655 results on '"Claudio Bruno"'
Search Results
2. Decreased free D-aspartate levels in the blood serum of patients with schizophrenia
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Martina Garofalo, Giuseppe De Simone, Zoraide Motta, Tommaso Nuzzo, Elisa De Grandis, Claudio Bruno, Silvia Boeri, Maria Pia Riccio, Lucio Pastore, Carmela Bravaccio, Felice Iasevoli, Francesco Salvatore, Loredano Pollegioni, Francesco Errico, Andrea de Bartolomeis, and Alessandro Usiello
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D-serine ,D-aspartate ,treatment-resistant ,antipsychotics ,schizophrenia ,autism spectrum disorder ,Psychiatry ,RC435-571 - Abstract
IntroductionSchizophrenia (SCZ) and autism spectrum disorder (ASD) are neurodevelopmental diseases characterized by different psychopathological manifestations and divergent clinical trajectories. Various alterations at glutamatergic synapses have been reported in both disorders, including abnormal NMDA and metabotropic receptor signaling.MethodsWe conducted a bicentric study to assess the blood serum levels of NMDA receptors-related glutamatergic amino acids and their precursors, including L-glutamate, L-glutamine, D-aspartate, L-aspartate, L-asparagine, D-serine, L-serine and glycine, in ASD, SCZ patients and their respective control subjects. Specifically, the SCZ patients were subdivided into treatment-resistant and non-treatment-resistant SCZ patients, based on their responsivity to conventional antipsychotics.ResultsD-serine and D-aspartate serum reductions were found in SCZ patients compared to controls. Conversely, no significant differences between cases and controls were found in amino acid concentrations in the two ASD cohorts analyzed.DiscussionThis result further encourages future research to evaluate the predictive role of selected D-amino acids as peripheral markers for SCZ pathophysiology and diagnosis.
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- 2024
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3. Myopathologic trajectory in Duchenne muscular dystrophy (DMD) reveals lack of regeneration due to senescence in satellite cells
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Nastasia Cardone, Valentina Taglietti, Serena Baratto, Kaouthar Kefi, Baptiste Periou, Ciryl Gitiaux, Christine Barnerias, Peggy Lafuste, France Leturcq Pharm, Juliette Nectoux Pharm, Chiara Panicucci, Isabelle Desguerre, Claudio Bruno, François-Jerome Authier, Chiara Fiorillo, Frederic Relaix, and Edoardo Malfatti
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Duchenne muscular dystrophy ,Fibrosis ,FAPs ,Muscle regeneration ,Cellular senescence ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Duchenne muscular dystrophy (DMD) is a devastating X-linked muscular disease, caused by mutations in the DMD gene encoding Dystrophin and affecting 1:5000 boys worldwide. Lack of Dystrophin leads to progressive muscle wasting and degeneration resulting in cardiorespiratory failure. Despite the absence of a definitive cure, innovative therapeutic avenues are emerging. Myopathologic studies are important to further understand the biological mechanisms of the disease and to identify histopathologic benchmarks for clinical evaluations. We conducted a myopathologic analysis on twenty-four muscle biopsies from DMD patients, with particular emphasis on regeneration, fibro-adipogenic progenitors and muscle stem cells behavior. We describe an increase in content of fibro-adipogenic progenitors, central orchestrators of fibrotic progression and lipid deposition, concurrently with a decline in muscle regenerative capacity. This regenerative impairment strongly correlates with compromised activation and expansion of muscle stem cells. Furthermore, our study uncovers an early acquisition of a senescence phenotype by DMD-afflicted muscle stem cells. Here we describe the myopathologic trajectory intrinsic to DMD and establish muscle stem cell senescence as a pivotal readout for future therapeutic interventions.
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- 2023
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4. Digital health and Clinical Patient Management System (CPMS) platform utility for data sharing of neuromuscular patients: the Italian EURO-NMD experience
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Fernanda Fortunato, Francesca Bianchi, Giulia Ricci, Francesca Torri, Francesca Gualandi, Marcella Neri, Marianna Farnè, Fabio Giannini, Alessandro Malandrini, Nila Volpi, Diego Lopergolo, Vincenzo Silani, Nicola Ticozzi, Federico Verde, Davide Pareyson, Silvia Fenu, Silvia Bonanno, Vincenzo Nigro, Cristina Peduto, Paola D’Ambrosio, Roberta Zeuli, Mariateresa Zanobio, Esther Picillo, Serenella Servidei, Guido Primiano, Cristina Sancricca, Monica Sciacco, Roberta Brusa, Massimiliano Filosto, Stefano Cotti Piccinelli, Elena Pegoraro, Tiziana Mongini, Luca Solero, Giulio Gadaleta, Chiara Brusa, Carlo Minetti, Claudio Bruno, Chiara Panicucci, Valeria A. Sansone, Christian Lunetta, Alice Zanolini, Antonio Toscano, Alessia Pugliese, Giulia Nicocia, Enrico Bertini, Michela Catteruccia, Daria Diodato, Antonio Atalaia, Teresinha Evangelista, Gabriele Siciliano, and Alessandra Ferlini
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Telemedicine ,CPMS ,ERN ,Rare diseases ,Digital health ,Medicine - Abstract
Abstract Background The development of e-health technologies for teleconsultation and exchange of knowledge is one of the core purposes of European Reference Networks (ERNs), including the ERN EURO-NMD for rare neuromuscular diseases. Within ERNs, the Clinical Patient Management System (CPMS) is a web-based platform that seeks to boost active collaboration within and across the network, implementing data sharing. Through CPMS, it is possible to both discuss patient cases and to make patients’ data available for registries and databases in a secure way. In this view, CPMS may be considered a sort of a temporary storage for patients’ data and an effective tool for data sharing; it facilitates specialists’ consultation since rare diseases (RDs) require multidisciplinary skills, specific, and outstanding clinical experience. Following European Union (EU) recommendation, and to promote the use of CPMS platform among EURO-NMD members, a twelve-month pilot project was set up to train the 15 Italian Health Care Providers (HCPs). In this paper, we report the structure, methods, and results of the teaching course, showing that tailored, ERN-oriented, training can significantly enhance the profitable use of the CPMS. Results Throughout the training course, 45 professionals learned how to use the many features of the CPMS, eventually opening 98 panels of discussion—amounting to 82% of the total panels included in the EURO-NMD. Since clinical, genetic, diagnostic, and therapeutic data of patients can be securely stored within the platform, we also highlight the importance of this platform as an effective tool to discuss and share clinical cases, in order to ease both case solving and data storing. Conclusions In this paper, we discuss how similar course could help implementing the use of the platform, highlighting strengths and weaknesses of e-health for ERNs. The expected result is the creation of a “map” of neuromuscular patients across Europe that might be improved by a wider use of CPMS.
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- 2023
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5. Correction to: Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study
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Claudia A. Chiriboga, Claudio Bruno, Tina Duong, Dirk Fischer, Eugenio Mercuri, Janbernd Kirschner, Anna Kostera-Pruszczyk, Birgit Jaber, Ksenija Gorni, Heidemarie Kletzl, Imogen Carruthers, Carmen Martin, Francis Warren, Renata S. Scalco, Kathryn R. Wagner, Francesco Muntoni, and the JEWELFISH Study Group
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Neurology. Diseases of the nervous system ,RC346-429 - Published
- 2023
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6. Toxicological Potential of the FDA-Approved Treatment against Monkeypox. Comment on Zovi et al. Pharmacological Agents with Antiviral Activity against Monkeypox Infection. Int. J. Mol. Sci. 2022, 23, 15941
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Gabriel Christian de Farias Morais, Umberto Laino Fulco, Edilson Dantas da Silva, Claudio Bruno Silva de Oliveira, and Jonas Ivan Nobre Oliveira
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Monkeypox ,tecovirimat ,physicochemical descriptors ,pharmacokinetic ,toxicity ,ADME-T ,Computer applications to medicine. Medical informatics ,R858-859.7 - Abstract
Recently, some drugs were approved to control Monkeypox (MPX), among them tecovirimat. This was recently approved by regulatory agencies around the world, the paper of Zovi et al entitled Pharmacological Agents with Antiviral Activity against Monkeypox Infection highlight it as safe and effective, although the safety data are still not very robust. In this Comment, we present some theoretical evaluations of its safety, considering that for use in humans it is essential to have a rich scientific literature in the area. After a series of analyses, a potential risk of liver, respiratory and kidney damage was found in addition to carcinogenic potential. Thus, while we agree that there is a need for rapid responses to infection, we reinforce that well-designed and adequately powered studies should not only focus on investigating the pharmacological efficacy of tecovirimat but also demonstrate its safety in humans. Therefore, in this Comment, we present some concerns that may help in formulating a safer treatment for patients infected with Monkeypox virus (MPXV).
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- 2023
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7. Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study
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Claudia A. Chiriboga, Claudio Bruno, Tina Duong, Dirk Fischer, Eugenio Mercuri, Janbernd Kirschner, Anna Kostera-Pruszczyk, Birgit Jaber, Ksenija Gorni, Heidemarie Kletzl, Imogen Carruthers, Carmen Martin, Francis Warren, Renata S. Scalco, Kathryn R. Wagner, Francesco Muntoni, and the JEWELFISH Study Group
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Evrysdi ,Pharmacodynamics ,Risdiplam ,Safety ,Spinal muscular atrophy ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Introduction Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier for the treatment of patients with spinal muscular atrophy (SMA). The JEWELFISH study (NCT03032172) was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of risdiplam in previously treated pediatric and adult patients with types 1–3 SMA. Here, an analysis was performed after all patients had received at least 1 year of treatment with risdiplam. Methods Patients with a confirmed diagnosis of 5q-autosomal recessive SMA between the ages of 6 months and 60 years were eligible for enrollment. Patients were previously enrolled in the MOONFISH study (NCT02240355) with splicing modifier RG7800 or treated with olesoxime, nusinersen, or onasemnogene abeparvovec. The primary objectives of the JEWELFISH study were to evaluate the safety and tolerability of risdiplam and investigate the PK after 2 years of treatment. Results A total of 174 patients enrolled: MOONFISH study (n = 13), olesoxime (n = 71 patients), nusinersen (n = 76), onasemnogene abeparvovec (n = 14). Most patients (78%) had three SMN2 copies. The median age and weight of patients at enrollment was 14.0 years (1–60 years) and 39.1 kg (9.2–108.9 kg), respectively. About 63% of patients aged 2–60 years had a baseline total score of less than 10 on the Hammersmith Functional Motor Scale–Expanded and 83% had scoliosis. The most common adverse event (AE) was upper respiratory tract infection and pyrexia (30 patients each; 17%). Pneumonia (four patients; 2%) was the most frequently reported serious AE (SAE). The rates of AEs and SAEs per 100 patient-years were lower in the second 6-month period compared with the first. An increase in SMN protein was observed in blood after risdiplam treatment and was comparable across all ages and body weight quartiles. Conclusions The safety and PD of risdiplam in patients who were previously treated were consistent with those of treatment-naïve patients.
