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1. Additional file 2 of Guidelines on the diagnosis, clinical assessments, treatment and management for CLN2 disease patients

Author

Mole, Sara E., Schulz, Angela, Eben Badoe, Berkovic, Samuel F., De Los Reyes, Emily C., Dulz, Simon, Gissen, Paul, Guelbert, Norberto, Lourenco, Charles M., Mason, Heather L., Mink, Jonathan W., Murphy, Noreen, Nickel, Miriam, Joffre E. Olaya, Scarpa, Maurizio, Scheffer, Ingrid E., Simonati, Alessandro, Specchio, Nicola, Von Löbbecke, Ina, Wang, Raymond Y., and Williams, Ruth E.

Subjects
education, human activities, health care economics and organizations
Abstract

Additional file 2: Poster. Methodology to develop guidelines for the management of patients with CLN2 disease.

Published
2021
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2. Additional file 1 of Guidelines on the diagnosis, clinical assessments, treatment and management for CLN2 disease patients

Author

Mole, Sara E., Schulz, Angela, Eben Badoe, Berkovic, Samuel F., De Los Reyes, Emily C., Dulz, Simon, Gissen, Paul, Guelbert, Norberto, Lourenco, Charles M., Mason, Heather L., Mink, Jonathan W., Murphy, Noreen, Nickel, Miriam, Joffre E. Olaya, Scarpa, Maurizio, Scheffer, Ingrid E., Simonati, Alessandro, Specchio, Nicola, Von Löbbecke, Ina, Wang, Raymond Y., and Williams, Ruth E.

Abstract

Additional file 1: Appendices. Appendices 1–9.

Published
2021
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3. Availability, accessibility and delivery to patients of the 28 orphan medicines approved by the European Medicine Agency for hereditary metabolic diseases in the MetabERN network

Author

Heard, Jean-Michel, Vrinten, Charlotte, Schlander, Michael, Bellettato, Cinzia Maria, van Lingen, Corine, Scarpa, Maurizio, Gert, Matthijs, Marie-Cécile, Nassogne, François-Guillaume, Debray, Dominique, Roland, Teodora, Chamova, Viktor, Kozich, Jesina, Pavel, Martin, Zenker, Christina, Lampe, Anihb Martin Das, Julia, Hennermann, Stefan, Kölker, Natalie, Weinhold, Klaus, Mohnike, Sarah, Gruenert, Allan Meldgaard Lund, Montserrat, Morales-Conejo, Mireia Del Toro-Riera, Luis, Aldámiz-Echevarría, Maria-Teresa, Garcia-Silva, Manuel, Schiff, Laurent, Gouya, Pascale de Lonlay, Nadia, Belmatoug, Dominique, P Germain, Aline, Cano, Dries, Dobbelaere, Simon, Jones, Charlotte, Dawson, Patrick, Deegan, Saikat, Santra, Suresh, Vijay, Danijela Petkovic Ramadza, Ivo, Barić, Tamara, Žigman, György, Pflieger, Katalin, Szakszon, Rita, Kaposta, Serena, Gasperini, Alberto, Burlina, Giancarlo, Parenti, Pietro, Strisciuglio, Giovanni, Ceccarini, Antonio, Federico, Simonati, Alessandro, Birute, Tumiene, Hidde, Huidekoper, Francian van Spronsen, Annet, Bosch, Maria-Estela, Rubio-Gozalbo, Gepke, Visser, Trine, Tangeraas, Aasne, Aarsand, Beata, Kieć-Wilk, Ana-Maria Simões Mendes Gaspar, Dulce, Quelhas, Elisa, Leao-Teles, Olga, Azevedo, Esmeralda-Maria Ferreira Rodriges Silva, Luísa-Maria de Abreu Freire Diogo Matos, Esmeralda, Martins, Svetlana, Lajic, Niklas, Darin, Urh, Groselj, Mojca-Zerjav, Tansek, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie pédiatrique, Pediatrics, RS: GROW - R4 - Reproductive and Perinatal Medicine, Kindergeneeskunde, MUMC+: MA Medische Staf Kindergeneeskunde (9), Paediatric Metabolic Diseases, and AGEM - Inborn errors of metabolism

Subjects
Orphan Drug Production, lcsh:Medicine, Disease, Research & Experimental Medicine, Hereditary Metabolic Diseases, European Reference Network, Surveys and Questionnaires, Health care, Agency (sociology), Access to treatment, Inborn errors of metabolism, Orphan medicinal product, Medicine, Genetics(clinical), Pharmacology (medical), Drug Approval, Genetics (clinical), media_common, Genetics & Heredity, General Medicine, Product (business), Medicine, Research & Experimental, Life Sciences & Biomedicine, medicine.medical_specialty, media_common.quotation_subject, Marketing authorization, Unmet needs, access to treatment, hereditary metabolic diseases, inborn errors of metabolism, orphan medicinal product, Rare Diseases, Metabolic Diseases, Excellence, DRUGS, Humans, Medical prescription, MetabERN collaboration group, Science & Technology, business.industry, Research, lcsh:R, Family medicine, business, Metabolism, Inborn Errors, 1199 Other Medical and Health Sciences
Abstract

