aminoacids critical for DNA interaction. In addition, we present evidences indicating that hZFP57 mutations and hypomethylation of the TNDM1 ICR both associated with Transient Neonatal Diabetes Mellitus type 1 result in loss of hZFP57 binding to the TNDM1 locus, likely causing PLAGL1 activation. © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Published
2013

18. Identification of novel cftr expression regulatory elements

Author

IANNONE C., RISO V., COZZOLINO F., COZZOLINO M, MONTI M., ELCE A., TOMAIUOLO R., AMATO F., CASTALDO G., PUCCI P., Iannone, C., Riso, V., Cozzolino, F., Cozzolino, M, Monti, M., Elce, A., Tomaiuolo, R., Amato, F., Castaldo, G., and Pucci, P.

Published
2010

21. Gamma ray imager on the DIII-D tokamak

Author

Pace, D. C., primary, Cooper, C. M., additional, Taussig, D., additional, Eidietis, N. W., additional, Hollmann, E. M., additional, Riso, V., additional, Van Zeeland, M. A., additional, and Watkins, M., additional

Published
2016
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22. Genetic and epigenetic mutations affect the DNA binding capability of human ZFP57 in transient neonatal diabetes type 1

Author

Baglivo I, Esposito S, De Cesare L, Sparago A, Anvar Z, Riso V, Cammisa M, Fattorusso R, Grimaldi G, Riccio A, and Pedone PV.

Abstract

In the mouse, ZFP57 contains three classical Cys2His2 zinc finger domains (ZF) and recognizes the methylated TGCmetCGC target sequence using the first and the second ZFs. In this study, we demonstrate that the human ZFP57 (hZFP57) containing six Cys2His2 ZFs, binds the same methylated sequence through the third and the fourth ZFs, and identify the aminoacids critical for DNA interaction. In addition, we present evidences indicating that hZFP57 mutations and hypomethylation of the TNDM1 ICR both associated with Transient Neonatal Diabetes Mellitus type 1 result in loss of hZFP57 binding to the TNDM1 locus, likely causing PLAGL1 activation.

Published
2013
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24. Il sistema aeroportuale campano: una nota metodologica

Author

CAPALDO F. S., DE RISO V., GALANTE G., ROMANO E., TOCCHETTI, ANDREA, Capaldo, FRANCESCO SAVERIO, V., DE RISO, G., Galante, E., Romano, A., Tocchetti, Capaldo, F. S., DE RISO, V., Galante, G., Romano, E., and Tocchetti, Andrea

Subjects
sistema aeroportuale campano, offerta di trasporto, domanda di trasporto
Abstract

L’obiettivo di questo studio è quello di fornire uno spunto metodologico relativo all’analisi dei sistemi aeroportuali. In particolare, verrà analizzata la possibilità di creare un sistema aeroportuale in Campania, costituito dall’insieme degli aeroporti e delle reciproche relazioni. Lo squilibrio esistente tra domanda che chiede di spostarsi con la modalità aerea e la scadente offerta di trasporto aereo campana, suggerisce la necessità di intervenire in termini di adeguamento delle infrastrutture aeroportuali esistenti ed in termini di nuove realizzazioni. Attualmente il “sistema” campano non è tale perché è mono – aeroportuale (è funzionante il solo aeroporto di Napoli). Metodologicamente il sistema sarà studiato mediante analisi quantitative. In diversi casi, sia a livello nazionale che internazionale, al problema dello squilibrio tra domanda ed offerta, è stata data diversa risposta: - nella maggior parte dei casi si considera il singolo aeroporto e si è interessati, prevalentemente alla determinazione di modelli che consentano di ottimizzare i livelli capacitativi dell’aeroporto; - talvolta, tuttavia, l’impossibilità di incrementare i livelli capacitativi, soprattutto attraverso interventi nel campo di realizzazioni infrastrutturali, indirizza l’attività ingegneristica nella valutazione di fattibilità di nuovi siti aeroportuali. Entrambi gli approcci non risolvono, a nostro avviso, il problema. Nel secondo caso, per esempio, si potrebbe obiettare che non sempre il raddoppio delle infrastrutture consente un raddoppio della capacità. Per tale ragione occorre proporre un diverso approccio metodologico alla risoluzione del problema di squilibrio domanda – offerta, che consideri l’insieme degli aeroporti di una medesima area come elementi interagenti fortemente tra loro, costituendo un “sistema aeroportuale metropolitano o regionale”. L’asserto fondamentale di questo “nuovo“ approccio è che l’entità “sistema” sia costituito da parti in interazione.

