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1. Maternally inherited cardiomyopathy and hearing loss associated with a novel mutation in the mitochondrial tRNA(Lys) gene (G8363A).

Author

Santorelli, FM, Mak, SC, El-Schahawi, M, Casali, C, Shanske, S, Baram, TZ, Madrid, RE, and DiMauro, S

Subjects
Genetics, Rare Diseases, Cardiovascular, 2.1 Biological and endogenous factors, Aetiology, Adolescent, Adult, Aged, Base Sequence, Cardiomyopathy, Dilated, Child, Child, Preschool, Female, Hearing Disorders, Humans, Male, Middle Aged, Molecular Sequence Data, Mutation, Pedigree, RNA, RNA, Mitochondrial, RNA, Transfer, Lys, Syndrome, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

A novel G8363A mutation in the mtDNA tRNA(Lys) gene was associated, in two unrelated families, with a syndrome consisting of encephalomyopathy, sensorineural hearing loss, and hypertrophic cardiomyopathy. Muscle biopsies from the probands showed mitochondrial proliferation and partial defects of complexes I, III, and IV of the electron-transport chain. The G8363A mutation was very abundant (>95%) in muscle samples from the probands and was less copious in blood from 18 maternal relatives (mean 81.3% +/- 8.5%). Single-muscle-fiber analysis showed significantly higher levels of mutant genomes in cytochrome (c) oxidase-negative fibers than in cytochrome (c) oxidase-positive fibers. The mutation was not found in >200 individuals, including normal controls and patients with other mitochondrial encephalomyopathies, thus fulfilling accepted criteria for pathogenicity.

Published
1996

2. Estimating the impact of COVID-19 pandemic on services provided by Italian Neuromuscular Centers: an Italian Association of Myology survey of the acute phase

Author

Mauri, E, Abati, E, Musumeci, O, Rodolico, C, D'Angelo, Mg, Mirabella, M, Lucchini, M, Bello, L, Pegoraro, E, Maggi, L, Manneschi, L, Gemelli, C, Grandis, M, Zuppa, A, Massucco, S, Benedetti, L, Caponnetto, C, Schenone, A, Prelle, A, Previtali, Sc, Scarlato, M, D'Amico, A, Bertini, E, Pennisi, Em, De Giglio, L, Pane, M, Mercuri, E, Mongini, T, Ricci, F, Berardinelli, A, Astrea, G, Lenzi, S, Battini, R, Ricci, G, Torri, F, Siciliano, G, Santorelli, Fm, Ariatti, A, Filosto, M, Passamano, L, Politano, L, Scutifero, M, Tonin, P, Fossati, B, Panicucci, C, Bruno, C, Ravaglia, S, Monforte, M, Tasca, G, Ricci, E, Petrucci, A, Santoro, L, Ruggiero, L, Barp, A, Albamonte, E, Sansone, V, Gagliardi, D, Costamagna, G, Govoni, A, Magri, F, Brusa, R, Velardo, D, Meneri, M, Sciacco, M, Corti, S, Bresolin, N, Moroni, I, Messina, S, Di Muzio, A, Nigro, V, Liguori, R, Antonini, G, Toscano, A, Minetti, C, Comi, Gp, Italian Association of, Myology., Mauri, Eleonora, Abati, Elena, Musumeci, Olimpia, Rodolico, Carmelo, D'Angelo, Maria Grazia, Mirabella, Massimiliano, Lucchini, Matteo, Bello, Luca, Pegoraro, Elena, Maggi, Lorenzo, Manneschi, Letizia, Gemelli, Chiara, Grandis, Marina, Zuppa, Angela, Massucco, Sara, Benedetti, Luana, Caponnetto, Claudia, Schenone, Angelo, Prelle, Alessandro, Previtali, Stefano C, Scarlato, Marina, D'Amico, Adele, Bertini, Enrico, Pennisi, Elena M, De Giglio, Laura, Pane, Marika, Mercuri, Eugenio, Mongini, Tiziana, Ricci, Federica, Berardinelli, Angela, Astrea, Guja, Lenzi, Sara, Battini, Roberta, Ricci, Giulia, Torri, Francesca, Siciliano, Gabriele, Santorelli, Filippo M, Ariatti, Alessandra, Filosto, Massimiliano, Passamano, Luigia, Politano, Luisa, Scutifero, Marianna, Tonin, Paola, Fossati, Barbara, Panicucci, Chiara, Bruno, Claudio, Ravaglia, Sabrina, Monforte, Mauro, Tasca, Giorgio, Ricci, Enzo, Petrucci, Antonio, Santoro, Lucio, Ruggiero, Lucia, Barp, Andrea, Albamonte, Emilio, Sansone, Valeria, Gagliardi, Delia, Costamagna, Gianluca, Govoni, Alessandra, Magri, Francesca, Brusa, Roberta, Velardo, Daniele, Meneri, Megi, Sciacco, Monica, Corti, Stefania, Bresolin, Nereo, Moroni, Isabella, Messina, Sonia, Di Muzio, Antonio, Nigro, Vincenzo, Liguori, Rocco, Antonini, Giovanni, Toscano, Antonio, Minetti, Carlo, Comi, Giacomo Pietro, Mauri E., Abati E., Musumeci O., Rodolico C., D'Angelo M.G., Mirabella M., Lucchini M., Bello L., Pegoraro E., Maggi L., Manneschi L., Gemelli C., Grandis M., Zuppa A., Massucco S., Benedetti L., Caponnetto C., Schenone A., Prelle A., Previtali S.C., Scarlato M., D'Amico A., Bertini E., Pennisi E.M., de Giglio L., Pane M., Mercuri E., Mongini T., Ricci F., Berardinelli A., Astrea G., Lenzi S., Battini R., Ricci G., Torri F., Siciliano G., Santorelli F.M., Ariatti A., Filosto M., Passamano L., Politano L., Scutifero M., Tonin P., Fossati B., Panicucci C., Bruno C., Ravaglia S., Monforte M., Tasca G., Ricci E., Petrucci A., Santoro L., Ruggiero L., Barp A., Albamonte E., Sansone V., Gagliardi D., Costamagna G., Govoni A., Magri F., Brusa R., Velardo D., Meneri M., Sciacco M., Corti S., Bresolin N., Moroni I., Messina S., Muzio A.D., Nigro V., Liguori R., Antonini G., Toscano A., Minetti C., Comi G.P., Mauri, E., Abati, E., Musumeci, O., Rodolico, C., D'Angelo, M. G., Mirabella, M., Lucchini, M., Bello, L., Pegoraro, E., Maggi, L., Manneschi, L., Gemelli, C., Grandis, M., Zuppa, A., Massucco, S., Benedetti, L., Caponnetto, C., Schenone, A., Prelle, A., Previtali, S. C., Scarlato, M., D'Amico, A., Bertini, E., Pennisi, E. M., de Giglio, L., Pane, M., Mercuri, E., Mongini, T., Ricci, F., Berardinelli, A., Astrea, G., Lenzi, S., Battini, R., Ricci, G., Torri, F., Siciliano, G., Santorelli, F. M., Ariatti, A., Filosto, M., Passamano, L., Politano, L., Scutifero, M., Tonin, P., Fossati, B., Panicucci, C., Bruno, C., Ravaglia, S., Monforte, M., Tasca, G., Ricci, E., Petrucci, A., Santoro, L., Ruggiero, L., Barp, A., Albamonte, E., Sansone, V., Gagliardi, D., Costamagna, G., Govoni, A., Magri, F., Brusa, R., Velardo, D., Meneri, M., Sciacco, M., Corti, S., Bresolin, N., Moroni, I., Messina, S., Muzio, A. D., Nigro, V., Liguori, R., Antonini, G., Toscano, A., Minetti, C., and Comi, G. P.