Background The European Medicine Agency granted marketing approval to 164 orphan medicinal products for rare diseases, among which 28 products intended for the treatment of hereditary metabolic diseases. Taking advantage of its privileged connection with 69 healthcare centres of excellence in this field, MetabERN, the European Reference Network for hereditary metabolic diseases, performed a survey asking health care providers from 18 European countries whether these products are available on the market, reimbursed and therefore accessible for prescription, and actually delivered in their centre. Results Responses received from 52 centres (75%) concerned the design of treatment plans, the access to marketed products, and the barriers to delivery. Treatment options are always discussed with patients, who are often involved in their treatment plan. Most products (26/28) are available in most countries (15/18). Among the 15 broadly accessible products (88.5% of the centres), 9 are delivered to most patients (mean 70.1%), and the others to only few (16.5%). Among the 10 less accessible products (40.2% of the centres), 6 are delivered to many patients (66.7%), and 4 are rarely used (6.3%). Information was missing for 3 products. Delay between prescription and delivery is on average one month. Beside the lack of availability or accessibility, the most frequent reasons for not prescribing a treatment are patients’ clinical status, characteristic, and personal choice. Conclusions Data collected from health care providers in the MetabERN network indicate that two-third of the orphan medicines approved by EMA for the treatment of hereditary metabolic diseases are accessible to treating patients, although often less than one-half of the patients with the relevant conditions actually received the approved product to treat their disease. Thus, in spite of the remarkable achievement of many products, patients concerned by EMA-approved orphan medicinal products have persistent unmet needs, which deserve consideration. The enormous investments made by the companies to develop products, and the high financial burden for the Member States to purchase these products emphasize the importance of a scrupulous appreciation of treatment value involving all stakeholders at early stage of development, before marketing authorization, and during follow up.

Published
2020
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4. Age and sex prevalence estimate of Joubert syndrome in Italy

Author

Nuovo, Sara, Bacigalupo, Ilaria, Ginevrino, Monia, Battini, Roberta, Bertini, Enrico, Borgatti, Renato, Casella, Antonella, Micalizzi, Alessia, Nardella, Marta, Romaniello, Romina, Serpieri, Valentina, Zanni, Ginevra, Valente, Enza Maria, Vanacore, Nicola, JS Italian Study Group, Patrizia, Accorsi, Enrico, Alfei, Elena, Andreucci, Gianluigi, Ardissino, Emanuela, Avola, Rita, Barone, Francesco, Benedicenti, Stefania, Bigoni, Loredana, Boccone, Bonati, Maria T., Stefania, Bova, Marilena, Briguglio, Silvana, Briuglia, Olga, Calabrese, Cantalupo, Gaetano, Gianluca, Caridi, Monica, Cazzagon, Celle, Maria E., Cilio, Maria R., Giangennaro, Coppola, Adele, D’Amico, Stefano, D’Arrigo, Daniele De Brasi, Maria Fulvia de Leva, Ennio Del Giudice, Marilena Carmela Di Giacomo, Maria Lucia Di Sabato, Bruno, Dallapiccola, Raffaella, Devescovi, Maria Cristina Digilio, Ilaria, Donati, Donati, Maria A., Dotti, Maria T., Francesco, Emma, Antonella, Fabretto, Elisa, Fazzi, Alessandra, Ferlini, Alessandro, Ferraris, Giovanni Battista Ferrero, Anna, Ficcadenti, Simona, Fiori, Rita, Fischetto, Elena, Freri, Livia, Garavelli, Mattia, Gentile, Lucio, Giordano, Donatella, Greco, Claudia, Izzi, Vincenzo, Leuzzi, Elisabetta, Lucarelli, Silvia, Majore, Mancardi, Maria M., Francesca, Mari, Giuseppina, Marra, Laura, Mazzanti, Daniela, Melis, Emanuele, Micaglio, Marisol, Mirabelli-Badenier, Isabella, Moroni, Nardo, Nardocci, Margherita, Nosadini, Simona, Orcesi, Giovanni, Pagani, Chiara, Pantaleoni, Francesco Papadia Papadia, Pasquale, Parisi, Maria Grazia Patricelli, Cinzia, Peruzzi, Alice, Pessagno, Maria, Piccione, Antonella, Pini, Tiziana, Pisano, Livia, Pisciotta, Marzia, Pollazzon, Francesca, Rivieri, Alfonso, Romano, Corrado, Romano, Leonardo, Salviati, Carmelo Damiano Salpietro, Margherita, Santucci, Emanuela, Scarano, Barbara, Scelsa, Alberto, Sensi, Marco, Seri, Sabrina, Signorini, Margherita, Silengo, Simonati, Alessandro, Fabio, Sirchia, Luigina, Spaccini, Franco, Stanzial, Gilda, Stringini, Eva, Trevisson, Antonella, Trivelli, Vera, Uliana, Graziella, Uziel, Gessica, Vasco, Marina, Vascotto, Giuseppina, Vitiello, Federica, Zibordi, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de neurologie pédiatrique

Subjects
IQR=interquartile range, 0301 basic medicine, Proband, Male, JS=Joubert syndrome, Prevalence, CI=confidence interval, CI = confidence interval, 0302 clinical medicine, Cerebellum, Epidemiology, Databases, Genetic, JS = Joubert syndrome, Medicine, Eye Abnormalities, Young adult, Age of Onset, Child, education.field_of_study, Age Factors, High-Throughput Nucleotide Sequencing, Kidney Diseases, Cystic, Middle Aged, Italy, Child, Preschool, Joubert syndrome, Italy, Cohort, Kidney Diseases, Female, MTS = molar tooth sign, Abnormalities, Multiple, NGS=next-generation sequencing, Adult, medicine.medical_specialty, Adolescent, IQR = interquartile range, NGS = next-generation sequencing, Population, Retina, Databases, Cystic, 03 medical and health sciences, Young Adult, Sex Factors, Genetic, Joubert syndrome, Humans, Abnormalities, Multiple, Infant, Preschool, CI=confidence interval, IQR=interquartile range, JS=Joubert syndrome, MTS=molar tooth sign, NGS=next-generation sequencing, education, business.industry, MTS=molar tooth sign, Confidence interval, 030104 developmental biology, Neurology (clinical), Age of onset, business, 030217 neurology & neurosurgery, Demography
Abstract