Published
2001

31. 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

34. 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

35. The 'crab sign': an imaging feature of spinocerebellar ataxia type 48

Author

Arturo Brunetti, Mario Quarantelli, Vittorio Riso, Teresa Perillo, Lorenzo Ugga, Elvira Guerriero, Giuseppe Pontillo, Sirio Cocozza, Giovanna De Michele, Elena Salvatore, Daniele Galatolo, Francesco Saccà, Cocozza, S., Pontillo, G., De Michele, G., Perillo, T., Guerriero, E., Ugga, L., Salvatore, E., Galatolo, D., Riso, V., Sacca, F., Quarantelli, M., and Brunetti, A.

Subjects
Adult, Male, Cerebellum, Ataxia, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Atrophy, SCA48, Medicine, Humans, Spinocerebellar Ataxias, Radiology, Nuclear Medicine and imaging, Retrospective Studies, Cerebellar ataxia, business.industry, Anatomy, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Hyperintensity, medicine.anatomical_structure, Dentate nucleus, Dentate nucleu, Spinocerebellar ataxia, Cerebellar atrophy, Female, Neurology (clinical), medicine.symptom, Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery, MRI
Abstract

Purpose: A new form of autosomal dominant hereditary spinocerebellar ataxia (SCA) has been recently described (SCA48), and here we investigate its conventional MRI findings to identify the presence of a possible imaging feature of this condition. Methods: In this retrospective observational study, we evaluated conventional MRI scans from 10 SCA48 patients (M/F = 5/5; 44.7 ± 7.8 years). For all subjects, atrophy of both supratentorial and infratentorial compartments were recorded, as well as the presence of possible T2-weighted imaging (T2WI) signal alterations. Results: In SCA48 patients, no meaningful supratentorial changes were found, both in terms of volume loss or MRI signal changes. Atrophy of the cerebellum was present in all cases, involving both the vermis and the hemispheres, but particularly affecting the postero-lateral portions of the cerebellar hemispheres. In all patients, with the exception of only one subject (90.0% of the cases), a T2WI hyperintensity of both dentate nuclei was found. The association of such signal alteration with the pattern of cerebellar atrophy resembled the appearance of a crab (“crab sign”). Conclusion: Our findings suggest that SCA48 patients are characterized by cerebellar atrophy, mainly involving the postero-lateral hemisphere areas, along with a T2WI hyperintensity of dentate nuclei. We propose that the association of such signal change, along with the atrophy of the lateral portion of the cerebellar hemispheres, resembled the appearance of a crab, and therefore, we propose the “crab sign” as a neuroradiological sign present in SCA48 patients.

Published
2020

36. The Control Region of Mitochondrial DNA Shows an Unusual CpG and Non-CpG Methylation Pattern

Author

Vincenzo Riso, Patrizia D'Aquila, Giuseppe Passarino, Marco Giordano, Andrea Riccio, Dina Bellizzi, Teresa Scafone, Bellizzi, D, D'Aquila, P, Scafone, T, Giordano, M, Riso, V, Riccio, Andrea, and Passarino, G.

Subjects
Adult, Male, Bisulfite sequencing, Biology, DNA, Mitochondrial, Cell Line, Dioxygenases, Mice, 03 medical and health sciences, 0302 clinical medicine, Epigenetics of physical exercise, Genetics, Animals, Humans, DNA (Cytosine-5-)-Methyltransferases, Methylated DNA immunoprecipitation, 5-methylcytosine, Molecular Biology, RNA-Directed DNA Methylation, Aged, 030304 developmental biology, Epigenomics, Aged, 80 and over, 0303 health sciences, 5-hydromethylcytosine, General Medicine, DNA Methylation, Middle Aged, Full Papers, Locus Control Region, Molecular biology, Mitochondria, Differentially methylated regions, CpG methylation, DNA methylation, Illumina Methylation Assay, CpG Islands, Female, mitochondrial D-loop region, non-CpG methylation, 030217 neurology & neurosurgery
Abstract

DNA methylation is a common epigenetic modification of the mammalian genome. Conflicting data regarding the possible presence of methylated cytosines within mitochondrial DNA (mtDNA) have been reported. To clarify this point, we analysed the methylation status of mtDNA control region (D-loop) on human and murine DNA samples from blood and cultured cells by bisulphite sequencing and methylated/hydroxymethylated DNA immunoprecipitation assays. We found methylated and hydroxymethylated cytosines in the L-strand of all samples analysed. MtDNA methylation particularly occurs within non-C-phosphate-G (non-CpG) nucleotides, mainly in the promoter region of the heavy strand and in conserved sequence blocks, suggesting its involvement in regulating mtDNA replication and/or transcription. We observed DNA methyltransferases within the mitochondria, but the inactivation of Dnmt1, Dnmt3a, and Dnmt3b in mouse embryonic stem (ES) cells results in a reduction of the CpG methylation, while the non-CpG methylation shows to be not affected. This suggests that D-loop epigenetic modification is only partially established by these enzymes. Our data show that DNA methylation occurs in the mtDNA control region of mammals, not only at symmetrical CpG dinucleotides, typical of nuclear genome, but in a peculiar non-CpG pattern previously reported for plants and fungi. The molecular mechanisms responsible for this pattern remain an open question. © The Author 2013.