Subjects
COVID-19, Myastenia gravis, Myopathies, Neuromuscular diseases, Neuromuscular services, Neuropathies, SARS-CoV-2, neuropathies, Ambulatory Care, Coronavirus Infections, Cross-Sectional Studies, Health Services Accessibility, Hospitalization, Humans, Italy, Neuromuscular Diseases, Pandemics, Pneumonia, Viral, Referral and Consultation, Surveys and Questionnaires, Telemedicine, Betacoronavirus, neuromuscular diseases, myastenia gravis, neuromuscular services, neuromuscular service, Surveys and Questionnaire, Viral, myopathie, Cross-Sectional Studie, Pandemic, Coronavirus Infection, Pneumonia, neuromuscular disease, myastenia gravi, Settore MED/26 - NEUROLOGIA, neuropathie, myopathies, Original Article, Human
Abstract

Introduction. Since February 2020, the outbreak of COVID-19 in Italy has forced the health care system to undergo profound rearrangements in its services and facilities, especially in the worst-hit areas in Northern Italy. In this setting, inpatient and outpatient services had to rethink and reorganize their activities to meet the needs of patients during the “lockdown”. The Italian Association of Myology developed a survey to estimate the impact of these changes on patients affected by neuromuscular disorders and on specialized neuromuscular centers during the acute phase of COVID-19 pandemic. Methods. We developed an electronic survey that was sent to neuromuscular centers affiliated with the Italian Association of Myology, assessing changes in pharmacological therapies provision, outpatient clinical and instrumental services, support services (physiotherapy, nursing care, psychological support) and clinical trials. Results. 40% of surveyed neuromuscular centers reported a reduction in outpatient visit and examinations (44.5% of centers in Northern regions; 25% of centers in Central regions; 50% of centers in Southern regions). Twenty-two% of centers postponed in-hospital administration of therapies for neuromuscular diseases (23.4% in Northern regions; 13.0% in Central regions; 20% in Southern regions). Diagnostic and support services (physiotherapy, nursing care, psychological support) were suspended in 57% of centers (66/43/44% in Northern, Central and Southern centers respectively) Overall, the most affected services were rehabilitative services and on-site outpatient visits, which were suspended in 93% of centers. Strategies adopted by neuromuscular centers to overcome these changes included maintaining urgent on-site visits, addressing patients to available services and promoting remote contact and telemedicine. Conclusions. Overall, COVID-19 pandemic resulted in a significant disruption of clinical and support services for patients with neuromuscular diseases. Despite the efforts to provide telemedicine consults to patients, this option could be promoted and improved further. A close collaboration between the different neuromuscular centers and service providers as well as further implementation of telehealth platforms are necessary to ensure quality care to NMD patients in the near future and in case of recurrent pandemic waves.

Published
2020

6. Copy Number Variants Account for a Tiny Fraction of Undiagnosed Myopathic Patients.

Author

Giugliano, T, Savarese, M, Garofalo, A, Picillo, E, Fiorillo, Claudio, D'Amico, Adele, Maggi, Loredana, De Ruggiero, L, Vercelli, L, Magri, F, Fattori, F, Torella, A, Ergoli, M, Rubegni, A, Fanin, M, Musumeci, O, Bleecker, J, Peverelli, L, Moggio, M, Mercuri, Eugenio Maria, Toscano, A, Mora, M, Santoro, Luca, Mongini, T, Bertini, Enrico Silvio, Bruno, Carmelina, Minetti, C, Comi, Gp, Santorelli, Fm, Angelini, C, Politano, L, Piluso, G, Nigro, V., Fiorillo C (ORCID:0000-0001-7681-3567), D'Amico A, Maggi L (ORCID:0000-0003-0822-8483), Mercuri E (ORCID:0000-0002-9851-5365), Santoro L, Bertini E, Bruno C, Giugliano, T, Savarese, M, Garofalo, A, Picillo, E, Fiorillo, Claudio, D'Amico, Adele, Maggi, Loredana, De Ruggiero, L, Vercelli, L, Magri, F, Fattori, F, Torella, A, Ergoli, M, Rubegni, A, Fanin, M, Musumeci, O, Bleecker, J, Peverelli, L, Moggio, M, Mercuri, Eugenio Maria, Toscano, A, Mora, M, Santoro, Luca, Mongini, T, Bertini, Enrico Silvio, Bruno, Carmelina, Minetti, C, Comi, Gp, Santorelli, Fm, Angelini, C, Politano, L, Piluso, G, Nigro, V., Fiorillo C (ORCID:0000-0001-7681-3567), D'Amico A, Maggi L (ORCID:0000-0003-0822-8483), Mercuri E (ORCID:0000-0002-9851-5365), Santoro L, Bertini E, and Bruno C

Abstract

Next-generation sequencing (NGS) technologies have led to an increase in the diagnosis of heterogeneous genetic conditions. However, over 50% of patients with a genetically inherited disease are still without a diagnosis. In these cases, different hypotheses are usually postulated, including variants in novel genes or elusive mutations. Although the impact of copy number variants (CNVs) in neuromuscular disorders has been largely ignored to date, missed CNVs are predicted to have a major role in disease causation as some very large genes, such as the dystrophin gene, have prone-to-deletion regions. Since muscle tissues express several large disease genes, the presence of elusive CNVs needs to be comprehensively assessed following an accurate and systematic approach. In this multicenter cohort study, we analyzed 234 undiagnosed myopathy patients using a custom array comparative genomic hybridization (CGH) that covers all muscle disease genes at high resolution. Twenty-two patients (9.4%) showed non-polymorphic CNVs. In 12 patients (5.1%), the identified CNVs were considered responsible for the observed phenotype. An additional ten patients (4.3%) presented candidate CNVs not yet proven to be causative. Our study indicates that deletions and duplications may account for 5−9% of genetically unsolved patients. This strongly suggests that other mechanisms of disease are yet to be discovered.

Published
2018

7. Interpreting Genetic Variants in Titin in Patients With Muscle Disorders.

Author

Savarese, M, Maggi, L, Vihola, A, Jonson, Ph, Tasca, G, De Ruggiero, Luigi, Bello, L, Magri, F, Giugliano, T, Torella, A, Evilä, A, Di Fruscio, G, Vanakker, O, Gibertini, S, Vercelli, L, Ruggieri, A, Antozzi, C, Luque, H, Janssens, S, Pasanisi, Mb, Fiorillo, Claudio, Raimondi, M, Ergoli, M, Politano, L, Bruno, C, Rubegni, A, Pane, Marika, Santorelli, Fm, Minetti, C, Angelini, Carlo, De Bleecker, J, Moggio, M, Mongini, T, Comi, Gp, Santoro, L, Mercuri, Eugenio Maria, Pegoraro, E, Mora, M, Hackman, P, Udd, B, Nigro, V., Fiorillo C (ORCID:0000-0001-7681-3567), Pane M (ORCID:0000-0002-4851-6124), Angelini C, Mercuri E (ORCID:0000-0002-9851-5365), Savarese, M, Maggi, L, Vihola, A, Jonson, Ph, Tasca, G, De Ruggiero, Luigi, Bello, L, Magri, F, Giugliano, T, Torella, A, Evilä, A, Di Fruscio, G, Vanakker, O, Gibertini, S, Vercelli, L, Ruggieri, A, Antozzi, C, Luque, H, Janssens, S, Pasanisi, Mb, Fiorillo, Claudio, Raimondi, M, Ergoli, M, Politano, L, Bruno, C, Rubegni, A, Pane, Marika, Santorelli, Fm, Minetti, C, Angelini, Carlo, De Bleecker, J, Moggio, M, Mongini, T, Comi, Gp, Santoro, L, Mercuri, Eugenio Maria, Pegoraro, E, Mora, M, Hackman, P, Udd, B, Nigro, V., Fiorillo C (ORCID:0000-0001-7681-3567), Pane M (ORCID:0000-0002-4851-6124), Angelini C, and Mercuri E (ORCID:0000-0002-9851-5365)

