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1. Nerve conduction velocity in CMT1A: what else can we tell?

Author

MANGANELLI, FIORE, PISCIOTTA, CHIARA, SANTORO, LUCIO, IODICE, ROSA, Reilly, Mm, Tozza, S, Schenone, A, Fabrizi, Gm, Cavallaro, T, Vita, G, Padua, L, Gemignani, F, Laurà, M, Hughes, Ra, Solari, A, Pareyson, D, Nolano, M, Grandis, M, Cabrini, I, Bertolasi, L, Mazzeo, A, Majorana, G, Vitetta, F, Scaioli, V, Ciano, C, Calabrese, D, Quattrone, A, Blake, J., Manganelli, Fiore, Pisciotta, Chiara, Reilly, Mm, Tozza, S, Schenone, A, Fabrizi, Gm, Cavallaro, T, Vita, G, Padua, L, Gemignani, F, Laurà, M, Hughes, Ra, Solari, A, Pareyson, D, Santoro, Lucio, Nolano, M, Iodice, Rosa, Grandis, M, Cabrini, I, Bertolasi, L, Mazzeo, A, Majorana, G, Vitetta, F, Scaioli, V, Ciano, C, Calabrese, D, Quattrone, A, and Blake, J.

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Charcot−Marie−Tooth disease, CMT-TRIAAL/CMT-TRAUK, CMT1A, hereditary neuropathies, nerve conduction velocity, Neurology, Neurology (clinical), Neural Conduction, Action Potentials, Sensory system, hereditary neuropathie, Nerve conduction velocity, Article, 03 medical and health sciences, Myelin, Young Adult, 0302 clinical medicine, Charcot-Marie-Tooth Disease, Internal medicine, medicine, Humans, Ulnar nerve, Aged, business.industry, Middle Aged, Ascorbic acid, Pathophysiology, Surgery, Electrophysiology, Settore MED/26 - NEUROLOGIA, 030104 developmental biology, medicine.anatomical_structure, Italy, Cardiology, Female, business, Axonal degeneration, 030217 neurology & neurosurgery, Settore MED/34 - MEDICINA FISICA E RIABILITATIVA
Abstract

Background and purpose Charcot-Marie-Tooth disease (CMT) type 1A is characterized by uniformly reduced nerve conduction velocity (NCV) that is fully penetrant since the first years of life, remains fairly stable through the life and does not correlate with disability whereas compound muscular action potential (CMAP) amplitude does. The aim of the present study was to analyze the large amount of electrophysiological data collected in the ascorbic acid trial in Italy and the UK (CMT-TRIAAL/CMT-TRAUK) and to use these data to gain insights into the pathophysiology of NCV in CMT1A. Methods Baseline electrophysiological data from 271 patients were analysed. Electrophysiological recordings were taken from the motor ulnar, median and peroneal nerves and the sensory ulnar nerve. Distal motor latency (DML), motor (MNCV) and sensory (SNCV) nerve conduction velocity, and amplitudes of CMAPs and sensory action potentials were assessed. Electrophysiological findings were correlated with age of patients at examination and the Charcot–Marie−Tooth Examination Score (CMTES). Results NCV was markedly and uniformly reduced. CMAP amplitudes were overall reduced but more severely in lower limbs. DML decreased and MNCV and SNCV increased with age of the patients, whereas CMAP amplitudes worsened with age and also correlated with CMTES. Conclusions This is the largest sample of electrophysiological data obtained so far from CMT1A patients. Axonal degeneration as assessed by means of CMAP amplitude reflected clinical impairment and was consistent with a slowly progressive length-dependent neuropathy. All patients typically had markedly slowed NCV that did, however, slightly increase with age of the patients. The improvement of NCV might depend on myelin thickness remodelling that occurs during the adult life of CMT1A patients.

Published
2016

3. Autonomic nervous system involvement in a new CMT2B family

Author

MANGANELLI, FIORE, PISCIOTTA, CHIARA, IODICE, ROSA, SANTORO, LUCIO, Provitera V, Taioli F, Topa A, Fabrizi GM, Nolano M, NOLANO, MARIA, Manganelli, Fiore, Pisciotta, Chiara, Provitera, V, Taioli, F, Iodice, Rosa, Topa, A, Fabrizi, Gm, Nolano, M, Santoro, Lucio, and Nolano, Maria

Subjects
Male, Charcot-Marie-Tooth type 2B, Pathology, medicine.medical_specialty, Disease, Biology, Charcot-Marie-Tooth Disease, RAB7, medicine, Humans, autonomic nervous system, skin biopsy, Pathological, Aged, 80 and over, medicine.diagnostic_test, General Neuroscience, Laminopathies, Middle Aged, Phenotype, Sudomotor, Autonomic nervous system, Autonomic Nervous System Diseases, Skin biopsy, Female, Neurology (clinical)
Abstract

We describe the first Italian family affected by CMT2B carrying a Val162Met substitution in the RAB7 gene. The clinical and electrophysiological features of our family are similar to those of previously reported families with RAB7 mutations, also for the higher occurrence of ulcers in males. However, in this family we evaluated the autonomic nervous system, never investigated in CMT2B, by means of skin biopsy and sudomotor and cardiovascular tests. Our findings provide both pathological and functional evidence of autonomic nervous system involvement in CMT2B and expand the phenotypic characterization of CMT2B disease.

