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6. Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials

Author

van Eijk, Ruben P. A, Jones, Ashley R., Sproviero, William, Shatunov, Aleksey, Shaw, Pamela J., Leigh, P. Nigel, Young, Carolyn A., Shaw, Christopher E., Mora, Gabriele, Mandrioli, Jessica, Borghero, Giuseppe, Volanti, Paolo, Diekstra, Frank P., van Rheenen, Wouter, Verstraete, Esther, Eijkemans, Marinus J. C, Veldink, Jan H., Chio, Adriano, Al-Chalabi, Ammar, van den Berg, Leonard H., van Es, Michael A, For UKMND-LiCALS and LITALS Study Group: Allen C, Counsell C, Farrin A, Al-Chalabi A, Dickie B, Kelly J, Leigh PN, Murphy CL, Payan C, Reynolds G, Shaw P, Steen IN, Thornhill M, Waters J, Zajicek J, Shaw PJ, Young CA, Morrison KE, Dhariwal S, Hornabrook R, Savage L, Burn DJ, Khoo TK, Dougherty A, Wijesekera L, Ellis CM, Ali R, O'Hanlon K, Panicker J, Pate L, Ray P, Wyatt L, Copeland L, Ealing J, Hamdalla H, Leroi I, Murphy C, O'Keeffe F, Oughton E, Partington L, Paterson P, Rog D, Sathish A, Sexton D, Smith J, Vanek H, Dodds S, Williams TL, Clarke J, Eziefula C, Howard R, Orrell R, Sidle K, Sylvester R, Barrett W, Merritt C, Talbot K, Turner MR, Whatley C, Williams C, Williams J, Cosby C, Hanemann CO, Imam I, Phillips C, Timings L, Crawford SE, Hewamadduma C, Hibberd R, Hollinger H, McDermott C, Mills G, Rafiq M, Taylor A, Waines E, Walsh T, Addison-Jones R, Birt J, Hare M, Majid T, Tortelli R, D'Errico E, Bartolomei I, Barbarossa E, Depau B, Costantino E, D'Amico E, Uncini A, Manzoli C, Quatrale R, Sette E, Montanari E, Merello M, Zarcone D, Mascolo M, Vignolo M, Messina S, Morelli C, Marinou K, Papetti L, Lunetta C, Gorni K, De Cicco D, Pipia C, Sola P, Georgoulopoulou E, Sagnelli A, Tedeschi, Gioacchino, Oggioni G, Nasuelli N, D'Ascenzo C, Cima V, Aiello M, Rizzi R, Rinaldi E, Luigetti M, Conte A, Torzini A, Greco G, Mutani R, Fuda G, Tommasi MA, van Eijk, Ruben P. A, Jones, Ashley R., Sproviero, William, Shatunov, Aleksey, Shaw, Pamela J., Leigh, P. Nigel, Young, Carolyn A., Shaw, Christopher E., Mora, Gabriele, Mandrioli, Jessica, Borghero, Giuseppe, Volanti, Paolo, Diekstra, Frank P., van Rheenen, Wouter, Verstraete, Esther, Eijkemans, Marinus J. C, Veldink, Jan H., Chio, Adriano, Al-Chalabi, Ammar, van den Berg, Leonard H., van Es, Michael A, For UKMND-LiCALS and LITALS Study Group: Allen, C, Counsell, C, Farrin, A, Al-Chalabi, A, Dickie, B, Kelly, J, Leigh, Pn, Murphy, Cl, Payan, C, Reynolds, G, Shaw, P, Steen, In, Thornhill, M, Waters, J, Zajicek, J, Shaw, Pj, Young, Ca, Morrison, Ke, Dhariwal, S, Hornabrook, R, Savage, L, Burn, Dj, Khoo, Tk, Dougherty, A, Wijesekera, L, Ellis, Cm, Ali, R, O'Hanlon, K, Panicker, J, Pate, L, Ray, P, Wyatt, L, Copeland, L, Ealing, J, Hamdalla, H, Leroi, I, Murphy, C, O'Keeffe, F, Oughton, E, Partington, L, Paterson, P, Rog, D, Sathish, A, Sexton, D, Smith, J, Vanek, H, Dodds, S, Williams, Tl, Clarke, J, Eziefula, C, Howard, R, Orrell, R, Sidle, K, Sylvester, R, Barrett, W, Merritt, C, Talbot, K, Turner, Mr, Whatley, C, Williams, C, Williams, J, Cosby, C, Hanemann, Co, Imam, I, Phillips, C, Timings, L, Crawford, Se, Hewamadduma, C, Hibberd, R, Hollinger, H, Mcdermott, C, Mills, G, Rafiq, M, Taylor, A, Waines, E, Walsh, T, Addison-Jones, R, Birt, J, Hare, M, Majid, T, Tortelli, R, D'Errico, E, Bartolomei, I, Barbarossa, E, Depau, B, Costantino, E, D'Amico, E, Uncini, A, Manzoli, C, Quatrale, R, Sette, E, Montanari, E, Merello, M, Zarcone, D, Mascolo, M, Vignolo, M, Messina, S, Morelli, C, Marinou, K, Papetti, L, Lunetta, C, Gorni, K, De Cicco, D, Pipia, C, Sola, P, Georgoulopoulou, E, Sagnelli, A, Tedeschi, Gioacchino, Oggioni, G, Nasuelli, N, D'Ascenzo, C, Cima, V, Aiello, M, Rizzi, R, Rinaldi, E, Luigetti, M, Conte, A, Torzini, A, Greco, G, Mutani, R, Fuda, G, and Tommasi, Ma

Subjects
Oncology, R853.C55, medicine.medical_specialty, Genotype, Neuroprotective Agent, Clinical Neurology, Nerve Tissue Proteins, Review, Amyotrophic Lateral Sclerosis, C9orf72 Protein, Lithium Carbonate, Neuroprotective Agents, Proportional Hazards Models, Proteins, Pharmacogenetics, Randomized Controlled Trials as Topic, Neurology (clinical), Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Journal Article, 030212 general & internal medicine, Amyotrophic lateral sclerosis, business.industry, Protein, Pharmacogenetic, medicine.disease, Clinical trial, RC0346, Meta-analysis, Nerve Tissue Protein, Proportional Hazards Model, business, 030217 neurology & neurosurgery, Meta-Analysis, Amyotrophic Lateral Sclerosi
Abstract

OBJECTIVE\ud \ud To assess whether genetic subgroups in recent amyotrophic lateral sclerosis (ALS) trials responded to treatment with lithium carbonate, but that the treatment effect was lost in a large cohort of nonresponders.\ud \ud METHODS\ud \ud Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. We matched clinical data with data regarding the UNC13A and C9orf72 genotype. Our primary outcome was survival at 12 months. On an exploratory basis, we assessed whether the effect of lithium depended on the genotype.\ud \ud RESULTS\ud \ud Clinical data were available for 518 of the 606 participants. Overall, treatment with lithium carbonate did not improve 12-month survival (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.7-1.4; p = 0.96). Both the UNC13A and C9orf72 genotype were independent predictors of survival (HR 2.4, 95% CI 1.3-4.3; p = 0.006 and HR 2.5, 95% CI 1.1-5.2; p = 0.032, respectively). The effect of lithium was different for UNC13A carriers (p = 0.027), but not for C9orf72 carriers (p = 0.22). The 12-month survival probability for UNC13A carriers treated with lithium carbonate improved from 40.1% (95% CI 23.2-69.1) to 69.7% (95% CI 50.4-96.3).\ud \ud CONCLUSIONS\ud \ud This study incorporated genetic data into past ALS trials to determine treatment effects in a genetic post hoc analysis. Our results suggest that we should reorient our strategies toward finding treatments for ALS, start focusing on genotype-targeted treatments, and standardize genotyping in order to optimize randomization and analysis for future clinical trials.

Published
2017

7. Disturbi Specifici di Apprendimento (DSA). Normativa e buone pratiche

Author

Shannon, K, Ferrari, M.G., Papetti, L., Ferrari, Maria Grazia, Meo, Damiano, Meo, Damiano (ORCID:0000-0003-1168-6194), Shannon, K, Ferrari, M.G., Papetti, L., Ferrari, Maria Grazia, Meo, Damiano, and Meo, Damiano (ORCID:0000-0003-1168-6194)

Abstract

Stilare obiettivi linguistici coerenti è un processo complesso. Al fine di guidare il setting degli obiettivi glottodidattici, in questa breve trattazione, si propone l'acronimo +STIMA. .

Published
2020

8. Treatment and outcome of aquaporin-4 antibody-positive NMOSD: A multinational pediatric study

Author

Paolilo, R.B., Hacohen, Y., Yazbeck, E., Armangue, T, Bruijstens, A., Lechner, C., Apostolos-Pereira, S.L., Martynenko, Y., Breu, M., Rimkus, C.D., Wassmer, E. (Evangeline), Baumann, M. (Marc), Papetti, L., Capobianco, M., Kornek, B. (Barbara), Rostasy, K. (Kevin), da Paz, J.A., Ciccarelli, O., Lim, M, Saiz, A. (Albert Abe), Neuteboom, R.F. (Rinze), Marignier, R. (Romain), Hemingway, C., Sato, D.K., Deiva, K., Paolilo, R.B., Hacohen, Y., Yazbeck, E., Armangue, T, Bruijstens, A., Lechner, C., Apostolos-Pereira, S.L., Martynenko, Y., Breu, M., Rimkus, C.D., Wassmer, E. (Evangeline), Baumann, M. (Marc), Papetti, L., Capobianco, M., Kornek, B. (Barbara), Rostasy, K. (Kevin), da Paz, J.A., Ciccarelli, O., Lim, M, Saiz, A. (Albert Abe), Neuteboom, R.F. (Rinze), Marignier, R. (Romain), Hemingway, C., Sato, D.K., and Deiva, K.