ObjectiveTo estimate the prevalence of Joubert syndrome (JS) in Italy applying standards of descriptive epidemiology and to provide a molecular characterization of the described patient cohort.MethodsWe enrolled all patients with a neuroradiologically confirmed diagnosis of JS who resided in Italy in 2018 and calculated age and sex prevalence, assuming a Poisson distribution. We also investigated the correlation between proband chronological age and age at diagnosis and performed next-generation sequencing (NGS) analysis on probands' DNA when available.ResultsWe identified 284 patients with JS: the overall, female- and male-specific population-based prevalence rates were 0.47 (95% confidence interval [CI] 0.41–0.53), 0.41 (95% CI 0.32–0.49), and 0.53 (95% CI 0.45–0.61) per 100,000 population, respectively. When we considered only patients in the age range from 0 to 19 years, the corresponding population-based prevalence rates rose to 1.7 (95% CI 1.49–1.97), 1.62 (95% CI 1.31–1.99), and 1.80 (95% CI 1.49–2.18) per 100,000 population. NGS analysis allowed identifying the genetic cause in 131 of 219 screened probands. Age at diagnosis was available for 223 probands, with a mean of 6.67 ± 8.10 years, and showed a statistically significant linear relationship with chronological age (r2 = 0.79; p < 0.001).ConclusionsWe estimated for the first time the age and sex prevalence of JS in Italy and investigated the patients’ genetic profile. The obtained population-based prevalence rate was ≈10 times higher than that available in literature for children population.

Published
2020

7. Chapter 12: CLN8

Author

Aiello, C., Cannelli, N., Cooper, J. D., Haltia, M., Herva, R., Lahtinen, U., Lehesjoki, A. E., Mole, S. E., Santorelli, F. M., Siintola, E., and Simonati, Alessandro

Subjects
CLN8 gene, Protein CLN8, neuronal ceroid lipofuscinoses
Published
2011

8. Chapter 3: NCL diagnosis and algorithms

Author

Kohlschütter, A., Williams, R. E., Goebel, H. H., Mole, S. E., Boustany, R. M., van Diggelen, O. P., Elleder, M., Mink, J. W., Niezen de Boer, R., Ribeiro, M. G., and Simonati, Alessandro

Subjects
neuronal ceroid lipofuscinoses, diagnosis, algorithms
Published
2011

11. Malattie mitocondriali

Author

Spinazzola, A., Farina, L., Simonati, Alessandro, and Zeviani, M.

Published
2006

20. Neuropatie immunitarie

Author

Ferrari, Sergio, Bonetti, Bruno, Monaco, Salvatore, Cavallaro, Tiziana, Morbin, M., Simonati, Alessandro, and Rizzuto, Nicolo'

Subjects
neuroimmunologia, Neuropatie immunitarie, neuropatologia
Published
1994

21. La patologia delle neuropatie periferiche

Author

Cavallaro, Tiziana, Morbin, M., Ferrari, Sergio, Simonati, Alessandro, and Rizzuto, Nicolo'

Subjects
neuropatie periferiche, neuropatologia
Published
1994

22. Neuropatie genetiche

Author

Simonati, Alessandro, Cavallaro, Tiziana, Ferrari, Sergio, Morbin, M., and Rizzuto, Nicolo'

Subjects
Neuropatie genetiche, genetica
Published
1994

25. ATP1A2- and ATP1A3- associated early profound epileptic encephalopathy and polymicrogyria

Author

Vetro, Annalisa, Nielsen, Hang N, Holm, Rikke, Hevner, Robert F, Parrini, Elena, Powis, Zoe, Møller, Rikke S, Bellan, Cristina, Simonati, Alessandro, Lesca, Gaétan, Helbig, Katherine L, Palmer, Elizabeth E, Mei, Davide, Ballardini, Elisa, Van Haeringen, Arie, Syrbe, Steffen, Leuzzi, Vincenzo, Cioni, Giovanni, Curry, Cynthia J, Costain, Gregory, Santucci, Margherita, Chong, Karen, Mancini, Grazia M S, Clayton-Smith, Jill, Bigoni, Stefania, Scheffer, Ingrid E, Dobyns, William B, Vilsen, Bente, Guerrini, Renzo, Sanlaville, Damien, Sachdev, Rani, Andrews, Ian, Mari, Francesco, Cavalli, Anna, Barba, Carmen, De Maria, Beatrice, Garani, Giampaolo, Lemke, Johannes R, Mastrangelo, Mario, Tam, Emily, Donner, Elizabeth, Branson, Helen, Monteiro, Fabiola P, Kok, Fernando, Howell, Katherine B, Leech, Stephanie, Mefford, Heather, Muir, Alison, and Clinical Genetics