Published
2012

4. Ascorbic acid in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial

Author

Pareyson, D, Reilly, Mm, Schenone, A, Fabrizi, Gm, Cavallaro, T, Vita, G, Quattrone, A, Padua, L, Gemignani, F, Visioli, F, Laurà, M, Radice, D, Calabrese, D, Hughes, Ra, Solari, A, Marchesi, C, Salsano, E, Nanetti, L, Marelli, C, Scaioli, V, Ciano, C, Rimoldi, M, Lauria, G, Rizzetto, E, Camozzi, F, Narciso, E, Grandis, M, Monti Bragadin, M, Nobbio, L, Casano, A, Bertolasi, L, Cabrini, I, Corrà, K, Rizzuto, N, Santoro, L, Nolano, M, Mazzeo, A, Aguennouz, M, Di Leo, R, Majorana, G, Lanzano, N, Valenti, F, Valentino, P, Nisticò, R, Pirritano, D, Lucisano, A, Canino, M, Pazzaglia, C, Granata, G, Foschini, M, Brindani, F, Vitetta, F, Allegri, I, Bogani, P, Blake, J, Koltzenburg, M, Hutton, E, Lunn, M, Mancardi, Gl, Cavaletti, G, Galimberti, S, Ferrari, G, Sereda, M., NOLANO, MARIA, SANTORO, LUCIO, MANGANELLI, FIORE, PISCIOTTA, CHIARA, Pareyson, D, Reilly, Mm, Schenone, A, Fabrizi, Gm, Cavallaro, T, Santoro, Lucio, Vita, G, Quattrone, A, Padua, L, Gemignani, F, Visioli, F, Laurà, M, Radice, D, Calabrese, D, Hughes, Ra, Solari, A, Marchesi, C, Salsano, E, Nanetti, L, Marelli, C, Scaioli, V, Ciano, C, Rimoldi, M, Lauria, G, Rizzetto, E, Camozzi, F, Narciso, E, Grandis, M, Monti Bragadin, M, Nobbio, L, Casano, A, Bertolasi, L, Cabrini, I, Corrà, K, Rizzuto, N, Santoro, L, Manganelli, Fiore, Pisciotta, Chiara, Nolano, M, Mazzeo, A, Aguennouz, M, Di Leo, R, Majorana, G, Lanzano, N, Valenti, F, Valentino, P, Nisticò, R, Pirritano, D, Lucisano, A, Canino, M, Pazzaglia, C, Granata, G, Foschini, M, Brindani, F, Vitetta, F, Allegri, I, Bogani, P, Blake, J, Koltzenburg, M, Hutton, E, Lunn, M, Mancardi, Gl, Cavaletti, G, Galimberti, S, Ferrari, G, Sereda, M., Nolano, Maria, Reilly, M, Fabrizi, G, Hughes, R, for the CMT, T, CMT TRAUK, G, and CMT TRAUK, g. r. o. u. p. s.

Subjects
Male, patients, Antioxidants, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Charcot-Marie-Tooth Disease, Charcot-Marie-Tooth disease type 1A, 0303 health sciences, CMT1A, ascorbic acid, neuropathy, trial, Middle Aged, Charcot-Marie-Tooth Disease Type 1A, drug therapy, 3. Good health, Settore MED/26 - NEUROLOGIA, Treatment Outcome, Tolerability, Female, Antioxidant, Human, Adult, medicine.medical_specialty, SF-36, Adolescent, Clinical Neurology, double-blind controlled trial, Placebo, Double blind, 03 medical and health sciences, Acido ascorbico, Double-Blind Method, Internal medicine, medicine, Fast track — Articles, Humans, Adverse effect, 030304 developmental biology, Aged, business.industry, Ascorbic acid, Adolescent, Adult, Aged, Antioxidants, therapeutic use, Ascorbic Acid, therapeutic use, Charcot-Marie-Tooth Disease, drug therapy, Double-Blind Method, Female, Humans, Male, Middle Aged, Treatment Outcome, Surgery, therapeutic use, Charcot Marie Tooth, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Summary Background Ascorbic acid reduced the severity of neuropathy in transgenic mice overexpressing peripheral myelin protein 22 ( PMP22 ), a model of Charcot–Marie–Tooth disease type 1A (CMT1A) associated with the PMP22 duplication. However, in three 1-year trials, ascorbic acid had no benefit in human beings. We did a multicentre 2-year trial to test the efficacy and tolerability of ascorbic acid in patients with CMT1A. Methods Adult patients (aged 18–70 years) with symptomatic CMT1A were enrolled from nine centres in Italy and the UK, and were randomly assigned (1:1 ratio) to receive 1·5 g/day oral ascorbic acid or matching placebo for 24 months. The randomisation sequence was computer generated by block randomisation, stratified by centre and disease severity, and patients were allocated to treatment by telephone. The primary outcome was change in the CMT neuropathy score (CMTNS) at 24 months. Secondary outcomes were timed 10 m walk test, nine-hole peg test, overall neuropathy limitations scale, distal maximal voluntary isometric contraction, visual analogue scales for pain and fatigue, 36-item short-form questionnaire, and electrophysiological measurements. Patients, treating physicians, and physicians assessing outcome measures were masked to treatment allocation. Analysis of the primary outcome was done on all randomised patients who received at least one dose of study drug. This study is registered, numbers ISRCTN61074476 (CMT-TRAUK) and EudraCT 2006-000032-27 (CMT-TRIAAL). Findings We enrolled and randomly assigned 277 patients, of whom six (four assigned to receive ascorbic acid) withdrew consent before receiving treatment; 138 receiving ascorbic acid and 133 receiving placebo were eligible for analysis. Treatment was well tolerated: 241 of 271 patients (89% in each group) completed the study; 20 patients (nine receiving ascorbic acid) dropped out because of adverse events. Mean CMTNS at baseline with missing data imputed was 14·7 (SD 4·8) in the ascorbic acid group and 13·9 (4·2) in the placebo group. Mean worsening of CMTNS was 0·2 (SD 2·8, 95% CI −0·3 to 0·7) in the ascorbic acid group and 0·2 (2·7, −0·2 to 0·7) in the placebo group (mean difference 0·0, 95% CI −0·6 to 0·7; p=0·93). We recorded no differences between the groups for the secondary outcomes at 24 months. 21 serious adverse events occurred in 20 patients, eight in the ascorbic acid group and 13 in the placebo group. Interpretation Ascorbic acid supplementation had no significant effect on neuropathy compared with placebo after 2 years, suggesting that no evidence is available to support treatment with ascorbic acid in adults with CMT1A. Funding Telethon-UILDM and AIFA (Italian Medicines Agency) for CMT-TRI AA L, and Muscular Dystrophy Campaign for CMT-TRAUK.