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- 2023
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8. Nusinersen mitigates neuroinflammation in severe spinal muscular atrophy patients
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Tommaso Nuzzo, Rosita Russo, Francesco Errico, Adele D’Amico, Awet G. Tewelde, Mariangela Valletta, Amber Hassan, Michele Tosi, Chiara Panicucci, Claudio Bruno, Enrico Bertini, Angela Chambery, Livio Pellizzoni, and Alessandro Usiello
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Medicine - Abstract
Nuzzo, Russo, Errico, D’Amico et al. investigate neuroinflammation in forty-eight pediatric spinal muscular atrophy patients before and after Nusinersen treatment. They find signatures of neuroinflammation that are specifically associated with severe disease and show that Nusinersen therapy has neuro-immunomodulatory effects.
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- 2023
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9. Long term follow-up in two siblings with Sengers syndrome: Case report
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Chiara Panicucci, Maria Cristina Schiaffino, Claudia Nesti, Maria Derchi, Gianluca Trocchio, Mariasavina Severino, Nicola Stagnaro, Enrico Priolo, Federico Zara, Filippo M. Santorelli, and Claudio Bruno
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Sengers syndrome ,AGK gene ,Mild phenotype ,Long term follow-up ,Case report ,Pediatrics ,RJ1-570 - Abstract
Abstract Background Sengers syndrome is characterized by congenital cataract, hypertrophic cardiomyopathy, mitochondrial myopathy, and lactic acidosis associated with mutations in AGK gene. Clinical course ranges from a severe fatal neonatal form, to a more benign form allowing survival into adulthood, to an isolated form of congenital cataract. Thus far few reported cases have survived the second decade at their latest examination, and no natural history data are available for the disease. Case presentation Here we provide a 20-year follow-up in two siblings with a benign form of Sengers syndrome, expanding the phenotypical spectrum of the disease by reporting a condition of ovarian agenesis. Conclusion To our knowledge, this report provides the first longitudinal data of Sengers syndrome patients.
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- 2022
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10. Onasemnogene abeparvovec in spinal muscular atrophy: predictors of efficacy and safety in naïve patients with spinal muscular atrophy and following switch from other therapiesResearch in context
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Marika Pane, Beatrice Berti, Anna Capasso, Giorgia Coratti, Antonio Varone, Adele D’Amico, Sonia Messina, Riccardo Masson, Valeria Ada Sansone, Maria Alice Donati, Caterina Agosto, Claudio Bruno, Federica Ricci, Antonella Pini, Delio Gagliardi, Massimiliano Filosto, Stefania Corti, Daniela Leone, Concetta Palermo, Roberta Onesimo, Roberto De Sanctis, Martina Ricci, Ilaria Bitetti, Maria Sframeli, Claudia Dosi, Emilio Albamonte, Chiara Ticci, Noemi Brolatti, Enrico Bertini, Richard Finkel, Eugenio Mercuri, Maria Carmela Pera, Chiara Bravetti, Marco Piastra, Orazio Genovese, Gianpaolo Cicala, Nicola Forcina, Sara Carnicella, Giulia Stanca, Michele Sacchini, Michela Catteruccia, Michele Tosi, Renato Cutrera, Claudio Chierchi, Maria Beatrice Chiarini, Francesca Salmin, Marina Pedemonte, Alessandra Govoni, Irene Mizzoni, Simone Morando, Riccardo Zanin, Enrica Rolle, Eleonora Salomon, Melania Giannotta, Gaia Scarpini, Antonio Toscano, Eloisa Gitto, Roberto Materia, and Rossella D’Alessandro
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Spinal muscular atrophy ,Gene therapy ,Follow-up ,Longitudinal ,Safety ,Medicine (General) ,R5-920 - Abstract
Summary: Background: Efficacy and safety of onasemnogene abeparvovec (OA) for Spinal Muscular Atrophy infants under 7 months and
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- 2023
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11. Structured Light Plethysmography for Non-Invasive Assessment of Respiratory Pattern in Spinal Muscular Atrophy Type 1
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Noemi Brolatti, Federica Trucco, Marta Ferretti, Chiara Avanti, Paola Tacchetti, Chiara Panicucci, Pasquale Striano, Carlo Minetti, Claudio Bruno, and Marina Pedemonte
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spinal muscular atrophy type 1 ,structured light plethysmography (SLP) ,CHOP-INTEND ,Medicine - Abstract
Background: Spinal muscular atrophy (SMA) type 1 is a severe condition leading to early respiratory failure. Treatment options have become available, yet respiratory outcome measures in SMA type 1 are limited. The aim of this study was to assess the respiratory pattern in SMA type 1 patients via structured light plethysmography (SLP). SLP measures the thoraco-abdominal movements by projecting a light grid onto the anterior thoraco-abdominal surface. Methods: Cross-sectional study of consecutive children with SMA type 1. All children underwent motor assessment (CHOP-INTEND) and one-minute tidal breathing recording by SLP in supine position while self-ventilating in room air. The Respiratory rate, the abdominal vs. chest contribution to breath (Relative Expired Abdomen%, Relative Expired Chest%) and the severity of thoraco-abdominal paradox (Phase Angle) were acquired. Results: Nineteen patients were included, median (IQR) age 2.3 years (1.4–7.9). Their respiratory pattern captured via SLP showed a raised median (IQR) respiratory rate per age of 33.5 bpm (26.6–41.7), a prevalent abdominal contribution to tidal breathing with median (IQR) Relative Expired Abdomen 77% (68–90) vs. Chest 23% (10–32). Thoracoabdominal paradox was detected (median Phase Angle 48.70°) and its severity correlated negatively with CHOP-INTEND (r −0.8, p < 0.01). Conclusions: SLP captured and quantified the respiratory features of infants and children with SMA type 1.
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- 2023
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12. Expanding the clinical-pathological and genetic spectrum of RYR1-related congenital myopathies with cores and minicores: an Italian population study
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Aurora Fusto, Denise Cassandrini, Chiara Fiorillo, Valentina Codemo, Guja Astrea, Adele D’Amico, Lorenzo Maggi, Francesca Magri, Marika Pane, Giorgio Tasca, Daniele Sabbatini, Luca Bello, Roberta Battini, Pia Bernasconi, Fabiana Fattori, Enrico Silvio Bertini, Giacomo Comi, Sonia Messina, Tiziana Mongini, Isabella Moroni, Chiara Panicucci, Angela Berardinelli, Alice Donati, Vincenzo Nigro, Antonella Pini, Melania Giannotta, Claudia Dosi, Enzo Ricci, Eugenio Mercuri, Giovanni Minervini, Silvio Tosatto, Filippo Santorelli, Claudio Bruno, and Elena Pegoraro
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RYR1-related myopathies ,Central core disease ,Multi-minicore disease ,Genotype–phenotype correlations ,Neuromuscular disorder ,Protein modelling ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Mutations in the RYR1 gene, encoding ryanodine receptor 1 (RyR1), are a well-known cause of Central Core Disease (CCD) and Multi-minicore Disease (MmD). We screened a cohort of 153 patients carrying an histopathological diagnosis of core myopathy (cores and minicores) for RYR1 mutation. At least one RYR1 mutation was identified in 69 of them and these patients were further studied. Clinical and histopathological features were collected. Clinical phenotype was highly heterogeneous ranging from asymptomatic or paucisymptomatic hyperCKemia to severe muscle weakness and skeletal deformity with loss of ambulation. Sixty-eight RYR1 mutations, generally missense, were identified, of which 16 were novel. The combined analysis of the clinical presentation, disease progression and the structural bioinformatic analyses of RYR1 allowed to associate some phenotypes to mutations in specific domains. In addition, this study highlighted the structural bioinformatics potential in the prediction of the pathogenicity of RYR1 mutations. Further improvement in the comprehension of genotype–phenotype relationship of core myopathies can be expected in the next future: the actual lack of the human RyR1 crystal structure paired with the presence of large intrinsically disordered regions in RyR1, and the frequent presence of more than one RYR1 mutation in core myopathy patients, require designing novel investigation strategies to completely address RyR1 mutation effect.
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- 2022
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13. Nusinersen efficacy data for 24‐month in type 2 and 3 spinal muscular atrophy
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Marika Pane, Giorgia Coratti, Maria Carmela Pera, Valeria A. Sansone, Sonia Messina, Adele d'Amico, Claudio Bruno, Francesca Salmin, Emilio Albamonte, Roberto De Sanctis, Maria Sframeli, Vincenzo Di Bella, Simone Morando, Concetta Palermo, Anna Lia Frongia, Laura Antonaci, Anna Capasso, Michela Catteruccia, Antonella Longo, Martina Ricci, Costanza Cutrona, Alice Pirola, Chiara Bravetti, Marina Pedemonte, Noemi Brolatti, Enrico Bertini, Eugenio Mercuri, and Italian ISMAC group
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract The study reports real world data in type 2 and 3 SMA patients treated for at least 2 years with nusinersen. Increase in motor function was observed after 12 months and during the second year. The magnitude of change was variable across age and functional subgroup, with the largest changes observed in young patients with higher function at baseline. When compared to natural history data, the difference between study cohort and untreated patients swas significant on both Hammersmith Functional Motor Scale and Revised Upper Limb Module both at 12 months and at 24 months.
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- 2022
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14. Clinical, imaging, biochemical and molecular features in Leigh syndrome: a study from the Italian network of mitochondrial diseases
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Anna Ardissone, Claudio Bruno, Daria Diodato, Alice Donati, Daniele Ghezzi, Eleonora Lamantea, Costanza Lamperti, Michelangelo Mancuso, Diego Martinelli, Guido Primiano, Elena Procopio, Anna Rubegni, Filippo Santorelli, Maria Cristina Schiaffino, Serenella Servidei, Flavia Tubili, Enrico Bertini, and Isabella Moroni
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Leigh syndrome ,Mitochondrial disease ,Childhood ,Basal ganglia ,Medicine - Abstract
Abstract Background Leigh syndrome (LS) is a progressive neurodegenerative disorder associated with primary or secondary dysfunction of mitochondrial oxidative phosphorylation and is the most common mitochondrial disease in childhood. Numerous reports on the biochemical and molecular profiles of LS have been published, but there are limited studies on genetically confirmed large series. We reviewed the clinical, imaging, biochemical and molecular data of 122 patients with a diagnosis of LS collected in the Italian Collaborative Network of Mitochondrial Diseases database. Results Clinical picture was characterized by early onset of several neurological signs dominated by central nervous system involvement associated with both supra- and sub-tentorial grey matter at MRI in the majority of cases. Extraneurological organ involvement is less frequent in LS than expected for a mitochondrial disorder. Complex I and IV deficiencies were the most common biochemical diagnoses, mostly associated with mutations in SURF1 or mitochondrial-DNA genes encoding complex I subunits. Our data showed SURF1 as the genotype with the most unfavorable prognosis, differently from other cohorts reported to date. Conclusion We report on a large genetically defined LS cohort, adding new data on phenotype-genotype correlation, prognostic factors and possible suggestions to diagnostic workup.