Subjects
Male, 0301 basic medicine, Pathology, Microcephaly, Na+/K+-ATPase pump, CHILDHOOD, PHENOTYPE, 0302 clinical medicine, Na + /K + -ATPase pump, ATP1A3, Chlorocebus aethiops, Polymicrogyria, polymicrogyria, Child, NEURONS, Familial hemiplegic migraine, Brain Diseases, FAMILIAL HEMIPLEGIC MIGRAINE, ATP1A2, 3. Good health, Phenotype, Child, Preschool, COS Cells, Female, Sodium-Potassium-Exchanging ATPase, medicine.symptom, medicine.medical_specialty, Adolescent, Genotype, NA,K-ATPASE, Socio-culturale, 03 medical and health sciences, Atrophy, ALTERNATING HEMIPLEGIA, medicine, Animals, Humans, developmental and epileptic encephalopathy, SPECTRUM, Epilepsy, Cerebellar ataxia, business.industry, Alternating hemiplegia of childhood, Infant, Newborn, Infant, medicine.disease, 030104 developmental biology, DE-NOVO MUTATIONS, SUBUNIT, Mutation, Na plus /K plus -ATPase pump, Neurology (clinical), business, Brain morphogenesis, 030217 neurology & neurosurgery
Abstract

Constitutional heterozygous mutations of ATP1A2 and ATP1A3, encoding for two distinct isoforms of the Na+/K+-ATPase (NKA) alpha-subunit, have been associated with familial hemiplegic migraine (ATP1A2), alternating hemiplegia of childhood (ATP1A2/A3), rapid-onset dystonia-parkinsonism, cerebellar ataxia-areflexia-progressive optic atrophy, and relapsing encephalopathy with cerebellar ataxia (all ATP1A3). A few reports have described single individuals with heterozygous mutations of ATP1A2/A3 associated with severe childhood epilepsies. Early lethal hydrops fetalis, arthrogryposis, microcephaly, and polymicrogyria have been associated with homozygous truncating mutations in ATP1A2. We investigated the genetic causes of developmental and epileptic encephalopathies variably associated with malformations of cortical development in a large cohort and identified 22 patients with de novo or inherited heterozygous ATP1A2/A3 mutations. We characterized clinical, neuroimaging and neuropathological findings, performed in silico and in vitro assays of the mutations’ effects on the NKA-pump function, and studied genotype-phenotype correlations. Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations) and ATP1A3 (16 patients, 14 mutations, including a mosaic individual). Polymicrogyria occurred in 10 (45%) patients, showing a mainly bilateral perisylvian pattern. Most patients manifested early, often neonatal, onset seizures with a multifocal or migrating pattern. A distinctive, ‘profound’ phenotype, featuring polymicrogyria or progressive brain atrophy and epilepsy, resulted in early lethality in seven patients (32%). In silico evaluation predicted all mutations to be detrimental. We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump activity, consistent with severe loss of function. Genotype-phenotype analysis suggested a link between the most severe phenotypes and lack of COS-1 cell survival, and also revealed a wide continuum of severity distributed across mutations that variably impair NKA-pump activity. We performed neuropathological analysis of the whole brain in two individuals with polymicrogyria respectively related to a heterozygous ATP1A3 mutation and a homozygous ATP1A2 mutation and found close similarities with findings suggesting a mainly neural pathogenesis, compounded by vascular and leptomeningeal abnormalities. Combining our report with other studies, we estimate that ∼5% of mutations in ATP1A2 and 12% in ATP1A3 can be associated with the severe and novel phenotypes that we describe here. Notably, a few of these mutations were associated with more than one phenotype. These findings assign novel, ‘profound’ and early lethal phenotypes of developmental and epileptic encephalopathies and polymicrogyria to the phenotypic spectrum associated with heterozygous ATP1A2/A3 mutations and indicate that severely impaired NKA pump function can disrupt brain morphogenesis.

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28. Le anomalie della migrazione neuronale

Author

Colamaria, V., Trevisan, E., Fontana, E., Capovilla, G., Simonati, Alessandro, Zapparoli, P., Tinazzi Martini, P., Mecca, E., and Dalla Bernardina, B.

Subjects
Migrazione neuronale, neuropatologia
Published
1989

29. Neuropatie immunitarie ed infiammatorie

Author

Rizzuto, Nicolo', Monaco, Salvatore, Simonati, Alessandro, Moretto, G., Salviati, Alessandro, Bonetti, Bruno, and Fincati, E.

Subjects
neuroimmunologia, neuropatia, neuropatologia
Published
1988

30. Multicystic encephalomalacia associated with symmetrical necrotizing brain stem lesions in an infant: a case report

Author

Simonati, Alessandro, Laverda, A. M., and Rizzuto, Nicolo'

Subjects
Necrosis, Encephalomalacia, Brain Diseases, Metabolic, Cerebellum, Brain, Humans, Infant, Female, Leigh Disease, Basal Ganglia, Brain Stem
Abstract

The simultaneous occurrence of multicystic encephalomalacia of the cerebral hemispheres, and symmetric necrotizing lesions of diencephalic and infratentorial structures is described in a 15 month-old infant. The baby developed clonic jerks of four limbs a few hours after delivery. She attained no developmental milestones, and remained bed-ridden with hypertonic posture until her death. Multicystic cavities of the cerebral hemispheres were well evident at CT scan when she was 7 months old. The topographic distributions of the different pathological pictures are described; their relationship to the regional properties of the developing brain are commented upon. Etiological aspects of this case are discussed according to present knowledge of the pathophysiological mechanisms leading either to multiple cyst formation or to necrotizing lesions.