Abstract

Objective To describe the clinical phenotypes, treatment response, and outcome of children with antibodies against aquaporin-4 (AQP4-Ab) neuromyelitis optica spectrum disorder (NMOSD). Methods Retrospective, multicenter, and multinational study of patients with AQP4-Ab NMOSD aged <18 years at disease onset from a center in Brazil and 13 European centers. Data on demographics, clinical findings, and laboratory results were analyzed; calculation of annualized relapse rates (ARRs) pre- and on-treatment with disease-modifying therapies (DMTs) and of ORs for predictors of poor outcome was performed. Results A total of 67 children were identified. At last follow-up (median 4 years, interquartile range 2–10 years), 37/67(57.8%) were found to have permanent disability. A more severe disease course was seen in the non-White ethnicity with both a shorter time to first relapse (p = 0.049) and a worse Expanded Disability Status Scale score at last follow-up (p = 0.008). The median ARR on treatment was 0.18 on azathioprine (n = 39, range 0–4), 0 on mycophenolate mofetil (n = 18, range 0–3), and 0 on rituximab (n = 29, range 0–2). No patient treated with rituximab as first-line therapy relapsed. Optic neuritis at onset was associated with a poor visual outcome below 20/200 (OR 8.669, 95% CI 1.764–42.616, p = 0.008), and a younger age at onset was associated with cognitive impairment (OR 0.786, 95% CI 0.644–0.959, p = 0.018). Conclusions AQP4-Ab NMOSD in children is an aggressive disease with permanent disabilities observed in over half the cohort. All DMTs were associated with a reduction of ARR. First-line rituximab prevented further clinical relapses. International consensus on treatment protocols for children is required to reduce heterogeneity of treatment regimens used worldwide. Classification of evidence This study provides Class IV evidence that for children with AQP4-Ab NMOSD, all DMTs, particularly first-line rituximab, reduced the ARR and prevented further clinical rel

Published
2020
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9. Treatment and outcome of aquaporin-4 antibody-positive NMOSD: A multinational pediatric study

Author

Paolilo, RB, Hacohen, Y, Yazbeck, E, Armangue, T, Bruijstens, A, Lechner, C, Apostolos-Pereira, SL, Martynenko, Y, Breu, M, Rimkus, CD, Wassmer, E, Baumann, M, Papetti, L, Capobianco, M, Kornek, B, Rostasy, K, da Paz, JA, Ciccarelli, O, Lim, M, Saiz, A, Neuteboom, R, Marignier, R, Hemingway, C, Sato, DK, Deiva, K, Paolilo, RB, Hacohen, Y, Yazbeck, E, Armangue, T, Bruijstens, A, Lechner, C, Apostolos-Pereira, SL, Martynenko, Y, Breu, M, Rimkus, CD, Wassmer, E, Baumann, M, Papetti, L, Capobianco, M, Kornek, B, Rostasy, K, da Paz, JA, Ciccarelli, O, Lim, M, Saiz, A, Neuteboom, R, Marignier, R, Hemingway, C, Sato, DK, and Deiva, K

Published
2020

11. Subgroup comparison according to clinical phenotype and serostatus in autoimmune encephalitis: a multicenter retrospective study

Author

Gastaldi, M., primary, Mariotto, S., additional, Giannoccaro, M. P., additional, Iorio, R., additional, Zoccarato, M., additional, Nosadini, M., additional, Benedetti, L., additional, Casagrande, S., additional, Di Filippo, M., additional, Valeriani, M., additional, Ricci, S., additional, Bova, S., additional, Arbasino, C., additional, Mauri, M., additional, Versino, M., additional, Vigevano, F., additional, Papetti, L., additional, Romoli, M., additional, Lapucci, C., additional, Massa, F., additional, Sartori, S., additional, Zuliani, L., additional, Barilaro, A., additional, De Gaspari, P., additional, Spagni, G., additional, Evoli, A., additional, Liguori, R., additional, Ferrari, S., additional, Marchioni, E., additional, Giometto, B., additional, Massacesi, L., additional, and Franciotta, D., additional

Published
2020
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12. Unilateral Opercular Polymicrogyria in a Girl with 22q13 Deletion Syndrome

Author

Alessandra Zicari, Fabiana Ursitti, Francesco Nicita, Novelli A, Pimpolari L, Alberto Spalice, Duse M, Papetti L, and Luigi Tarani

Subjects
business.industry, media_common.quotation_subject, Polymicrogyria, Medicine, 22q13 deletion syndrome, Girl, Anatomy, business, medicine.disease, media_common
Published
2017

13. T-cell depleted HLA-haploidentical HSCT in a child with neuromyelitis optica

Author

Ceglie, G., Papetti, L., Figa Talamanca, L., Lucarelli, B., Algeri, M., Gaspari, S., Li Pira, G., Colafati, G. -S., Montanari, M., Valeriani, M., Locatelli, Franco, Merli, P., Locatelli F. (ORCID:0000-0002-7976-3654), Ceglie, G., Papetti, L., Figa Talamanca, L., Lucarelli, B., Algeri, M., Gaspari, S., Li Pira, G., Colafati, G. -S., Montanari, M., Valeriani, M., Locatelli, Franco, Merli, P., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Neuromyelitis optica is an immune-mediated disease characterized by a relapsing course, resulting in progressive disability. In children, given the long life expectancy, a disease-modifying treatment could be particularly desirable. Unfortunately, the currently available treatment strategies with this potential are scarce. Very limited data are available about the use of allogeneic hematopoietic stem cell transplantation (HSCT) for autoimmune neurological diseases. In this report, we present a pediatric case successfully treated with allogeneic HSCT from an HLA-haploidentical donor, after ex vivo TCR/CD19-depletion of the graft. To the best of our knowledge, this is the first case of a pediatric patient to benefit from such a treatment.

Published
2019

14. Subgroup comparison according to clinical phenotype and serostatus in autoimmune encephalitis: a multicenter retrospective study

Author

Gastaldi, M, Mariotto, S, Giannoccaro, M P, Iorio, R, Zoccarato, M, Nosadini, M, Benedetti, L, Casagrande, S, Di Filippo, M, Valeriani, M, Ricci, S, Bova, S, Arbasino, C, Mauri, M, Versino, M, Vigevano, F, Papetti, L, Romoli, M, Lapucci, C, Massa, F, Sartori, S, Zuliani, Danilo, Barilaro, Cynthia, De Gaspari, P, Spagni, Gregorio, Evoli Stampanoni-B, Amelia, Liguori, R, Ferrari, S, Marchioni, E, Giometto, B, Massacesi, L, Franciotta, D, Zuliani, L, Barilaro, A (ORCID:0000-0002-6576-8921), Spagni, G, Evoli, A (ORCID:0000-0003-0282-8787), Gastaldi, M, Mariotto, S, Giannoccaro, M P, Iorio, R, Zoccarato, M, Nosadini, M, Benedetti, L, Casagrande, S, Di Filippo, M, Valeriani, M, Ricci, S, Bova, S, Arbasino, C, Mauri, M, Versino, M, Vigevano, F, Papetti, L, Romoli, M, Lapucci, C, Massa, F, Sartori, S, Zuliani, Danilo, Barilaro, Cynthia, De Gaspari, P, Spagni, Gregorio, Evoli Stampanoni-B, Amelia, Liguori, R, Ferrari, S, Marchioni, E, Giometto, B, Massacesi, L, Franciotta, D, Zuliani, L, Barilaro, A (ORCID:0000-0002-6576-8921), Spagni, G, and Evoli, A (ORCID:0000-0003-0282-8787)

Abstract

BACKGROUND AND PURPOSE: Autoimmune encephalitides (AE) include a spectrum of neurological disorders whose diagnosis revolves around the detection of neuronal antibodies (Abs). Consensus-based diagnostic criteria (AE-DC) allow clinic-serological subgrouping of AE, with unclear prognostic implications. The impact of AE-DC on patients' management was studied, focusing on the subgroup of Ab-negative-AE. METHODS: This was a retrospective multicenter study on patients fulfilling AE-DC. All patients underwent Ab testing with commercial cell-based assays (CBAs) and, when available, in-house assays (immunohistochemistry, live/fixed CBAs, neuronal cultures) that contributed to defining final categories. Patients were classified as Ab-positive-AE [N-methyl-d-aspartate-receptor encephalitis (NMDAR-E), Ab-positive limbic encephalitis (LE), definite-AE] or Ab-negative-AE (Ab-negative-LE, probable-AE, possible-AE). RESULTS: Commercial CBAs detected neuronal Abs in 70/118 (59.3%) patients. Testing 37/48 Ab-negative cases, in-house assays identified Abs in 11 patients (29.7%). A hundred and eighteen patients fulfilled the AE-DC, 81 (68.6%) with Ab-positive-AE (Ab-positive-LE, 40; NMDAR-E, 32; definite-AE, nine) and 37 (31.4%) with Ab-negative-AE (Ab-negative-LE, 17; probable/possible-AE, 20). Clinical phenotypes were similar in Ab-positive-LE versus Ab-negative-LE. Twenty-four/118 (20.3%) patients had tumors, and 19/118 (16.1%) relapsed, regardless of being Ab-positive or Ab-negative. Ab-positive-AE patients were treated earlier than Ab-negative-AE patients (P = 0.045), responded more frequently to treatments (92.3% vs. 65.6%, P < 0.001) and received second-line therapies more often (33.3% vs. 10.8%, P = 0.01). Delays in first-line therapy initiation were associated with poor response (P = 0.022; odds ratio 1.02; confidence interval 1.00-1.04). CONCLUSIONS: In-house diagnostics improved Ab detection allowing better patient management but was available in a patient subgro

Published
2019

16. PACAP38 and PAC1 receptor blockade: a new target for headache?

Author

Rubio-Beltrán, A.E. (Eloísa), Correnti, E. (Edvige), Deen, M. (Marie), Kamm, K. (Katharina), Kelderman, T. (Tim), Papetti, L. (Laura), Vigneri, S. (Simone), Maassen van den Brink, A. (Antoinette), Edvinsson, L. (Lars), Rubio-Beltrán, A.E. (Eloísa), Correnti, E. (Edvige), Deen, M. (Marie), Kamm, K. (Katharina), Kelderman, T. (Tim), Papetti, L. (Laura), Vigneri, S. (Simone), Maassen van den Brink, A. (Antoinette), and Edvinsson, L. (Lars)

Abstract

Pituitary adenylate cyclase activating polypeptide-38 (PACAP38) is a widely distributed neuropeptide involved in neuroprotection, neurodevelopment, nociception and inflammation. Moreover, PACAP38 is a potent inducer of migraine-like attacks, but the mechanism behind this has not been fully elucidated.Migraine is a neurovascular disorder, recognized as the second most disabling disease. Nevertheless, the antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor are the only prophylactic treatment developed specifically for migraine. These antibodies have displayed positive results in clinical trials, but are not effective for all patients; therefore, new pharmacological targets need to be identified.Due to the ability of PACAP38 to induce migraine-like attacks, its location in structures previously associated with migraine pathophysiology and the 100-fold selectivity for the PAC1 receptor when compared to VIP, new attention has been drawn to this pathway and its potential role as a novel target for migraine treatment. In accordance with this, antibodies against PACAP38 (ALD 1910) and PAC1 receptor (AMG 301) are being developed, with AMG 301 already in Phase II clinical trials. No results have been published so far, but in preclinical studies, AMG 301 has shown responses comparable to those observed with triptans. If these antibodies prove to be effective for the treatment of migraine, several considerations should be addressed, for instance, the potential side effects of long-term blockade of the PACAP (receptor) pathway. Moreover, it is important to investigate whether these antibodies will indeed represent a therapeutic advantage for the patients that do not respond the CGRP (receptor)-antibodies.In conclusion, the data presented in this review indicate that PACAP38 and PAC1 receptor blockade are promising antimigraine therapies, but results from clinical trials are needed in order to confirm their efficacy and side effect profile.