Abstract

Importance: Mutations in the titin gene (TTN) cause a wide spectrum of genetic diseases. The interpretation of the numerous rare variants identified in TTN is a difficult challenge given its large size. Objective: To identify genetic variants in titin in a cohort of patients with muscle disorders. Design, Setting, and Participants: In this case series, 9 patients with titinopathy and 4 other patients with possibly disease-causing variants in TTN were identified. Titin mutations were detected through targeted resequencing performed on DNA from 504 patients with muscular dystrophy, congenital myopathy, or other skeletal muscle disorders. Patients were enrolled from 10 clinical centers in April 2012 to December 2013. All of them had not received a diagnosis after undergoing an extensive investigation, including Sanger sequencing of candidate genes. The data analysis was performed between September 2013 and January 2017. Sequencing data were analyzed using an internal custom bioinformatics pipeline. Main Outcomes and Measures: The identification of novel mutations in the TTN gene and novel patients with titinopathy. We performed an evaluation of putative causative variants in the TTN gene, combining genetic, clinical, and imaging data with messenger RNA and/or protein studies. Results: Of the 9 novel patients with titinopathy, 5 (55.5%) were men and the mean (SD) age at onset was 25 (15.8) years (range, 0-46 years). Of the 4 other patients (3 men and 1 woman) with possibly disease-causing TTN variants, 2 (50%) had a congenital myopathy and 2 (50%) had a slowly progressive distal myopathy with onset in the second decade. Most of the identified mutations were previously unreported. However, all the variants, even the already described mutations, require careful clinical and molecular evaluation of probands and relatives. Heterozygous truncating variants or unique missense changes are not sufficient to make a diagnosis of titinopathy. Conclusions and Relevance: The interpr

Published
2018

9. Reading impairment in Duchenne muscular dystrophy: A pilot study to investigate similarities and differences with developmental dyslexia

Author

Astrea G, Pecini C, Gasperini F, Brisca G, Scutifero M, Bruno C, Santorelli FM, Cioni G, Chilosi AM, Battini R., POLITANO, Luisa, Astrea, G, Pecini, C, Gasperini, F, Brisca, G, Scutifero, M, Bruno, C, Santorelli, Fm, Cioni, G, Politano, Luisa, Chilosi, Am, and Battini, R.

Subjects
DMD
Abstract

Below-average reading performances have been reported in individuals with Duchenne muscular dystrophy (DMD), but literacy problems in these subjects have yet to be characterized. In this study, the presence and characteristics of literacy deficits in boys with DMD were investigated through a comparison with typically developing children and with children affected by developmental dyslexia, with the aim of clarifying whether DMD and developmental dyslexia have overlapping profiles of literacy deficits and whether these deficits are associated, as in children with dyslexia, with impairments in phonological processing and rapid lexical access. The results confirmed the high incidence of literacy problems in boys with DMD and revealed a profile less severe than, but qualitatively similar to, that of Italian children with developmental dyslexia. Both groups showed specific difficulties in reading and writing words and a reduced rapid automatized naming (RAN) speed. This is the first time that a RAN speed deficit has been documented in DMD. Moreover, the boys with DMD and the subgroup of dyslexic children with a previous language delay showed additional deficits in phonological processing. The impairments highlighted in this study could explain the reading difficulties observed in boys with DMD and suggest that there is a need for targeted preschool interventions.

Published
2015

11. TMEM5-associated dystroglycanopathy presenting with CMD and mild limb-girdle muscle involvement

Author

Astrea G, Pezzini I, Picillo E, Pasquariello R, Moro F, Ergoli M, D'Ambrosio P, D'Amico A, Politano L, Santorelli FM.

Subjects
Cochlear dysplasia, Congenital muscular dystrophy, Polymicrogyria, Limb-girdle muscle weakness, TMEM5
Abstract

The dystroglycanopathies, which are caused by reduced glycosylation of alpha-dystroglycan, are a heterogeneous group of neurodegenerative disorders characterized by variable brain and skeletal muscle involvement. Recently, mutations in TMEM5 have been described in severe dystroglycanopathies. We present the clinical, molecular and neuroimaging features of an Italian boy who had delayed developmental milestones with mild limb-girdle muscle involvement, bilateral frontotemporal polymicrogyria, moderate intellectual disability, and no cerebellar involvement. He also presented a cochlear dysplasia and harbored a reported mutation (p.A47Rfs*42) in TMEM5, detected using targeted next-generation sequencing. The relatively milder muscular phenotype and associated structural brain abnormalities distinguish this case from previously reported patients with severe dystroglycanopathies and expand the spectrum of TMEM5-associated disorders.

Published
2016

12. GBX2: a candidate gene for midline cerebellar defects

Author

Zanni, G., Savini, F., Santorelli, FM., Neri, G., Giannotti, A., and Bertini, E.

Subjects
Human genetics -- Research, Genetic disorders -- Research, Cerebellum -- Abnormalities, Genetic regulation -- Analysis, Joubert syndrome, Biological sciences
Published
2001

14. Myoclonus in mitochondrial disorders

Author

Mancuso, M, Orsucci, D, Angelini, C, Bertini, E, Catteruccia, M, Pegoraro, E, Carelli, V, Valentino, Ml, Comi, Gp, Minetti, C, Bruno, C, Moggio, M, Ienco, Ec, Mongini, T, Vercelli, L, Primiano, Guido Alessandro, Servidei, Serenella, Tonin, P, Scarpelli, M, Toscano, A, Musumeci, O, Moroni, I, Uziel, G, Santorelli, Fm, Nesti, C, Filosto, M, Lamperti, C, Zeviani, M, Siciliano, G., Mancuso, M., Orsucci, D., Angelini, C., Bertini, E., Catteruccia, M., Pegoraro, E., Carelli, V., Valentino, M.L., Comi, G.P., Minetti, C., Bruno, C., Moggio, M., Ienco, E.C., Mongini, T., Vercelli, L., Primiano, G., Servidei, S., Tonin, P., Scarpelli, M., Toscano, A., Musumeci, O., Moroni, I., Uziel, G., Santorelli, F.M., Nesti, C., Filosto, M., Lamperti, C., Zeviani, M., and Siciliano, G.