Published
1986

35. Chronic inflammatory demyelinating polyneuropathy

Author

Rizzuto, Nicolo' and Simonati, Alessandro

Subjects
Adult, Adolescent, Polyradiculoneuropathy, Middle Aged, Nerve Fibers, Myelinated, Autoimmune Diseases, Microscopy, Electron, Immunoglobulin M, Immunoglobulin G, Chronic Disease, Humans, Peripheral Nerves, Schwann Cells, Child, Immunosuppressive Agents, Demyelinating Diseases
Abstract

In 12 cases of CIDP under surveillance for 14 years, the main nerve biopsy findings were endoneural oedema and demyelination of nerve fibres. IgM deposition was found in 1 patient and IgG deposits in another. Electron microscopy revealed proliferation of the Schwann cells and mononuclear cell infiltration. The diagnostic criteria and nerve biopsy findings in CIDP are listed in the tables.

Published
1985

39. Congenital myopathies: clinical phenotypes and new diagnostic tools

Author

Alessandro Malandrini, Maria Teresa Dotti, Enrico Bertini, Marina Mora, Gabriele Siciliano, Denise Cassandrini, Marina Grandis, Adele D'Amico, Eugenio Mercuri, Lorenzo Peverelli, Maria Antonietta Maioli, Giacomo P. Comi, Lucia Ruggiero, Sara Lenzi, Maurizio Moggio, Fabiana Fattori, Marika Pane, Michele Sacchini, Lorenzo Maggi, Angela Berardinelli, Carmelo Rodolico, Giulia Ricci, Antonio Toscano, Alessandro Simonati, Marco Savarese, Rosanna Trovato, Vincenzo Nigro, Francesca Magri, Chiara Fiorillo, Elena Pegoraro, Paola Tonin, Anna Rubegni, Filippo M. Santorelli, Claudio Bruno, Luciano Merlini, Maria Alice Donati, Guja Astrea, Elena Maria Pennisi, Francesco Mari, Lucia Morandi, Lucio Santoro, Olimpia Musumeci, Carlo Minetti, Jacopo Baldacci, Roberto Massa, Cassandrini, Denise, Trovato, Rosanna, Rubegni, Anna, Lenzi, Sara, Fiorillo, Chiara, Baldacci, Jacopo, Minetti, Carlo, Astrea, Guja, Bruno, Claudio, Santorelli, Filippo M., Berardinelli, Angela, Bertini, Enrico S., Comi, Giacomo, D'Amico, Adele, Donati, Maria Alice, Dotti, Maria Teresa, Fattori, Fabiana, Grandis, Marina, Maggi, Lorenzo, Magri, Francesca, Maioli, Maria A., Malandrini, Alessandro, Mari, Francesco, Massa, Roberto, Mercuri, Eugenio, Merlini, Luciano, Moggio, Maurizio, Mora, Marina, Morandi, Lucia O., Musumeci, Olimpia, Nigro, Vincenzo, Pane, Marika, Pegoraro, Elena, Pennisi, Elena M., Peverelli, Lorenzo, Ricci, Giulia, Rodolico, Carmelo, Ruggiero, Lucia, Sacchini, Michele, Santoro, Lucio, Savarese, Marco, Siciliano, Gabriele, Simonati, Alessandro, Tonin, Paola, Toscano, Antonio, and Santorelli, FILIPPO MARIA

Subjects
0301 basic medicine, Male, Pathology, Biopsy, Review, Myopathies, Nemaline, Severity of Illness Index, Pediatrics, Muscular Dystrophies, 0302 clinical medicine, Nemaline myopathy, Needle, Congenital myopathy, medicine.diagnostic_test, Incidence, Biopsy, Needle, lcsh:RJ1-570, Perinatology and Child Health, Prognosis, Immunohistochemistry, Magnetic Resonance Imaging, Hypotonia, Muscle biopsy, Muscle MRI, Next generation sequencing, Disease Progression, Female, Genetic Predisposition to Disease, Genotype, Humans, Risk Assessment, Pediatrics, Perinatology and Child Health, Myopathies, medicine.symptom, medicine.medical_specialty, Nemaline, Muscle disorder, Settore MED/26, 03 medical and health sciences, medicine, Centronuclear myopathy, Myopathy, business.industry, lcsh:Pediatrics, medicine.disease, 030104 developmental biology, business, 030217 neurology & neurosurgery, Central core disease
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.

Published
2017
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40. Broad phenotypic spectrum and genotype-phenotype correlations in GMPPB-related dystroglycanopathies: an Italian cross-sectional study

