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ABSTRACT: Though clinical picture of ALS is a stereotypical one, resulting from combination of signs secondary to dysfunction of both upper and lower motor neurons, clinical heterogeneity is a consistent feature of the disease. Age of onset, relative mix of upper and lower motor neuron signs, duration of the disease and association with other conditions are major factors contributing to variable clinical phenotypes. Genetically, familial forms of ALS are associated with a large number of pleiotropic genes whose mutations impair different biochemical pathways, resulting in overlapping clinical and pathological phenotypes. Over the last few years contribution of large- and low-effect genes to sporadic ALS is increasingly recognized.
Clinical Genetics 02/2013; · 3.13 Impact Factor
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ABSTRACT: IgM-related neuropathy generally presents as a late-onset demyelinating polyneuropathy with predominant sensory loss and ataxia. Sporadic cases with atypical presentation have been described.
We report clinical and pathological findings from 31 patients with IgM-related neuropathy followed in our Institute of Neurology over a 20-year period.
Typical presentation with predominant sensory ataxic neuropathy was observed in 18/31 patients. In the remaining 13/31 (42%), we observed an atypical phenotype, characterized by multiple mononeuropathy or polyneuropathy with predominant motor impairment; one patient had polyneuropathy with predominant small-fibre involvement. Uncommon pathological findings consisting in inflammatory infiltrates, focal axonal loss or light chain deposition were observed in 8 patients, all with atypical clinical phenotype. Almost all patients with atypical phenotype improved with immunosuppressive therapy.
A significant proportion of patients with IgM-related neuropathy presents with atypical clinical features. In these patients, sural nerve biopsy helps clarify heterogeneous disease mechanisms and identify patients who might benefit from immunosuppressive therapy.
Journal of the neurological sciences 05/2012; 319(1-2):75-80. · 2.32 Impact Factor
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Neurology 02/2012; 78(7):e46-7. · 8.31 Impact Factor
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Clinical neurology and neurosurgery 12/2011; 114(6):748-50. · 1.30 Impact Factor
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Neurology 11/2011; 77(18):e109. · 8.31 Impact Factor
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Acta neurologica Belgica 09/2011; 111(3):257. · 0.54 Impact Factor
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ABSTRACT: We describe three sporadic ALS patients in which a D11Y SOD1 mutation was detected. All three patients disclosed a prolonged survival and a stereotypical distal limbs involvement in the initial stages of the disease. By this report we demonstrate that D11Y SOD1 mutation is associated with a peculiar phenotype and we confirm its probable pathogenetic role.
Journal of the neurological sciences 08/2011; 309(1-2):31-3. · 2.32 Impact Factor
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D Cocito,
S Grimaldi,
I Paolasso,
Y Falcone,
G Antonini,
L Benedetti,
C Briani,
R Fazio,
S Jann,
S Matà, M Sabatelli,
E Nobile-Orazio
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ABSTRACT: There are other options open to patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who are non-responders to conventional treatment, including immunosuppressive and immunomodulatory agents (IA). The aim of this study was to assess whether the use of IA is able to increase the number of responders.
Clinical and electrophysiological data of patients with refractory CIDP, followed at 10 Italian centres, were collected, and the clinical outcome (Rankin Scale) and drug side effects (SE) for the different therapies were analysed.
A total of 110 patients were included. These patients underwent 158 different therapeutic procedures with IA. Seventy-seven patients were treated with azathioprine, 18 rituximab, 13 cyclophosphamide, 12 mycophenolate mofetil, 12 cyclosporine, 12 methotrexate, 11 interferon-alpha and three interferon beta-1a. The percentage of patients who responded to azathioprine (27%) was comparable to the percentage of responders to other therapies, after the exclusion of interferon beta-1a that was not effective in any of the three patients treated. The percentage of SE ranges from 8% (methotrexate) to 50% (cyclosporine).