Published
2018
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17. PACAP38 and PAC1 receptor blockade: a new target for headache?

Author

Rubio Beltran, Amada, Correnti, E, Deen, M (Marie), Kamm, K, Kelderman, T, Papetti, L, Vigneri, S, Maassen van den Brink, Antoinette, Edvinsson, L, Rubio Beltran, Amada, Correnti, E, Deen, M (Marie), Kamm, K, Kelderman, T, Papetti, L, Vigneri, S, Maassen van den Brink, Antoinette, and Edvinsson, L

Published
2018

18. Is firstly diagnosed ALS really ALS? Results of a population-based study with long-term follow-up

Author

Pupillo, E., Bianchi, E., Poloni, M., Beghi, E., Micheli, A., Rosettani, P., Tettamanzi, F., Baldini, D., Bianchi, G., Rigamonti, A., Bonito, V., Chiveri, L., Guidotti, M., Rezzonico, M., Vidale, S., Corbo, M., Lunetta, C., Maestri, E., Cotelli, M. S., Filosto, M., Filippini, G., Lauria, G., Mora, G., Papetti, L., Morelli, C., Perini, M., Tavernelli, F., Perrone, P., Guaita, M. C., Testa, D., Sasanelli, F., Galbussera, A., Tremolizzo, L., Ferrarese, C., Galli, A., Vitelli, E., Prelle, A., Riva, N., Ceroni, M., Delodovici, L., Clerici, M., Bono, G., Buzzi, P., Previdi, P., Guarneri, G., Abruzzi, L., Riccardi, T., Lorusso, L., Mazzini, L., Pupillo, E, Bianchi, E, Poloni, M, Beghi, E, Slalom, G, Tremolizzo, L, and Ferrarese, C

Subjects
Adult, Male, medicine.medical_specialty, Pediatrics, Neurology, Adolescent, Long term follow up, Encephalopathy, Population, Disease, Cohort Studies, Diagnosis, Differential, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Epidemiology, medicine, Humans, False Positive Reactions, 030212 general & internal medicine, Registries, Medical diagnosis, Amyotrophic lateral sclerosis, Age of Onset, Amyotrophic lateral sclerosi, Aged, Aged, 80 and over, business.industry, false positive diagnosis, Reproducibility of Results, Middle Aged, medicine.disease, Survival Analysis, Population based study, false positive diagnosi, Italy, Physical therapy, motor neuron disease, Female, epidemiology, Neurology (clinical), business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Objective: To revise the first diagnosis of amyotrophic lateral sclerosis (ALS) in patients from a well-defined population. Methods: Patients diagnosed with ALS in the years 1998-2002 and resident of Lombardy Region, Northern Italy were followed until death or April 30 2016 to assess long-term survival. During follow-up, the caring neurologists were asked to confirm the first diagnosis. Revised diagnoses were classified as confirmed and unconfirmed motor neuron disease (MND) with further specification where available. The two groups were compared for age, sex, disease duration at diagnosis, site of onset, and El Escorial category. Survival with predictors were also compared. Results: Included were 280 men and 203 women aged 18-93 years. During follow-up, 25 cases (5.2%) received a diagnosis different from MND. Diseases of spinal roots and peripheral nerves and vascular encephalopathy predominated. Patients with definite (OR 0.15; 95%CI 0.04-0.52) and probable (OR 0.15; 95%CI 0.04-0.62) ALS were least likely to have an unconfirmed MND diagnosis. At end of follow-up, 2.2% of patients with confirmed MND and 44.0% of patients with unconfirmed MND were reported alive (HR 0.14; 95%CI 0.08-0.25). Conclusions: At the time of a first diagnosis of ALS, the possibility still exists that another, less severe clinical condition, is present.

Published
2017

19. Genetic counselling in ALS: facts, uncertainties and clinical suggestions

Author

Chio, A., Battistini, Stefania, Calvo, A., Caponnetto, C., Conforti, F. L., Corbo, M., Giannini, Fabio, Mandrioli, J., Mora, G., Sabatelli, M., Ajmone, C., Mastro, E., Pain, D., Mandich, P., Penco, S., Restagno, G., Zollino, M., Surbone, A., Monsurro, M. R., Tedeschi, G., Conte, A., Luigetti, M., Lattante, S., Marangi, G., Volanti, P., Marinou, K., Papetti, L., Lunetta, C., Pintor, G. L., Salvi, F., Bartolomei, I., Quattrone, A., Gambardella, A., Logroscino, G., Simone, I., Pisano, F., Spataro, R., La Bella, V., Colletti, T., Mancardi, G., Origone, P., Sola, P., Borghero, G., Marrosu, F., Marrosu, M. G., Murru, M. R., Floris, G., Cannas, A., Piras, V., Costantino, E., Pani, C., Sotgiu, M. A., Pugliatti, M., Parish, L. D., Cossu, P., Ticca, A., Rodolico, C., Portaro, S., Ricci, Claudia, Moglia, C., Ossola, I., Brunetti, M., Barberis, M., Canosa, A., Cammarosano, S., Bertuzzo, D., Fuda, G., Ilardi, A., Manera, U., Pastore, I., Sproviero, W., Logullo, F., Tanel, R., Chiò, A, Battistini, S, Calvo, A, Caponnetto, C, Conforti, FL, Corbo, M, Giannini, F, Mandrioli, J, Mora, G, Sabatelli, M, Cammarosano, S, Canosa, A, Moglia, C, Ajmone, C, Mastro, E, Pain, D, Mandich, P, Penco, S, Restagno, G, Zollino, M, Surbone, A, Conforti, Fl, Italsgen, Consortium, Among, Collaborator, Tedeschi, Gioacchino, and Surbone, A.

Subjects
medicine.medical_specialty, Genotype, GENETICS, Genetic counseling, Genetic Counseling, Gene mutation, Settore MED/03 - GENETICA MEDICA, medicine, Humans, Genetic Testing, Amyotrophic lateral sclerosis, Genetic discrimination, Psychiatry, Genetic testing, medicine.diagnostic_test, business.industry, Amyotrophic Lateral Sclerosis, medicine.disease, Penetrance, ALS, 3. Good health, Psychiatry and Mental health, Phenotype, Frontotemporal Dementia, Mutation, Surgery, Settore MED/26 - Neurologia, Neurology (clinical), business, Motor neurone disease, Frontotemporal dementia
Abstract

The clinical approach to patients with amyotrophic lateral sclerosis (ALS) has been largely modified by the identification of novel genes, the detection of gene mutations in apparently sporadic patients, and the discovery of the strict genetic and clinical relation between ALS and frontotemporal dementia (FTD). As a consequence, clinicians are increasingly facing the dilemma on how to handle genetic counselling and testing both for ALS patients and their relatives. On the basis of existing literature on genetics of ALS and of other late-onset life-threatening disorders, we propose clinical suggestions to enable neurologists to provide optimal clinical and genetic counselling to patients and families. Genetic testing should be offered to ALS patients who have a first-degree or second-degree relative with ALS, FTD or both, and should be discussed with, but not offered to, all other ALS patients, with special emphasis on its major uncertainties. Presently, genetic testing should not be proposed to asymptomatic at-risk subjects, unless they request it or are enrolled in research programmes. Genetic counselling in ALS should take into account the uncertainties about the pathogenicity and penetrance of some genetic mutations; the possible presence of mutations of different genes in the same individual; the poor genotypic/phenotypic correlation in most ALS genes; and the phenotypic pleiotropy of some genes. Though psychological, social and ethical implications of genetic testing are still relatively unexplored in ALS, we recommend multidisciplinary counselling that addresses all relevant issues, including disclosure of tests results to family members and the risk for genetic discrimination.

Published
2014
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20. MITOCHONDRIAL DISEASES (Posters)

Author

Bertini, E., primary, Verrigni, D., additional, Battaglia, D., additional, Torraco, A., additional, Figa Talamanca, L., additional, Carrozzo, R., additional, Diodato, D., additional, D'Amico, A., additional, Papetti, L., additional, Ghezzi, D., additional, Ardissone, A., additional, Lamperti, C., additional, Legati, A., additional, and Goffrini, P., additional

Published
2018
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21. Blocking CGRP in migraine patients – a review of pros and cons

Author

Deen, M. (Marie), Correnti, E. (Edvige), Kamm, K. (Katharina), Kelderman, T. (Tim), Papetti, L. (Laura), Rubio-Beltrán, A.E. (Eloísa), Vigneri, S. (Simone), Edvinsson, L. (Lars), Maassen van den Brink, A. (Antoinette), Deen, M. (Marie), Correnti, E. (Edvige), Kamm, K. (Katharina), Kelderman, T. (Tim), Papetti, L. (Laura), Rubio-Beltrán, A.E. (Eloísa), Vigneri, S. (Simone), Edvinsson, L. (Lars), and Maassen van den Brink, A. (Antoinette)

Abstract

Migraine is the most prevalent neurological disorder worldwide and it has immense socioeconomic impact. Currently, preventative treatment options for migraine include drugs developed for diseases other than migraine such as hypertension, depression and epilepsy. During the last decade, however, blocking calcitonin gene-related peptide (CGRP) has emerged as a possible mechanism for prevention of migraine attacks. CGRP has been shown to be released during migraine attacks and it may play a causative role in induction of migraine attacks. Here, we review the pros and cons of blocking CGRP in migraine patients. To date, two different classes of drugs blocking CGRP have been developed: small molecule CGRP receptor antagonists (gepants), and monoclonal antibodies, targeting either CGRP or the CGRP receptor. Several trials have been conducted to test the efficacy and safety of these drugs. In general, a superior efficacy compared to placebo has been shown, especially with regards to the antibodies. In addition, the efficacy is in line with other currently used prophylactic treatments. The drugs have also been well tolerated, except for some of the gepants, which induced a transient increase in transaminases. Thus, blocking CGRP in migraine patients is seemingly both efficient and well tolerated. However, CGRP and its receptor are abundantly present in both the vasculature, and in the peripheral and central nervous system, and are involved in several physiological processes. Therefore, blocking CGRP may pose a risk in subjects with comorbidities such as cardiovascular diseases. In addition, long-term effects are still unknown. Evidence from animal studies suggests that blocking CGRP may induce constipation, affect the homeostatic functions of the pituitary hormones or attenuate wound healing. However, these effects have so far not been reported in human studies. In conclusion, this review suggests that, based on current knowledge, the pros of blocking CGRP in migraine patie

Published
2017
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22. Blocking CGRP in migraine patients - a review of pros and cons