Subjects
Myoclonus, Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, Mitochondrial Diseases, Adolescent, myoclonic epilepsy with ragged red fiber, Severity of Illness Index, MERRF, Cohort Studies, Young Adult, Humans, Child, Preschool, myoclonu, mtDNA, Medicine (all), Middle Aged, mitochondrial, G%22">8344A>G, ataxia, myoclonic epilepsy, myoclonus, nervous system diseases, Settore MED/26 - NEUROLOGIA, Ataxia, Myoclonic epilepsy, Italy, Neurology, Child, Preschool, Female, Neurology (clinical)
Abstract

Myoclonus is a possible manifestation of mitochondrial disorders, and its presence is considered, in association with epilepsy and the ragged red fibers, pivotal for the syndromic diagnosis of MERRF (myoclonic epilepsy with ragged red fibers). However, its prevalence in mitochondrial diseases is not known. The aims of this study are the evaluation of the prevalence of myoclonus in a big cohort of mitochondrial patients and the clinical characterization of these subjects. Based on the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases," we reviewed the clinical and molecular data of mitochondrial patients with myoclonus among their clinical features. Myoclonus is a rather uncommon clinical feature of mitochondrial diseases (3.6% of 1,086 patients registered in our database). It is not strictly linked to a specific genotype or phenotype, and only 1 of 3 patients with MERRF harbors the 8344A>G mutation (frequently labeled as "the MERRF mutation"). Finally, myoclonus is not inextricably linked to epilepsy in MERRF patients, but more to cerebellar ataxia. In a myoclonic patient, evidences of mitochondrial dysfunction must be investigated, even though myoclonus is not a common sign of mitochondriopathy. Clinical, histological, and biochemical data may predict the finding of a mitochondrial or nuclear DNA mutation. Finally, this study reinforces the notion that myoclonus is not inextricably linked to epilepsy in MERRF patients, and therefore the term "myoclonic epilepsy" seems inadequate and potentially misleading. © 2014 International Parkinson and Movement Disorder Society.

Published
2014

17. Redefining phenotypes associated with mitochondrial DNA single deletion

Author

Mancuso, M, Orsucci, D, Angelini, C, Bertini, E, Carelli, V, Comi, Gp, Donati, Ma, Federico, A, Minetti, C, Moggio, M, Mongini, T, Santorelli, Fm, Servidei, Serenella, Tonin, P, Toscano, A, Bruno, C, Bello, L, Caldarazzo Ienco, E, Cardaioli, E, Catteruccia, M, Da Pozzo, P, Filosto, M, Lamperti, C, Moroni, I, Musumeci, O, Pegoraro, E, Ronchi, D, Sauchelli, Donato, Scarpelli, M, Sciacco, M, Valentino, Ml, Vercelli, L, Zeviani, M, Siciliano, G., Servidei, Serenella (ORCID:0000-0001-8478-2799), Mancuso, M, Orsucci, D, Angelini, C, Bertini, E, Carelli, V, Comi, Gp, Donati, Ma, Federico, A, Minetti, C, Moggio, M, Mongini, T, Santorelli, Fm, Servidei, Serenella, Tonin, P, Toscano, A, Bruno, C, Bello, L, Caldarazzo Ienco, E, Cardaioli, E, Catteruccia, M, Da Pozzo, P, Filosto, M, Lamperti, C, Moroni, I, Musumeci, O, Pegoraro, E, Ronchi, D, Sauchelli, Donato, Scarpelli, M, Sciacco, M, Valentino, Ml, Vercelli, L, Zeviani, M, Siciliano, G., and Servidei, Serenella (ORCID:0000-0001-8478-2799)

Abstract

Progressive external ophthalmoplegia (PEO), Kearns-Sayre syndrome (KSS) and Pearson syndrome are the three sporadic clinical syndromes classically associated with single large-scale deletions of mitochondrial DNA (mtDNA). PEO plus is a term frequently utilized in the clinical setting to identify patients with PEO and some degree of multisystem involvement, but a precise definition is not available. The purpose of the present study is to better define the clinical phenotypes associated with a single mtDNA deletion, by a retrospective study on a large cohort of 228 patients from the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases". In our database, single deletions account for about a third of all patients with mtDNA-related disease, more than previously recognized. We elaborated new criteria for the definition of PEO and "KSS spectrum" (a category of which classic KSS represents the most severe extreme). The criteria for "KSS spectrum" include the resulting multisystem clinical features associated with the KSS features, and which therefore can predict their presence or subsequent development. With the new criteria, we were able to classify nearly all our single-deletion patients: 64.5% PEO, 31.6% KSS spectrum (including classic KSS 6.6%) and 2.6% Pearson syndrome. The deletion length was greater in KSS spectrum than in PEO, whereas heteroplasmy was inversely related with age at onset. We believe that the new phenotype definitions implemented here may contribute to a more homogeneous patient categorization, which will be useful in future cohort studies of natural history and clinical trials.

Published
2015

18. Prevalence of congenital muscular dystrophy in Italy: a population study

Author

Graziano, A, Bianco, F, D'Amico, A, Moroni, I, Messina, S, Bruno, C, Pegoraro, E, Mora, M, Astrea, G, Magri, F, Comi, Gp, Berardinelli, A, Moggio, M, Morandi, L, Pini, A, Petillo, R, Tasca, G, Monforte, M, Minetti, C, Mongini, T, Ricci, Enzo, Gorni, K, Battini, R, Villanova, M, Politano, L, Gualandi, F, Ferlini, A, Muntoni, F, Santorelli, Fm, Bertini, E, Pane, M, Mercuri, Eugenio Maria, Ricci, Enzo (ORCID:0000-0003-3092-3597), Mercuri, Eugenio Maria (ORCID:0000-0002-9851-5365), Graziano, A, Bianco, F, D'Amico, A, Moroni, I, Messina, S, Bruno, C, Pegoraro, E, Mora, M, Astrea, G, Magri, F, Comi, Gp, Berardinelli, A, Moggio, M, Morandi, L, Pini, A, Petillo, R, Tasca, G, Monforte, M, Minetti, C, Mongini, T, Ricci, Enzo, Gorni, K, Battini, R, Villanova, M, Politano, L, Gualandi, F, Ferlini, A, Muntoni, F, Santorelli, Fm, Bertini, E, Pane, M, Mercuri, Eugenio Maria, Ricci, Enzo (ORCID:0000-0003-3092-3597), and Mercuri, Eugenio Maria (ORCID:0000-0002-9851-5365)

Abstract

We provide a nationwide population study of patients with congenital muscular dystrophy in Italy.

Published
2015

19. A novel mutation in SACS gene in a family from southern Italia

Author

Criscuolo C, Orio M, Gasparini P, Monticelli A, Scarano V, Santorelli FM, Perretti A, Santoro L, De Michele G, Filla A., BANFI, Sandro, Criscuolo, C, Banfi, Sandro, Orio, M, Gasparini, P, Monticelli, A, Scarano, V, Santorelli, Fm, Perretti, A, Santoro, L, De Michele, G, and Filla, A.

Published
2004

21. Hereditary spastic paraplegia type 5: a potentially treatable disorder of cholesterol metabolism.

Author

Mignarri, A, Malandrini, A, DEL PUPPO, M, Magni, A, Monti, L, Ginanneschi, F, Tessa, A, Santorelli, F, Federico, A, Dotti, M, Santorelli, FM, Dotti, MT, DEL PUPPO, MARINA, MAGNI, ALESSANDRO, Mignarri, A, Malandrini, A, DEL PUPPO, M, Magni, A, Monti, L, Ginanneschi, F, Tessa, A, Santorelli, F, Federico, A, Dotti, M, Santorelli, FM, Dotti, MT, DEL PUPPO, MARINA, and MAGNI, ALESSANDRO

Published
2014

22. Congenital muscular dystrophies with defective glycosylation of dystroglycan: apopulation study

Author

Mercuri, E, Messina, S, Bruno, C, Mora, M, Pegoraro, Elena, Comi, Gp, D'Amico, A, Aiello, C, Biancheri, R, Berardinelli, A, Boffi, P, Cassandrini, D, Laverda, ANNA MARIA, Moggio, M, Morandi, L, Moroni, I, Pane, M, Pezzani, Raffaele, Pichiecchio, A, Pini, A, Minetti, C, Mongini, T, Mottarelli, E, Ricci, E, Ruggieri, A, Saredi, S, Scuderi, C, Tessa, A, Toscano, A, Tortorella, G, Trevisan, CARLO PIETRO, Uggetti, C, Vasco, G, Santorelli, Fm, and Bertini, E.