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- 2021
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15. Growth patterns in children with spinal muscular atrophy
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Ramona De Amicis, Giovanni Baranello, Andrea Foppiani, Alessandro Leone, Alberto Battezzati, Giorgio Bedogni, Simone Ravella, Ester Giaquinto, Chiara Mastella, Caterina Agosto, Enrico Bertini, Adele D’Amico, Marina Pedemonte, Claudio Bruno, Jonathan C. Wells, Mary Fewtrell, and Simona Bertoli
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Spinal muscular atrophy ,Growth ,Percentiles ,Nutritional status ,Medicine - Abstract
Abstract Background Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by muscle atrophy and weakness. SMA type 1 (SMA1) is the most severe form: affected infants are unable to sit unaided; SMA type 2 (SMA2) children can sit, but are not able to walk independently. The Standards of Care has improved quality of life and the increasing availability of disease-modifying treatments is progressively changing the natural history; so, the clinical assessment of nutritional status has become even more crucial. Aims of this multicenter study were to present the growth pattern of treatment-naïve SMA1 and SMA2, and to compare it with the general growth standards. Results Body Weight (BW, kg) and Supine Length (SL, cm) were collected using a published standardized procedure. SMA-specific growth percentiles curves were developed and compared to the WHO reference data. We recruited 133 SMA1 and 82 SMA2 (48.8% females). Mean ages were 0.6 (0.4–1.6) and 4.1 (2.1–6.7) years, respectively. We present here a set of disease-specific percentiles curves of BW, SL, and BMI-for-age for girls and boys with SMA1 and SMA2. These curves show that BW is significantly lower in SMA than healthy peers, while SL is more variable. BMI is also typically lower in both sexes and at all ages. Conclusions These data on treatment-naïve patients point toward a better understanding of growth in SMA and could be useful to improve the clinical management and to assess the efficacy of the available and forthcoming therapies not only on motor function, but also on growth.
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- 2021
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16. Nusinersen in pediatric and adult patients with type III spinal muscular atrophy
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Maria Carmela Pera, Giorgia Coratti, Francesca Bovis, Marika Pane, Amy Pasternak, Jacqueline Montes, Valeria A. Sansone, Sally Dunaway Young, Tina Duong, Sonia Messina, Irene Mizzoni, Adele D’Amico, Matthew Civitello, Allan M. Glanzman, Claudio Bruno, Francesca Salmin, Simone Morando, Roberto De Sanctis, Maria Sframeli, Laura Antonaci, Anna Lia Frongia, Annemarie Rohwer, Mariacristina Scoto, Darryl C. De Vivo, Basil T. Darras, John Day, William Martens, Katia A. Patanella, Enrico Bertini, Francesco Muntoni, Richard Finkel, Eugenio Mercuri, and the iSMAC group
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Objective We report longitudinal data from 144 type III SMA pediatric and adult patients treated with nusinersen as part of an international effort. Methods Patients were assessed using Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and 6‐Minute Walk Test (6MWT) with a mean follow‐up of 1.83 years after nusinersen treatment. Results Over 75% of the 144 patients had a 12‐month follow‐up. There was an increase in the mean scores from baseline to 12 months on both HFMSE (1.18 points, p = 0.004) and RULM scores (0.58 points, p = 0.014) but not on the 6MWT (mean difference = 6.65 m, p = 0.33). When the 12‐month HFMSE changes in the treated cohort were compared to an external cohort of untreated patients, in all untreated patients older than 7 years, the mean changes were always negative, while always positive in the treated ones. To reduce a selection bias, we also used a multivariable analysis. On the HFMSE scale, age, gender, baseline value, and functional status contributed significantly to the changes, while the number of SMN2 copies did not contribute. The effect of these variables was less obvious on the RULM and 6MWT. Interpretation Our results expand the available data on the effect of Nusinersen on type III patients, so far mostly limited to data from adult type III patients.
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- 2021
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17. Are atypical lymphocytes a new predictive factor in the development of COVID-19?
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Claudio Bruno Silva de Oliveira, Joelma Maria de Araújo Andrade, and Jonas Ivan Nobre Oliveira
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Arctic medicine. Tropical medicine ,RC955-962 - Published
- 2022
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18. Mars One-Year Mission Craft
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Claudio Bruno, Antonella Ingenito, and Domenico Simone
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nuclear propulsion ,Mars mission ,human mission ,Motor vehicles. Aeronautics. Astronautics ,TL1-4050 - Abstract
A human Mars mission is more challenging to astronauts than the Apollo mission because of travel time, life support requirements, and the space environment. Although plans for Mars exploration by NASA and SpaceX based on conventional rockets have been presented, there are considerations that suggest alternatives for the mid- or long-term. The purpose of this paper is to outline a fast mission enabled by advanced (nuclear) propulsion and by internationally shared technology. Whether the destination is the Mars surface or Phobos, for a chemical powered spacecraft, the round trip takes about 990 days, including a 480-day surface stay, compared to only 370 days, including a 41-day surface stay, for the nuclear-powered spacecraft assumed here. Since nuclear propulsion can provide higher speed than chemical, the radiation dose can be drastically reduced. The logistics of such a mission involve one or more cargo craft that must precede the astronauts. Ballistic entry into Mars’ atmosphere depends on accurate knowledge of its features, to date poorly known, that may result in uncertainty in landing coordinates. For a single vehicle, this is not critical, but for a human crew ballistic landing kilometers away from cargo is unacceptable: walking for anything but the shortest distance cannot be afforded with current space suits. In this context, the concept of a modest L/D maneuvering cargo glider based on the past Russian “Kliper” is recommended and developed to ensure landing within a hundred meters of each spacecraft. The crewed lander vehicle is based on the high L/D, inherently stable USAF FDL-7C/D hypersonic glider experience. In a similar approach, an exploration vehicle powered by in situ manufactured CO2 and silane is described that can explore the Martian surface much faster and efficiently than with rovers or rocket-powered ‘hoppers’.
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- 2023
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19. Upper Limb Changes in DMD Patients Amenable to Skipping Exons 44, 45, 51 and 53: A 24-Month Study
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Claudia Brogna, Marika Pane, Giorgia Coratti, Adele D’Amico, Elena Pegoraro, Luca Bello, Valeria Ada Maria Sansone, Emilio Albamonte, Sonia Messina, Antonella Pini, Maria Grazia D’Angelo, Claudio Bruno, Tiziana Mongini, Federica Silvia Ricci, Angela Berardinelli, Roberta Battini, Riccardo Masson, Enrico Silvio Bertini, Luisa Politano, Eugenio Mercuri, and Italian DMD Group
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DMD ,PUL 2.0 ,exon skipping ,Pediatrics ,RJ1-570 - Abstract
Introduction: The Performance of Upper Limb version 2.0 (PUL 2.0) is increasingly used in Duchenne Muscular Dystrophy (DMD) to study longitudinal functional changes of motor upper limb function in ambulant and non-ambulant patients. The aim of this study was to evaluate changes in upper limb functions in patients carrying mutations amenable to skipping exons 44, 45, 51 and 53. Methods: All DMD patients were assessed using the PUL 2.0 for at least 2 years, focusing on 24-month paired visits in those with mutations eligible for skipping exons 44, 45, 51 and 53. Results: 285 paired assessments were available. The mean total PUL 2.0 12-month change was −0.67 (2.80), −1.15 (3.98), −1.46 (3.37) and −1.95 (4.04) in patients carrying mutations amenable to skipping exon 44, 45, 51 and 53, respectively. The mean total PUL 2.0 24-month change was −1.47 (3.73), −2.78 (5.86), −2.95 (4.56) and −4.53 (6.13) in patients amenable to skipping exon 44, 45, 51 and 53, respectively. The difference in PUL 2.0 mean changes among the type of exon skip class for the total score was not significant at 12 months but was significant at 24 months for the total score (p < 0.001), the shoulder (p = 0.01) and the elbow domain (p < 0.001), with patients amenable to skipping exon 44 having smaller changes compared to those amenable to skipping exon 53. There was no difference within ambulant or non-ambulant cohorts when subdivided by exon skip class for the total and subdomains score (p > 0.05). Conclusions: Our results expand the information on upper limb function changes detected by the PUL 2.0 in a relatively large group of DMD patients with distinct exon-skipping classes. This information can be of help when designing clinical trials or in the interpretation of the real world data including non-ambulant patients.
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- 2023
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20. Management and outcome of benign acute childhood myositis in pediatric emergency department
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Giacomo Brisca, Marcello Mariani, Daniela Pirlo, Marta Romanengo, Angela Pistorio, Alberto Gaiero, Chiara Panicucci, Emanuela Piccotti, and Claudio Bruno
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Children ,Creatine kinase ,Rhabdomyolysis ,Gait abnormalities ,Clinical pathway ,Pediatrics ,RJ1-570 - Abstract
Abstract Background Benign acute childhood myositis (BACM) is a self-limited syndrome associated with viral infections characterized by symmetric lower extremity pain typically affecting school-aged children. Evolution in rhabdomyolysis and kidney damage is rarely reported. Despite this, the acute presentation commonly concerns both parents and health care providers, often leading to unnecessary workup. The aim of the study was to determine the features and outcome of a large series of children with BACM identifying a management pathway for pediatricians in Emergency Department (ED). Methods We conducted a retrospective study of patients with BACM managed in 2 Italian pediatric ED during a period of 8 and a half years. Demographic data, clinical, and laboratory results were extracted from electronic medical records. Recurrence, complications, treatments, and outcomes were also recorded. Descriptive statistics were produced for first-episode patients and for those with recurrence of myositis. A comparison between groups was performed. Results One hundred and thirteen patients with BACM were identified. Ninety-two children (65 males) had a single episode, while ten (nine males) had recurrence. The mean age at presentation was 6.0 years (range 2–13,2). All patients had normal neurological examination and no one developed myoglobinuria, or renal failure. At first evaluation median CK level was 1413 UI/l (normal values
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- 2021
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21. Animal models for inducing inflammatory bowel diseases: integrative review
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Nadja Maria da Costa Melo, Marília Virgo Silva Almeida, Daniel Melo de Oliveira Campos, Claudio Bruno Silva de Oliveira, and Jonas Ivan Nobre Oliveira
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inflammatory bowel diseases ,ulcerative colitis ,animal disease models ,Nursing ,RT1-120 ,Medicine (General) ,R5-920 - Abstract
Objective: To identify and describe comparatively the chemical models of the induction of inflammatory bowel diseases (IBD) in rodents most used and that best mimic the pathogenesis in humans. Methods: Based on an integrative review in the MEDLINE and LILACS databases, it was investigated which experimental induction models were most cited in articles published from 2004 to 2020, with the descriptors "Colitis/CI", "Colitis model ulcerative" and "Intestinal inflammation model." All empirical articles that addressed one or more inflammation models in rats or mice were included. Results: 239 articles were identified; of these, only ten empirical articles were selected. The most used models were colitis induced by TNBS acid, DSS, and colitis induced by acetic acid (AA). Conclusion: It was possible to identify the most used models to promote the induction of intestinal inflammation in rats, and both models proved to be effective according to the limitations observed in the models described, suggesting the need for new works that use more well-defined protocols and that more fully represent the pathophysiological complexity of the disease.