Published
2011

5. Is overwork weakness relevant in Charcot-Marie-Tooth disease?

Author

Piscosquito, G, Reilly, Mm, Schenone, A, Fabrizi, Gm, Cavallaro, T, Santoro, L, Vita, G, Quattrone, A, Padua, L, Gemignani, F, Visioli, F, Laurà, M, Calabrese, D, Hughes, Ra, Radice, D, Solari, A, Pareyson, D, Marchesi, C, Salsano, E, Nanetti, L, Marelli, C, Scaioli, V, Ciano, C, Rimoldi, M, Lauria, G, Ferrari, G, Rizzetto, E, Camozzi, F, CARLO STELLA, Narciso, Grandis, M, Monti-Bragadin, M, Nobbio, L, Casano, A, Bertolasi, L, Cabrini, I, Corrà, K, Rizzuto, N, Pisciotta, C, Nolano, M, Mazzeo, A, Di Leo, R, Majorana, G, Russo, M, Valentino, P, Nisticò, R, Pirritano, D, Lucisano, A, Canino, M, Pazzaglia, C, Granata, G, Foschini, M, Brindani, F, Vitetta, F, Allegri, I, Bogani, P, Blake, J, Koltzenburg, M, Hutton, E, and Lunn, M.

Subjects
HAND, STRENGTH, HYPOTHESIS, NEUROPATHY, DOMINANT, MUSCLES, TRIAL, GAIT, CMT1A
Published
2014

6. Reliability of clinical outcome measures in Charcot-Marie-Tooth disease

Author

Solari, A, Laurà, M, Salsano, E, Radice, D, Pareyson, D, Marelli, C, Scaioli, V, Ciano, C, Rimoldi, M, Lauria, G, Rizzetto, E, Camozzi, F, Schenone, A, Grandis, M, Narciso, E, Nobbio, L, Benedetti, L, Rizzuto, N, Fabrizi, Gm, Cavallaro, T, Bertolasi, L, Casano, A, Nolano, M, Vita, G, Mazzeo, A, Di Leo, R, Girlanda, P, Majorana, G, Aguennouz, M, Ciranni, A, Lanzano, N, Quattrone, A, Valentino, P, Nisticò, R, Pirritano, D, Clodomiro, A, Canino, M, Padua, L, Pazzaglia, C, Mignogna, T, Gemignani, F, Brindani, F, Vitetta, F, Visioli, F, Bogani, P, Hughes, Ra, Mancardi, Gl, Cavaletti, G, Galimberti, S, Calabrese, D, Ferrari, G, Santoro, L, Sereda, Mw, Lauria, G., SANTORO, LUCIO, MANGANELLI, FIORE, PISCIOTTA, CHIARA, Solari, A, Laurà, M, Salsano, E, Radice, D, Pareyson, D, Marelli, C, Scaioli, V, Ciano, C, Rimoldi, M, Lauria, G, Rizzetto, E, Camozzi, F, Schenone, A, Grandis, M, Narciso, E, Nobbio, L, Benedetti, L, Rizzuto, N, Fabrizi, Gm, Cavallaro, T, Bertolasi, L, Casano, A, Santoro, Lucio, Manganelli, Fiore, Pisciotta, Chiara, Nolano, M, Vita, G, Mazzeo, A, Di Leo, R, Girlanda, P, Majorana, G, Aguennouz, M, Ciranni, A, Lanzano, N, Quattrone, A, Valentino, P, Nisticò, R, Pirritano, D, Clodomiro, A, Canino, M, Padua, L, Pazzaglia, C, Mignogna, T, Gemignani, F, Brindani, F, Vitetta, F, Visioli, F, Bogani, P, Hughes, Ra, Mancardi, Gl, Cavaletti, G, Galimberti, S, Calabrese, D, Ferrari, G, Santoro, L, Sereda, Mw, and Lauria, G.