Author

Astrea, G., Romano, A., Angelini, C., Antozzi, C. G., Barresi, R., Battini, R., Battisti, C., Bertini, E., Bruno, C., Cassandrini, D., Fanin, M., Fattori, F., Fiorillo, C., Guerrini, R., Maggi, L., Mercuri, E., Morani, F., Mora, M., Moro, F., Pezzini, I., Picillo, E., Pinelli, M., Politano, L., Rubegni, A., Sanseverino, W., Savarese, M., Striano, P., Torella, A., Trevisan, C. P., Trovato, R., Zaraieva, I., Muntoni, F., Nigro, V., D'Amico, A., Santorelli, F. M., Italian CMD Network, Berardinelli, A., Comi, G., Donati, M. A., Dotti, M., Grandis, M., Magri, F., Maioli, M. A., Malandrini, A., Mari, F., Massa, R., Merlini, L., Moggio, M., Morandi, L. O., Musumeci, O., Pane, M., Pini, A., Pegoraro, E., Pennisi, E. M., Peverelli, L., Ricci, G., Rodolico, C., Ruggiero, L., Sacchini, M., Santoro, L., Siciliano, G., Simonati, A., Tonin, P., Toscano, A., Astrea, Guja, Romano, Alessandro, Angelini, Corrado, Antozzi, Carlo Giuseppe, Barresi, Rita, Battini, Roberta, Battisti, Carla, Bertini, Enrico, Bruno, Claudio, Cassandrini, Denise, Fanin, Marina, Fattori, Fabiana, Fiorillo, Chiara, Guerrini, Renzo, Maggi, Lorenzo, Mercuri, Eugenio, Morani, Federica, Mora, Marina, Moro, Francesca, Pezzini, Ilaria, Picillo, Esther, Pinelli, Michele, Politano, Luisa, Rubegni, Anna, Sanseverino, Walter, Savarese, Marco, Striano, Pasquale, Torella, Annalaura, Trevisan, Carlo Pietro, Trovato, Rosanna, Zaraieva, Irina, Muntoni, Francesco, Nigro, Vincenzo, D'Amico, Adele, Santorelli, Filippo M., Berardinelli, Angela, Comi, Giacomo, Donati, Maria Alice, Dotti, Maria Teresa, Grandis, Marina, Magri, Francesca, Maioli, Maria A, Malandrini, Alessandro, Mari, Francesco, Massa, Roberto, Merlini, Luciano, Moggio, Maurizio, Morandi, Lucia O, Musumeci, Olimpia, Pane, Marika, Pini, Antonella, Pegoraro, Elena, Pennisi, Elena M, Peverelli, Lorenzo, Ricci, Giulia, Rodolico, Carmelo, Ruggiero, Lucia, Sacchini, Michele, Santoro, Lucio, Siciliano, Gabriele, Simonati, Alessandro, Tonin, Paola, Toscano, Antonio, Astrea, G., Romano, A., Angelini, C., Antozzi, C. G., Barresi, R., Battini, R., Battisti, C., Bertini, E., Bruno, C., Cassandrini, D., Fanin, M., Fattori, F., Fiorillo, C., Guerrini, R., Maggi, L., Mercuri, E., Morani, F., Mora, M., Moro, F., Pezzini, I., Picillo, E., Pinelli, M., Politano, L., Rubegni, A., Sanseverino, W., Savarese, M., Striano, P., Torella, A., Trevisan, C. P., Trovato, R., Zaraieva, I., Muntoni, F., Nigro, V., D'Amico, A., Santorelli, F. M., Berardinelli, A., Comi, G., Donati, M. A., Dotti, M. T., Grandis, M., Magri, F., Maioli, M. A., Malandrini, A., Mari, F., Massa, R., Merlini, L., Moggio, M., Morandi, L. O., Musumeci, O., Pane, M., Pini, A., Pegoraro, E., Pennisi, E. M., Peverelli, L., Ricci, G., Rodolico, C., Ruggiero, L., Sacchini, M., Santoro, Lucio., Siciliano, G., Simonati, A., Tonin, P., Toscano, A., Department of Medical and Clinical Genetics, and Medicum

Subjects
0301 basic medicine, Male, Genotype-phenotype correlation, Dystriglycanopathies, lcsh:Medicine, GMPPB, Genotype-phenotype correlations, Dystroglycanopathie, Nucleotidyltransferase, Muscular Dystrophies, Limb-Girdle, 0302 clinical medicine, Missense mutation, Pharmacology (medical), Dystroglycan, Muscular dystrophy, Dystroglycans, Muscular Dystrophie, Genetics (clinical), Genetics, Arthrogryposis, education.field_of_study, 1184 Genetics, developmental biology, physiology, General Medicine, Middle Aged, Nucleotidyltransferases, Dystroglycanopathies, 3. Good health, Congenital muscular dystrophy, Female, Limb-girdle muscular dystrophy, medicine.symptom, Human, Adult, Population, Mutation, Missense, Genetic Association Studie, Biology, Settore MED/26, Aged, Cross-Sectional Studies, Genetic Association Studies, Humans, Muscular Dystrophies, Limb-Girdle, Mutation, Young Adult, 03 medical and health sciences, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, Congenital muscular dystrophy, Dystroglycanopathies, Genotype-phenotype correlations, GMPPB, Limb-girdle muscular dystrophy, Genetics (clinical), Pharmacology (medical), medicine, Congenital muscular dystrophy, Dystroglycanopathies, Genotype-phenotype correlations, GMPPB, Limb-girdle muscular dystrophy, Myopathy, education, SERVER, Cross-Sectional Studie, STABILITY, MUTATIONS, Genetic heterogeneity, Research, lcsh:R, medicine.disease, 030104 developmental biology, CONGENITAL MUSCULAR-DYSTROPHY, DEFECTIVE GLYCOSYLATION, 3111 Biomedicine, Missense, 030217 neurology & neurosurgery
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. Electronic supplementary material The online version of this article (10.1186/s13023-018-0863-x) contains supplementary material, which is available to authorized users.