Published
2013
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37. Genetic and epigenetic mutations affect the DNA binding capability of human ZFP57 in transient neonatal diabetes type 1

Author

BAGLIVO, Ilaria, ESPOSITO, Sabrina, CAMMISA, MARCO, FATTORUSSO, Roberto, GRIMALDI, Giuseppe, RICCIO, Andrea, PEDONE, Paolo Vincenzo, L, De Cesare, A, Rivellino, A, Sparago, Z, Anvar, V, Riso, I, Baglivo, S, Esposito, L, De Cesare, A, Rivellino, A, Sparago, Z, Anvar, V, Riso, M, Cammisa, R, Fattorusso, G, Grimaldi, A, Riccio, PV, Pedone, Baglivo, Ilaria, Esposito, Sabrina, De Cesare, L, Rivellino, A, Sparago, A, Anvar, Z, Riso, V, Cammisa, Marco, Fattorusso, Roberto, Grimaldi, Giuseppe, Riccio, Andrea, and Pedone, Paolo Vincenzo

Subjects
Hypomethylation, Cell Cycle Proteins, Biochemistry, Infant, Newborn, Diseases, Epigenesis, Genetic, chemistry.chemical_compound, Mice, 0302 clinical medicine, Transient neonatal diabete, Structural Biology, Peptide sequence, ZFP57, Cells, Cultured, Zinc finger, Genetics, 0303 health sciences, Imprinting, DNA-Binding Proteins, 030220 oncology & carcinogenesis, DNA methylation, Protein Binding, Molecular Sequence Data, Biophysics, Biology, Imprintin g, DNA-binding protein, Article, 03 medical and health sciences, medicine, Diabetes Mellitus, Animals, Humans, Epigenetics, Amino Acid Sequence, DNA binding, Molecular Biology, Transcription factor, Embryonic Stem Cells, 030304 developmental biology, Sequence Homology, Amino Acid, Tumor Suppressor Proteins, Infant, Newborn, Cell Biology, DNA, DNA Methylation, medicine.disease, Transient neonatal diabetes, Repressor Proteins, chemistry, Transient neonatal diabetes mellitus, Mutation, Transcription Factors
Abstract

Highlights ► hZFP57 zinc finger 3 and 4 are sufficient for high affinity DNA binding. ► hZFP57 TNDM1 mutations (R248H and H277N) affect DNA binding. ► DNA sequences in the TNDM1 ICR show DNA methylation-dependent binding to hZFP57. ► mZfp57 inactivation results in loss of DNA promoter methylation and Plagl1 activation., In the mouse, ZFP57 contains three classical Cys2His2 zinc finger domains (ZF) and recognizes the methylated TGCmetCGC target sequence using the first and the second ZFs. In this study, we demonstrate that the human ZFP57 (hZFP57) containing six Cys2His2 ZFs, binds the same methylated sequence through the third and the fourth ZFs, and identify the aminoacids critical for DNA interaction. In addition, we present evidences indicating that hZFP57 mutations and hypomethylation of the TNDM1 ICR both associated with Transient Neonatal Diabetes Mellitus type 1 result in loss of hZFP57 binding to the TNDM1 locus, likely causing PLAGL1 activation.

Published
2013

38. Sabratha. La necropoli a Nord-Est del Teatro nell'insula 8 della Regio IV e il riuso dello spazio urbano a scopo funerario

Author

VITALE, Emma, CARRA, RM, Bonacasa, N, Aiosa, S, Mandruzzato, A, Bonacasa Carra, RM, Vitale, E, Cipriano, G, Falzone, G, Scirè, F, Bacigalupo, C, De Meo, A, Leti Messina, T, Tomasello, F, Riso, V, Trapani, F., and Garraffo, S

Subjects
Late Antiquity, Tipologie funerarie, rifunzionalizzazione dello spazio urbano, urban space refunctionalization, Tarda Antichità, Cristianizzazione, road system, Christianization, urban topography, Topografia urbana, grave typology, Settore L-ANT/08 - Archeologia Cristiana E Medievale
Abstract