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- 2021
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22. Type I SMA 'new natural history': long‐term data in nusinersen‐treated patients
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Marika Pane, Giorgia Coratti, Valeria A. Sansone, Sonia Messina, Michela Catteruccia, Claudio Bruno, Maria Sframeli, Emilio Albamonte, Marina Pedemonte, Adele D’Amico, Chiara Bravetti, Beatrice Berti, Concetta Palermo, Daniela Leone, Giorgia Brigati, Paola Tacchetti, Francesca Salmin, Roberto De Sanctis, Simona Lucibello, Maria Carmela Pera, Marco Piastra, Orazio Genovese, Enrico Bertini, Gianluca Vita, Francesco Danilo Tiziano, Eugenio Mercuri, and the Italian EAP Working Group
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Objective The aim of this paper was to report the 2‐year follow‐up in type I patients treated with Nusinersen and to assess whether possible changes in motor function are related to the subtype, age, or SMN2 copy number. Methods Sixty‐eight patients, with ages ranging from 0.20 to 15.92 years (mean: 3.96; standard deviation: +3.90) were enrolled in the study. All patients were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the developmental section of the Hammersmith Infant Neurological Examination (HINE‐2) at the time they started treatment and 12 and 24 months after that. Results For both CHOP and HINE‐2 repeated measures analysis of variance showed a significant difference (P
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- 2021
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23. 2-Year Change in Revised Hammersmith Scale Scores in a Large Cohort of Untreated Paediatric Type 2 and 3 SMA Participants
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Georgia Stimpson, Danielle Ramsey, Amy Wolfe, Anna Mayhew, Mariacristina Scoto, Giovanni Baranello, Robert Muni Lofra, Marion Main, Evelin Milev, Giorgia Coratti, Marika Pane, Valeria Sansone, Adele D’Amico, Enrico Bertini, Sonia Messina, Claudio Bruno, Emilio Albamonte, Elena Stacy Mazzone, Jacqueline Montes, Allan M. Glanzman, Zarazuela Zolkipli-Cunningham, Amy Pasternak, Tina Duong, Sally Dunaway Young, Matthew Civitello, Chiara Marini-Bettolo, John W. Day, Basil T. Darras, Darryl C. De Vivo, Richard S. Finkel, Eugenio Mercuri, and Francesco Muntoni
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motor function ,natural history ,spinal muscular atrophy ,Medicine - Abstract
The Revised Hammersmith Scale (RHS) is a 36-item ordinal scale developed using clinical expertise and sound psychometrics to investigate motor function in participants with Spinal Muscular Atrophy (SMA). In this study, we investigate median change in the RHS score up to two years in paediatric SMA 2 and 3 participants and contextualise it to the Hammersmith Functional Motor Scale–Expanded (HFMSE). These change scores were considered by SMA type, motor function, and baseline RHS score. We consider a new transitional group, spanning crawlers, standers, and walkers-with-assistance, and analyse that alongside non-sitters, sitters, and walkers. The transitional group exhibit the most definitive change score trend, with an average 1-year decline of 3 points. In the weakest patients, we are most able to detect positive change in the RHS in the under-5 age group, whereas in the stronger patients, we are most able to detect decline in the RHS in the 8–13 age group. The RHS has a reduced floor effect compared to the HFMSE, although we show that the RHS should be used in conjunction with the RULM for participants scoring less than 20 points on the RHS. The timed items in the RHS have high between-participant variability, so participants with the same RHS total can be differentiated by their timed test items.
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- 2023
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24. Using Cluster Analysis to Overcome the Limits of Traditional Phenotype–Genotype Correlations: The Example of RYR1-Related Myopathies
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Claudia Dosi, Anna Rubegni, Jacopo Baldacci, Daniele Galatolo, Stefano Doccini, Guja Astrea, Angela Berardinelli, Claudio Bruno, Giorgia Bruno, Giacomo Pietro Comi, Maria Alice Donati, Maria Teresa Dotti, Massimiliano Filosto, Chiara Fiorillo, Fabio Giannini, Gian Luigi Gigli, Marina Grandis, Diego Lopergolo, Francesca Magri, Maria Antonietta Maioli, Alessandro Malandrini, Roberto Massa, Sabrina Matà, Federico Melani, Sonia Messina, Andrea Mignarri, Maurizio Moggio, Elena Maria Pennisi, Elena Pegoraro, Giulia Ricci, Michele Sacchini, Angelo Schenone, Simone Sampaolo, Monica Sciacco, Gabriele Siciliano, Giorgio Tasca, Paola Tonin, Rossella Tupler, Mariarosaria Valente, Nila Volpi, Denise Cassandrini, and Filippo Maria Santorelli
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RYR1-related myopathies ,unsupervised cluster analysis ,NGS ,genotype–phenotype correlation ,Genetics ,QH426-470 - Abstract
Thanks to advances in gene sequencing, RYR1-related myopathy (RYR1-RM) is now known to manifest itself in vastly heterogeneous forms, whose clinical interpretation is, therefore, highly challenging. We set out to develop a novel unsupervised cluster analysis method in a large patient population. The objective was to analyze the main RYR1-related characteristics to identify distinctive features of RYR1-RM and, thus, offer more precise genotype–phenotype correlations in a group of potentially life-threatening disorders. We studied 600 patients presenting with a suspicion of inherited myopathy, who were investigated using next-generation sequencing. Among them, 73 index cases harbored variants in RYR1. In an attempt to group genetic variants and fully exploit information derived from genetic, morphological, and clinical datasets, we performed unsupervised cluster analysis in 64 probands carrying monoallelic variants. Most of the 73 patients with positive molecular diagnoses were clinically asymptomatic or pauci-symptomatic. Multimodal integration of clinical and histological data, performed using a non-metric multi-dimensional scaling analysis with k-means clustering, grouped the 64 patients into 4 clusters with distinctive patterns of clinical and morphological findings. In addressing the need for more specific genotype–phenotype correlations, we found clustering to overcome the limits of the “single-dimension” paradigm traditionally used to describe genotype–phenotype relationships.
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- 2023
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25. Creation and implementation of a European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC registry)
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Tomàs Pinós, Antoni L. Andreu, Claudio Bruno, Georgios M. Hadjigeorgiou, Ronald G. Haller, Pascal Laforêt, Alejandro Lucía, Miguel A. Martín, Andrea Martinuzzi, Carmen Navarro, Piraye Oflazer, Jean Pouget, Ros Quinlivan, Sabrina Sacconi, Renata S. Scalco, Antonio Toscano, John Vissing, Matthias Vorgerd, Andrew Wakelin, Ramon Martí, and EUROMAC Consortium
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Myopathy ,Rare diseases ,International registry ,McArdle disease ,Metabolic diseases ,Glycogen storage disease ,Medicine - Abstract
Abstract Background International patient registries are of particular importance for rare disorders, as they may contribute to overcome the lack of knowledge derived from low number of patients and limited awareness of these diseases, and help to learn more about their geographical or population-based specificities, which is relevant for research purposes and for promoting better standards of care and diagnosis. Our objective was to create and implement a European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC) and to disseminate the knowledge of these disorders. Results Teams from nine different countries (United Kingdom, Spain, Italy, France, Germany, Denmark, Greece, Turkey and USA) created a consortium that developed the first European registry dedicated to rare muscle glycogenoses. A work plan was implemented to design the database and platform that constitute the registry, by choosing clinical, genetics and molecular variables of interest, based on experience gained from previous national registries for similar metabolic disorders. Among dissemination activities, several teaching events were organized in different countries, especially those where the consortium considered the awareness of these diseases needs to be promoted among health professionals and patients. Conclusion EUROMAC represents a step forward in the knowledge of those disorders to which it is dedicated, and will have relevant clinical outcomes at the diagnostic, epidemiological, clinical and research level.
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- 2020
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26. Age, corticosteroid treatment and site of mutations affect motor functional changes in young boys with Duchenne Muscular Dystrophy.
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Giorgia Coratti, Jacopo Lenkowicz, Giulia Norcia, Simona Lucibello, Elisabetta Ferraroli, Adele d'Amico, Luca Bello, Elena Pegoraro, Sonia Messina, Federica Ricci, Tiziana Mongini, Angela Berardinelli, Riccardo Masson, Stefano C Previtali, Grazia D'angelo, Francesca Magri, Giacomo P Comi, Luisa Politano, Luigia Passamano, Gianluca Vita, Valeria A Sansone, Emilio Albamonte, Chiara Panicucci, Claudio Bruno, Antonella Pini, Enrico Bertini, Stefano Patarnello, Marika Pane, Eugenio Mercuri, and italian DMD study group
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Medicine ,Science - Abstract
The aim of this study was to establish the possible effect of age, corticosteroid treatment and brain dystrophin involvement on motor function in young boys affected by Duchenne Muscular Dystrophy who were assessed using the North Star Ambulatory Assessment between the age of 4 and 7 years. The study includes 951 North Star assessments from 226 patients. Patients were subdivided according to age, to the site of mutation and therefore to the involvement of different brain dystrophin isoforms and to corticosteroids duration. There was a difference in the maximum North Star score achieved among patients with different brain dystrophin isoforms (p = 0.007). Patients with the involvement of Dp427, Dp140 and Dp71, had lower maximum NSAA scores when compared to those with involvement of Dp427 and Dp140 or of Dp427 only. The difference in the age when the maximum score was achieved in the different subgroups did not reach statistical significance. Using a linear regression model on all assessments we found that each of the three variables, age, site of mutation and corticosteroid treatment had an influence on the NSAA values and their progression over time. A second analysis, looking at 12-month changes showed that within this time interval the magnitude of changes was related to corticosteroid treatment but not to site of mutation. Our findings suggest that each of the considered variables appear to play a role in the progression of North Star scores in patients between the age of 4 and 7 years and that these should be carefully considered in the trial design of boys in this age range.