Published
2009

23. Screening of ARHSP-TCC patients expands the spectrum of SPG11 mutations and includes a large scale gene deletion

Author

Denora, Ps, Schlesinger, D, Casali, Carlo, Kok, F, Tessa, A, Boukhris, A, Azzedine, H, Dotti, Mt, Bruno, C, Truchetto, J, Biancheri, R, Fedirko, E, DI ROCCO, M, Bueno, C, Malandrini, A, Battini, R, Sickl, E, DE LEVA MF, BOESPFLUG TANGUY, O, Silvestri, G, Simonati, A, Said, E, Ferbert, A, Criscuolo, C, Heinimann, K, Modoni, A, Weber, P, Palmeri, S, Plasilova, M, Pauri, Flavia, Cassandrini, D, Battisti, C, Pini, A, Tosetti, M, Hauser, E, Masciullo, M, DI FABIO, R, Piccolo, F, Denis, E, Cioni, G, Massa, R, Della, Giustina, E, Calabrese, O, Melone, Ma, DE MICHELE, G, Federico, A, Bertini, E, Durr, A, Brockmann, K, VAN DER KNAAP MS, Zatz, M, Filla, A, Brice, A, Stevanin, G, Santorelli, Fm, Denora, P., Schlesinger, D., Casali, C., Kok, F., Tessa, A., Boukhris, A., Azzedine, H., Dotti, M., Bruno, C., Trucchetto, J., Biancheri, R., Fedirko, E., DI ROCCO, M., Bueno, C., Malandrini, A., Battini, R., Sickl, E., DE LEVA, F., BOESPFLUG TANGUY, O., Silvestri, G., Simonati, A., Said, E., Ferbert, A., Criscuolo, C., Heinimann, K., Modoni, A., Weber, P., Palmeri, S., Plasilova, M., Pauri, F., Cassandrini, D., Battisti, C., Pini, A., Tosetti, M., Hauser, E., Masciullo, M., DI FABIO, R., Piccolo, F., Denis, E., Cioni, G., Massa, R., DELLA GIUSTINA, E., Calabrese, O., Melone, Mariarosa Anna Beatrice, DE MICHELE, G., Federico, A., Bertini, E., Durr, A., Brockmann, K., VAN DER KNAPP, M., Zatz, M., Filla, A., Brice, A., Stevanin, G., Santorelli, F., Pediatric surgery, NCA - Childhood White Matter Diseases, Denora, P, Schlesinger, D, Casali, C, Kok, F, Tessa, A, Boukhris, A, Azzedine, H, Dotti, Mt, Bruno, C, Truchetto, J, Biancheri, R, Fedirko, E, Di Rocco, M, Bueno, C, Malandrini, A, Battini, R, Sickl, E, de Leva, Mf, Boespflug Tanguy, O, Silvestri, G, Simonati, A, Said, E, Ferbert, A, Criscuolo, C, Heinimann, K, Modoni, A, Weber, P, Palmeri, S, Plasilova, M, Pauri, F, Cassandrini, D, Battisti, C, Pini, A, Tosetti, M, Hauser, E, Masciullo, M, Fabio, Rd, Piccolo, F, Denis, E, Cioni, G, Massa, R, Giustina, Ed, Calabrese, O, Melone, Ma, DE MICHELE, Giuseppe, Federico, A, Bertini, E, Durr, A, Brockmann, K, van der Knaap, M, Zatz, M, Filla, Alessandro, Brice, A, Stevanin, G, Santorelli, F. M., Di Fabio, R, Della Giustina, E, and Other departments

Subjects
Male, ARHSP, DNA Mutational Analysis, medicine.disease_cause, Mutation screening, SPG11, TCC, 0302 clinical medicine, Gene Frequency, Genotype, Gene duplication, Missense mutation, Genetics (clinical), Genetics, 0303 health sciences, Mutation, education.field_of_study, medicine.diagnostic_test, mutation screening, Middle Aged, Pedigree, 3. Good health, Morocco, Female, Settore MED/26 - Neurologia, Brazil, Adult, Adolescent, ARHSP, TCC, SPG11, mutation screening, Population, Genes, Recessive, Biology, Young Adult, 03 medical and health sciences, medicine, Humans, Genetic Testing, education, Allele frequency, 030304 developmental biology, Genetic testing, Family Health, Base Sequence, Portugal, Spastic Paraplegia, Hereditary, MUTAÇÃO GENÉTICA, Haplotype, Proteins, Haplotypes, Algeria, Agenesis of Corpus Callosum, Gene Deletion, 030217 neurology & neurosurgery
Abstract

Autosomal recessive spastic paraplegia with thinning of corpus callosum (ARHSP-TCC) is a complex form of HSP initially described in Japan but subsequently reported to have a worldwide distribution with a particular high frequency in multiple families from the Mediterranean basin. We recently showed that ARHSP-TCC is commonly associated with mutations in SPG11/KIAA1840 on chromosome 15q. We have now screened a collection of new patients mainly originating from Italy and Brazil, in order to further ascertain the spectrum of mutations in SPG11, enlarge the ethnic origin of SPG11 patients, determine the relative frequency at the level of single Countries (i.e., Italy), and establish whether there is one or more common mutation. In 25 index cases we identified 32 mutations; 22 are novel, including 9 nonsense, 3 small deletions, 4 insertions, 1 in/del, 1 small duplication, 1 missense, 2 splice-site, and for the first time a large genomic rearrangement. This brings the total number of SPG11 mutated patients in the SPATAX collection to 111 cases in 44 families and in 17 isolated cases, from 16 Countries, all assessed using homogeneous clinical criteria. While expanding the spectrum of mutations in SPG11, this larger series also corroborated the notion that even within apparently homogeneous population a molecular diagnosis cannot be achieved without full gene sequencing.

Published
2009
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25. Correlazioni genotipo-fenotipo nelle distrofie muscolari congenite con riduzione dell'alfa-distroglicano: uno studio italiano multicentrico

Author

Messina, Sonia, Bruno, C, Mora, M, Pegoraro, E, Comi, Gp, D'Amico, A, Aiello, C, Biancheri, R, Berardinelli, A, Boffi, P, Cassandrini, D, Laverda, A, Moggio, M, Morandi, L, Moroni, I, Pane, M, Pezzani, R, Pichiecchio, A, Pini, A, Minetti, C, Mongini, T, Mottarelli, E, Ricci, E, Ruggieri, A, Saredi, S, Scuderi, C, Tessa, A, Toscano, A, Tortorella, G, Trevisan, Cp, Uggetti, C, Vasco, G, Santorelli, Fm, and Bertini, E.

Published
2008

26. Genotype-phenotype correlations in congenital muscular dystrophies with defective glycosylation of dystroglycan: a multicentric study

Author

Messina, Sonia, Bruno, C, Mora, M, Pegoraro, E, Comi, Gp, D'Amico, A, Aiello, C, Biancheri, R, Berardinelli, A, Boffi, P, Cassandrini, D, Laverda, A, Moggio, M, Morandi, L, Moroni, I, Pane, M, Pezzani, R, Pichiecchio, A, Pini, A, Minetti, C, Mongini, T, Mottarelli, E, Ricci, E, Ruggieri, A, Saredi, S, Scuderi, C, Tessa, A, Toscano, A, Trevisan, Cp, Uggetti, C, Vasco, G, Santorelli, Fm, and Bertini, E.