The cemetery (m 29 x 39), excavated and restored by G. Caputo in the Thirties of the twentieth century, borders westwards the cardo which leads to the Early Christian churches of Regio III, and southwards the Theatre decumanus. The burial area comprises 84 tomb sub-divo, violated or with the gravestones moved. The burial types are: 1) the forma, attested by 43 specimens, 2) the case, rectangular or anthropomorphic, with 26 specimens, 3) nine cupae, characterized by a semi-cylindrical crown placed directly on the gravestones or on a base of limestone blocks, and 4) the mound, only one example. The space organization seems to follow clear rules: all the burials are in fact concentrated in the southern half of the insula, in parallel rows of 4-5 tombs or in less ordered groups of cases. Along the cardo and the decumanus, the cemetery continues beyond its limits with a row of cupae for children. The graveyard covered an area abandoned after the earthquake of 365 d.C.; it was related to some Late Roman houses built on the ruins of the Theatre.

Published
2012

39. Sabratha. Le trasformazioni dello spazio urbano e lo sviluppo delle aree paleocristiane nelle Regiones III -V: studio preliminare per un GIS archeologico

Author

CARRA, Rosa Maria, Carra, Rosa Maria, Bonacasa, N. Carra,R.M. Aiosa,S. Mandruzzato, A. Cipriano, G. Vitale, E.Falzone, G. Tomasello,F. Trapani,F. Riso,V. Garraffo,S. Bacigalupo,C. Scirè,F. De Meo,A., and Carra,R

Subjects
Sabratha, Regiones III-V, urban spaces, IV-VII centuries, Settore L-ANT/08 - Archeologia Cristiana E Medievale
Abstract

Researchers at the University of Palermo, in collaboration with the CNR ITABC for the project PRIN 2008, they have made a preliminary study for an archaeological GIS divided into areas I-XI of Sabratha to gather information on the monuments already studied, or under study, and to promote analysis regarding the reuse of space in the Regiones III-V, after the destruction attributed to the earthquake on 21th of July 365. We present the results of the studies on the Roman Baths of the Regio V and on the Episcopal Complex. The roman baths in the Regio V, insula 1 was born in the second century, with the planning of the Theatre District. Stratigraphic excavations conducted under the mosaics had pointed out the pre-existing structures of the Theatre District (period I); by means of the analysis of the surviving structures has been possible to propose a return of the volumes of the bathroom calculated on the Roman foot (29.60 centimeters) and its phases: the project of the second century (period II.1) and the expansion of the third century (period II.2) with the occupation of the south and east streets. It was assumed continuity of use after the earthquake of 365 for the extraordinary state of preservation of the structures with respect to the Baths of Ocean that were completely destroyed and the Baths of the Regio III, which were transformed into the early Christian Episcopal Complex and had determined the funerary use of adjacent spaces (areas VIII, IX and X of the GIS). The Theater District had lost the characteristics which had distinguished it from the second till the fourth centuries. The transformations of the urban spaces, between the last quarter of the fourth and the fifth centuries, was realized through the bishops and the Christian community; the Episcopal complex had the primary role of the catechetical and the baptismal liturgy even in the late-Vandalic and pre-Byzantine periods, but the most prestigious building in the Forum - the ancient Roman Basilica transformed by the Vandals in the Arian church - was converted to the Orthodox creed after the Byzantine conquest and it become the new cathedral. Justinian himself promoted the built of a new church in the Forum square, which is a rare example of Byzantine church for the splendid mosaic with “Tree of Life”. * La ricerca è stata concordata e condivisa con i Colleghi del Dipartimento alle Antichità di Sabratha, cui sono profondamente grata per il sostegno e l’amichevole ospitalità garantiti a tutti i componenti la Missione dell’Università di Palermo. 47

Published
2012

40. Comprehensive Observational and Longitudinal study on the Outbreak of Stroke-related Spasticity focusing on the Early Onset management with Botulinum NeuroToxin (COLOSSEO-BoNT): protocol for a real-world prospective observational study on upper limb spasticity.