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- 2022
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27. Genetic modifiers of respiratory function in Duchenne muscular dystrophy
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Luca Bello, Grazia D’Angelo, Matteo Villa, Aurora Fusto, Sara Vianello, Beatrice Merlo, Daniele Sabbatini, Andrea Barp, Sandra Gandossini, Francesca Magri, Giacomo P. Comi, Marina Pedemonte, Paola Tacchetti, Valentina Lanzillotta, Federica Trucco, Adele D’Amico, Enrico Bertini, Guja Astrea, Luisa Politano, Riccardo Masson, Giovanni Baranello, Emilio Albamonte, Elisa De Mattia, Fabrizio Rao, Valeria A. Sansone, Stefano Previtali, Sonia Messina, Gian Luca Vita, Angela Berardinelli, Tiziana Mongini, Antonella Pini, Marika Pane, Eugenio Mercuri, Andrea Vianello, Claudio Bruno, Eric P. Hoffman, Lauren Morgenroth, Heather Gordish‐Dressman, Craig M. McDonald, CINRG‐DNHS Investigators, and Elena Pegoraro
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Objective Respiratory insufficiency is a major complication of Duchenne muscular dystrophy (DMD). Its progression shows considerable interindividual variability, which has been less thoroughly characterized and understood than in skeletal muscle. We collected pulmonary function testing (PFT) data from a large retrospective cohort followed at Centers collaborating in the Italian DMD Network. Furthermore, we analyzed PFT associations with different DMD mutation types, and with genetic variants in SPP1, LTBP4, CD40, and ACTN3, known to modify skeletal muscle weakness in DMD. Genetic association findings were independently validated in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG‐DNHS). Methods and Results Generalized estimating equation analysis of 1852 PFTs from 327 Italian DMD patients, over an average follow‐up time of 4.5 years, estimated that forced vital capacity (FVC) declined yearly by −4.2%, forced expiratory volume in 1 sec by −5.0%, and peak expiratory flow (PEF) by −2.9%. Glucocorticoid (GC) treatment was associated with higher values of all PFT measures (approximately + 15% across disease stages). Mutations situated 3’ of DMD intron 44, thus predicted to alter the expression of short dystrophin isoforms, were associated with lower (approximately −6%) PFT values, a finding independently validated in the CINRG‐DNHS. Deletions amenable to skipping of exon 51 and 53 were independently associated with worse PFT outcomes. A meta‐analysis of the two cohorts identified detrimental effects of SPP1 rs28357094 and CD40 rs1883832 minor alleles on both FVC and PEF. Interpretation These findings support GC efficacy in delaying respiratory insufficiency, and will be useful for the design and interpretation of clinical trials focused on respiratory endpoints in DMD.
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- 2020
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28. The Role of Muscle Biopsy in Diagnostic Process of Infant Hypotonia: From Clinical Classification to the Genetic Outcome
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Marco Veneruso, Chiara Fiorillo, Paolo Broda, Serena Baratto, Monica Traverso, Alice Donati, Salvatore Savasta, Raffaele Falsaperla, Maria Margherita Mancardi, Marina Pedemonte, Chiara Panicucci, Gianluca Piatelli, Mattia Pacetti, Andrea Moscatelli, Luca Antonio Ramenghi, Lino Nobili, Carlo Minetti, and Claudio Bruno
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muscle biopsy ,floppy infant ,muscular dystrophy ,congenital myopathy ,genetic outcome ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
The role of muscle biopsy in the diagnostic workup of floppy infants is controversial. Muscle sampling is invasive, and often, results are not specific. The rapid expansion of genetic approach has made the muscle histopathology analysis less crucial. This study aims to assess the role and efficacy of muscle histopathology in the diagnostic algorithm of hypotonia in early infancy through a retrospective analysis of 197 infants who underwent muscle biopsy in their first 18 months of life. Data analysis revealed that 92/197 (46.7%) of muscle biopsies were non-specific (80) or normal (12), not allowing a specific diagnosis. In 41/197 (20.8%) cases, biopsy suggested a metabolic or mitochondrial myopathy, while in 23/197 cases (11.7%), we found evidence of muscular dystrophy. In 19/197 cases (9.7%), histopathology characteristics of a congenital myopathy were reported. In 22/197 cases (11.7%), the histopathological study indicated presence of a neurogenic damage. Overall, 46 diagnoses were then achieved by oriented genetic tests. Muscle biopsy results were consistent with genetic results in 90% of cases. Diagnostic algorithms for the diagnosis of a floppy infant are largely missing. Muscle biopsy alone can lead to a diagnosis, help the clinician in the choice of a genetic test, or even modify a diagnosis made previously.
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- 2021
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29. Nusinersen Induces Disease-Severity-Specific Neurometabolic Effects in Spinal Muscular Atrophy
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Francesco Errico, Carmen Marino, Manuela Grimaldi, Tommaso Nuzzo, Valentina Bassareo, Valeria Valsecchi, Chiara Panicucci, Elia Di Schiavi, Tommaso Mazza, Claudio Bruno, Adele D’Amico, Manolo Carta, Anna Maria D’Ursi, Enrico Bertini, Livio Pellizzoni, and Alessandro Usiello
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spinal muscular atrophy (SMA) ,survival motor neuron (SMN) ,nusinersen ,cerebrospinal fluid (CSF) ,nuclear magnetic resonance (NMR) ,Microbiology ,QR1-502 - Abstract
Intrathecal delivery of Nusinersen–an antisense oligonucleotide that promotes survival motor neuron (SMN) protein induction–is an approved therapy for spinal muscular atrophy (SMA). Here, we employed nuclear magnetic resonance (NMR) spectroscopy to longitudinally characterize the unknown metabolic effects of Nusinersen in the cerebrospinal fluid (CSF) of SMA patients across disease severity. Modulation of amino acid metabolism is a common denominator of biochemical changes induced by Nusinersen, with distinct downstream metabolic effects according to disease severity. In severe SMA1 patients, Nusinersen stimulates energy-related glucose metabolism. In intermediate SMA2 patients, Nusinersen effects are also related to energy homeostasis but involve ketone body and fatty acid biosynthesis. In milder SMA3 patients, Nusinersen mainly modulates amino acid metabolism. Moreover, Nusinersen modifies the CSF metabolome of a more severe clinical group towards the profile of untreated SMA patients with milder disease. These findings reveal disease severity-specific neurometabolic signatures of Nusinersen treatment, suggesting a selective modulation of peripheral organ metabolism by this CNS-directed therapy in severe SMA patients.
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- 2022
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30. SMA-miRs (miR-181a-5p, -324-5p, and -451a) are overexpressed in spinal muscular atrophy skeletal muscle and serum samples
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Emanuela Abiusi, Paola Infante, Cinzia Cagnoli, Ludovica Lospinoso Severini, Marika Pane, Giorgia Coratti, Maria Carmela Pera, Adele D'Amico, Federica Diano, Agnese Novelli, Serena Spartano, Stefania Fiori, Giovanni Baranello, Isabella Moroni, Marina Mora, Maria Barbara Pasanisi, Krizia Pocino, Loredana Le Pera, Davide D'Amico, Lorena Travaglini, Francesco Ria, Claudio Bruno, Denise Locatelli, Enrico Silvio Bertini, Lucia Ovidia Morandi, Eugenio Mercuri, Lucia Di Marcotullio, and Francesco Danilo Tiziano
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spinal muscular atrophy ,mRNA ,miRNA ,biomarker ,SMN1 ,skeletal muscle ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by the degeneration of the second motor neuron. The phenotype ranges from very severe to very mild forms. All patients have the homozygous loss of the SMN1 gene and a variable number of SMN2 (generally 2–4 copies), inversely related to the severity. The amazing results of the available treatments have made compelling the need of prognostic biomarkers to predict the progression trajectories of patients. Besides the SMN2 products, few other biomarkers have been evaluated so far, including some miRs. Methods: We performed whole miRNome analysis of muscle samples of patients and controls (14 biopsies and 9 cultures). The levels of muscle differentially expressed miRs were evaluated in serum samples (51 patients and 37 controls) and integrated with SMN2 copies, SMN2 full-length transcript levels in blood and age (SMA-score). Results: Over 100 miRs were differentially expressed in SMA muscle; 3 of them (hsa-miR-181a-5p, -324-5p, -451a; SMA-miRs) were significantly upregulated in the serum of patients. The severity predicted by the SMA-score was related to that of the clinical classification at a correlation coefficient of 0.87 (p
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- 2021
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31. Monkeypox: A looming concern for children?
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Claudio Bruno Silva de Oliveira, Joelma Maria de Araújo Andrade, and Jonas Ivan Nobre Oliveira
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Arctic medicine. Tropical medicine ,RC955-962 - Published
- 2022
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32. Targeting of Ubiquitin E3 Ligase RNF5 as a Novel Therapeutic Strategy in Neuroectodermal Tumors
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Elisa Principi, Elvira Sondo, Giovanna Bianchi, Silvia Ravera, Martina Morini, Valeria Tomati, Cristina Pastorino, Federico Zara, Claudio Bruno, Alessandra Eva, Nicoletta Pedemonte, and Lizzia Raffaghello
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RNF5 ,neuroblastoma ,melanoma ,ubiquitin ligase ,endoplasmic reticulum associated protein degradation ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
RNF5, an endoplasmic reticulum (ER) E3 ubiquitin ligase, participates to the ER-associated protein degradation guaranteeing the protein homeostasis. Depending on tumor model tested, RNF5 exerts pro- or anti-tumor activity. The aim of this study was to elucidate the controversial role of RNF5 in neuroblastoma and melanoma, two neuroectodermal tumors of infancy and adulthood, respectively. RNF5 gene levels are evaluated in publicly available datasets reporting the gene expression profile of melanoma and neuroblastoma primary tumors at diagnosis. The therapeutic effect of Analog-1, an RNF5 pharmacological activator, was investigated on in vitro and in vivo neuroblastoma and melanoma models. In both neuroblastoma and melanoma patients the high expression of RNF5 correlated with a better prognostic outcome. Treatment of neuroblastoma and melanoma cell lines with Analog-1 reduced cell viability by impairing the glutamine availability and energy metabolism through inhibition of F1Fo ATP-synthase activity. This latter event led to a marked increase in oxidative stress, which, in turn, caused cell death. Similarly, neuroblastoma- and melanoma-bearing mice treated with Analog-1 showed a significant delay of tumor growth in comparison to those treated with vehicle only. These findings validate RNF5 as an innovative drug target and support the development of Analog-1 in early phase clinical trials for neuroblastoma and melanoma patients.
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- 2022
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33. Local occurrence and fast spread of B.1.1.7 lineage: A glimpse into Friuli Venezia Giulia.