Author

Deen, M (Marie), Correnti, E, Kamm, K, Kelderman, T, Papetti, L, Rubio-Beltran, E, Vigneri, S, Edvinsson, L, Brink, A, Deen, M (Marie), Correnti, E, Kamm, K, Kelderman, T, Papetti, L, Rubio-Beltran, E, Vigneri, S, Edvinsson, L, and Brink, A

Published
2017

23. Clinical guidelines in pediatric headache: evaluation of quality using the AGREE II instrument

Author

Parisi, P, Vanacore, N, Belcastro, V, Carotenuto, M, Giudice, Ed, Mariani, R, Papetti, L, Pavone, P, Savasta, S, Striano, P, Toldo, I, Tozzi, Elisabetta, Verrotti, A, Raucci, U, 'Pediatric Headache Commission' of Società Italiana di Neurologia, P. e. d. i. a. t. r. i. c. a., VERROTTI di PIANELLA, Alberto, Parisi, P, Vanacore, N, Belcastro, V, Carotenuto, Marco, Del Giudice, E, Mariani, R, Papetti, L, Pavone, P, Savasta, S, Striano, P, Toldo, I, Tozzi, E, Verrotti, A, Raucci, U., Carotenuto, M, and DEL GIUDICE, Ennio

Subjects
medicine.medical_specialty, media_common.quotation_subject, Clinical Neurology, Nice, Agree II instrument, Children, Guidelines, Pediatric headache, Quality of guidelines, Child, Evidence-Based Medicine, Headache, Humans, Pediatrics, Practice Guidelines as Topic, Quality of Health Care, State Medicine, Anesthesiology and Pain Medicine, Neurology (clinical), Medicine (all), Cephalalgia, medicine, Quality (business), Pediatricagree II instrument, Psychiatry, National Guideline Clearinghouse, book, media_common, computer.programming_language, book.periodical, guidelines, pediatric headache, quality of guidelines, child, evidence-based medicine, headache, humans, childrens, practice guidelines as topic, quality of health care, state medicine, neurology (clinical), anesthesiology and pain medicine, business.industry, General Medicine, Evidence-based medicine, Guideline, Quality Score, Inclusion and exclusion criteria, Physical therapy, business, computer, Research Article
Abstract

Background The Appraisal of Guidelines for Research and Evaluation (AGREE II) tool is a validated questionnaire used to assess the methodological quality of clinical guidelines (CGs). We used the AGREE II tool to assess the development process, the methodological quality, and the quality of reporting of available pediatric CGs for the management of headache in children. We also studied the variability in responses related to the characteristics of eleven Italian neuropediatric centers, showing similarities and differences in the main recommendations reported in CGs. Methods A systematic literature search was conducted from January 2002 to June 2013 on Mediline, the Cochrane database, the National Guideline Clearinghouse website and the NHS evidence search tool, using the following terms: headache, cephalalgia, guidelines and children (MESH or text words). Six CGs providing information on the diagnosis and management of headache and specific recommendations for children were selected. Eleven neuropediatric centers assessed the overall quality and the appropriateness of all available CGs using of the AGREE II instrument. Results Six CGs meeting the inclusion and exclusion criteria were identified and assessed by 11 reviewers. Our study showed that the NICE CGs was “strongly recommended” while the French and Danish CGs were mainly “not recommended”. The comparison between the overall quality score of the French CGs and the NICE CGs was statistically significant (6.54 ± 0.69 vs 4.18 ± 1.08; p =0.001). The correlation analysis between quality domain score and guideline publication date showed a statistically significant association only for the “editorial independence” domain (r = 0.842 p = 0.035). The intra-class coefficients showed that the 11 reviewers had the highest agreement for the Lewis CGs (r = 0.857), and the lowest one for the NICE CGs (r = 0.656). Statistical analyses showed that professionals from outpatient services dedicated pediatric headache assigned a higher overall quality score to the NICE CGs as compared to professionals from non-outpatient services (6.86 ± 0.38 vs 6.0 ± 0.82; p = 0.038). Conclusions CGs resulted definitely of low-moderate quality and non “homogeneous”. Further major efforts are needed to update the existing CGs according to the principles of evidence based medicine.

Published
2014

24. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study

Author

Majounie, E1, Renton, Ae, Mok, K, Dopper, Eg, Waite, A, Rollinson, S, Chiò, A, Restagno, G, Nicolaou, N, Simon-Sanchez, J, van Swieten JC, Abramzon, Y, Johnson, Jo, Sendtner, M, Pamphlett, R, Orrell, Rw, Mead, S, Sidle, Kc, Houlden, H, Rohrer, Jd, Morrison, Ke, Pall, H, Talbot, K, Ansorge, O, Hernandez, Dg, Arepalli, S, Sabatelli, M, Mora, G, Corbo, M, Giannini, F, Calvo, A, Englund, E, Borghero, G, Floris, Gl, Remes, Am, Laaksovirta, H, Mccluskey, L, Trojanowski, Jq, Van Deerlin VM, Schellenberg, Gd, Nalls, Ma, Drory, Ve, Lu, Cs, Yeh, Th, Ishiura, H, Takahashi, Y, Tsuji, S, Le Ber, I, Brice, A, Drepper, C, Williams, N, Kirby, J, Shaw, P, Hardy, J, Tienari, Pj, Heutink, P, Morris, Hr, Pickering-Brown, S, Traynor, Bj, Adamson, G, Bayer, Aj, Beck, J, Callister, Jb, Blake, Dj, Blumen, Sc, Collinge, J, Dunckley, T, Ealing, J, East, S, Elman, L, Gerhard, A, Guerreiro, Rj, Gwinn, K, Halliwell, N, Hamdalla, Hh, Hewitt, C, Ince, P, Jablonka, S, James, C, Kent, L, Knock, Jc, Lynch, T, Mahoney, C, Mann, D, Neal, J, Norris, D, O'Dowd, S, Richardson, A, Rossor, M, Rothstein, J, Scholz, Sw, Snowden, J, Stephan, Da, Toulson, G, Turner, Mr, Warren, Jd, Young, K, Weng, Yh, Kuo, Hc, Lai, Sc, Huang, Cl, Camuzat, A, Entraingues, L, Guillot-Noël, Verpillat, P, Blanc, F, Camu, W, Clerget-Darpoux, F, Corcia, P, Couratier, P, Didic, M, Dubois, B, Duyckaerts, C, Guedj, E, Golfier, V, Habert, Mo, Hannequin, D, Lacomblez, L, Meininger, V, Salachas, F, Levy, R, Michel, Bf, Pasquier, F, Puel, M, Thomas-Anterion, C, Sellal, F, Vercelletto, M, Moglia, C, Cammarosano, S, Canosa, A, Gallo, S, Brunetti, M, Ossola, I, Marinou, K, Papetti, L, Pisano, F, Pinter, Gl, Conte, A, Luigetti, M, Zollino, M, Lattante, S, Marangi, G, la Bella, V, Spataro, R, Colletti, T, Battistini, S, Ricci, C, Caponnetto, C, Mancardi, G, Mandich, P, Salvi, F, Bartolomei, I, Mandrioli, J, Sola, P, Lunetta, C, Penco, S, Monsurrò, Mr, Tedeschi, G, Conforti, Fl, Gambardella, A, Quattrone, A, Volanti, P, Floris, G, Cannas, A, Piras, V, Marrosu, F, Marrosu, Mg, Murru, Mr, Pugliatti, M, Parish, Ld, Sotgiu, A, Solinas, G, Ulgheri, L, Ticca, A, Simone, I, Logroscino, G., Neurology, Erasmus MC other, The Chromosome 9-ALS/FTD Consortium, Human genetics, NCA - Neurodegeneration, Università degli studi di Torino (UNITO), Department of Clinical Genetics, Institute for Clinical Neurobiology, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), MRC Prion Unit, UCL Institute of neurology, UCL Institute of Neurology, UCL Institute of Neurology, Queen Square, London, Department of Neuroscience, Catholic University, Roma, Fondazione Maugeri, Department of Neuroscience, University of Siena, Siena, Department of Neurology, Chang Gung Memorial Hospital [Taipei] (CGMH), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council (MRC)-School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Università degli studi di Torino = University of Turin (UNITO), Julius-Maximilians-Universität Würzburg (JMU), UCL Institute of Neurology, Queen Square [London], Università degli Studi di Siena = University of Siena (UNISI), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
MESH: Signal Transduction, Male, MESH: Vesicular Transport Proteins, MESH: Membrane Glycoproteins, MESH: DNA Repeat Expansion, MESH: Genotype, Cohort Studies, MESH: Protein Structure, Tertiary, MESH: Aged, 80 and over, MESH: Interferon Regulatory Factor-3, 0302 clinical medicine, C9orf72, MESH: Child, MESH: RNA, Small Interfering, 80 and over, genetics, Age of Onset, Child, MESH: Cohort Studies, MESH: Amyotrophic Lateral Sclerosis, MESH: Aged, Genetics, Aged, 80 and over, 0303 health sciences, MESH: Middle Aged, DNA Repeat Expansion, MESH: Toll-Like Receptor 4, Middle Aged, Penetrance, 3. Good health, Settore MED/26 - NEUROLOGIA, Neurology, MESH: Young Adult, MESH: HEK293 Cells, Child, Preschool, Frontotemporal Dementia, Female, Sample collection, Chromosomes, Human, Pair 9, MESH: Myeloid Differentiation Factor 88, Frontotemporal dementia, Human, Pair 9, Adult, MESH: Protein Transport, medicine.medical_specialty, Adolescent, Genotype, MESH: Age of Onset, MESH: RNA Interference, Clinical Neurology, MESH: Frontotemporal Dementia, MESH: Genetic Loci, TARDBP, Chromosomes, 03 medical and health sciences, Open Reading Frames, Young Adult, MESH: Cross-Sectional Studies, Internal medicine, medicine, MESH: Chemokine CCL5, Humans, ddc:610, Preschool, MESH: Adaptor Proteins, Signal Transducing, 030304 developmental biology, Aged, MESH: Adolescent, MESH: Humans, business.industry, MESH: Transfection, MESH: Child, Preschool, Haplotype, Amyotrophic Lateral Sclerosis, MESH: Adult, MESH: Adaptor Proteins, Vesicular Transport, MESH: Open Reading Frames, medicine.disease, MESH: Male, MESH: Cell Line, C9orf72 Protein, Cross-Sectional Studies, MESH: Endosomes, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), MESH: Lipopolysaccharides, MESH: Chromosomes, Human, Pair 9, business, Trinucleotide repeat expansion, MESH: Female, Adolescent, Adult, Age of Onset, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, genetics, Child, Child, Preschool, Chromosomes, genetics, Cohort Studies, Cross-Sectional Studies, DNA Repeat Expansion, genetics, Female, Frontotemporal Dementia, genetics, Genetic Loci, Genotype, Humans, Male, Middle Aged, Open Reading Frames, genetics, Young Adult, 030217 neurology & neurosurgery
Abstract

International audience; BACKGROUND: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). METHODS: We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. FINDINGS: In patients with sporadic ALS, we identified the repeat expansion in 236 (7*0%) of 3377 white individuals from the USA, Europe, and Australia, two (4*1%) of 49 black individuals from the USA, and six (8*3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39*3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6*0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24*8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. INTERPRETATION: A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).