Published
2018

41. Survey on treatments for primary headaches in 13 specialized juvenile Headache Centers: The first multicenter Italian study

Author

D De Carlo, Irene Toldo, Martina Rattin, Vincenzo Raieli, Elisabetta Tozzi, Marco Carotenuto, Massimiliano Valeriani, Alessandro Simonati, Giovanni Mazzotta, Egle Perissinotto, Vincenzo Guidetti, Umberto Balottin, Carlo Cianchetti, Pier Antonio Battistella, Cinzia Scalas, Vittorio Sciruicchio, L. N. Rossi, Margherita Nosadini, Stefano Sartori, A Vecchio, Barbara Bolzonella, Toldo, Irene, Rattin, Martina, Perissinotto, Egle, De Carlo, Debora, Bolzonella, Barbara, Nosadini, Margherita, Rossi, Livia Nicoletta, Vecchio, Angelo, Simonati, Alessandro, Carotenuto, Marco, Scalas, Cinzia, Sciruicchio, Vittorio, Raieli, Vincenzo, Mazzotta, Giovanni, Tozzi, Elisabetta, Valeriani, Massimiliano, Cianchetti, Carlo, Balottin, Umberto, Guidetti, Vincenzo, Sartori, Stefano, and Battistella, Pier Antonio

Subjects
Male, Pediatrics, medicine.medical_specialty, Adolescent, Migraine Disorders, Adolescents, Children, Migraine, Primary headaches, Tension-type headache, Treatment, Pediatrics, Perinatology and Child Health, Neurology (clinical), Tension-type, Triptans, Pizotifen, 03 medical and health sciences, 0302 clinical medicine, children, Primary headache, Behavior Therapy, Surveys and Questionnaires, medicine, Acupuncture, Humans, Amitriptyline, migraine, 030212 general & internal medicine, adolescents, Practice Patterns, Physicians', Child, Flunarizine, Retrospective Studies, treatment, business.industry, Anti-Inflammatory Agents, Non-Steroidal, General Medicine, primary headaches, tension-type headache, Perinatology and Child Health, medicine.disease, Tolerability, Italy, Cohort, Anticonvulsants, Female, business, headache, 030217 neurology & neurosurgery, medicine.drug
Abstract

Aim The purpose of this retrospective multicenter study was to evaluate the use and the self-perceived efficacy and tolerability of pharmacological and non-pharmacological treatments in children and adolescents with primary headaches. Methods Study of a cohort of children and adolescents diagnosed with primary headache, consecutively referred to 13 juvenile Italian Headache Centers. An ad hoc questionnaire was used for clinical data collection. Results Among 706 patients with primary headaches included in the study, 637 cases with a single type of headache (migraine 76% – with and without aura in 10% and 67% respectively; tension-type headache 24%) were selected (mean age at clinical interview: 12 years). Acetaminophen and non-steroidal anti-inflammatory drugs (in particular ibuprofen) were commonly used to treat attacks, by 76% and 46% of cases respectively. Triptans were used overall by 6% of migraineurs and by 13% of adolescents with migraine, with better efficacy than acetaminophen and non-steroidal anti-inflammatory drugs. Preventive drugs were used by 19% of migraineurs and by 3% of subjects with tension-type headache. In migraineurs, flunarizine was the most frequently used drug (18%), followed by antiepileptic drugs (7%) and pizotifen (6%), while cyproheptadine, propanolol and amitriptyline were rarely used. Pizotifen showed the best perceived efficacy and tolerability. Melatonin and nutraceuticals were used by 10% and 32% of subjects, respectively, both for migraine and tension-type headache, with good results in terms of perceived efficacy and tolerability. Non-pharmacological preventive treatments (i.e. relaxation techniques, biofeedback, cognitive-behavioral therapy, acupuncture) were used only by 10% of cases (migraine 9%, tension-type headache 15%). Discussion Non-steroidal anti-inflammatory drugs, especially ibuprofen, should be preferred to acetaminophen for acute attacks of migraine or tension-type headache, because they were usually more effective and well tolerated. Triptans could be used more frequently as first or almost second choice for treating migraine attack in adolescents. Non-pharmacological preventive treatments are recommended by some pediatric guidelines as first-line interventions for primary headaches and their use should be implemented in clinical practice. Prospective multicenter studies based on larger series are warranted to better understand the best treatment strategies for young people with primary headaches.

Published
2017

42. Oral-facial-digital syndrome type VI: is C5orf42 really the major gene?

Author

Alessia Micalizzi, Maja Steinlin, Patrizia Accorsi, Lorenzo Pinelli, Serdar Ceylaner, Eugen Boltshauser, Renato Borgatti, Franco Stanzial, Ronen Spiegel, Emanuela Avola, P Póo, Enrico Bertini, Tommaso Mazza, Giangennaro Coppola, Mario Lituania, Andrea Poretti, Loreto Martorell, Marta Romani, Nicole I. Wolf, Andreas R. Janecke, Sabrina Signorini, Elide Miccinilli, Kathrin Ludwig, Brahim Tabarki, Romina Romaniello, Sylvie Odent, Alessandro Simonati, Margherita Santucci, Francesca Mancini, Stefano D'Arrigo, Federica Zibordi, Enza Maria Valente, Lucio Giordano, Romani, Marta, Mancini, Francesca, Micalizzi, Alessia, Poretti, Andrea, Miccinilli, Elide, Accorsi, Patrizia, Avola, Emanuela, Bertini, Enrico, Borgatti, Renato, Romaniello, Romina, Ceylaner, Serdar, Coppola, Giangennaro, D’Arrigo, Stefano, Giordano, Lucio, Janecke, Andreas R., Lituania, Mario, Ludwig, Kathrin, Martorell, Loreto, Mazza, Tommaso, Odent, Sylvie, Pinelli, Lorenzo, Poo, Pilar, Santucci, Margherita, Signorini, Sabrina, Simonati, Alessandro, Spiegel, Ronen, Stanzial, Franco, Steinlin, Maja, Tabarki, Brahim, Wolf, Nicole I., Zibordi, Federica, Boltshauser, Eugen, Valente, Enza Maria, Cytogenetics, INGEMM, Institute of Medical and Molecular Genetics, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Division of Anatomic Pathology, Department of Critical Care Medicine and Surgery, University of Florence Medical School, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Department of Neurological and Visual Sciences, University of Verona (UNIVR), Servizio aziendale di Consulenza Genetica, Ospedale di Bolzano, Pediatric surgery, NCA - Brain mechanisms in health and disease, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Università degli Studi di Firenze = University of Florence (UniFI), and Università degli studi di Verona = University of Verona (UNIVR)