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Catia Mio, Chiara Dal Secco, Stefania Marzinotto, Claudio Bruno, Santa Pimpo, Elena Betto, Martina Bertoni, Corrado Pipan, Emanuela Sozio, Carlo Tascini, Giuseppe Damante, and Francesco Curcio
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Medicine ,Science - Abstract
In-depth study of the entire SARS-CoV-2 genome has uncovered many mutations, which have replaced the lineage that characterized the first wave of infections all around the world. In December 2020, the outbreak of variant of concern (VOC) 202012/01 (lineage B.1.1.7) in the United Kingdom defined a turning point during the pandemic, immediately posing a worldwide threat on the Covid-19 vaccination campaign. Here, we reported the evolution of B.1.1.7 lineage-related infections, analyzing samples collected from January 1st 2021, until April 15th 2021, in Friuli Venezia Giulia, a northeastern region of Italy. A cohort of 1508 nasopharyngeal swabs was analyzed by High Resolution Melting (HRM) and 479 randomly selected samples underwent Next Generation Sequencing analysis (NGS), uncovering a steady and continuous accumulation of B.1.1.7 lineage-related specimens, joined by sporadic cases of other known lineages (i.e. harboring the Spike glycoprotein p.E484K mutation). All the SARS-CoV-2 genome has been analyzed in order to highlight all the rare mutations that may eventually result in a new variant of interest. This work suggests that a thorough monitoring of the SARS-CoV-2 genome by NGS is essential to contain any new variant that could jeopardize all the efforts that have been made so far to resolve the emergence of the pandemic.
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- 2021
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34. North Star Ambulatory Assessment changes in ambulant Duchenne boys amenable to skip exons 44, 45, 51, and 53: A 3 year follow up.
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Giorgia Coratti, Marika Pane, Claudia Brogna, Valeria Ricotti, Sonia Messina, Adele D'Amico, Claudio Bruno, Gianluca Vita, Angela Berardinelli, Elena Mazzone, Francesca Magri, Federica Ricci, Tiziana Mongini, Roberta Battini, Luca Bello, Elena Pegoraro, Giovanni Baranello, Stefano C Previtali, Luisa Politano, Giacomo P Comi, Valeria A Sansone, Alice Donati, Jean Yves Hogrel, Volker Straub, Silvana De Lucia, Erik Niks, Laurent Servais, Imelda De Groot, Mary Chesshyre, Enrico Bertini, Nathalie Goemans, Francesco Muntoni, Eugenio Mercuri, and on behalf on the International DMD Group and the iMDEX Consortium
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Medicine ,Science - Abstract
IntroductionThe aim of this study was to report 36-month longitudinal changes using the North Star Ambulatory Assessment (NSAA) in ambulant patients affected by Duchenne muscular dystrophy amenable to skip exons 44, 45, 51 or 53.Materials and methodsWe included 101 patients, 34 had deletions amenable to skip exon 44, 25 exon 45, 19 exon 51, and 28 exon 53, not recruited in any ongoing clinical trials. Five patients were counted to skip exon 51 and 53 since they had a single deletion of exon 52.ResultsThe difference between subgroups (skip 44, 45, 51 and 53) was significant at 12 (p = 0.043), 24 (p = 0.005) and 36 months (p≤0.001).DiscussionMutations amenable to skip exons 53 and 51 had lower baseline values and more negative changes than the other subgroups while those amenable to skip exon 44 had higher scores both at baseline and at follow up.ConclusionOur results confirm different progression of disease in subgroups of patients with deletions amenable to skip different exons. This information is relevant as current long term clinical trials are using the NSAA in these subgroups of mutations.
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- 2021
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35. P2X7 Receptor Antagonist Reduces Fibrosis and Inflammation in a Mouse Model of Alpha-Sarcoglycan Muscular Dystrophy
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Lizzia Raffaghello, Elisa Principi, Serena Baratto, Chiara Panicucci, Sara Pintus, Francesca Antonini, Genny Del Zotto, Andrea Benzi, Santina Bruzzone, Paolo Scudieri, Carlo Minetti, Elisabetta Gazzerro, and Claudio Bruno
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muscular dystrophy ,limb girdle muscular dystrophy ,purinergic receptors ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
Limb-girdle muscular dystrophy R3, a rare genetic disorder affecting the limb proximal muscles, is caused by mutations in the α-sarcoglycan gene (Sgca) and aggravated by an immune-mediated damage, finely modulated by the extracellular (e)ATP/purinoceptors axis. Currently, no specific drugs are available. The aim of this study was to evaluate the therapeutic effectiveness of a selective P2X7 purinoreceptor antagonist, A438079. Sgca knockout mice were treated with A438079 every two days at 3 mg/Kg for 24 weeks. The P2X7 antagonist improved clinical parameters by ameliorating mice motor function and decreasing serum creatine kinase levels. Histological analysis of muscle morphology indicated a significant reduction of the percentage of central nuclei, of fiber size variability and of the extent of local fibrosis and inflammation. A cytometric characterization of the muscle inflammatory infiltrates showed that A438079 significantly decreased innate immune cells and upregulated the immunosuppressive regulatory T cell subpopulation. In α-sarcoglycan null mice, the selective P2X7 antagonist A438079 has been shown to be effective to counteract the progression of the dystrophic phenotype and to reduce the inflammatory response. P2X7 antagonism via selective inhibitors could be included in the immunosuppressant strategies aimed to dampen the basal immune-mediated damage and to favor a better engraftment of gene-cell therapies.
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- 2022
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36. Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian Patients
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Lorenzo Maggi, Raffaella Brugnoni, Eleonora Canioni, Paola Tonin, Veronica Saletti, Patrizia Sola, Stefano Cotti Piccinelli, Lara Colleoni, Paola Ferrigno, Antonella Pini, Riccardo Masson, Fiore Manganelli, Daniele Lietti, Liliana Vercelli, Giulia Ricci, Claudio Bruno, Giorgio Tasca, Antonio Pizzuti, Alessandro Padovani, Carlo Fusco, Elena Pegoraro, Lucia Ruggiero, Sabrina Ravaglia, Gabriele Siciliano, Lucia Morandi, Raffaele Dubbioso, Tiziana Mongini, Massimiliano Filosto, Irene Tramacere, Renato Mantegazza, and Pia Bernasconi
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myotonia ,periodic paralysis ,SNEL ,channelopathies ,voltage-gated sodium channel NaV1.4 ,SCN4A gene mutation ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Background: Four main clinical phenotypes have been traditionally described in patients mutated in SCN4A, including sodium-channel myotonia (SCM), paramyotonia congenita (PMC), Hypokaliemic type II (HypoPP2), and Hyperkaliemic/Normokaliemic periodic paralysis (HyperPP/NormoPP); in addition, rare phenotypes associated with mutations in SCN4A are congenital myasthenic syndrome and congenital myopathy. However, only scarce data have been reported in literature on large patient cohorts including phenotypes characterized by myotonia and episodes of paralysis.Methods: We retrospectively investigated clinical and molecular features of 80 patients fulfilling the following criteria: (1) clinical and neurophysiological diagnosis of myotonia, or clinical diagnosis of PP, and (2) presence of a pathogenic SCN4A gene variant. Patients presenting at birth with episodic laryngospasm or congenital myopathy-like phenotype with later onset of myotonia were considered as neonatal SCN4A.Results: PMC was observed in 36 (45%) patients, SCM in 30 (37.5%), Hyper/NormoPP in 7 (8.7%), HypoPP2 in 3 (3.7%), and neonatal SCN4A in 4 (5%). The median age at onset was significantly earlier in PMC than in SCM (p < 0.01) and in Hyper/NormoPP than in HypoPP2 (p = 0.02). Cold-induced myotonia was more frequently observed in PMC (n = 34) than in SCM (n = 23) (p = 0.04). No significant difference was found in age at onset of episodes of paralysis among PMC and PP or in frequency of permanent weakness between PP (n = 4), SCM (n = 5), and PMC (n = 10). PP was more frequently associated with mutations in the S4 region of the NaV1.4 channel protein compared to SCM and PMC (p < 0.01); mutations causing PMC were concentrated in the C-terminal region of the protein, while SCM-associated mutations were detected in all the protein domains.Conclusions: Our data suggest that skeletal muscle channelopathies associated with mutations in SCN4A represent a continuum in the clinical spectrum.
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- 2020
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37. Cell Death by Toxoplasma gondii
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Claudio Bruno Silva de Oliveira, Isabelle Luna de Oliveira Dantas Berto, and Valter Ferreira de Andrade Neto
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Arctic medicine. Tropical medicine ,RC955-962 - Published
- 2020
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38. The Genetic Landscape of Dystrophin Mutations in Italy: A Nationwide Study
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Marcella Neri, Rachele Rossi, Cecilia Trabanelli, Antonio Mauro, Rita Selvatici, Maria Sofia Falzarano, Noemi Spedicato, Alice Margutti, Paola Rimessi, Fernanda Fortunato, Marina Fabris, Francesca Gualandi, Giacomo Comi, Silvana Tedeschi, Manuela Seia, Chiara Fiorillo, Monica Traverso, Claudio Bruno, Emiliano Giardina, Maria Rosaria Piemontese, Giuseppe Merla, Milena Cau, Monica Marica, Carmela Scuderi, Eugenia Borgione, Alessandra Tessa, Guia Astrea, Filippo Maria Santorelli, Luciano Merlini, Marina Mora, Pia Bernasconi, Sara Gibertini, Valeria Sansone, Tiziana Mongini, Angela Berardinelli, Antonella Pini, Rocco Liguori, Massimiliano Filosto, Sonia Messina, Gianluca Vita, Antonio Toscano, Giuseppe Vita, Marika Pane, Serenella Servidei, Elena Pegoraro, Luca Bello, Lorena Travaglini, Enrico Bertini, Adele D'Amico, Manuela Ergoli, Luisa Politano, Annalaura Torella, Vincenzo Nigro, Eugenio Mercuri, and Alessandra Ferlini
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dystrophin ,muscular dystrophy ,nationwide study ,exon skipping therapy ,read-through therapy ,Genetics ,QH426-470 - Abstract
Dystrophinopathies are inherited diseases caused by mutations in the dystrophin (DMD) gene for which testing is mandatory for genetic diagnosis, reproductive choices and eligibility for personalized trials. We genotyped the DMD gene in our Italian cohort of 1902 patients (BMD n = 740, 39%; DMD n =1162, 61%) within a nationwide study involving 11 diagnostic centers in a 10-year window (2008–2017). In DMD patients, we found deletions in 57%, duplications in 11% and small mutations in 32%. In BMD, we found deletions in 78%, duplications in 9% and small mutations in 13%. In BMD, there are a higher number of deletions, and small mutations are more frequent than duplications. Among small mutations that are generally frequent in both phenotypes, 44% of DMD and 36% of BMD are nonsense, thus, eligible for stop codon read-through therapy; 63% of all out-of-frame deletions are eligible for single exon skipping. Patients were also assigned to Italian regions and showed interesting regional differences in mutation distribution. The full genetic characterization in this large, nationwide cohort has allowed us to draw several correlations between DMD/BMD genotype landscapes and mutation frequency, mutation types, mutation locations along the gene, exon/intron architecture, and relevant protein domain, with effects on population genetic characteristics and new personalized therapies.
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- 2020
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39. Diagnostic journey in Spinal Muscular Atrophy: Is it still an odyssey?