Author

Marano M, Suppa A, Palmieri MG, Cecconi E, Frisullo G, Bovenzi R, Riso V, Anzini A, Brienza M, Anticoli S, Crupi D, Giovannelli M, Massimiani A, Rinalduzzi S, Morena E, Massara MC, Cupini L, Bressi F, Pilato F, Maggi L, Sauchelli D, Iezzi E, Centonze D, Aprile I, Di Lazzaro V, Toni D, and Altavista MC

Subjects
Female, Humans, Male, Longitudinal Studies, Observational Studies as Topic, Prospective Studies, Stroke Rehabilitation methods, Botulinum Toxins, Type A therapeutic use, Botulinum Toxins, Type A administration & dosage, Muscle Spasticity drug therapy, Muscle Spasticity etiology, Neuromuscular Agents therapeutic use, Neuromuscular Agents administration & dosage, Stroke complications, Upper Extremity physiopathology
Abstract

Introduction: Poststroke spasticity (PSS) affects up to 40% of patients who had a stroke. Botulinum neurotoxin type A (BoNT-A) has been shown to improve spasticity, but the optimal timing of its application remains unclear. While several predictors of upper limb PSS are known, their utility in clinical practice in relation to BoNT-A treatment has yet to be fully elucidated. The COLOSSEO-BoNT study aims to investigate predictors of PSS and the effects of BoNT-A timing on spasticity-related metrics in a real-world setting., Methods and Analysis: The recruitment will involve approximately 960 patients who have recently experienced an ischaemic stroke (within 10 days, V0) and will follow them up for 24 months. Parameters will be gathered at specific intervals: (V1) 4, (V2) 8, (V3) 12, (V4) 18 months and (V5) 24 months following enrolment. Patients will be monitored throughout their rehabilitation and outpatient clinic journeys and will be compared based on their BoNT-A treatment status-distinguishing between patients receiving treatment at different timings and those who undergo rehabilitation without treatment. Potential predictors will encompass the Fugl-Meyer assessment, the National Institute of Health Stroke Scale (NIHSS), stroke radiological characteristics, performance status, therapies and access to patient care pathways. Outcomes will evaluate muscle stiffness using the modified Ashworth scale and passive range of motion, along with measures of quality of life, pain, and functionality., Ethics and Dissemination: This study underwent review and approval by the Ethics Committee of the Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy. Regardless of the outcome, the findings will be disseminated through publication in peer-reviewed journals and presentations at national and international conferences., Trial Registration Number: NCT05379413., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2024
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41. Correction to: Retrospective observational study on the use of acetyl-L-carnitine in ALS.

Author

Sassi S, Bianchi E, Diamanti L, Tornabene D, Sette E, Medici D, Matà S, Leccese D, Sperti M, Martinelli I, Ghezzi A, Mandrioli J, Iuzzolino VV, Dubbioso R, Trojsi F, Passaniti C, D'Alvano G, Filosto M, Padovani A, Mazzini L, De Marchi F, Zinno L, Nuredini A, Bongioanni P, Dolciotti C, Canali E, Toschi G, Petrucci A, Perna A, Riso V, Inghilleri M, Libonati L, Cambieri C, and Pupillo E

Published
2023
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42. Retrospective observational study on the use of acetyl-L-carnitine in ALS.

Author

Sassi S, Bianchi E, Diamanti L, Tornabene D, Sette E, Medici D, Matà S, Leccese D, Sperti M, Martinelli I, Ghezzi A, Mandrioli J, Iuzzolino VV, Dubbioso R, Trojsi F, Passaniti C, D'Alvano G, Filosto M, Padovani A, Mazzini L, De Marchi F, Zinno L, Nuredini A, Bongioanni P, Dolciotti C, Canali E, Toschi G, Petrucci A, Perna A, Riso V, Inghilleri M, Libonati L, Cambieri C, and Pupillo E

Subjects
Humans, Retrospective Studies, Case-Control Studies, Double-Blind Method, Acetylcarnitine therapeutic use, Amyotrophic Lateral Sclerosis diagnosis
Abstract

ALCAR (Acetyl-L-carnitine) is a donor of acetyl groups and increases the intracellular levels of carnitine, the primary transporter of fatty acids across the mitochondrial membranes. In vivo studies showed that ALCAR decrease oxidative stress markers and pro-inflammatory cytokines. In a previous double-blind placebo-controlled phase II trial showed positive effects on self-sufficiency (defined as a score of 3+ on the ALSFRS-R items for swallowing, cutting food and handling utensils, and walking) ALSFRS-R total score and FVC. We conducted an observational, retrospective, multicentre, case-control study to provide additional data on the effects of ALCAR in subjects with ALS in Italy. Subjects treated with ALCAR 1.5 g/day or 3 g/day were included and matched with not treated subjects by sex, age at diagnosis, site of onset, and time from diagnosis to baseline, (45 subjects per group). ALCAR 3 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 23 (51.1%) treated subjects (adj. OR 1.18, 95% CI 0.46-3.02). No statistically significant differences were detected in ALSFRS nor FVC nor self-sufficiency. ALCAR 1.5 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 32 (71.1%) treated subjects (adj. OR 0.27, 95% CI 0.10-0.71). For ALSFRS-R, a mean slope of - 1.0 was observed in treated subjects compared to - 1.4 in those not treated (p = 0.0575). No statistically significant difference was detected in the FVC nor self-sufficiency. Additional evidence should be provided to confirm the efficacy of the drug and provide a rationale for the dosage., (© 2023. The Author(s).)