Published
2008

7. A multicenter, randomized, double-blind, placebo-controlled trial of long-term ascorbic acid treatment in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL): the study protocol [EudraCT no.: 2006-000032-27]

Author

Pareyson, D, Schenone, A, Fabrizi, Gm, Padua, L, Quattrone, A, Vita, G, Gemignani, F, Visioli, F, Solari, A, SANTORO, LUCIO, MANGANELLI, FIORE, Pareyson, D, Schenone, A, Fabrizi, Gm, Santoro, Lucio, Padua, L, Quattrone, A, Vita, G, Gemignani, F, Visioli, F, Solari, A, and Manganelli, Fiore

Published
2006

8. Vitamin C and Charcot-Marie-Tooth 1A: Pharmacokinetic considerations

Author

Visioli, F, Reilly, Mm, Rimoldi, M, Solari, A, Pareyson, D, Marchesi, C, Salsano, E, Nanetti, L, Marelli, C, Scaioli, V, Ciano, C, Lauria, G, Rizzetto, E, Camozzi, F, Schenone, Angelo, Narciso, E, Grandis, Marina, Monti Bragadin, M, Nobbio, Lucilla, Fabrizi, Gm, Cavallaro, T, Casano, A, Bertolasi, L, Cabrini, I, Corrà, K, Rizzuto, N, Santoro, L, Manganelli, F, Pisciotta, C, Nolano, M, Vita, G, Mazzeo A, ., Aguennouz, M, Di Leo, R, Majorana, G, Lanzano N, ., Valenti, F, Quattrone, A, Valentino, P, Nisticò, R, Pirritano, D, Lucisano, A, Canino, M, Padua, L, Pazzaglia, C, Granata, G, Foschini, M, Gemignani, F, Brindani, F, Vitetta, F, Allegri, I, Bogani, P. ., Visioli, F, Reilly, Mm, Rimoldi, M, Solari, A, Pareyson, D, Manganelli, Fiore, Cmt, Triaal2, CMT TRAUK, Group, Pisciotta, Chiara, Santoro, Lucio, and for the CMT, Triaal

Subjects
Drug, congenital, hereditary, and neonatal diseases and abnormalities, Ascorbic acid, Charcot-Marie-Tooth disease, Myelin, Neuromuscular disorders, Pharmacology, Pharmacology (medical), Food Science, media_common.quotation_subject, Disease, Charcot–Marie–Tooth disease, Article, law.invention, Randomized controlled trial, Pharmacokinetics, law, Medicine, media_common, Vitamin C, business.industry, Clinical trial, Tolerability, business
Abstract

Highlights ► Charcot-Marie-Tooth 1A cannot rely on effective pharmacological treatment. ► Several human trials failed to provide evidence of a therapeutic role of vitamin C. ► Human vitamin C's pharmacokinetics are tightly regulated. ► Ascorbic acid should not be given in excess of its transport system capacity., Charcot–Marie–Tooth 1A disease (CMT1A) is a disease for which no drug treatments are available. In 2004, it was reported that ascorbic acid reduced the severity of neuropathy in transgenic mice overexpressing PMP22, an animal model of human CMT1A, compared with untreated mice. Based on those results, clinical trials were undertaken at different centers worldwide and four of them have been completed, but none of them resulted in significant improvements. Based on the pharmacokinetics of ascorbic acid, we propose that the randomized clinical trial carried out thus far confirmed the tight control of ascorbic acid's absorption and proved its tolerability at one and two years. The pharmacokinetic considerations discussed in this article might largely explain the disappointing results of the recent CMT1A trials.

Published
2013

9. A pan-European study of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability, and intermediate repeats

Author

van der Zee, J, Gijselinck, I, Dillen, L, Van Langenhove, T, Theuns, J, Engelborghs, S, Philtjens, S, Vandenbulcke, M, Sleegers, K, Sieben, A, Bäumer, V, Maes, G, Corsmit, E, Borroni, Barbara, Padovani, Alessandro, Archetti, S, Perneczky, R, Diehl Schmid, J, de Mendonça, A, Miltenberger Miltenyi, G, Pereira, S, Pimentel, J, Nacmias, B, Bagnoli, S, Sorbi, S, Graff, C, Chiang, Hh, Westerlund, M, Sanchez Valle, R, Llado, A, Gelpi, E, Santana, I, Almeida, Mr, Santiago, B, Frisoni, G, Zanetti, O, Bonvicini, C, Synofzik, M, Maetzler, W, Vom Hagen JM, Schöls, L, Heneka, Mt, Jessen, F, Matej, R, Parobkova, E, Kovacs, Gg, Ströbel, T, Sarafov, S, Tournev, I, Jordanova, A, Danek, A, Arzberger, T, Fabrizi, Gm, Testi, S, Salmon, E, Santens, P, Martin, Jj, Cras, P, Vandenberghe, R, De Deyn PP, Cruts, M, Van Broeckhoven, C, and Van Broeckhoven, C.