Published
2012
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25. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study

Author

Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S, Chiò A, Restagno G, Nicolaou N, Simon Sanchez J, van Swieten JC, Abramzon Y, Johnson JO, Sendtner M, Pamphlett R, Orrell RW, Mead S, Sidle KC, Houlden H, Rohrer JD, Morrison KE, Pall H, Talbot K, Ansorge O, Chromosome 9 ALS/FTD Consortium, French research network on FTLD/FTLD/ALS, ITALSGEN Consortium, Adamson G, Bayer AJ, Beck J, Callister JB, Blake DJ, Blumen SC, Collinge J, Dunckley T, Ealing J, East S, Elman L, Gerhard A, Guerreiro RJ, Gwinn K, Halliwell N, Hamdalla HH, Hewitt C, Ince P, Jablonka S, James C, Kent L, Knock JC, Lynch T, Mahoney C, Mann D, Neal J, Norris D, O'Dowd S, Richardson A, Rossor M, Rothstein J, Scholz SW, Snowden J, Stephan DA, Toulson G, Turner MR, Warren JD, Young K, Weng YH, Kuo HC, Lai SC, Huang CL, Camuzat A, Entraingues L, Guillot Noël, Verpillat P, Blanc F, Camu W, Clerget Darpoux F, Corcia P, Couratier P, Didic M, Dubois B, Duyckaerts C, Guedj E, Golfier V, Habert MO, Hannequin D, Lacomblez L, Meininger V, Salachas F, Levy R, Michel BF, Pasquier F, Puel M, Thomas Anterion C, Sellal F, Vercelletto M, Moglia C, Cammarosano S, Canosa A, Gallo S, Brunetti M, Ossola I, Marinou K, Papetti L, Pisano F, Pinter GL, Conte A, Luigetti M, Zollino M, Lattante S, Marangi G, la Bella V, Spataro R, Colletti T, Battistini S, Ricci C, Caponnetto C, Mancardi G, Mandich P, Salvi F, Bartolomei I, Mandrioli J, Sola P, Lunetta C, Penco S, Conforti FL, Gambardella A, Quattrone A, Volanti P, Floris G, Cannas A, Piras V, Marrosu F, Marrosu MG, Murru MR, Pugliatti M, Parish LD, Sotgiu A, Solinas G, Ulgheri L, Ticca A, Simone I, Logroscino G, Hernandez DG, Arepalli S, Sabatelli M, Mora G, Corbo M, Giannini F, Calvo A, Englund E, Borghero G, Floris GL, Remes AM, Laaksovirta H, McCluskey L, Trojanowski JQ, Van Deerlin VM, Schellenberg GD, Nalls MA, Drory VE, Lu CS, Yeh TH, Ishiura H, Takahashi Y, Tsuji S, Le Ber I, Brice A, Drepper C, Williams N, Kirby J, Shaw P, Hardy J, Tienari PJ, Heutink P, Morris HR, Pickering Brown S, Traynor BJ, MONSURRO', Maria Rosaria, TEDESCHI, Gioacchino, Majounie, E, Renton, Ae, Mok, K, Dopper, Eg, Waite, A, Rollinson, S, Chiò, A, Restagno, G, Nicolaou, N, Simon Sanchez, J, van Swieten, Jc, Abramzon, Y, Johnson, Jo, Sendtner, M, Pamphlett, R, Orrell, Rw, Mead, S, Sidle, Kc, Houlden, H, Rohrer, Jd, Morrison, Ke, Pall, H, Talbot, K, Ansorge, O, Chromosome, 9 ALS/FTD Consortium, French research network on, Ftld/ftld/al, Italsgen, Consortium, Adamson, G, Bayer, Aj, Beck, J, Callister, Jb, Blake, Dj, Blumen, Sc, Collinge, J, Dunckley, T, Ealing, J, East, S, Elman, L, Gerhard, A, Guerreiro, Rj, Gwinn, K, Halliwell, N, Hamdalla, Hh, Hewitt, C, Ince, P, Jablonka, S, James, C, Kent, L, Knock, Jc, Lynch, T, Mahoney, C, Mann, D, Neal, J, Norris, D, O'Dowd, S, Richardson, A, Rossor, M, Rothstein, J, Scholz, Sw, Snowden, J, Stephan, Da, Toulson, G, Turner, Mr, Warren, Jd, Young, K, Weng, Yh, Kuo, Hc, Lai, Sc, Huang, Cl, Camuzat, A, Entraingues, L, Guillot, Noël, Verpillat, P, Blanc, F, Camu, W, Clerget Darpoux, F, Corcia, P, Couratier, P, Didic, M, Dubois, B, Duyckaerts, C, Guedj, E, Golfier, V, Habert, Mo, Hannequin, D, Lacomblez, L, Meininger, V, Salachas, F, Levy, R, Michel, Bf, Pasquier, F, Puel, M, Thomas Anterion, C, Sellal, F, Vercelletto, M, Moglia, C, Cammarosano, S, Canosa, A, Gallo, S, Brunetti, M, Ossola, I, Marinou, K, Papetti, L, Pisano, F, Pinter, Gl, Conte, A, Luigetti, M, Zollino, M, Lattante, S, Marangi, G, la Bella, V, Spataro, R, Colletti, T, Battistini, S, Ricci, C, Caponnetto, C, Mancardi, G, Mandich, P, Salvi, F, Bartolomei, I, Mandrioli, J, Sola, P, Lunetta, C, Penco, S, Monsurro', Maria Rosaria, Tedeschi, Gioacchino, Conforti, Fl, Gambardella, A, Quattrone, A, Volanti, P, Floris, G, Cannas, A, Piras, V, Marrosu, F, Marrosu, Mg, Murru, Mr, Pugliatti, M, Parish, Ld, Sotgiu, A, Solinas, G, Ulgheri, L, Ticca, A, Simone, I, Logroscino, G, Hernandez, Dg, Arepalli, S, Sabatelli, M, Mora, G, Corbo, M, Giannini, F, Calvo, A, Englund, E, Borghero, G, Floris, Gl, Remes, Am, Laaksovirta, H, Mccluskey, L, Trojanowski, Jq, Van Deerlin, Vm, Schellenberg, Gd, Nalls, Ma, Drory, Ve, Lu, C, Yeh, Th, Ishiura, H, Takahashi, Y, Tsuji, S, Le Ber, I, Brice, A, Drepper, C, Williams, N, Kirby, J, Shaw, P, Hardy, J, Tienari, Pj, Heutink, P, Morris, Hr, Pickering Brown, S, and Traynor, Bj

Published
2012

26. Large proportion of amyotrophic lateral sclerosis cases in Sardinia due to a single founder mutation of the TARDBP gene

Author

Chiò A, Borghero G, Pugliatti M, Ticca A, Calvo A, Moglia C, Mutani R, Brunetti M, Ossola I, Marrosu MG, Murru MR, Floris G, Cannas A, Parish LD, Cossu P, Abramzon Y, Johnson JO, Nalls MA, Arepalli S, Chong S, Hernandez DG, Traynor BJ, Restagno G, Battistini S, Giannini F, Ricci C, Canosa A, Gallo S, Mandrioli J, Sola P, Salvi F, Bartolomei I, Mora G, Marinou K, Papetti L, Conte A, Sabatelli M, Luigetti M, Spataro R, La Bella V, Paladino P, Caponnetto C, Volanti P., MONSURRO', Maria Rosaria, TEDESCHI, Gioacchino, Chiò, A, Borghero, G, Pugliatti, M, Ticca, A, Calvo, A, Moglia, C, Mutani, R, Brunetti, M, Ossola, I, Marrosu, Mg, Murru, Mr, Floris, G, Cannas, A, Parish, Ld, Cossu, P, Abramzon, Y, Johnson, Jo, Nalls, Ma, Arepalli, S, Chong, S, Hernandez, Dg, Traynor, Bj, Restagno, G, Battistini, S, Giannini, F, Ricci, C, Canosa, A, Gallo, S, Monsurro', Maria Rosaria, Tedeschi, Gioacchino, Mandrioli, J, Sola, P, Salvi, F, Bartolomei, I, Mora, G, Marinou, K, Papetti, L, Conte, A, Sabatelli, M, Luigetti, M, Spataro, R, La Bella, V, Paladino, P, Caponnetto, C, and Volanti, P.

Subjects
Male, Threonine, Genotype, DNA Mutational Analysis, Mutation, Missense, Biology, medicine.disease_cause, Article, Degenerative disease, Superoxide Dismutase-1, Arts and Humanities (miscellaneous), medicine, Humans, Genetic Predisposition to Disease, Prospective Studies, Amyotrophic lateral sclerosis, Gene, Aged, Genetics, Mutation, Alanine, Superoxide Dismutase, Amyotrophic Lateral Sclerosis, Case-control study, Middle Aged, medicine.disease, Founder Effect, DNA-Binding Proteins, Phenotype, Amino Acid Substitution, Italy, Case-Control Studies, RNA-Binding Protein FUS, Female, Neurology (clinical), Genetic isolate, Founder effect
Abstract

To perform an extensive screening for mutations of amyotrophic lateral sclerosis (ALS)-related genes in a consecutive cohort of Sardinian patients, a genetic isolate phylogenically distinct from other European populations.Population-based, prospective cohort study.A total of 135 Sardinian patients with ALS and 156 healthy control subjects of Sardinian origin who were age- and sex-matched to patients.Patients underwent mutational analysis for SOD1, FUS, and TARDBP.Mutational screening of the entire cohort found that 39 patients (28.7%) carried the c.1144GA (p.A382T) missense mutation of the TARDBP gene. Of these, 15 had familial ALS (belonging to 10 distinct pedigrees) and 24 had apparently sporadic ALS. None of the 156 age-, sex-, and ethnicity-matched controls carried the pathogenic variant. Genotype data obtained for 5 ALS cases carrying the p.A382T mutation found that they shared a 94-single-nucleotide polymorphism risk haplotype that spanned 663 Kb across the TARDBP locus on chromosome 1p36.22. Three patients with ALS who carry the p.A382T mutation developed extrapyramidal symptoms several years after their initial presentation with motor weakness.The TARDBP p.A382T missense mutation accounts for approximately one-third of all ALS cases in this island population. These patients share a large risk haplotype across the TARDBP locus, indicating that they have a common ancestor.