Published
2008

29. Autosomal dominant hereditary spastic paraplegia: DHPLC-based mutation analysis of SPG4 reveals eleven novel mutations

Author

Patrono, C, Scarano, V, Cricchi, F, Melone, Ma, Chiriaco, M, Napolitano, A, Malandrini, A, DE MICHELE, G, Petrozzi, L, Giraldi, C, Santoro, L, Servidei, S, Casali, Carlo, C, Filla, A, Santorelli, Fm, Patrono, C, Scarano, V, Cricchi, F, Melone, Ma, Chiriaco, M, Napolitano, A, Malandrini, A, DE MICHELE, Giuseppe, Petrozzi, L, Giraldi, C, Santoro, Lucio, Servidei, S, Casali, C, Filla, Alessandro, Santorelli, F. M., Melone, Mariarosa Anna Beatrice, DE MICHELE, G, Santoro, L, and Filla, A

Subjects
Adult, Spastin, Hereditary spastic paraplegia, Genetic counseling, DNA Mutational Analysis, Molecular Sequence Data, Mutation, Missense, Biology, Bioinformatics, medicine.disease_cause, Frameshift mutation, Cohort Studies, Genetics, medicine, Missense mutation, HSP, Humans, Amino Acid Sequence, Genetic Testing, Family history, Frameshift Mutation, Genetics (clinical), Chromatography, High Pressure Liquid, Genes, Dominant, Adenosine Triphosphatases, Mutation, Polymorphism, Genetic, Spastic Paraplegia, Hereditary, Middle Aged, medicine.disease, HSP, DHPLC, Penetrance, Settore MED/26 - NEUROLOGIA, Phenotype, Italy, hereditary spastic paraplegia, SPG4, Sequence Alignment, Polymorphism, Restriction Fragment Length
Abstract

We set up a new denaturing high-performance liquid chromatography (DHPLC)-based protocol to screen patients with autosomal dominant hereditary spastic paraplegia (AD-HSP) for mutations in SPG4. Six patients had a complicated form and 49 a pure HSP phenotype. We also analyzed 19 unrelated patients presenting with an HSP phenotype (pure in 17 and complicated in two subjects) but no clear family history, as such patients may be cases of dominant inheritance with low penetrance. The overall frequency of SPG4 mutations in our study of HSP (in which prior linkage data were unavailable) was 32.4%, rising to 46.9% when only pure AD-HSP patients were considered. This figure falls well within the range reported in different populations. Rather as expected, the clinical data available for the patients did not support an easy genotype-phenotype correlation. Moreover, the clinical picture was not influenced by the length of the predicted residual gene product. As well as identifying novel variants in SPG4, this study constitutes the molecular characterization of the largest cohort of Italian AD-HSP patients studied to date. In addition, it provided an efficient, cost-effective, and reliable detection protocol for mutational screening of SPG4, which might facilitate medical genetic counseling.

Published
2005

31. Phenotypic heterogeneity of the 8344A>G mtDNA 'MERRF' mutation

Author

Mancuso, M, Orsucci, D, Angelini, C, Bertini, E, Carelli, V, Comi, Gp, Minetti, C, Moggio, M, Mongini, T, Servidei, Serenella, Tonin, P, Toscano, A, Uziel, G, Bruno, C, Caldarazzo Ienco, E, Filosto, M, Lamperti, C, Martinelli, D, Moroni, I, Musumeci, O, Pegoraro, E, Ronchi, D, Santorelli, Fm, Sauchelli, Donato, Scarpelli, M, Sciacco, M, Spinazzi, M, Valentino, Ml, Vercelli, L, Zeviani, M, Siciliano, G., Servidei, Serenella (ORCID:0000-0001-8478-2799), Mancuso, M, Orsucci, D, Angelini, C, Bertini, E, Carelli, V, Comi, Gp, Minetti, C, Moggio, M, Mongini, T, Servidei, Serenella, Tonin, P, Toscano, A, Uziel, G, Bruno, C, Caldarazzo Ienco, E, Filosto, M, Lamperti, C, Martinelli, D, Moroni, I, Musumeci, O, Pegoraro, E, Ronchi, D, Santorelli, Fm, Sauchelli, Donato, Scarpelli, M, Sciacco, M, Spinazzi, M, Valentino, Ml, Vercelli, L, Zeviani, M, Siciliano, G., and Servidei, Serenella (ORCID:0000-0001-8478-2799)

Abstract

Myoclonic epilepsy with ragged-red fibers (MERRF) is a rare mitochondrial syndrome, mostly caused by the 8344A>G mitochondrial DNA mutation. Most of the previous studies have been based on single case/family reports or series with few patients. The primary aim of this study was the characterization of a large cohort of patients with the 8344A>G mutation. The secondary aim was revision of the previously published data.

Published
2013

32. The m.3243A>G mitochondrial DNA mutation and related phenotypes. A matter of gender?

Author

Mancuso, M, Orsucci, D, Angelini, C, Bertini, E, Carelli, V, Comi, Gp, Donati, A, Minetti, C, Moggio, M, Mongini, T, Servidei, Serenella, Tonin, P, Toscano, A, Uziel, G, Bruno, C, Ienco, Ec, Filosto, M, Lamperti, C, Catteruccia, M, Moroni, I, Musumeci, O, Pegoraro, E, Ronchi, D, Santorelli, Fm, Sauchelli, Donato, Scarpelli, M, Sciacco, M, Valentino, Ml, Vercelli, L, Zeviani, M, Siciliano, G., Servidei, Serenella (ORCID:0000-0001-8478-2799), Mancuso, M, Orsucci, D, Angelini, C, Bertini, E, Carelli, V, Comi, Gp, Donati, A, Minetti, C, Moggio, M, Mongini, T, Servidei, Serenella, Tonin, P, Toscano, A, Uziel, G, Bruno, C, Ienco, Ec, Filosto, M, Lamperti, C, Catteruccia, M, Moroni, I, Musumeci, O, Pegoraro, E, Ronchi, D, Santorelli, Fm, Sauchelli, Donato, Scarpelli, M, Sciacco, M, Valentino, Ml, Vercelli, L, Zeviani, M, Siciliano, G., and Servidei, Serenella (ORCID:0000-0001-8478-2799)

Abstract

The m.3243A>G "MELAS" (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) mutation is one of the most common point mutations of the mitochondrial DNA, but its phenotypic variability is incompletely understood. The aim of this study was to revise the phenotypic spectrum associated with the mitochondrial m.3243A>G mutation in 126 Italian carriers of the mutation, by a retrospective, database-based study ("Nation-wide Italian Collaborative Network of Mitochondrial Diseases"). Our results confirmed the high clinical heterogeneity of the m.3243A>G mutation. Hearing loss and diabetes were the most frequent clinical features, followed by stroke-like episodes. "MIDD" (maternally-inherited diabetes and deafness) and "PEO" (progressive external ophthalmoplegia) are nosographic terms without any real prognostic value, because these patients may be even more prone to the development of multisystem complications such as stroke-like episodes and heart involvement. The "MELAS" acronym is convincing and useful to denote patients with histological, biochemical and/or molecular evidence of mitochondrial disease who experience stroke-like episodes. Of note, we observed for the first time that male gender could represent a risk factor for the development of stroke-like episodes in Italian m.3243A>G carriers. Gender effect is not a new concept in mitochondrial medicine, but it has never been observed in MELAS. A better elucidation of the complex network linking mitochondrial dysfunction, apoptosis, estrogen effects and stroke-like episodes may hold therapeutic promises.