One-fourth of patients, refractory to conventional treatment, showed an improvement in their disability with IA. Methotrexate had the lowest SE; cyclosporine was associated with severe SE and often led to drug discontinuation.
European Journal of Neurology 08/2011; 18(12):1417-21. · 3.69 Impact Factor
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ABSTRACT: Mutations in the gene encoding mitofusin 2 (MFN2) are responsible of about 20% of Charcot-Marie-Tooth disease type 2 (CMT2) case. A great variability exists among CMT2A concerning severity and associated clinical features. Generally patients with an early onset CMT2A disclose a severe phenotype while the cases with a late onset present a more benign clinical course. We describe clinical, electrophysiological and pathological findings of a patient with a mild CMT2A due to the c.2213C>T, p.Ala738Val MFN2 mutation. This mutation has been already described to be only associated with an early onset and moderately severe CMT2A phenotype.
Journal of the neurological sciences 05/2011; 307(1-2):168-70. · 2.32 Impact Factor
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L Benedetti,
C Briani,
D Franciotta,
R Fazio,
I Paolasso,
C Comi,
M Luigetti, M Sabatelli,
F Giannini,
G L Mancardi,
A Schenone,
E Nobile-Orazio,
D Cocito
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ABSTRACT: A few case reports have shown controversial results of rituximab efficacy in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).
To analyse the efficacy of rituximab in a large CIDP cohort.
A retrospective, observational and multicentre study on the use of rituximab in CIDP. 13 Italian CIDP patients were treated with rituximab after the partial or complete lack of efficacy of conventional therapies. Eight patients had co-occurring haematological diseases. Patients who improved by at least two points in standard clinical scales, or who reduced or discontinued the pre-rituximab therapies, were considered as responders.
Nine patients (seven with haematological diseases) responded to rituximab: six of them, who were non-responders to conventional therapies, improved clinically, and the other three maintained the improvement that they usually achieved with intravenous immunoglobulin or plasma exchange. Significantly associated with shorter disease duration, rituximab responses started after a median period of 2.0 months (range, 1-6) and lasted for a median period of 1 year (range, 1-5).
Rituximab seems to be a promising therapeutic choice when it targets both CIDP and co-occurring haematological diseases. Timely post-onset administration of rituximab seems to be associated with better responses.
Journal of neurology, neurosurgery, and psychiatry 03/2011; 82(3):306-8. · 4.87 Impact Factor
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ABSTRACT: Mutations in the gene encoding 27-kDa small heat-shock protein B1 (HSPB1) have been reported in association with Charcot-Marie-Tooth disease type 2F or dHMN type II. We describe an Italian patient with wasting and weakness of distal muscles, involving primarily and mostly the lower limbs and later the upper limbs, in which a novel mutation of HSPB1, T180I, was detected. Electrophysiological evaluation disclosed a pure motor axonal neuropathy. Sural nerve biopsy showed a mild reduction of myelinated fibre density. All these findings suggested a CMT2/dHMN phenotype.
Journal of the neurological sciences 11/2010; 298(1-2):114-7. · 2.32 Impact Factor
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M Luigetti,
A Modoni,
R Renna,
G Silvestri,
E Ricci,
N Montano,
G Tasca,
M Papacci,
M Monforte,
A Conte,
M G Pomponi, M Sabatelli
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ABSTRACT: Charcot-Marie-Tooth disease (CMT) is a group of clinically and genetically heterogeneous neuropathies classically divided into demyelinating (CMT1) and axonal forms (CMT2). The most common demyelinating form is CMT1A, due to a duplication in the gene encoding the peripheral myelin protein 22 (PMP22). Less frequently, mutations in the myelin protein zero gene (MPZ/P0) account for demyelinating CMT1B. Herein, we report a patient presenting with an isolated hyperCKemia in whom electrophysiological and pathological findings revealed a demyelinating and axonal neuropathy. Sequencing of the MPZ gene revealed a 306delA at codon 102 in the proband and in two relatives. This mutation has been already described in association with paucisymptomatic CMT without hyperCKemia.