Published
2011

27. A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD

Author

Renton, Ae, Majounie, E, Waite, A, Simón Sánchez, J, Rollinson, S, Gibbs, Jr, Schymick, Jc, Laaksovirta, H, van Swieten, Jc, Myllykangas, L, Kalimo, H, Paetau, A, Abramzon, Y, Remes, Am, Kaganovich, A, Scholz, Sw, Duckworth, J, Ding, J, Harmer, Dw, Hernandez, Dg, Johnson, Jo, Mok, K, Ryten, M, Trabzuni, D, Guerreiro, Rj, Orrell, Rw, Neal, J, Murray, A, Pearson, J, Jansen, Ie, Sondervan, D, Seelaar, H, Blake, D, Young, K, Halliwell, N, Callister, Jb, Toulson, G, Richardson, A, Gerhard, A, Snowden, J, Mann, D, Neary, D, Nalls, Ma, Peuralinna, T, Jansson, L, Isoviita, Vm, Kaivorinne, Al, Hölttä Vuori, M, Ikonen, E, Sulkava, R, Benatar, M, Wuu, J, Chiò, A, Restagno, G, Borghero, G, Sabatelli, M, Italsgen, Consortium, Heckerman, D, Rogaeva, E, Zinman, L, Rothstein, Jd, Sendtner, M, Drepper, C, Eichler, Ee, Alkan, C, Abdullaev, Z, Pack, Sd, Dutra, A, Pak, E, Hardy, J, Singleton, A, Williams, Nm, Heutink, P, Pickering Brown, S, Morris, Hr, Tienari, Pj, Traynor, Bj, Calvo, A, Cammarosano, S, Moglia, C, Canosa, A, Gallo, S, Brunetti, M, Ossola, I, Mora, G, Marinou, K, Papetti, L, Conte, A, Luigetti, M, La Bella, V, Spataro, R, Colletti, T, Battistini, S, Giannini, Fabio, Ricci, C, Caponnetto, C, Mancardi, G, Mandich, P, Salvi, F, Bartolomei, I, Mandrioli, J, Sola, P, Corbo, M, Lunetta, C, Penco, S, Monsurrò, Mr, Tedeschi, G, Conforti, Fl, Volanti, P, Floris, G, Cannas, A, Piras, V, Murru, Mr, Marrosu, Mg, Pugliatti, M, Ticca, A, Simone, I, Logroscino, G, Neuroscience Campus Amsterdam - Systems Biology of the Synapse, Neuroscience Campus Amsterdam - Neurodegeneration, Renton, Ae, Majounie, E, Waite, A, Simón Sánchez, J, Rollinson, S, Gibbs, Jr, Schymick, Jc, Laaksovirta, H, van Swieten, Jc, Myllykangas, L, Kalimo, H, Paetau, A, Abramzon, Y, Remes, Am, Kaganovich, A, Scholz, Sw, Duckworth, J, Ding, J, Harmer, Dw, Hernandez, Dg, Johnson, Jo, Mok, K, Ryten, M, Trabzuni, D, Guerreiro, Rj, Orrell, Rw, Neal, J, Murray, A, Pearson, J, Jansen, Ie, Sondervan, D, Seelaar, H, Blake, D, Young, K, Halliwell, N, Callister, Jb, Toulson, G, Richardson, A, Gerhard, A, Snowden, J, Mann, D, Neary, D, Nalls, Ma, Peuralinna, T, Jansson, L, Isoviita, Vm, Kaivorinne, Al, Hölttä Vuori, M, Ikonen, E, Sulkava, R, Benatar, M, Wuu, J, Chiò, A, Restagno, G, Borghero, G, Sabatelli, M, Italsgen, Consortium, Heckerman, D, Rogaeva, E, Zinman, L, Rothstein, Jd, Sendtner, M, Drepper, C, Eichler, Ee, Alkan, C, Abdullaev, Z, Pack, Sd, Dutra, A, Pak, E, Hardy, J, Singleton, A, Williams, Nm, Heutink, P, Pickering Brown, S, Morris, Hr, Tienari, Pj, COLLABORATORS: Calvo A, Traynor B. J., Cammarosano, S, Moglia, C, Canosa, A, Gallo, S, Brunetti, M, Ossola, I, Mora, G, Marinou, K, Papetti, L, Conte, A, Luigetti, M, La Bella, V, Spataro, R, Colletti, T, Battistini, S, Giannini, F, Ricci, C, Caponnetto, C, Mancardi, G, Mandich, P, Salvi, F, Bartolomei, I, Mandrioli, J, Sola, P, Corbo, M, Lunetta, C, Penco, S, Monsurro', Maria Rosaria, Tedeschi, Gioacchino, Conforti, Fl, Volanti, P, Floris, G, Cannas, A, Piras, V, Murru, Mr, Marrosu, Mg, Pugliatti, M, Ticca, A, Simone, I, Logroscino, G., Neurology, Human genetics, NCA - Systems Biology of the Synapse, and NCA - Neurodegeneration

Subjects
Male, Genotype, Neuroscience(all), Population, Biology, TARDBP, Chromosomes, 03 medical and health sciences, 0302 clinical medicine, Alleles, Amyotrophic Lateral Sclerosis, genetics, Chromosomes, Human, Pair 9, Female, Finland, Frontotemporal Dementia, genetics, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Male, Microsatellite Repeats, Pedigree, Polymorphism, Single Nucleotide, SDG 3 - Good Health and Well-being, C9orf72, Humans, genetics, Genetic Predisposition to Disease, Polymorphism, education, Alleles, Finland, 030304 developmental biology, Genetics, 0303 health sciences, education.field_of_study, General Neuroscience, Haplotype, Amyotrophic Lateral Sclerosis, Charged multivesicular body protein 2B, DNA Repeat Expansion, 3. Good health, Pedigree, C9orf72 Protein, Haplotypes, Frontotemporal Dementia, Female, Trinucleotide repeat expansion, 030217 neurology & neurosurgery, Pair 9, Microsatellite Repeats
Abstract

The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date. © 2011 Elsevier Inc.

Published
2011

28. Two Italian kindreds with familial amyotrophic lateral sclerosis due to FUS mutation

Author

Chio', Adriano, Restagno, G, Brunetti, Maura, Ossola, I, Calvo, Andrea, Mora, G, Sabatelli, M, Monsurrò, Mr, Battistini, S, Mandrioli, J, Salvi, F, Spataro, R, Schymick, J, Traynor, Bj, La Bella, V, Giannini, F, Ricci, C, Moglia, Cristina, Lombardo, F, Sbaiz, L, Cammarosano, Stefania, Tedeschi, G, Sola, P, Bartolomei, I, Marinou, K, Papetti, L, Conte, A, Luigetti, M, Paladino, P, Caponnetto, C, Siciliano, G., Chiò A, Restagno G, Brunetti M, Ossola I, Calvo, A, Mora, G, Sabatelli, M, Monsurrò, MR, Battistini, S, Mandrioli, J, Salvi, F, Spataro, R, Schymick, J, Traynor, BJ, La Bella, V, Chiò, A, Restagno, G, Brunetti, M, Ossola, I, Monsurro', Maria Rosaria, Traynor, Bj, LA BELLA, V, ITALSGEN CONSORTIUM: Giannini, F, Ricci, C, Moglia, C, Lombardo, F, Sbaiz, L, Cammarosano, S, Tedeschi, Gioacchino, Sola, P, Bartolomei, I, Marinou, K, Papetti, L, Conte, A, Luigetti, M, Paladino, P, Caponnetto, C, and Siciliano, G.

Subjects
Adult, Male, Aging, amyotrophic lateral sclerosis, Adolescent, DNA Mutational Analysis, Mutation, Missense, Biology, Article, Cohort Studies, Exon, Young Adult, Degenerative disease, medicine, Missense mutation, Humans, Family, genetics, Amyotrophic lateral sclerosis, Age of Onset, Gene, Aged, Genetics, General Neuroscience, Middle Aged, medicine.disease, Phenotype, Pedigree, SLA - FUS mutation - genetics, Italy, Mutation, Disease Progression, RNA-Binding Protein FUS, Female, Settore MED/26 - Neurologia, Neurology (clinical), Geriatrics and Gerontology, Age of onset, Missense, Family pedigrees, FUS gene, Developmental Biology
Abstract

Recently, fused in sarcoma/translated in liposarcoma (FUS/TLS) gene, located on chromosome 16p11.2, has been identified as a disease gene in familial amyotrophic lateral sclerosis (FALS). We have analyzed FUS/TLS in a cohort of 52 index cases from seven Italian regions with non-SOD1 and non-TARDBP FALS. We identified a heterozygous c.G1542C missense mutation in a family of northern Italian origin, and a heterozygous c.C1574T missense mutation in a family of Sicilian origin. Both variants are located in exon 15 encoding the RNA-recognition motif, and result in a substitution of an arginine with a serine in position 514 (p.R514S) and substitution of a proline with a leucine at position 525 (p.P525L), respectively. Overall, the two mutations accounted for 3.8% of 52 non-SOD1 and non-TDP43 index cases of FALS. The clinical phenotype was similar within each of the families, with a predominantly upper limb onset in the family carrying the p.R514S mutation and bulbar onset, with very young age and a rapid course in the family carrying the p.P525L mutation.

Published
2009

29. Long-term survival in amyotrophic lateral sclerosis: A population-based study

Author

Pupillo, E., Messina, P., Logroscino, G., Beghi, E., the SLALOM Group: Micheli, A., Rosettani, P., Baldini, D., Bianchi, G., Rigamonti, A., Bonito, V., Chiveri, L., Guidotti, M., Rezzonico, M., Vidale, S., Corbo, M., Lunetta, C., Maestri, E., Cotelli, M. S., Filosto, M., Filippini, G., Lauria, G., Mora, G., Papetti, L., Morelli, C., Perini, M., Tavernelli, F., Perrone, P., Guaita, M. C., Testa, D., Sasanelli, F., Galbussera, A., Tremolizzo, L., Ferrarese, C., Galli, A., Vitelli, E., Prelle, A., Riva, N., Ceroni, M., Delodovici, L., Clerici, M., Bono, GIORGIO GIOVANNI, Buzzi, P., Previdi, P., Guarneri, G., Abruzzi, L., Riccardi, T., Lorusso, L., Mazzini, L., Pupillo, E, Messina, P, Logroscino, G, Beghi, E, and Tremolizzo, L

Subjects
Adult, Male, Adolescent, Predictive Value of Test, Sex Factor, Community Health Planning, Cohort Studies, Young Adult, Sex Factors, Predictive Value of Tests, Humans, Age Factor, Survivors, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Age Factors, Middle Aged, Survival Analysis, Italy, Neurology, Female, Survival Analysi, Neurology (clinical), Cohort Studie, Survivor, Amyotrophic Lateral Sclerosi, Human
Abstract

Objective To determine the long-term survival in amyotrophic lateral sclerosis (ALS) and identify predictors of prolonged survival in a population-based cohort of newly diagnosed patients. Methods An incident cohort from a population-based registry during the years 1998 through 2002 in Lombardy, Italy was followed until death or to February 28, 2013. Age, sex, date of onset of symptoms, site of onset, date of diagnosis, and El Escorial diagnostic category were collected. Survival was assessed using Kaplan-Meier curves. Cox proportional hazards function was used to identify independent prognostic predictors. Standardized mortality ratios (SMRs) were used to assess the 5-year and 10-year excess mortality of ALS patients. Results Included were 280 men and 203 women aged 18 to 93 years. Spinal onset ALS was present in 312 cases (64.6%). Definite ALS was diagnosed in 213 cases (44.1%), probable ALS in 130 (26.9%), possible ALS in 93 (19.3%), and suspected ALS in 47 (9.7%). The cumulative time-dependent survival at 1, 5, and 10 years from diagnosis was 76.2%, 23.4%, and 11.8%, respectively. Independent predictors included younger age, the diagnosis of possible/suspected ALS, spinal onset, and symptoms having started >12 months previously at diagnosis. SMR was 9.4 at 5 years and 5.4 at 10 years. SMR at 10 years was higher until age 75 year, predominating in women, and became nonsignificant for males thereafter. Interpretation The outcome in ALS varies with phenotype. Longer survival is predicted by younger age, spinal onset, male gender, and suspected ALS. After age 75 years, 10-year survival in men with ALS is similar to the general population. © 2014 American Neurological Association.