Published
2013

10. A conserved sorting-associated protein is mutant in chorea-acanthocytosis RID C-2505-2009 RID A-4495-2010

Author

Rampoldi L, Dobson-Stone C, Rubio JP, Danek A, Chalmers RM, Wood NW, Verellen C, Ferrer X, Malandrini A, Fabrizi GM, Brown R, Vance J, Pericak-Vance M, Rudolf G, Carre S, Alonso E, Manfredi M, Nemeth AH, Monaco AP, Rampoldi, L, Dobson-Stone, C, Rubio, Jp, Danek, A, Chalmers, Rm, Wood, Nw, Verellen, C, Ferrer, X, Malandrini, A, Fabrizi, Gm, Brown, R, Vance, J, Pericak-Vance, M, Rudolf, G, Carre, S, Alonso, E, Manfredi, M, Nemeth, Ah, and Monaco, Ap

Published
2001

11. ERRATUM: Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria

Author

Spelbrink JN, Li FY, Tiranti V, Nikali K, Yuan QP, Tariq M, Wanrooij S, Garrido N, Comi G, Morandi L, Toscano A, Fabrizi GM, Somer H, Croxen R, Beeson D, Poulton J, Suomalainen A, Jacobs HT, Zeviani M, Larsson C., SANTORO, LUCIO, Spelbrink, Jn, Li, Fy, Tiranti, V, Nikali, K, Yuan, Qp, Tariq, M, Wanrooij, S, Garrido, N, Comi, G, Morandi, L, Santoro, Lucio, Toscano, A, Fabrizi, Gm, Somer, H, Croxen, R, Beeson, D, Poulton, J, Suomalainen, A, Jacobs, Ht, Zeviani, M, and Larsson, C.

Published
2001

14. Vascular endothelial growth factor helps differentiate neuropathies in rare plasma cell dyscrasias

Author

Briani, Chiara, Fabrizi, Gm, Ruggero, S, Torre, Cd, Ferrarini, M, Campagnolo, M, Cavallaro, T, Ferrari, S, Scarlato, M, Taioli, F, and Adami, Fausto

Subjects
Adult, Male, Vascular Endothelial Growth Factor A, POEMS Syndrome, Paraproteinemias, Humans, Female, Middle Aged, Statistics, Nonparametric, Aged
Abstract

POEMS syndrome and amyloidosis are rare plasma cell diseases that share common features, including polyneuropathy. The aim of this study was to investigate serum vascular endothelial growth factor (sVEGF) in patients with amyloidosis and to evaluate changes in response to treatment. Twenty-five patients [17 primary light-chain amyloidosis (AL-A), 7 transthyretin amyloidosis (TTR-A), 1 senile wild-type TTR-A] were studied. sVEGF was analyzed by ELISA. Sera from 8 myeloma and 7 POEMS patients were also evaluated. The median sVEGF level was 420 pg/ml in AL-A and 179 pg/ml in TTR-A patients; this was significantly lower than in POEMS syndrome (median 2580 pg/ml, P = 0.0002 and 0.001, respectively). sVEGF of AL-A patients showed no changes in response to treatment. sVEGF was not increased in amyloid patients regardless of neuropathy, and did not mirror the course of the disease. sVEGF should be tested in patients with overlapping and atypical clinical features.

Published
2010

19. Natural history of CMT1A including QoL: a 2 year prospective study

Author

Padua, L, Pareyson, D, Aprile, I, Cavallaro, T, Quattrone, A, Rizzuto, N, Vita, Giuseppe, Tonali, P, Schenone, A, Grandis, M, Benedetti, L, Caliandro, P, Pazzaglia, C, Mignogna, T, Mangiola, F, Fabrizi, Gm, Laura`, M, Di Monda, T, Mazzeo, Anna, Majorana, G, Valentino, P, and Nistico`, R.

Published
2008

23. A multicenter, randomized, double-blind, placebo-controlled trial of long-term ascorbic acid treatment in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL): the study protocol

Author

Pareyson, D, Schenone, A, Fabrizi, Gm, Santoro, L, Padua, L, Quattrone, A, Vita, Giuseppe, Gemignani, F, Visioli, F, Solari, A, Salsano, E., Scaioli, V., Ciano, C., Rimoldi, M., Lauria, G., Rizzetto, E., Camozzi, F., Grandis, M., Narciso, E., Nobbio, L., Benedetti, L., Rizzuto, N., Cavallaro, T., Bertolasi, L., Casano, A., Manganelli, F., Nolano, M., Pazzaglia, C., Valentino, P., Nistico’, R., Pirritano, D., Lucisano, A., Canino, M., Mazzeo, Anna, Aguennouz, M'Hammed, DI LEO, Rita, Girlanda, Paolo, Majorana, G., Ciranni, Annamaria, Lanzano, N., Brindani, F., Lettieri, C., and Bogani, P.

Published
2006

24. A multicenter, randomized, double-blind, placebo-controlled trial of long-term ascorbic acid treatment in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL): the study protocol [EudraCT no.: 2006-000032-27]

Author

Pareyson D, Schenone A, Fabrizi GM, Santoro L, Padua L, Quattrone A, Vita G, Gemignani F, Visioli F, Solari A and CMT-TRIAAL Group.