Clinical neurology and neurosurgery 11/2010; 112(9):794-7. · 1.30 Impact Factor
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Internal Medicine Journal 10/2010; 40(10):732-3. · 1.54 Impact Factor
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ABSTRACT: Heterozygous mutations in the Berardinelli-Seip congenital lipodystrophy (BSCL2) gene have been associated with different clinical phenotypes including Silver syndrome/spastic paraplegia 17, distal hereditary motor neuropathy type V, and Charcot-Marie-Tooth disease type 2 (CMT2) with predominant hand involvement. We studied an Italian family with a CMT2 phenotype with pyramidal signs that had subclinical sensory involvement on sural nerve biopsy. Direct sequencing analysis of the BSCL2 gene in the three affected siblings revealed an S90L mutation. This report confirms the variability of clinical phenotypes associated with a BSCL2 Ser90Leu mutation and describes the first Italian family with this mutation.
Muscle & Nerve 09/2010; 42(3):448-51. · 2.37 Impact Factor
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V Nociti,
G Frisullo,
A Marti,
M Luigetti,
R Iorio,
A K Patanella,
A Bianco,
P A Tonali,
R L Grillo, M Sabatelli,
A P Batocchi
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ABSTRACT: Elevated anti-Epstein-Barr virus (EBV) antibody levels are present in serum of Multiple sclerosis (MS) patients but literature lacks of studies comparing anti-EBV antibody levels between MS and other neurological diseases. We evaluate anti-VCA IgG and IgM, anti-EBNA1 IgG, anti-Cytomegalovirus IgG and IgM titres in serum and cerebrospinal fluid (CSF) of 267 MS, 50 Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) and 88 Amyotrophic Lateral Sclerosis (ALS) patients. We found increased titres of anti-EBV-IgG in serum and CSF of MS subjects as compared to CIDP and ALS patients thus providing additional evidence for a possible involvement of EBV in MS.
Journal of neuroimmunology 08/2010; 225(1-2):149-52. · 2.84 Impact Factor
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A Chiò,
G Borghero,
A Calvo,
M Capasso,
C Caponnetto,
M Corbo,
F Giannini,
G Logroscino,
J Mandrioli,
N Marcello, [......],
F Pisano,
E Pupillo, M Sabatelli,
F Salvi,
V Silani,
I L Simone,
G Sorarù,
M R Tola,
P Volanti,
E Beghi
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ABSTRACT: A neuroprotective effect of lithium in amyotrophic lateral sclerosis (ALS) has been recently reported. We performed a multicenter trial with lithium carbonate to assess its tolerability, safety, and efficacy in patients with ALS, comparing 2 different target blood levels (0.4-0.8 mEq/L, therapeutic group [TG], vs 0.2-0.4 mEq/L, subtherapeutic group [STG]).
The study was a multicenter, single-blind, randomized, dose-finding trial, conducted from May 2008 to November 2009 in 21 Italian ALS centers. The trial was registered with the public database of the Italian Agency for Drugs (http://oss-sper-clin.agenziafarmaco.it/) (EudraCT number 2008-001094-15).
As of October 2009, a total of 171 patients had been enrolled, 87 randomized to the TG and 84 to the STG. The interim data analysis, performed per protocol, showed that 117 patients (68.4%) discontinued the study because of death/tracheotomy/severe disability, adverse events (AEs)/serious AEs (SAEs), or lack of efficacy. The Data Monitoring Committee recommended stopping the trial on November 2, 2009.
Lithium was not well-tolerated in this cohort of patients with ALS, even at subtherapeutic doses. The 2 doses were equivalent in terms of survival/severe disability and functional data. The relatively high frequency of AEs/SAEs and the reduced tolerability of lithium raised serious doubts about its safety in ALS. Classification of evidence: The study provides Class II evidence that therapeutic (0.4-0.8 mEq/L) vs subtherapeutic (0.2-0.4 mEq/L) lithium carbonate did not differ in the primary outcome of efficacy (survival/loss of autonomy) in ALS. Both target levels led to dropouts in more than 30% of participants due to patient-perceived lack of efficacy and AEs.