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Maria Carmela Pera, Giorgia Coratti, Beatrice Berti, Adele D'Amico, Maria Sframeli, Emilio Albamonte, Roberto de Sanctis, Sonia Messina, Michela Catteruccia, Giorgia Brigati, Laura Antonaci, Simona Lucibello, Claudio Bruno, Valeria A Sansone, Enrico Bertini, Danilo Tiziano, Marika Pane, and Eugenio Mercuri
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Medicine ,Science - Abstract
BACKGROUND:The advent of new therapies has increased the need to achieve early diagnosis in Spinal Muscular Atrophy (SMA). The aim of the present study was to define the age of diagnosis in the three main types of SMA with pediatric-onset and the timing between the recognition of clinical signs and confirmed genetic diagnosis. METHODS:All patients with a confirmed diagnosis of type I, II, III SMA followed in 5 Italian centers were included in this study, assessing age at symptoms onset, presenting sign or symptom, age at diagnosis, interval between clinical onset and diagnosis and type of medical investigations conducted in order to obtain the diagnosis. RESULTS:The cohort included 480 patients, 191 affected by SMA type I, 210 by type II and 79 by type III. The mean age at diagnosis was 4.70 months (SD ±2.82) in type I, 15.6 months (SD±5.88) in type II, and 4.34 years (SD±4.01) in type III. The mean time between symptom onset and diagnosis was 1.94 months (SD±1.84) in type I, 5.28 months (SD±4.68) in type II and 16.8 months (SD±18.72) in type III. CONCLUSIONS:Our results suggest that despite improved care recommendations there is still a marked diagnostic delay, especially in type III. At the time new therapies are becoming available more attention should be devoted to reducing such delay as there is consistent evidence of the benefit of early treatment.
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- 2020
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40. Broad phenotypic spectrum and genotype-phenotype correlations in GMPPB-related dystroglycanopathies: an Italian cross-sectional study
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Guja Astrea, Alessandro Romano, Corrado Angelini, Carlo Giuseppe Antozzi, Rita Barresi, Roberta Battini, Carla Battisti, Enrico Bertini, Claudio Bruno, Denise Cassandrini, Marina Fanin, Fabiana Fattori, Chiara Fiorillo, Renzo Guerrini, Lorenzo Maggi, Eugenio Mercuri, Federica Morani, Marina Mora, Francesca Moro, Ilaria Pezzini, Esther Picillo, Michele Pinelli, Luisa Politano, Anna Rubegni, Walter Sanseverino, Marco Savarese, Pasquale Striano, Annalaura Torella, Carlo Pietro Trevisan, Rosanna Trovato, Irina Zaraieva, Francesco Muntoni, Vincenzo Nigro, Adele D’Amico, Filippo M. Santorelli, and the Italian CMD Network
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Congenital muscular dystrophy ,Limb-girdle muscular dystrophy ,GMPPB ,Dystroglycanopathies ,Genotype-phenotype correlations ,Medicine - Abstract
Abstract Background Dystroglycanopathy (α-DG) is a relatively common, clinically and genetically heterogeneous category of congenital forms of muscular dystrophy (CMD) and limb-girdle muscular dystrophy (LGMD) associated with hypoglycosylated α-dystroglycan. To date, mutations in at least 19 genes have been associated with α-DG. One of them, GMPPB, encoding the guanosine-diphosphate-mannose (GDP-mannose) pyrophosphorylase B protein, has recently been associated with a wide clinical spectrum ranging from severe Walker-Warburg syndrome to pseudo-metabolic myopathy and even congenital myasthenic syndromes. We re-sequenced the full set of known disease genes in 73 Italian patients with evidence of either reduced or nearly absent α-dystroglycan to assess genotype-phenotype correlations in this cohort. We used innovative bioinformatic tools to calculate the effects of all described GMPPB mutations on protein function and attempted to correlate them with phenotypic expressions. Results We identified 13 additional cases from 12 families and defined seven novel mutations. Patients displayed variable phenotypes including less typical pictures, ranging from asymptomatic hyperCKemia, to arthrogryposis and congenital clubfoot at birth, and also showed neurodevelopmental comorbidities, such as seizures and ataxic gait, as well as autism-spectrum disorder, which is seldom described in clinical reports of dystroglycanopathies. We also demonstrated that few mutations recur in the Italian GMPPB-mutated population and that alterations of protein stability are the main effects of GMPPB missense variants. Conclusion This work adds to the data on genotype-phenotype correlations in α-DG and offers new bionformatic tools to provide the conceptual framework needed to understand the complexity of these disorders.
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- 2018
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41. Zidovudine ameliorates pathology in the mouse model of Duchenne muscular dystrophy via P2RX7 purinoceptor antagonism
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Rasha Al-Khalidi, Chiara Panicucci, Paul Cox, Natalia Chira, Justyna Róg, Christopher N. J. Young, Rhiannon E. McGeehan, Kameshwari Ambati, Jayakrishna Ambati, Krzysztof Zabłocki, Elisabetta Gazzerro, Stephen Arkle, Claudio Bruno, and Dariusz C. Górecki
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AZT ,Duchenne muscular dystrophy ,eATP ,mdx ,Purinergic receptors ,P2RX7 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Duchenne muscular dystrophy (DMD) is the most common inherited muscle disorder that causes severe disability and death of young men. This disease is characterized by progressive muscle degeneration aggravated by sterile inflammation and is also associated with cognitive impairment and low bone density. Given that no current treatment can improve the long-term outcome, approaches with a strong translational potential are urgently needed. Duchenne muscular dystrophy (DMD) alters P2RX7 signaling in both muscle and inflammatory cells and inhibition of this receptor resulted in a significant attenuation of muscle and non-muscle symptoms in DMDmdx mouse model. As P2RX7 is an attractive target in a range of human diseases, specific antagonists have been developed. Yet, these will require lengthy safety testing in the pediatric population of Duchenne muscular dystrophy (DMD) patients. In contrast, Nucleoside Reverse Transcriptase Inhibitors (NRTIs) can act as P2RX7 antagonists and are drugs with an established safety record, including in children. We demonstrate here that AZT (Zidovudine) inhibits P2RX7 functions acting via the same allosteric site as other antagonists. Moreover, short-term AZT treatment at the peak of disease in DMDmdx mice attenuated the phenotype without any detectable side effects. Recovery was evident in the key parameters such as reduced sarcolemma permeability confirmed by lower serum creatine kinase levels and IgG influx into myofibres, decreased inflammatory cell numbers and inflammation markers in leg and heart muscles of treated mice. Moreover, this short-term therapy had some positive impact on muscle strength in vivo and no detrimental effect on mitochondria, which is the main side-effect of Nucleoside Reverse Transcriptase Inhibitors (NRTIs). Given these results, we postulate that AZT could be quickly re-purposed for the treatment of this highly debilitating and lethal disease. This approach is not constrained by causative DMD mutations and may be effective in alleviating both muscle and non-muscle abnormalities.
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- 2018
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42. Congenital myopathies: clinical phenotypes and new diagnostic tools
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Denise Cassandrini, Rosanna Trovato, Anna Rubegni, Sara Lenzi, Chiara Fiorillo, Jacopo Baldacci, Carlo Minetti, Guja Astrea, Claudio Bruno, Filippo M. Santorelli, and the Italian Network on Congenital Myopathies
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Congenital myopathy ,Next generation sequencing ,Muscle MRI ,Muscle biopsy ,Pediatrics ,RJ1-570 - Abstract
Abstract Congenital myopathies are a group of genetic muscle disorders characterized clinically by hypotonia and weakness, usually from birth, and a static or slowly progressive clinical course. Historically, congenital myopathies have been classified on the basis of major morphological features seen on muscle biopsy. However, different genes have now been identified as associated with the various phenotypic and histological expressions of these disorders, and in recent years, because of their unexpectedly wide genetic and clinical heterogeneity, next-generation sequencing has increasingly been used for their diagnosis. We reviewed clinical and genetic forms of congenital myopathy and defined possible strategies to improve cost-effectiveness in histological and imaging diagnosis.
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- 2017
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43. The Diagnostic Approach to Mitochondrial Disorders in Children in the Era of Next-Generation Sequencing: A 4-Year Cohort Study
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Deborah Tolomeo, Daniele Orsucci, Claudia Nesti, Jacopo Baldacci, Roberta Battini, Claudio Bruno, Giorgia Bruno, Denise Cassandrini, Stefano Doccini, M. Alice Donati, Annarita Ferrari, Simona Fiori, Chiara Fiorillo, Renzo Guerrini, Francesco Mari, Martino Montomoli, Francesca Pochiero, Elena Procopio, Lucia Ruggiero, Simone Sampaolo, Federico Sicca, Chiara Ticci, Anna Rubegni, and Filippo M. Santorelli
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diagnostic approach ,mitochondrial disorders ,next-generation sequencing ,mtDNA ,nDNA ,muscle biopsy ,Medicine - Abstract
Mitochondrial diseases (MDs) are a large group of genetically determined multisystem disorders, characterized by extreme phenotypic heterogeneity, attributable in part to the dual genomic control (nuclear and mitochondrial DNA) of the mitochondrial proteome. Advances in next-generation sequencing technologies over the past two decades have presented clinicians with a challenge: to select the candidate disease-causing variants among the huge number of data provided. Unfortunately, the clinical tools available to support genetic interpretations still lack specificity and sensitivity. For this reason, the diagnosis of MDs continues to be difficult, with the new “genotype first” approach still failing to diagnose a large group of patients. With the aim of investigating possible relationships between clinical and/or biochemical phenotypes and definitive molecular diagnoses, we performed a retrospective multicenter study of 111 pediatric patients with clinical suspicion of MD. In this cohort, the strongest predictor of a molecular (in particular an mtDNA-related) diagnosis of MD was neuroimaging evidence of basal ganglia (BG) involvement. Regression analysis confirmed that normal BG imaging predicted negative genetic studies for MD. Psychomotor regression was confirmed as an independent predictor of a definitive diagnosis of MD. The findings of this study corroborate previous data supporting a role for neuroimaging in the diagnostic approach to MDs and reinforce the idea that mtDNA sequencing should be considered for first-line testing, at least in specific groups of children.
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- 2021
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44. Some Key Issues in Hypersonic Propulsion
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Claudio Bruno and Antonella Ingenito
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scramjet engine ,hypersonic propulsion ,Technology - Abstract
This paper summarizes and discusses some critical aspects of flying hypersonically. The first is the L/D (lift over drag) ratio determining thrust and that in turn depends on the slenderness Küchemann’s τ parameter. This second parameter is found to depend on the relative importance of wave versus friction drag. Ultimately, all engineering drag is argued to depend on vorticity formed at the expense of the vehicle kinetic energy, thus requiring work by thrust. Different mixing strategies are discussed and shown to depend also on mechanisms forming vorticity when the regime is compressible. Supersonic combustion is briefly analyzed and found, at sufficiently high combustor Mach, to take place locally at constant volume, unlike conventional Brayton cycles.