Subjects
congenital, hereditary, and neonatal diseases and abnormalities
Abstract

There is no treatment for Charcot-Marie-Tooth disease 1A (CMT1A), but ascorbic acid (AA) is efficacious in the transgenic mouse model. Thus, a clinical trial of AA in CMT1A is warranted. The CMT-TRIAAL is a phase III randomized, double-blind, placebo-controlled study involving 222 CMT1A adults from eight Italian centers. Eligible for the study are symptomatic adults with genetically confirmed CMT1A. Treatment consists of 2-year oral AA (1500mg/day) or placebo. The primary trial endpoint is an improvement in CMT Neuropathy Score. Secondary efficacy endpoints are changes in distal arm and leg maximum voluntary isometric contraction; 10m timed walking; 9-hole-peg test; overall neuropathy limitations scale; pain and fatigue visual analog scales; health-related quality of life (SF-36); and electrophysiology. Clinical-electrophysiological assessments are performed at baseline and every 6 months thereafter. In consenting patients from three centers, skin biopsy is performed to evaluate PMP22 expression. The study will last 34 months, starting from March 2006.

Published
2006

38. Genetic spectrum of hereditary neuropathies with onset in the first year of life.

Author

Baets J, Deconinck T, De Vriendt E, Zimon M, Yperzeele L, Van Hoorenbeeck K, Peeters K, Spiegel R, Parman Y, Ceulemans B, Van Bogaert P, Pou-Serradell A, Bernert G, Dinopoulos A, Auer-Grumbach M, Sallinen SL, Fabrizi GM, Pauly F, Van den Bergh P, and Bilir B

Abstract

Early onset hereditary motor and sensory neuropathies are rare disorders encompassing congenital hypomyelinating neuropathy with disease onset in the direct post-natal period and Dejerine-Sottas neuropathy starting in infancy. The clinical spectrum, however, reaches beyond the boundaries of these two historically defined disease entities. De novo dominant mutations in PMP22, MPZ and EGR2 are known to be a typical cause of very early onset hereditary neuropathies. In addition, mutations in several other dominant and recessive genes for Charcot-Marie-Tooth disease may lead to similar phenotypes. To estimate mutation frequencies and to gain detailed insights into the genetic and phenotypic heterogeneity of early onset hereditary neuropathies, we selected a heterogeneous cohort of 77 unrelated patients who presented with symptoms of peripheral neuropathy within the first year of life. The majority of these patients were isolated in their family. We performed systematic mutation screening by means of direct sequencing of the coding regions of 11 genes: MFN2, PMP22, MPZ, EGR2, GDAP1, NEFL, FGD4, MTMR2, PRX, SBF2 and SH3TC2. In addition, screening for the Charcot-Marie-Tooth type 1A duplication on chromosome 17p11.2-12 was performed. In 35 patients (45%), mutations were identified. Mutations in MPZ, PMP22 and EGR2 were found most frequently in patients presenting with early hypotonia and breathing difficulties. The recessive genes FGD4, PRX, MTMR2, SBF2, SH3TC2 and GDAP1 were mutated in patients presenting with early foot deformities and variable delay in motor milestones after an uneventful neonatal period. Several patients displaying congenital foot deformities but an otherwise normal early development carried the Charcot-Marie-Tooth type 1A duplication. This study clearly illustrates the genetic heterogeneity underlying hereditary neuropathies with infantile onset. [ABSTRACT FROM AUTHOR]

Published
2011
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42. Charcot-Marie-Tooth disease type 2E, a disorder of the cytoskeleton.

Author

Fabrizi GM, Cavallaro T, Angiari C, Cabrini I, Taioli F, Malerba G, Bertolasi L, Rizzuto N, Fabrizi, Gian Maria, Cavallaro, Tiziana, Angiari, Chiara, Cabrini, Ilaria, Taioli, Federica, Malerba, Giovanni, Bertolasi, Laura, and Rizzuto, Nicoló

Abstract

The neurofilament light chain (NF-L) is a major constituent of intermediate filaments and plays a pivotal function in the assembly and maintenance of axonal cytoskeleton. Mutations in the NF-L gene (NEFL) cause autosomal dominant neuropathies that are classified either as axonal Charcot-Marie-Tooth (CMT) type 2E (CMT2E) or demyelinating CMT type 1F (CMT1F). The pathophysiological bases of the disorder(s) are elusive. We performed a mutational analysis of NEFL in a series of 177 index cases with CMT and without mutations in the genes for peripheral myelin protein zero (MPZ), peripheral myelin protein 22 (PMP22) and connexin 32 (GJB1); the motor nerve conduction velocity (MNCV) at the median nerve was below 38 m/s in 76 cases and above 38 m/s in 101. We identified five new pedigrees with four mutations in the head and rod domains of NF-L, including a novel Leu268Pro substitution and a novel del322Cys_326Asn deletion. Several examined affected members exhibited marked variability in the severity of disease and age at onset. Nerve conduction alterations were consistent with an axonal neuropathy often associated with demyelinating features, such as prolonged distal latencies (DL). Pathological examination of sural nerve biopsies in the probands detected in four cases a chronic axonal neuropathy dominated by focal accumulations of NF with axonal swellings (giant axons) and significant secondary demyelination; in the fifth case no NFs accumulations were evident but many myelinated fibres consisted exclusively of microtubules with few or absent NF. The pathological phenotype correlated with the pattern of nerve conduction alterations and indicated that NEFL mutations cause a profound alteration of the cytoskeleton possibly related to defective targeting of NF. [ABSTRACT FROM AUTHOR]

Published
2007
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46. Clinical presentation of CADASIL in an Italian patient with a rare Gly528Cys exon 10 NOTCH3 gene mutation