Neurology 08/2010; 75(7):619-25. · 8.31 Impact Factor
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ABSTRACT: Allgrove syndrome (or triple A syndrome) is a rare autosomal recessive disorder characterized by alacrima, achalasia, ACTH-resistant adrenal insufficiency and autonomic/neurological abnormalities. It is caused by mutations in the AAAS gene, located on chromosome 12q13. We describe a 42-year-old patient who presented with neuropathy and was found to have alacrima, achalasia, mild autonomic dysfunction with significant central and peripheral nervous system involvement. She was later diagnosed with oligosymptomatic triple A syndrome. Sequencing of the AAAS gene identified two heterozygous mutations within exon 14 and its donor splice site (p.L430F-c.1288C>T and c.1331+1G>T), one of which is novel. Allgrove syndrome should be suspected in patients with neurological impairment associated with two or more of the main symptoms (alacrima, achalasia or adrenal insufficiency).
Journal of the neurological sciences 03/2010; 290(1-2):150-2. · 2.32 Impact Factor
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M Luigetti,
G Frisullo,
L Laurenti,
A Conte,
F Madia,
P Profice,
A P Batocchi,
N Montano,
M Tarnani,
P A Tonali, M Sabatelli
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ABSTRACT: Waldenström's macroglobulinaemia is a form of monoclonal IgM gammopathy associated with a rare B-cell lympho-plasmacytic lymphoma, characterized by the involvement of bone marrow, lymph nodes and spleen. Neurological complications involving peripheral nerves are common and different pathogenic mechanisms have been reported. We describe a patient with severe multineuropathy associated with Waldenström's macroglobulinaemia. Nerve biopsy revealed copious light chain deposition which subverted the normal architecture of the endoneurium and epineurium resulting in massive fascicular hyalinosis and epineural arteries disruption, respectively. This report confirms that massive immunoglobulin deposition is one of the several mechanisms of nerve damage in IgM-related neuropathy. Since their recognition has important therapeutical consequences, nerve biopsy is an essential diagnostic tool in patients with an unusual clinical presentation of IgM-related neuropathies.
Journal of the neurological sciences 02/2010; 291(1-2):89-91. · 2.32 Impact Factor
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D Cocito,
I Paolasso,
G Antonini,
L Benedetti,
C Briani,
C Comi,
R Fazio,
S Jann,
S Matà,
A Mazzeo, M Sabatelli,
E Nobile-Orazio
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ABSTRACT: The guidelines for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) therapy suggest to use immunoglobulins (IVIg) and steroid as first-line therapies. Patients who do not respond to one of the two drugs should be switched to the other drug. We collected therapeutic outcome data in patients followed at 11 centres in order to document the clinical practice in Italy.
Clinical and electrophysiological data of patients with CIDP were entered into a central database. The clinical outcome (Rankin Scale) and drug side effects (SE) for first- and second-line therapies were recorded.
A total of 267 patients were included. The percentage of responders (R) to first-line therapy [steroid or IVIg or plasma exchange (PE)] was 69%; this number increased to 81% when patients who switched to different therapies were included. Overall, the percentage of R to IVIg was similar to R to steroids (P = 0.07) and higher than R to PE (P < 0.001). Of the main therapies, PE frequently caused SE (19%), followed by steroids (12.5%) and IVIg (4%).
Switching between traditional therapies increases the number of responder patients. IVIg was confirmed to be a therapy with low SE.
European Journal of Neurology 10/2009; 17(2):289-94. · 3.69 Impact Factor
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Neurology 10/2009; 73(14):1165; author reply 1165-6. · 8.31 Impact Factor