Published
2023
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43. Neurological Erdheim-Chester Disease Manifesting with Subacute or Progressive Cerebellar Ataxia: Novel Case Series and Review of the Literature.

Author

Riso V, Nicoletti TF, Rossi S, Vita MG, Alessia P, Di Natale D, and Silvestri G

Abstract

Neurological involvement is relatively common in Erdheim-Chester disease (ECD), a rare clonal disorder of histiocytic myeloid precursors characterized by multisystem involvement. In ECD patients, neurological symptoms can occur either at onset or during the disease course and may lead to various degrees of neurological disability or affect patients' life expectancy. The clinical neurological presentation of ECD often consists of cerebellar symptoms, showing either a subacute or progressive course. In this latter case, patients manifest with a slowly progressive cerebellar ataxia, variably associated with other non-specific neurological signs, infratentorial leukoencephalopathy, and cerebellar atrophy, possibly mimicking either adult-onset degenerative or immune-mediated ataxia. In such cases, diagnosis of ECD may be particularly challenging, yet some peculiar features are helpful to address it. Here, we retrospectively describe four novel ECD patients, all manifesting cerebellar symptoms at onset. In two cases, slow disease progression and associated brain MRI features simulated a degenerative cerebellar ataxia. Three patients received a definite diagnosis of histiocytosis, whereas one case lacked histology confirmation, although clinical diagnostic features were strongly suggestive. Our findings regarding existing literature data focused on neurological ECD will be also discussed to highlight those diagnostic clues helpful to address diagnosis.

Published
2022
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44. Clinical-Genetic Features Influencing Disability in Spastic Paraplegia Type 4: A Cross-sectional Study by the Italian DAISY Network.

Author

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, and Casali C

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., 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%, 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)., 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., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Published
2022
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45. Episodic ataxia and severe infantile phenotype in spinocerebellar ataxia type 14: expansion of the phenotype and novel mutations.

Author

De Michele G, Galatolo D, Galosi S, Mignarri A, Silvestri G, Casali C, Leuzzi V, Ricca I, Barghigiani M, Tessa A, Cioffi E, Caputi C, Riso V, Dotti MT, Saccà F, De Michele G, Cocozza S, Filla A, and Santorelli FM

Subjects
Ataxia, Female, Heterozygote, Humans, Mutation, Phenotype, Protein Kinase C genetics, Spinocerebellar Ataxias diagnosis, Spinocerebellar Ataxias genetics
Abstract

Introduction: Spinocerebellar ataxia type 14 (SCA14) is a dominantly inherited neurological disorder characterized by slowly progressive cerebellar ataxia. SCA14 is caused by mutations in PRKCG, a gene encoding protein kinase C gamma (PKCγ), a master regulator of Purkinje cells development., Methods: We performed next-generation sequencing targeted resequencing panel encompassing 273 ataxia genes in 358 patients with genetically undiagnosed ataxia., Results: We identified fourteen patients in ten families harboring nine pathogenic heterozygous variants in PRKCG, seven of which were novel. We encountered four patients with not previously described phenotypes: one with episodic ataxia, one with a spastic paraparesis dominating her clinical manifestations, and two children with an unusually severe phenotype., Conclusions: Our study broadens the genetic and clinical spectrum of SCA14., (© 2021. The Author(s).)

Published
2022
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46. POLR3A variants in hereditary spastic paraparesis and ataxia: clinical, genetic, and neuroradiological findings in a cohort of Italian patients.