Published
2014

30. Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis

Author

Johnson, J. O., Pioro, E. P., Boehringer, A., Chia, R., Feit, H., Renton, A. E., Pliner, H. A., Abramzon, Y., Marangi, G., Winborn, B. J., Gibbs, J. R., Nalls, M. A., Morgan, S., Shoai, M., Hardy, J., Pittman, A., Orrell, R. W., Malaspina, A., Sidle, K. C., Fratta, P., Harms, M. B., Baloh, R. H., Pestronk, A., Weihl, C. C., Rogaeva, E., Zinman, L., Drory, V. E., Borghero, G., Mora, G., Calvo, A., Rothstein, J. D., Drepper, C., Sendtner, M., Singleton, A. B., Taylor, J. P., Cookson, M. R., Restagno, G., Sabatelli, M., Bowser, R., Chio`, A., Traynor, B. J., Moglia, C., Cammarosano, S., Canosa, A., Gallo, S., Brunetti, M., Ossola, I., Marinou, K., Papetti, L., Pisano, F., Pinter, G. L., Conte, A., Luigetti, M., Zollino, M., Lattante, S., la Bella, V., Spataro, R., Colletti, T., Battistini, S., Ricci, C., Caponnetto, C., Mancardi, G., Mandich, P., Salvi, F., Bartolomei, I., Mandrioli, J., Sola, P., Lunetta, C., Penco, S., Monsurro, M. R., Conforti, F. L., Tedeschi, G., Gambardella, A., Quattrone, A., Volanti, P., Floris, G., Cannas, A., Piras, V., Marrosu, F., Marrosu, M. G., Murru, M. R., Pugliatti, M., Parish, L. D., Sotgiu, A., Solinas, G., Ulgheri, L., Ticca, A., Simone, I., Logroscino, G., Pirisi, A., Johnson, JO, Pioro, EP, Boehringer, A, Chia, R, Feit, H5, Renton, AE, Pliner, HA, Abramzon, Y6, Marangi, G, Winborn, BJ, Gibbs, JR, Nalls, MA, Morgan, S, Shoai, M, Hardy, J, Pittman, A, Orrell, RW, Malaspina, A, Sidle, KC, Fratta, P, Harms, MB, Baloh, RH, Pestronk, A, Weihl, CC, Rogaeva, E, Zinman, L, Drory, VE, Borghero, G, Mora, G, Calvo, A, Rothstein, JD, ITALSGEN Consortium (including Cammarosano,S, Canosa, A, Moglia, C), Drepper, C, Sendtner, M, Singleton, AB, Taylor, JP, Cookson, MR, Restagno, G, Sabatelli, M, Bowser, R, Chiò, A, Traynor, BJ., Moglia, C., Canosa, A., Johnson, Jo, Pioro, Ep, Feit, H, Renton, Ae, Pliner, Ha, Abramzon, Y, Winborn, Bj, Gibbs, Jr, Nalls, Ma, Orrell, Rw, Sidle, Kc, Harms, Mb, Baloh, Rh, Weihl, Cc, Drory, Ve, Rothstein, Jd, Italsgen, Consortium, Among the, Collaborator, Monsurro', Maria Rosaria, Tedeschi, Gioacchino, Singleton, Ab, Taylor, Jp, Cookson, Mr, and Traynor, B. J.

Subjects
Male, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, genetics/pathology, Computational Biology, DNA Mutational Analysis, DNA-Binding Proteins, metabolism, Family Health, Female, Genetic Predisposition to Disease, genetics, Genotype, Humans, Male, Middle Aged, Muscle, Skeletal, metabolism/pathology, Mutation, genetics, Neurologic Examination, Nuclear Matrix-Associated Proteins, genetics/metabolism, RNA-Binding Proteins, genetics/metabolism, Spinal Cord, metabolism/pathology, DNA Mutational Analysis, genetics/metabolism, RNA-binding protein, Settore MED/03 - GENETICA MEDICA, medicine.disease_cause, 0302 clinical medicine, Nuclear Matrix-Associated Proteins, Genotype, 80 and over, genetics, Amyotrophic lateral sclerosis, Exome sequencing, Genetics, Aged, 80 and over, Neurologic Examination, 0303 health sciences, Mutation, General Neuroscience, RNA-Binding Proteins, Middle Aged, DNA-Binding Proteins, MATR3, medicine.anatomical_structure, Spinal Cord, familial amyotrophic lateral sclerosis, Muscle, Settore MED/26 - Neurologia, Female, Frontotemporal dementia, Article, 03 medical and health sciences, mental disorders, medicine, Humans, Genetic Predisposition to Disease, Muscle, Skeletal, 030304 developmental biology, Aged, Family Health, business.industry, Amyotrophic Lateral Sclerosis, genetics/pathology, RNA, Computational Biology, Spinal cord, medicine.disease, genetic, business, Neuroscience, metabolism, 030217 neurology & neurosurgery
Abstract

MATR3 is an RNA- and DNA-binding protein that interacts with TDP-43, a disease protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Using exome sequencing, we identified mutations in MATR3 in ALS kindreds. We also observed MATR3 pathology in ALS-affected spinal cords with and without MATR3 mutations. Our data provide more evidence supporting the role of aberrant RNA processing in motor neuron degeneration. © 2014 Nature America, Inc. All rights reserved.

Published
2014

34. Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for ALS

Author

Beghi, E, Pupillo, E, Bonito, V, Buzzi, P, Caponnetto, C, Chiò, A, Corbo, M, Giannini, F, Inghilleri, M, Bella, Vl, Logroscino, G, Lorusso, L, Lunetta, C, Mazzini, L, Messina, P, Mora, G, Perini, M, Quadrelli, Ml, Silani, V, Simone, Il, Tremolizzo, L, Samarelli, V, Tortelli, R, D'Errico, E, Merello, M, Tavernelli, F, Mancardi, GIOVANNI LUIGI, Mascolo, M, Bendotti, C, Buratti, M, Floriani, I, Giordano, L, Giussani, G, Maderna, L, Maestri, E, Marinou, K, Mennini, T, Messina, S, Morelli, C, Papetti, L, Rizzo, A, Ticozzi, N, Verde, F, Ferrarese, C, Marzorati, L, Testa, L, Valentino, F, Frasca, V, Giacomelli, E, Casali, S, Malentacchi, M, Calvo, A, Cammarosano, S, Moglia, C, Cavallo, E, Fuda, G., Beghi,E, Pupillo, E, Bonito, V, Buzzi, P, Caponnetto, C, Chiò, A, Corbo, M, Giannini, F, Inghilleri, M, La Bella, V, Logroscino,G, Lorusso,L, Lunetta,C, Mazzini, L, Messina, P, Mora, G, Perini, M, Quadrelli, ML, Silani, V, Simone, IL, Tremolizzo, L, Valentino, F, The Italian ALS, Study Group, Beghi, E, Bella, V, Logroscino, G, Lorusso, L, Lunetta, C, Quadrelli, M, Simone, I, The Italian ALS Study Group, I, and Ferrarese, C

Subjects
Male, amyotrophic lateral sclerosis, Vital Capacity, Placebo-controlled study, Pilot Projects, Gastroenterology, law.invention, Randomized controlled trial, law, Acetyl-L-carnitine, motor neuron disease, randomized trial, acetyl-l-carnitine, Amyotrophic lateral sclerosis, Acetylcarnitine, ALS, acetyl-L-carnitine, Nootropic Agents, Riluzole, Middle Aged, Treatment Outcome, Neurology, Combination, Disease Progression, Drug Therapy, Combination, Settore MED/26 - Neurologia, Female, medicine.drug, Adult, medicine.medical_specialty, Acetyl-L-carnitine, amyotrophic lateral sclerosis, motor neuron disease, randomized trial, Double blind, Double-Blind Method, Drug Therapy, Internal medicine, medicine, Humans, Aged, MED/26 - NEUROLOGIA, business.industry, Disease progression, medicine.disease, Surgery, Quality of Life, Amyotrophic Lateral Sclerosis, Excitatory Amino Acid Antagonists, Neurology (clinical), business
Abstract

Our objective was to assess the effects of acetyl-L-carnitine (ALC) with riluzole on disability and mortality of amyotrophic lateral sclerosis (ALS). Definite/probable ALS patients, 40-70 years of age, duration 6-24 months, self-sufficient (i.e. able to swallow, cut food/handle utensils, and walk), and with forced vital capacity (FVC) > 80% entered a pilot double-blind, placebo-controlled, parallel group trial and were followed for 48 weeks. ALC or placebo 3 g/day was added to riluzole 100 mg/day. Primary endpoint: number of patients no longer self-sufficient. Secondary endpoints: changes in ALSFRS-R, MRC, FVC and McGill Quality of Life (QoL) scores. Analysis was made in the intention-to-treat (ITT) and per-protocol (PP) population, completers and completers/compliers (i.e. taking > 75% of study drug). Forty-two patients received ALC and 40 placebo. In the ITT population, 34 (80.9%) patients receiving ALC and 39 (97.5%) receiving placebo became non-self-sufficient (p = 0.0296). In the PP analysis, percentages were 84.4 and 100.0% (p = 0.0538), respectively. Mean ALSFRS-R scores at 48 weeks were 33.6 (SD 10.4) and 27.6 (9.9) (p = 0.0388), respectively, and mean FVC scores 90.3 (32.6) and 58.6 (31.2) (p = 0.0158), respectively. Median survival was 45 months (ALC) and 22 months (placebo) (p = 0.0176). MRC, QoL and adverse events were similar. In conclusion, ALC may be effective, well-tolerated and safe in ALS. A pivotal phase III trial is needed.