Published
2013

33. Glutathione in blood of patients with Friedreich's ataxia

Author

Piemonte, F, Pastore, A, Tozzi, G, Tagliacozzi, D, Santorelli, Fm, Carrozzo, R, Casali, Carlo, Damiano, M, Federici, G, and Bertini, E.

Subjects
Adult, Male, Hemoglobins, Oxidative Stress, Spectrometry, Mass, Electrospray Ionization, Adolescent, Friedreich Ataxia, Humans, Female, Child, Glutathione, Chromatography, High Pressure Liquid
Abstract

Oxidative stress and mitochondrial dysfunction have long been considered to play a role in Friedreich's ataxia, a neurodegenerative disease due to a GAA expansion in a gene coding for a mitochondrial protein (frataxin), implicated in the regulation of iron metabolism. Since glutathione is an important antioxidant whose role has been recently proposed in the pathogenesis of some neurodegenerative diseases, we investigated glutathione metabolism in the blood of 14 patients with Friedreich's ataxia by measuring total, free and protein-bound glutathione concentrations.Blood samples were obtained from 14 unrelated patients with Friedreich's ataxia (nine males, five females) and 20 age-matched healthy controls (10 males, 10 females). Total and free glutathione concentrations were determined by reverse-phase liquid chromatography with fluorescence detection; the glutathionyl-haemoglobin separation from healthy and pathological subjects was obtained by electrospray ionization-mass spectrometry.We consistently found a reduction of free glutathione levels (0.55 +/- 0.06 nmol mg(-1) haemoglobin, vs. 8.4 +/- 1.79 nmol mg(-1) haemoglobin, P0.001) in the blood of patients with Friedreich's ataxia, a total glutathione concentration comparable to the controls (15 +/- 2.6 nmol mg(-1) haemoglobin, vs. 15.4 +/- 1.4 nmol mg(-1) haemoglobin), and a significant increase of glutathione bound to haemoglobin (15 +/- 1.5 vs. 8 +/- 1.8%, P0.05) in erythrocytes.Our findings give evidence of an impairment in vivo of glutathione homeostasis in Friedreich's ataxia, suggesting a relevant role of free radical cytotoxicity in the pathophysiology of the disease; this study may also prove useful in the search for an oxidative stress marker in neurodegeneration.

Published
2001

34. Clinical and Molecular Findings in Four New Patients Harbouring the mtDNA 8993T C Mutation

Author

Vilarinho, L, Carrozzo, R, Barbot, C, Calado, E, Tessa, A, Dionisi-Vici, C, Guimarães, A, and Santorelli, FM

Subjects
HDE NEU PED, Caso Clínico, DNA Mitocondrial, Mutação
Abstract

Submitted by Dulce Barreto (mdulce.barreto@chlc.min-saude.pt) on 2015-03-31T09:37:42Z No. of bitstreams: 1 J Inherit Metab Dis 2001_883.pdf: 45812 bytes, checksum: 6cc162f15b8c5a35d99ba48c44a33518 (MD5) Made available in DSpace on 2015-03-31T09:37:42Z (GMT). No. of bitstreams: 1 J Inherit Metab Dis 2001_883.pdf: 45812 bytes, checksum: 6cc162f15b8c5a35d99ba48c44a33518 (MD5) Previous issue date: 2001

Published
2001

38. Novel mutations in SPG11 cause hereditary spastic paraplegia associated with early-onset levodopa responsive parkinsonism

Author

Silvestri, Gabriella, Guidubaldi, Arianna, Tessa, A, Petracca, Martina, Bentivoglio, Anna Rita, Santorelli, Fm, Silvestri, Gabriella (ORCID:0000-0002-1950-1468), Bentivoglio, Anna Rita (ORCID:0000-0002-9663-095X), Silvestri, Gabriella, Guidubaldi, Arianna, Tessa, A, Petracca, Martina, Bentivoglio, Anna Rita, Santorelli, Fm, Silvestri, Gabriella (ORCID:0000-0002-1950-1468), and Bentivoglio, Anna Rita (ORCID:0000-0002-9663-095X)

Abstract

BACKGROUND: Autosomal recessive hereditary spastic paraplegia with thin corpus callosum is a neurodegenerative disorder characterized by spastic paraparesis, cognitive impairment, and peripheral neuropathy. The neuroradiologic hallmarks are thin corpus callosum and periventricular white matter changes. Mutations in the SPG11 gene have been identified to be a major cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and recently also proven to be responsible for juvenile parkinsonism associated with spastic paraplegia. METHODS: We describe one Italian autosomal recessive hereditary spastic paraplegia with thin corpus callosum patient who unusually presented at onset, 16 years, with parkinsonism-like features, responsive to dopaminergic therapy. Then the clinical picture evolved and became more complex. A brain magnetic resonance imaging scan showed thin corpus callosum and hyperintense T(2)-weighted lesions in periventricular regions, and the (123)I-ioflupane single-photon emission coupled tomography was abnormal. RESULTS: Genetic analysis detected two novel mutations, a c.3664insT variant in compound heterozygosity with a c.6331insG mutation, in SPG11. DISCUSSION: This case confirms the high genetic and clinical heterogeneity associated with SPG11 mutations. It also offers further evidence that parkinsonism may initiate autosomal recessive hereditary spastic paraplegia with thin corpus callosum and that parkinsonian symptoms can have variable dopaminergic response in these patients.

Published
2011

40. Congenital muscular dystrophies with cognitive impairment. A population study

Author

Messina, Salvatore, Bruno, Cristina, Moroni, I, Pegoraro, E, D'Amico, Anna, Biancheri, R, Berardinelli, A, Boffi, Pietro, Cassandrini, D, Farina, Luigi Maria, Minetti, C, Moggio, M, Mongini, T, Mottarelli, E, Pane, Marika, Pantaleoni, C, Pichiecchio, A, Pini, A, Ricci, Enzo, Saredi, S, Sframeli, M, Tortorella, G, Toscano, A, Trevisan, Cp, Uggetti, C, Vasco, Gessica, Comi, Gp, Santorelli, Fm, Bertini, Enrico Silvio, Mercuri, Eugenio Maria, Pane, Marika (ORCID:0000-0002-4851-6124), Ricci, Enzo (ORCID:0000-0003-3092-3597), Mercuri, Eugenio Maria (ORCID:0000-0002-9851-5365), Messina, Salvatore, Bruno, Cristina, Moroni, I, Pegoraro, E, D'Amico, Anna, Biancheri, R, Berardinelli, A, Boffi, Pietro, Cassandrini, D, Farina, Luigi Maria, Minetti, C, Moggio, M, Mongini, T, Mottarelli, E, Pane, Marika, Pantaleoni, C, Pichiecchio, A, Pini, A, Ricci, Enzo, Saredi, S, Sframeli, M, Tortorella, G, Toscano, A, Trevisan, Cp, Uggetti, C, Vasco, Gessica, Comi, Gp, Santorelli, Fm, Bertini, Enrico Silvio, Mercuri, Eugenio Maria, Pane, Marika (ORCID:0000-0002-4851-6124), Ricci, Enzo (ORCID:0000-0003-3092-3597), and Mercuri, Eugenio Maria (ORCID:0000-0002-9851-5365)

Abstract

Cognitive impairment has been reported in a significant proportion of patients with congenital muscular dystrophies (CMD), generally associated with brain changes.

Published
2010

41. Spastic paraplegia with thinning of the corpus callosum and white matter abnormalities: Further mutations and relative frequency in ZFYVE26/SPG15 in the Italian population.