Author

Federica Taioli, Flavia Silvaggio, Gabriella Cacchiò, Maria Scarcella, Tiziana Cavallaro, Luigi Trojano, M. Ragno, Gian Maria Fabrizi, Ragno, M, Cacchi, G, Fabrizi, Gm, Scarcella, M, Silvaggio, F, Cavallaro, T, Taioli, F, and Trojano, Luigi

Subjects
Male, Pathology, medicine.medical_specialty, Neurology, Glycine, CADASIL, Dermatology, Gene mutation, Biology, Exon, Neuroimaging, medicine, Humans, genetics, Receptor, Notch3, Neuroradiology, Aged, Family Health, Receptors, Notch, imaging, General Medicine, Exons, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Hyperintensity, Migraine with aura, Psychiatry and Mental health, Italy, Mutation, Cystine, Female, Neurology (clinical), medicine.symptom
Abstract

CADASIL is an autosomal dominant arteriopathy characterised by diffuse white matter lesions and small subcortical infarcts on neuroimaging and a variable combination of recurrent cerebral ischaemic episodes, cognitive deficits, migraine with aura and psychiatric symptoms. It is caused by mutations in the NOTCH3 gene encoding a NOTCH3 receptor protein. Here, we describe the genetical, clinical, neuropsychological and neuroimaging findings in an Italian CADASIL patient with a rare mutation in exon 10 leading to a Gly528Cys substitution.

Published
2007

47. Two novel Italian CADASIL families from Central Italy with mutation CGC-TGC at codon 1006 in the exon 19 Notch3 gene

Author

F Selvaggio, Gabriella Cacchiò, Michele Ragno, Luigi Trojano, Federica Taioli, Moreno Ferrarini, Maria Scarcella, Gian Maria Fabrizi, G Sirocchi, Ragno, M, Fabrizi, Gm, Cacchio, G, Scarcella, M, Sirocchi, G, Selvaggio, F, Taioli, F, Ferrarini, M, and Trojano, Luigi

Subjects
Male, Pediatrics, medicine.medical_specialty, Neurology, DNA Mutational Analysis, CADASIL, Dermatology, Neuropsychological Tests, Arginine, Asymptomatic, Vascular dementia, Leukoencephalopathy, Neuropsychology, medicine, Genetics, Humans, Cysteine, Cognitive impairment, Psychiatry, Pathological, Receptor, Notch3, Aged, Family Health, Receptors, Notch, business.industry, General Medicine, Exons, Middle Aged, medicine.disease, Psychiatry and Mental health, Migraine, Italy, Mutation, Female, Neurology (clinical), medicine.symptom, business
Abstract

Here we describe clinical, neuropsychological and neuroradiological findings in 6 subjects belonging to two unrelated Italian cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) kindreds from the same geographic area who shared a common Arg1006Cys mutation. Subjects from Family A were virtually asymptomatic, and yet showed MRI pathological findings and a cluster of sub-clinical neuropsychological defects mainly centred on the visuospatial domain; patients from Family B had presented several clinically relevant episodes and showed a general cognitive impairment compatible with the clinical picture of vascular dementia. The present clinical observations are consistent with the hypothesis of a geographical clustering for CADASIL, and highlight that sub-clinical cognitive impairment may help to identify this syndrome in families presenting with only migraine.

Published
2006

48. Human mitochondrail DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene4-like protein localized in mitochondria

Author

Catharina Larsson, David Beeson, Nuria Garrido, Giacomo P. Comi, Muhammed Tariq, Massimo Zeviani, Valeria Tiranti, Qiu Ping Yuan, Anu Suomalainen, Joanna Poulton, Fang Yuan Li, Johannes N. Spelbrink, Lucia Morandi, Kaisu Nikali, Howard T. Jacobs, Hannu Somer, Antonio Toscano, Gian Maria Fabrizi, Lucio Santoro, R Croxen, Sjoerd Wanrooij, Spelbrink, Jn, Li, Fy, Tiranti, V, Nikali, K, Yuan, Qp, Tariq, M, Wanrooij, S, Garrido, N, Comi, G, Morandi, L, Santoro, Lucio, Toscano, A, Fabrizi, Gm, Somer, H, Croxen, R, Beeson, D, Poulton, J, Suomalainen, A, Jacobs, Ht, Zeviani, M, and Larsson, C.

Subjects
Male, Ophthalmoplegia, Chronic Progressive External, Genetic Linkage, Protein Conformation, Sequence Homology, 0302 clinical medicine, Pakistan, Pair 10, MPV17, Finland, Mitochondrial nucleoid, Sequence Deletion, Genetics, 0303 health sciences, Ophthalmoplegia, Mitochondrial, Pedigree, DNA mitocondriale, PEO, delezioni, Amino Acid, Protein Transport, Amino Acid Sequence, Cell Compartmentation, Chromosomes, Human, Pair 10, DNA Helicases, DNA Primase, DNA, Mitochondrial, Female, Heterozygote, Humans, Italy, Mitochondrial Proteins, Molecular Sequence Data, Mutation, Sequence Homology, Amino Acid, Primase, Mitochondrial DNA replication, Human, Mitochondrial DNA, Biology, Human mitochondrial genetics, Chromosomes, 03 medical and health sciences, Gene, 030304 developmental biology, Multiple mitochondrial DNA deletions, DNA, Chronic Progressive External, 030217 neurology & neurosurgery
Abstract