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- 2021
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45. Movement Disorders in Children with a Mitochondrial Disease: A Cross-Sectional Survey from the Nationwide Italian Collaborative Network of Mitochondrial Diseases
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Chiara Ticci, Daniele Orsucci, Anna Ardissone, Luca Bello, Enrico Bertini, Irene Bonato, Claudio Bruno, Valerio Carelli, Daria Diodato, Stefano Doccini, Maria Alice Donati, Claudia Dosi, Massimiliano Filosto, Chiara Fiorillo, Chiara La Morgia, Costanza Lamperti, Silvia Marchet, Diego Martinelli, Carlo Minetti, Maurizio Moggio, Tiziana Enrica Mongini, Vincenzo Montano, Isabella Moroni, Olimpia Musumeci, Elia Pancheri, Elena Pegoraro, Guido Primiano, Elena Procopio, Anna Rubegni, Roberta Scalise, Monica Sciacco, Serenella Servidei, Gabriele Siciliano, Costanza Simoncini, Deborah Tolomeo, Paola Tonin, Antonio Toscano, Flavia Tubili, Michelangelo Mancuso, Roberta Battini, and Filippo Maria Santorelli
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mitochondrial disease ,movement disorder ,childhood onset ,multicenter cross-sectional study ,Medicine - Abstract
Movement disorders are increasingly being recognized as a manifestation of childhood-onset mitochondrial diseases (MDs). However, the spectrum and characteristics of these conditions have not been studied in detail in the context of a well-defined cohort of patients. We retrospectively explored a cohort of individuals with childhood-onset MDs querying the Nationwide Italian Collaborative Network of Mitochondrial Diseases database. Using a customized online questionnaire, we attempted to collect data from the subgroup of patients with movement disorders. Complete information was available for 102 patients. Movement disorder was the presenting feature of MD in 45 individuals, with a mean age at onset of 11 years. Ataxia was the most common movement disorder at onset, followed by dystonia, tremor, hypokinetic disorders, chorea, and myoclonus. During the disease course, most patients (67.7%) encountered a worsening of their movement disorder. Basal ganglia involvement, cerebral white matter changes, and cerebellar atrophy were the most commonly associated neuroradiological patterns. Forty-one patients harbored point mutations in the mitochondrial DNA, 10 carried mitochondrial DNA rearrangements, and 41 cases presented mutations in nuclear-DNA-encoded genes, the latter being associated with an earlier onset and a higher impairment in activities of daily living. Among our patients, 32 individuals received pharmacological treatment; clonazepam and oral baclofen were the most commonly used drugs, whereas levodopa and intrathecal baclofen administration were the most effective. A better delineation of the movement disorders phenotypes starting in childhood may improve our diagnostic workup in MDs, fine tuning management, and treatment of affected patients.
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- 2021
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46. Neutral Lipid Storage Diseases: clinical/genetic features and natural history in a large cohort of Italian patients
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Elena Maria Pennisi, Marcello Arca, Enrico Bertini, Claudio Bruno, Denise Cassandrini, Adele D’amico, Matteo Garibaldi, Francesca Gragnani, Lorenzo Maggi, Roberto Massa, Sara Missaglia, Lucia Morandi, Olimpia Musumeci, Elena Pegoraro, Emanuele Rastelli, Filippo Maria Santorelli, Elisabetta Tasca, Daniela Tavian, Antonio Toscano, Corrado Angelini, and The Italian NLSD Group
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NLSD ,PNPLA2 ,CGI58 ,Myopathy ,Lipid metabolism ,Natural history ,Medicine - Abstract
Abstract Background A small number of patients affected by Neutral Lipid Storage Diseases (NLSDs: NLSD type M with Myopathy and NLSD type I with Ichthyosis) have been described in various ethnic groups worldwide. However, relatively little is known about the progression and phenotypic variability of the disease in large specific populations. The aim of our study was to assess the natural history, disability and genotype-phenotype correlations in Italian patients with NLSDs. Twenty-one patients who satisfied the criteria for NLSDs were enrolled in a retrospective cross-sectional study to evaluate the genetic aspects, clinical signs at onset, disability progression and comorbidities associated with this group of diseases. Results During the clinical follow-up (range: 2–44 years, median: 17.8 years), two patients (9.5%, both with NLSD-I) died of hepatic failure, and a further five (24%) lost their ability to walk or needed help when walking after a mean period of 30.6 years of disease. None of the patients required mechanical ventilation. No patient required a heart transplant, one patient with NLSD-M was implanted with a cardioverter defibrillator for severe arrhythmias. Conclusion The genotype/phenotype correlation analysis in our population showed that the same gene mutations were associated with a varying clinical onset and course. This study highlights peculiar aspects of Italian NLSD patients that differ from those observed in Japanese patients, who were found to be affected by a marked hypertrophic cardiopathy. Owing to the varying phenotypic expression of the same mutations, it is conceivable that some additional genetic or epigenetic factors affect the symptoms and progression in this group of diseases.
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- 2017
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47. Long-term natural history data in Duchenne muscular dystrophy ambulant patients with mutations amenable to skip exons 44, 45, 51 and 53.
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Claudia Brogna, Giorgia Coratti, Marika Pane, Valeria Ricotti, Sonia Messina, Adele D'Amico, Claudio Bruno, Gianluca Vita, Angela Berardinelli, Elena Mazzone, Francesca Magri, Federica Ricci, Tiziana Mongini, Roberta Battini, Luca Bello, Elena Pegoraro, Giovanni Baranello, Stefano C Previtali, Luisa Politano, Giacomo P Comi, Valeria A Sansone, Alice Donati, Enrico Bertini, Francesco Muntoni, Nathalie Goemans, Eugenio Mercuri, and on behalf on the International DMD group
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Medicine ,Science - Abstract
IntroductionThe aim of this international collaborative effort was to report 36-month longitudinal changes using the 6MWT in ambulant patients affected by Duchenne muscular dystrophy amenable to skip exons 44, 45, 51 or 53.Materials and methodsOf the 92 patients included in the study, 24 had deletions amenable to skip exon 44, 27 exon 45, 18 exon 51, and 28 exon 53. Five patients with a single deletion of exon 52 were counted in both subgroups skipping exon 51 and 53.ResultsThe difference between subgroups amenable to skip different exons was not significant at 12 months but became significant at both 24 (p≤0.05) and 36 months (p≤0.01).DiscussionMutations amenable to skip exon 53 had lower baseline values and more negative changes than the other subgroups while those amenable to skip exon 44 had better results both at baseline and at follow up. Deletions amenable to skip exon 45 were associated with a more variable pattern of progression. Single exon deletions were more often associated with less drastic changes but this was not always true in individual cases.ConclusionOur results confirm that the progression of disease can differ between patients with different deletions, although the changes only become significant from 24 months onwards. This information is relevant because there are current clinical trials specifically targeting patients with these subgroups of mutations.
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- 2019
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48. Correction: Long-term natural history data in Duchenne muscular dystrophy ambulant patients with mutations amenable to skip exons 44, 45, 51 and 53.
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Claudia Brogna, Giorgia Coratt, Marika Pane, Valeria Ricotti, Sonia Messina, Adele D'Amico, Claudio Bruno, Gianluca Vita, Angela Berardinelli, Elena Mazzone, Francesca Magri, Federica Ricci, Tiziana Mongini, Roberta Battini, Luca Bello, Elena Pegoraro, Giovanni Baranello, Stefano C Previtali, Luisa Politano, Giacomo P Comi, Valeria A Sansone, Alice Donati, Enrico Bertini, Francesco Muntoni, Nathalie Goemans, Eugenio Mercuri, and on behalf on the International DMD group
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Medicine ,Science - Abstract
[This corrects the article DOI: 10.1371/journal.pone.0218683.].
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- 2019
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49. eATP/P2X7R Axis: An Orchestrated Pathway Triggering Inflammasome Activation in Muscle Diseases
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Chiara Panicucci, Lizzia Raffaghello, Santina Bruzzone, Serena Baratto, Elisa Principi, Carlo Minetti, Elisabetta Gazzerro, and Claudio Bruno
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eATP ,P2X7R ,inflammasome ,muscular dystrophies ,Duchenne Muscular Dystrophy ,Sarcoglycanopathies ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
In muscle ATP is primarily known for its function as an energy source and as a mediator of the “excitation-transcription” process, which guarantees muscle plasticity in response to environmental stimuli. When quickly released in massive concentrations in the extracellular space as in presence of muscle membrane damage, ATP acts as a damage-associated molecular pattern molecule (DAMP). In experimental murine models of muscular dystrophies characterized by membrane instability, blockade of eATP/P2X7 receptor (R) purinergic signaling delayed the progression of the dystrophic phenotype dampening the local inflammatory response and inducing Foxp3+ T Regulatory lymphocytes. These discoveries highlighted the relevance of ATP as a harbinger of immune-tissue damage in muscular genetic diseases. Given the interactions between the immune system and muscle regeneration, the comprehension of ATP/purinerigic pathway articulated organization in muscle cells has become of extreme interest. This review explores ATP release, metabolism, feedback control and cross-talk with members of muscle inflammasome in the context of muscular dystrophies.
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- 2020
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50. Detection of early nocturnal hypoventilation in neuromuscular disorders
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Federica Trucco, Marina Pedemonte, Chiara Fiorillo, Hui-leng Tan, Annalisa Carlucci, Giacomo Brisca, Paola Tacchetti, Claudio Bruno, and Carlo Minetti
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Medicine (General) ,R5-920 - Abstract
Objective Nocturnal hypoventilation (NH) is a complication of respiratory involvement in neuromuscular disorders (NMD) that can evolve into symptomatic daytime hypercapnia if not treated proactively with non-invasive ventilation. This study aimed to assess whether NH can be detected in the absence of other signs of nocturnal altered gas exchange. Methods We performed nocturnal transcutaneous coupled (tc) pCO 2 /SpO 2 monitoring in 46 consecutive cases of paediatric-onset NMD with a restrictive respiratory defect (forced vital capacity 50 mmHg for > 25% of recorded time, and hypoxemia as tcSpO 2 5 minutes. Daytime symptoms and bicarbonate were recorded after overnight monitoring. Results Twenty-nine of 46 consecutive patients showed NH. Twenty-three patients did not have nocturnal hypoxemia and 18 were clinically asymptomatic. In 20 patients, PaCO 2 in daytime blood samples was normal. Finally, 13/29 patients with NH had isolated nocturnal hypercapnia without nocturnal hypoxia, clinical NH symptoms, or daytime hypercapnia. Conclusions Paediatric patients with NMD can develop NH in the absence of clinical symptoms or significant nocturnal desaturation. Therefore, monitoring of NH should be included among nocturnal respiratory assessments of these patients as an additional tool to determine when to commence non-invasive ventilation.
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- 2018
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