Author

Denora, P, Muglia, M, Casali, C, Truchetto, J, Silvestri, G, Messina, D, Boukrhis, A, Magariello, A, Modoni, A, Masciullo, M, Malandrini, A, Morelli, M, de Leva, Mf, Villanova, M, Giugni, E, Citrigno, L, Rizza, T, Federico, A, Pierallini, A, Quattrone, A, Filla, A, Brice, A, Stevanin, G, Santorelli, Fm., Silvestri G (ORCID:0000-0002-1950-1468), Modoni A, Denora, P, Muglia, M, Casali, C, Truchetto, J, Silvestri, G, Messina, D, Boukrhis, A, Magariello, A, Modoni, A, Masciullo, M, Malandrini, A, Morelli, M, de Leva, Mf, Villanova, M, Giugni, E, Citrigno, L, Rizza, T, Federico, A, Pierallini, A, Quattrone, A, Filla, A, Brice, A, Stevanin, G, Santorelli, Fm., Silvestri G (ORCID:0000-0002-1950-1468), and Modoni A

Abstract

Spastic paraplegia with thinning of the corpus callosum (ARHSP-TCC) is a relatively frequent form of complicated hereditary spastic paraplegia in which mental retardation and muscle stiffness at onset are followed by slowly progressive paraparesis and cognitive deterioration. Although genetically heterogeneous, ARHSP-TCC is frequently associated with mutations in the SPG11 gene, on chromosome 15q. However, it is becoming evident that ARHSP-TCC can also be the clinical presentation of mutations in ZFYVE26 (SPG15), as shown by the recent identification of eight families with a variable phenotype. Here, we present an additional Italian ARHSP-TCC patient harboring two new, probably loss-of-function mutations in ZFYVE26. This finding, together with the report of a mutation in another Italian family, provides confirmation that ZFYVE26 is the second gene responsible for ARHSP-TCC in the Italian population

Published
2009

42. Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study

Author

Mercuri, Eugenio Maria, Messina, Salvatore, Bruno, Cristina, Mora, M, Pegoraro, E, Comi, Gp, D'Amico, Anna, Aiello, C, Biancheri, R, Berardinelli, A, Boffi, Pietro, Cassandrini, D, Laverda, A, Moggio, M, Morandi, Laura, Moroni, I, Pane, Marika, Pezzani, R, Pichiecchio, A, Pini, A, Minetti, C, Mongini, T, Mottarelli, E, Ricci, Enzo, Ruggieri, Antonello, Saredi, S, Scuderi, C, Tessa, A, Toscano, A, Tortorella, G, Trevisan, Cp, Uggetti, C, Vasco, Gessica, Santorelli, Fm, Bertini, Enrico Silvio, Mercuri, Eugenio Maria (ORCID:0000-0002-9851-5365), Pane, Marika (ORCID:0000-0002-4851-6124), Ricci, Enzo (ORCID:0000-0003-3092-3597), Mercuri, Eugenio Maria, Messina, Salvatore, Bruno, Cristina, Mora, M, Pegoraro, E, Comi, Gp, D'Amico, Anna, Aiello, C, Biancheri, R, Berardinelli, A, Boffi, Pietro, Cassandrini, D, Laverda, A, Moggio, M, Morandi, Laura, Moroni, I, Pane, Marika, Pezzani, R, Pichiecchio, A, Pini, A, Minetti, C, Mongini, T, Mottarelli, E, Ricci, Enzo, Ruggieri, Antonello, Saredi, S, Scuderi, C, Tessa, A, Toscano, A, Tortorella, G, Trevisan, Cp, Uggetti, C, Vasco, Gessica, Santorelli, Fm, Bertini, Enrico Silvio, Mercuri, Eugenio Maria (ORCID:0000-0002-9851-5365), Pane, Marika (ORCID:0000-0002-4851-6124), and Ricci, Enzo (ORCID:0000-0003-3092-3597)

Abstract

Congenital muscular dystrophies (CMD) with reduced glycosylation of alpha-dystroglycan (alpha-DG) are a heterogeneous group of conditions associated with mutations in six genes encoding proven or putative glycosyltransferases.

Published
2009

43. Rippling muscle disease and cardiomyopathy associated with a mutation in the CAV3 gene

Author

Catteruccia, Michela, Sanna, Tommaso, Santorelli, Fm, Tessa, A, Di Giacopo, Raffaella, Sauchelli, Donato, Verbo, Alessandro, Lo Monaco, Mauro, Servidei, Serenella, Sanna, Tommaso (ORCID:0000-0002-5760-6885), Verbo, Alessandro (ORCID:0000-0003-4993-6638), Lo Monaco, Mauro (ORCID:0000-0002-8681-291X), Servidei, Serenella (ORCID:0000-0001-8478-2799), Catteruccia, Michela, Sanna, Tommaso, Santorelli, Fm, Tessa, A, Di Giacopo, Raffaella, Sauchelli, Donato, Verbo, Alessandro, Lo Monaco, Mauro, Servidei, Serenella, Sanna, Tommaso (ORCID:0000-0002-5760-6885), Verbo, Alessandro (ORCID:0000-0003-4993-6638), Lo Monaco, Mauro (ORCID:0000-0002-8681-291X), and Servidei, Serenella (ORCID:0000-0001-8478-2799)

Abstract

Caveolin-3, the myocyte-specific isoform of caveolins, is preferentially expressed in skeletal, cardiac and smooth muscles. Mutations in the CAV3 gene cause clinically heterogeneous neuromuscular disorders, including rippling muscle disease, or cardiopathies. The same mutation may lead to different phenotypes, but cardiac and muscle involvement rarely coexists suggesting that the molecular network acting with caveolin-3 in skeletal muscle and heart may differ. Here we describe an Italian family (a father and his two sons) with clinical and neurophysiological features of rippling muscle disease and heart involvement characterized by atrio-ventricular conduction defects and dilated cardiomyopathy. Muscle biopsy showed loss of caveolin-3 immunosignal. Molecular studies identified the p.A46V mutation in CAV3 previously reported in a German family with autosomal dominant rippling muscle disease and sudden death in few individuals. We suggest that cardiac dysfunction in myopathic patients with CAV3 mutations may be underestimated and recommend a more thorough evaluation for the presence of cardiomyopathy and potentially lethal arrhythmias.

Published
2009

44. Ataxia, cognitive impairment, and ocular motor apraxia with cerebellar cysts and dysplasia: A new form of dystroglycanopathy?

Author

Poretti, A, primary, Häusler, M, additional, van Moers, A, additional, Baumgartner, B, additional, Zerres, K, additional, Klein, A, additional, Aiello, C, additional, Zanni, G, additional, Santorelli, FM, additional, Huisman, TAGM, additional, Valente, EM, additional, Weis, J, additional, Bertini, E, additional, and Boltshauser, E, additional

Published
2013
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45. A Novel ATP1A2 Mutation in a Family with FHM Type II

Author

Pierelli, F, primary, Grieco, GS, additional, Pauri, F, additional, Pirro, C, additional, Fiermonte, G, additional, Ambrosini, A, additional, Costa, A, additional, Buzzi, MG, additional, Valoppi, M, additional, Caltagirone, C, additional, Nappi, G, additional, and Santorelli, FM, additional

Published
2006
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48. SACS MUTATIONS IN AUTOSOMAL RECESSIVE SPASTIC ATAXIAS

Author

Di Giandomenico, S, primary, Santorelli, FM, additional, Criscuolo, C, additional, Mariotti, C, additional, Simonati, A, additional, Greco, GS, additional, Brice, A, additional, Durr, A, additional, Filla, A, additional, Stevanin, G, additional, and Bertini, E, additional

Published
2006
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