Published
2013

36. Seizures and epilepsy in Sotos syndrome: Analysis of 19 Caucasian patients with long-term follow-up

Author

Nicita, F, Ruggieri, M, Polizzi, A, Mauceri, L, Salpietro, V, Briuglia, S, Papetti, L, Ursiti, F, Grosso, S, Tarani, L, Segni, M, Savasta, S, Parisi, P, Verotti, A, and Spalice, A

Subjects
Male, Epilepsy, Adolescent, Sotos Syndrome, European Continental Ancestry Group, Cerebral gigantism, Overgrowth syndrome, White People, Seizures, Sotos syndrome, epilepsy, cerebral gigantism, seizures, sotos syndrome, overgrowth syndrome, Child, Female, Humans, Longitudinal Studies, Retrospective Studies, Young Adult, Neurology (clinical), Neurology
Abstract

Sotos syndrome (SS) is an overgrowth syndrome characterized by typical facial appearance, learning disability, and macrocephaly as cardinal diagnostic features. Febrile (FS) and afebrile seizures are reported in 9-50% of cases. There is no evidence that patients with SS and FS later develop epilepsy, and no studies have investigated the electroclinical features and the long-term outcome in epileptic SS patients. The authors report a series of 19 SS patients with FS and/or epilepsy during childhood and a long-term follow-up. More than half of FS evolved to epilepsy. Temporal lobe seizures were recorded in 40% of patients with SS. Seizures were easy to control with common antiepileptic drugs in almost all patients. A careful neurologic evaluation is useful for SS patients, since seizures are an important finding among people with this overgrowth syndrome.

Published
2012

37. Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72

Author

Chiò, A1, Borghero, G, Restagno, G, Mora, G, Drepper, C, Traynor, Bj, Sendtner, M, Brunetti, M, Ossola, I, Calvo, A, Pugliatti, M, Sotgiu, Ma, Murru, Mr, Marrosu, Mg, Marrosu, F, Marinou, K, Mandrioli, J, Sola, P, Caponnetto, C, Mancardi, G, Mandich, P, La Bella, V, Spataro, R, Conte, A, Monsurrò, Mr, Tedeschi, G, Pisano, F, Bartolomei, I, Salvi, F, Lauria Pinter, G, Simone, I, Logroscino, G, Gambardella, A, Quattrone, A, Lunetta, C, Volanti, P, Zollino, M, Penco, S, Battistini, S, Renton, Ae, Majounie, E, Abramzon, Y, Conforti, Fl, Giannini, F, Corbo, M, Sabatelli, M, Moglia, C, Cammarosano, S, Fuda, G, Canosa, A, Gallo, S, Papetti, L, Luigetti, M, Lattante, S, Marangi, G, Colletti, T, Ricci, C, Origone, P, Floris, G, Cannas, A, Piras, V, Parish, Ld, Solinas, G, Ulgheri, L, Ticca, A, Izzo, F, Laiola, A, Trojsi, F., Chiò, A, Borghero, G, Restagno, G, Mora, G, Drepper, C, Traynor, Bj, Sendtner, M, Brunetti, M, Ossola, I, Calvo, A, Pugliatti, M, Sotgiu, Ma, Murru, Mr, Marrosu, Mg, Marrosu, F, Marinou, K, Mandrioli, J, Sola, P, Caponnetto, C, Mancardi, G, Mandich, P, La Bella, V, Spataro, R, Conte, A, Monsurro', Maria Rosaria, Tedeschi, Gioacchino, Pisano, F, Bartolomei, I, Salvi, F, Lauria Pinter, G, Simone, I, Logroscino, G, Gambardella, A, Quattrone, A, Lunetta, C, Volanti, P, Zollino, M, Penco, S, Battistini, S, the ITALSGEN consortium: Moglia, Cristina, Cammarosano, Stefania, Fuda, Giuseppe, Canosa, Antonio, Gallo, Sara, Papetti, Laura, Luigetti, Marco, Lattante, Serena, Marangi, Giuseppe, Colletti, Tiziana, Ricci, Claudia, Origone, Paola, Floris, Gianluca, Cannas, Antonino, Piras, Valeria, Parish, Leslie D, Solinas, Giuliana, Ulgheri, Lucia, Ticca, Anna, Izzo, Francesco, Laiola, Anna, Trojsi, Francesca, Renton, Ae, Majounie, E, Abramzon, Y, Conforti, Fl, Giannini, F, Corbo, M, Sabatelli, M., Chiò, A., Borghero, G., Restagno, G., Mora, G., Drepper, C., Traynor, B., Sendtner, M., Brunetti, M., Ossola, I., Calvo, A., Pugliatti, M., Sotgiu, M., Murru, M., Marrosu, G., Marrosu, F., Marinou, K., Mandrioli, J., Sola, P., Caponnetto, C., Mancardi, G., Mandich, P., LA BELLA, V., Spataro, R., Conte, A., Monsurrò, M., Tedeschi, G., Pisano, F., Bartolomei, I., Salvi, F., Lauria, G., Simone, I., Logroscino, G., Gambardella, A., Quattrone, A., Lunetta, C., Volanti, P., Zollino, M., Penco, S., Battistini, S., the ITALSGEN, C., Renton, A., Majounie, E., Abramzon, Y., Conforti, F., Giannini, F., and Corbo, M.

Subjects
Male, Parents, Pathology, phenotype-genotype correlation, Cohort Studies, 0302 clinical medicine, C9orf72, amyotrophic lateral sclerosi, genetics, Amyotrophic lateral sclerosis, Age of Onset, amyotrophic lateral sclerosis, familial als, C9Orf72, 0303 health sciences, Sex Characteristics, DNA Repeat Expansion, Adult, Age of Onset, Aged, Amyotrophic Lateral Sclerosis, genetics/pathology, Cohort Studies, DNA Repeat Expansion, DNA, genetics, Female, Humans, Italy, Male, Middle Aged, Mutation, genetics, Parents, Pedigree, Phenotype, Proteins, genetics, Sex Characteristics, Survival Analysis, Middle Aged, 3. Good health, Pedigree, Settore MED/26 - NEUROLOGIA, Phenotype, Italy, Settore MED/26 - Neurologia, Female, Frontotemporal dementia, Adult, medicine.medical_specialty, SOD1, Biology, TARDBP, 03 medical and health sciences, Internal medicine, medicine, Humans, 030304 developmental biology, Aged, amyotrophic lateral sclerosis, familial ALS, C9ORF72 gene, phenotype–genotype correlation, C9orf72 Protein, Amyotrophic Lateral Sclerosis, genetics/pathology, Proteins, Original Articles, DNA, medicine.disease, Survival Analysis, Settore BIO/18 - Genetica, familial ALS, C9ORF72 gene, Mutation, Neurology (clinical), Age of onset, Trinucleotide repeat expansion, familial al, 030217 neurology & neurosurgery
Abstract

A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for 40% of familial amyotrophic lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic lateral sclerosis cases (21 of Sardinian ancestry) and 41 German index familial amyotrophic lateral sclerosis cases. Pathogenic repeat expansions were detected in 45 (37.5%) patients from mainland Italy, 12 (57.1%) patients of Sardinian ancestry and nine (22.0%) of the 41 German index familial amyotrophic lateral sclerosis cases. The disease was maternally transmitted in 27 (49.1%) pedigrees and paternally transmitted in 28 (50.9%) pedigrees (P = non-significant). On average, children developed disease 7.0 years earlier than their parents [children: 55.8 years (standard deviation 7.9), parents: 62.8 (standard deviation 10.9); P = 0.003]. Parental phenotype influenced the type of clinical symptoms manifested by the child: of the 13 cases where the affected parent had an amyotrophic lateral sclerosis–frontotemporal dementia or frontotemporal dementia, the affected child also developed amyotrophic lateral sclerosis–frontotemporal dementia in nine cases. When compared with patients carrying mutations of other amyotrophic lateral sclerosis-related genes, those with C9ORF72 expansion had commonly a bulbar onset (42.2% compared with 25.0% among non-C9ORF72 expansion cases, P = 0.03) and cognitive impairment (46.7% compared with 9.1% among non-C9ORF72 expansion cases, P = 0.0001). Median survival from symptom onset among cases carrying C9ORF72 repeat expansion was 3.2 years lower than that of patients carrying TARDBP mutations (5.0 years; 95% confidence interval: 3.6–7.2) and longer than those with FUS mutations (1.9 years; 95% confidence interval: 1.7–2.1). We conclude that C9ORF72 hexanucleotide repeat expansions were the most frequent mutation in our large cohort of patients with familial amyotrophic lateral sclerosis of Italian, Sardinian and German ancestry. Together with mutation of SOD1, TARDBP and FUS, mutations of C9ORF72 account for 60% of familial amyotrophic lateral sclerosis in Italy. Patients with C9ORF72 hexanucleotide repeat expansions present some phenotypic differences compared with patients with mutations of other genes or with unknown mutations, namely a high incidence of bulbar-onset disease and comorbidity with frontotemporal dementia. Their pedigrees typically display a high frequency of cases with pure frontotemporal dementia, widening the concept of familial amyotrophic lateral sclerosis. Keywords

Published
2012

38. Tension-type headache in paediatric age

Author

Parisi, P., Papetti, L, Spalice, A, Nicita, F, Ursitti, F, and Villa, Mp

Subjects
children, treatment, Adolescent, Tension-Type Headache, Humans, Biofeedback, Psychology, tension-type headache, Relaxation Therapy, Child
Abstract

The aim of this paper is to review the main topics about the management of paediatric tension-type headache. A Medline search was undertaken of all reports and reviews published between 1990 and 2010 using MeSH search terms 'tension-type headache (TTH), 'treatment' and 'children'. TTH is a very common disorder in childhood and adolescents. In many cases, the frequency and intensity of episodes may be likely to interfere with school and social activities. For this reason, a correct diagnosis and appropriate management of TTH are essential. A detailed history and proper examination, as well as a headache diary, are essential for this purpose and help to distinguish secondary causes of headache. Lacking are studies to test the efficacy and safety of pharmacological treatment in children, and a few well-tested drugs are available for this purpose. To date, relaxation techniques and biofeedback are therefore best placed as the first-line therapies.A thorough evaluation of headache in paediatric age is necessary to make a correct diagnosis and start the appropriate treatment. In particular, an appropriate management requires an individually tailored strategy which should include both pharmacological and nonpharmacological therapies. New treatment options for elderly patients with headache including acute, prophylactic and interventional techniques are needed.

Published
2010

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