Author

Di Donato I, Gallo A, Ricca I, Fini N, Silvestri G, Gurrieri F, Cirillo M, Cerase A, Natale G, Matrone F, Riso V, Melone MAB, Tessa A, De Michele G, Federico A, Filla A, Dotti MT, and Santorelli FM

Subjects
Ataxia diagnostic imaging, Ataxia genetics, Child, Humans, Mutation, Phenotype, RNA Polymerase III genetics, Optic Atrophy, Paraparesis, Spastic, Spastic Paraplegia, Hereditary diagnostic imaging, Spastic Paraplegia, Hereditary genetics, Spinocerebellar Ataxias
Abstract

Mutations in POLR3A are characterized by high phenotypic heterogeneity, with manifestations ranging from severe childhood-onset hypomyelinating leukodystrophic syndromes to milder and later-onset gait disorders with central hypomyelination, with or without additional non-neurological signs. Recently, a milder phenotype consisting of late-onset spastic ataxia without hypomyelinating leukodystrophy has been suggested to be specific to the intronic c.1909 + 22G > A mutation in POLR3A. Here, we present 10 patients from 8 unrelated families with POLR3A-related late-onset spastic ataxia, all harboring the c.1909 + 22G > A variant. Most of them showed an ataxic-spastic picture, two a "pure" cerebellar phenotype, and one a "pure" spastic presentation. The non-neurological findings typically associated with POLR3A mutations were absent in all the patients. The main findings on brain MRI were bilateral hyperintensity along the superior cerebellar peduncles on FLAIR sequences, observed in most of the patients, and cerebellar and/or spinal cord atrophy, found in half of the patients. Only one patient exhibited central hypomyelination. The POLR3A mutations present in this cohort were the c.1909 + 22G > A splice site variant found in compound heterozygosity with six additional variants (three missense, two nonsense, one splice) and, in one patient, with a novel large deletion involving exons 14-18. Interestingly, this patient had the most "complex" presentation among those observed in our cohort; it included some neurological and non-neurological features, such as seizures, neurosensory deafness, and lipomas, that have not previously been reported in association with late-onset POLR3A-related disorders, and therefore further expand the phenotype., (© 2021. The Author(s).)

Published
2022
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47. Clinical features and outcome of patients with autoimmune cerebellar ataxia evaluated with the Scale for the Assessment and Rating of Ataxia.

Author

Damato V, Papi C, Spagni G, Evoli A, Silvestri G, Masi G, Sabatelli E, Campetella L, McKeon A, Andreetta F, Riso V, Monte G, Luigetti M, Primiano G, Calabresi P, and Iorio R

Subjects
Animals, Autoantibodies, Humans, Immunologic Factors therapeutic use, Immunotherapy, Mice, Radioimmunoassay, Cerebellar Ataxia diagnosis, Cerebellar Ataxia therapy
Abstract

Background and Purpose: This study was undertaken to assess the long-term outcome of patients with paraneoplastic and non paraneoplastic autoimmune cerebellar ataxia (ACA) using the Scale for the Assessment and Rating of Ataxia (SARA)., Methods: Patients with subacute cerebellar ataxia admitted to our institution between September 2012 and April 2020 were prospectively recruited. Serum and/or cerebrospinal fluid was tested for neural autoantibodies by indirect immunofluorescence on mouse brain, cell-based assays, and radioimmunoassay. SARA and modified Rankin Scale (mRS) score were employed to assess patients' outcome., Results: Fifty-five patients were recruited, of whom 23 (42%) met the criteria for cerebellar ataxia of autoimmune etiology. Neural autoantibodies were detected in 22 of 23 patients (Yo-immunoglobulin G [IgG], n = 6; glutamic acid decarboxylase 65-IgG, n = 3; metabotropic glutamate receptor 1-IgG, n = 2; voltage-gated calcium channel P/Q type-IgG, n = 2; Hu-IgG, n = 1; glial fibrillary acidic protein-IgG, n = 1; IgG-binding unclassified antigens, n = 7). Thirteen patients were diagnosed with paraneoplastic cerebellar syndrome (PCS) and 10 with idiopathic ACA. All patients received immunotherapy. Median SARA score was higher in the PCS group at all time points (p = 0.0002), while it decreased significantly within the ACA group (p = 0.049) after immunotherapy. Patients with good outcome (mRS ≤ 2) had less neurological disability (SARA < 15) at disease nadir (p = 0.039) and presented less frequently with paraneoplastic neurological syndrome (p = 0.0028). The univariate linear regression model revealed a good correlation between mRS and SARA score both at disease onset (p < 0.0001) and at last follow-up (p < 0.0001). SARA score < 11 identified patients with good outcome., Conclusions: Patients with idiopathic ACA significantly improved after immunotherapy. SARA score accurately reflects patients' clinical status and may be a suitable outcome measure for patients with ACA., (© 2021 European Academy of Neurology.)

Published
2022
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48. Clinical characteristics of metabolic associated fatty liver disease (MAFLD) in subjects with myotonic dystrophy type 1 (DM1).