The gene products involved in mammalian mitochondrial DNA (mtDNA) maintenance and organization remain largely unknown. We report here a novel mitochondrial protein, Twinkle, with structural similarity to phage T7 gene 4 primase/helicase and other hexameric ring helicases. Twinkle colocalizes with mtDNA in mitochondrial nucleoids. Screening of the gene encoding Twinkle in individuals with autosomal dominant progressive external ophthalmoplegia (adPEO), associated with multiple mtDNA deletions, identified 11 different coding-region mutations co-segregating with the disorder in 12 adPEO pedigrees of various ethnic origins. The mutations cluster in a region of the protein proposed to be involved in subunit interactions. The function of Twinkle is inferred to be critical for lifetime maintenance of human mtDNA integrity.

Published
2001

49. Congenital hypomyelination neuropathy with Ser72Leu substitution in PMP22

Author

Nicolo' Rizzuto, Federica Taioli, Michela Morbin, A. Pasquinelli, Alessandro Simonati, Tiziana Cavallaro, G. Marcon, Gian Maria Fabrizi, M. Papini, Simonati, A, Fabrizi, Gm, Pasquinelli, A, Taioli, F, Cavallaro, T, Morbin, M, Marcon, G, Papini, M, and Rizzuto, N

Subjects
Dejerine-Sottas disease, Male, Pathology, medicine.medical_specialty, hypomyelination, Sequence analysis, Mutation, Missense, medicine.disease_cause, Sural Nerve, Humans, Point Mutation, Medicine, Missense mutation, Pathological, Genetics (clinical), PMP22, Genetics, Congenital hypomyelination neuropathy, Mutation, Electromyography, business.industry, Point mutation, Infant, DNA, medicine.disease, congenital hypomyelination neuropathy, Phenotype, Transmembrane protein, Dejerine–Sottas disease, Electrophysiology, Hypomyelination, Amino Acid Substitution, Neurology, Pediatrics, Perinatology and Child Health, Neurology (clinical), business, Myelin Proteins, Demyelinating Diseases
Abstract

We describe a patient with congenital hypomyelination neuropathy. The pathological and morphometrical findings in the sural nerve biopsy were consistent with a defect of myelin formation and maintenance. Direct sequence analysis of the genomic regions coding the peripheral myelin proteins P0 and PMP22 disclosed a heterozygous missense point mutation that leads to a Ser72Leu substitution in the second transmembrane of PMP22. Codon 72 mutations of PMP22 are associated with different phenotypes encompassing the Dejerine-Sottas syndrome and including congenital hypomyelination neuropathy.

Published
1999

50. Clinical and pathological correlations in Charcot-Marie-Tooth neuropathy type 1A with the 17p11.2p12 duplication: a cross-sectional morphometric and immunohistochemical study in twenty cases

Author

Maria Donata Benedetti, Nicolo' Rizzuto, Gian Maria Fabrizi, Paolo Edomi, Michela Morbin, Alessandro Simonati, Tiziana Cavallaro, Federica Taioli, Fabrizi, Gm, Simonati, A, Morbin, M, Cavallaro, T, Taioli, F, Benedetti, Md, Edomi, Paolo, and Rizzuto, N.

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Adolescent, Physiology, Biopsy, peripheral myelin protein 22, Motor nerve, Fluorescent Antibody Technique, Charcot-Marie-Tooth type 1 neuropathy, Nerve conduction velocity, Central nervous system disease, Immunoenzyme Techniques, Cellular and Molecular Neuroscience, Myelin, Degenerative disease, Sural Nerve, Charcot-Marie-Tooth Disease, Physiology (medical), Peripheral myelin protein 22, medicine, Humans, Child, Pathological, 17p11.2p12 duplication, Aged, business.industry, Antibodies, Monoclonal, Anatomy, Middle Aged, medicine.disease, Pedigree, Blotting, Southern, Peripheral neuropathy, medicine.anatomical_structure, Cross-Sectional Studies, Multigene Family, immunohistochemistry, Regression Analysis, Female, Neurology (clinical), morphometry, business, Myelin P0 Protein, Myelin Proteins, Chromosomes, Human, Pair 17
Abstract

In a cross-sectional, clinical, and morphometric analysis we assessed the correlation between the clinical and pathological evolution of disease in 20 unrelated patients of various ages affected by Charcot-Marie-Tooth neuropathy type 1A (CMT1A) with the 17p11.2p12 (peripheral myelin protein 22, PMP22) duplication. The severity of neurologic deficits and slowing of motor conduction velocity at the median nerve did not vary significantly with the patients' age. The amount of demyelination was significantly higher below 15 years than in older age groups; in contrast, myelinated fiber and onion bulb densities were similar at all ages. The results indicate that in duplicated CMT1A, the pathological process develops early in life and progresses little during the course of the disease. Younger patients had lower g-ratio values, suggesting that the trigger of demyelination in early years could be a hypermyelination, resulting from PMP22 overexpression. Yet none of the 20 patients examined had immunohistochemical evidence of altered PMP22 expression. The early onset and development of the disorder make it difficult to detect PMP22 overdosage in nerve biopsies.

Published
1998

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