Subjects
Male, Proband, Oral-facial-digital type VI syndrome, [SDV]Life Sciences [q-bio], Joubert syndrome, C5orf42 gene, medicine.disease_cause, Cohort Studies, Cerebellum, Genetics(clinical), Eye Abnormalities, 610 Medicine & health, Orofaciodigital Syndrome, Membrane Protein, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Genetics, 0303 health sciences, Mutation, Polydactyly, 030305 genetics & heredity, Hypothalamic Disease, Cerebellar Disease, Kidney Diseases, Cystic, Orofaciodigital Syndromes, Major gene, Phenotype, Kidney Diseases, Female, Hypothalamic Diseases, Human, Hamartoma, Short Report, Biology, Retina, Follow-Up Studie, Cystic, 03 medical and health sciences, Genetic, Hypothalamic hamartoma, Cerebellar Diseases, Family, Follow-Up Studies, Humans, Membrane Proteins, medicine, Abnormalities, Multiple, 030304 developmental biology, medicine.disease, Eye Abnormalitie, Cohort Studie
Abstract

Oral-facial-digital type VI syndrome (OFDVI) is a rare phenotype of Joubert syndrome (JS). Recently, C5orf42 was suggested as the major OFDVI gene, being mutated in 9 of 11 families (82 %). We sequenced C5orf42 in 313 JS probands and identified mutations in 28 (8.9 %), most with a phenotype of pure JS. Only 2 out of 17 OFDVI patients (11.7 %) were mutated. A comparison of mutated vs. non-mutated OFDVI patients showed that preaxial and mesoaxial polydactyly, hypothalamic hamartoma and other congenital defects may predict C5orf42 mutations, while tongue hamartomas are more common in negative patients. Electronic supplementary material The online version of this article (doi:10.1007/s00439-014-1508-3) contains supplementary material, which is available to authorized users.

Published
2014
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43. C19orf12 and FA2H Mutations Are Rare in Italian Patients With Neurodegeneration With Brain Iron Accumulation

Author

Celeste, Panteghini, Giovanna, Zorzi, Paola, Venco, Sabrina, Dusi, Chiara, Reale, Dario, Brunetti, Luisa, Chiapparini, Federica, Zibordi, Birgit, Siegel, Brigitte, Siegel, Barbara, Garavaglia, Alessandro, Simonati, Enrico, Bertini, Nardo, Nardocci, Valeria, Tiranti, Panteghini, Celeste, Zorzi, Giovanna, Venco, Paola, Dusi, Sabrina, Reale, Chiara, Brunetti, Dario, Chiapparini, Luisa, Zibordi, Federica, Siegel, Brigitte, Garavaglia, Barbara, Simonati, Alessandro, Bertini, Enrico, Nardocci, Nardo, and Tiranti, Valeria

Subjects
Adult, Male, Iron metabolism disorder, medicine.medical_specialty, Italian, Adolescent, Genotype, Neurodegeneration with brain iron accumulation, DNA Mutational Analysis, NBIA, C19orf12 mutation, FA2H Mutation, patients, Neuroaxonal Dystrophies, Biology, Bioinformatics, Mixed Function Oxygenases, DNA Mutational Analysi, Cohort Studies, Mitochondrial Proteins, Young Adult, Microscopy, Electron, Transmission, Molecular genetics, Basal ganglia, medicine, Iron Metabolism Disorder, Mitochondrial Protein, Humans, Neuroaxonal Dystrophie, Genetic Predisposition to Disease, Gene, Mixed Function Oxygenase, Skin, Early onset, Genetics, PANK2, Iron Metabolism Disorders, Italy, Mutation, Pediatrics, Perinatology and Child Health, Female, Neurology (clinical), Cohort Studie, Human
Abstract

Neurodegeneration with brain iron accumulation (NBIA) defines a wide spectrum of clinical entities characterized by iron accumulation in specific regions of the brain, predominantly in the basal ganglia. We evaluated the presence of FA2H and C19orf12 mutations in a cohort of 46 Italian patients with early onset NBIA, which were negative for mutations in the PANK2 and PLA2G6 genes. Follow-up molecular genetic and in vitro analyses were then performed. We did not find any mutations in the FA2H gene, although we identified 3 patients carrying novel mutations in the C19orf12 gene. The recent discovery of new genes responsible for NBIA extends the spectrum of the genetic investigation now available for these disorders and makes it possible to delineate a clearer clinical-genetic classification of different forms of this syndrome. A large fraction of patients still remain without a molecular genetics diagnosis, suggesting that additional NBIA genes are still to be discovered. © 2012 Elsevier Inc.

Published
2012
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