Author

Miele L, Perna A, Dajko M, Zocco MA, De Magistris A, Nicoletti TF, Biolato M, Marrone G, Liguori A, Maccora D, Valenza V, Rossi S, Riso V, Di Natale D, Gasbarrini A, Grieco A, and Silvestri G

Subjects
Adult, Case-Control Studies, Comorbidity, Female, Humans, Insulin Resistance, Liver Cirrhosis epidemiology, Male, Middle Aged, Myotonic Dystrophy epidemiology, Non-alcoholic Fatty Liver Disease epidemiology, Prevalence, Prospective Studies, Myotonic Dystrophy physiopathology, Non-alcoholic Fatty Liver Disease physiopathology
Abstract

Background: Myotonic dystrophy type 1 (DM1) is a rare inherited neuromuscular disease associated with insulin resistance, and its association with metabolically associated fatty liver disease (MAFLD) has never been explored in prospective studies. The aim of this study was to assess the clinical features of MAFLD in DM1 patients., Methods: We investigated the prevalence and the diagnostic features of MAFLD in a cohort of 29 outpatient fully characterized DM1 patients; afterward, we compared the selected cohort of DM1-MAFLD individuals with a propensity-matched cohort of non-DM1-MAFLD RESULTS: 13/29 (44.83%) DM1 patients received a clinical diagnosis of MAFLD. Compared to DM1 patients with normal liver, DM1-MAFLD individuals showed a higher male prevalence (p = 0.008), BMI (p = 0.014), HOMA score (p = 0.012), and GGT levels (p = 0.050). The statistical comparison showed that the DM1-MAFLD group had a more severe MAFLD according to the FIB4 score than non-DM1-MAFLD patients. This association of a more severe form of liver disease with DM1 remained significant after logistic regression analysis (OR: 6.12, 95% CI 1.44- 26.55)., Competing Interests: Conflict of interest None declared., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Published
2021
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49. NGS in Hereditary Ataxia: When Rare Becomes Frequent.

Author

Galatolo D, De Michele G, Silvestri G, Leuzzi V, Casali C, Musumeci O, Antenora A, Astrea G, Barghigiani M, Battini R, Battisti C, Caputi C, Cioffi E, De Michele G, Dotti MT, Fico T, Fiorillo C, Galosi S, Lieto M, 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, Filla A, and Santorelli FM

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Female, Genetic Testing, Humans, Male, Middle Aged, Mutation, Exome Sequencing, Young Adult, High-Throughput Nucleotide Sequencing, Spinocerebellar Degenerations genetics
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
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50. A next generation sequencing-based analysis of a large cohort of ataxic patients refines the clinical spectrum associated with spinocerebellar ataxia 21.

Author

Riso V, Galatolo D, Barghigiani M, Galosi S, Tessa A, Ricca I, Rossi S, Caputi C, Cioffi E, Leuzzi V, Casali C, Santorelli FM, and Silvestri G

Subjects
Adult, Ataxia, Humans, Membrane Proteins genetics, Mutation, Pedigree, High-Throughput Nucleotide Sequencing, Spinocerebellar Degenerations
Abstract

Background and Purpose: Spinocerebellar ataxia 21 (SCA21) is a rare autosomal dominant neurodegenerative disorder caused by TMEM240 gene mutations. To date, SCA21 has been reported only in a limited number of families worldwide. Here, we describe clinical and molecular findings in five additional SCA21 patients from four unrelated families, diagnosed through a multicentre next generation sequencing-based molecular screening project on a large cohort of patients with degenerative and congenital ataxias., Methods: A cohort of 393 patients with ataxia of unknown aetiology was selected. Following the identification of heterozygous pathogenic TMEM240 variants using a target resequencing panel, we carried out an in-depth phenotyping of the novel SCA21 patients., Results: Five patients from four unrelated families, three of Italian and one of Libyan origin, were identified. These patients were carriers of previously reported TMEM240 mutations. Clinically, our SCA21 cohort includes both adult onset, slowly progressive cerebellar ataxias associated with cognitive impairment resembling cerebellar cognitive affective syndrome and early onset forms associated with cognitive delay, neuropsychiatric features, or evidence of hypomyelination on brain magnetic resonance imaging. None of our patients exhibited signs of extrapyramidal involvement. The so-called "recurrent" c.509C>T (p.Pro170Leu) mutation was detected in two of four families, corroborating its role as a hot spot., Conclusions: Our results confirm that SCA21 is present also in Italy, suggesting that it might not be as rare as previously thought. The phenotype of these novel SCA21 patients indicates that slowly progressive cerebellar ataxia, and cognitive and psychiatric symptoms are the most typical clinical features associated with mutations in the TMEM240 gene., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Published
2021
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