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2.
Genes (Basel) ; 12(10)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34680939

RESUMO

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disorder characterized by degeneration of motor neurons in the cerebral cortex, brain stem, and spinal cord. Most cases of ALS appear sporadically, but 5-10% of patients have a family history of disease. Mutations in the superoxide dismutase 1 gene (SOD1) have been found in 12-23% of familial cases and in 1-2% of sporadic cases. Currently, more than 180 different SOD1 gene variants have been identified in ALS patients. Here, we describe two apparently sporadic ALS patients carrying the same SOD1 c.355G>A variant, leading to the p.V119M substitution, not previously described. Both the patients showed pure lower motor neuron phenotype. The former presented with the flail leg syndrome, a rare ALS variant, characterized by progressive distal onset weakness and atrophy of lower limbs, slow progression and better survival than typical ALS. The latter exhibited rapidly progressive weakness of upper and lower limbs, neither upper motor neuron nor bulbar involvement, and shorter survival than typical ALS. We provide an accurate description of the phenotype, and a bioinformatics analysis of the p.V119M variant on protein structure. This study may increase the knowledge about genotype-phenotype correlations in ALS and improve the approach to ALS patients.

3.
Brain ; 144(9): 2635-2647, 2021 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-33905493

RESUMO

Strong evidence suggests that endoplasmic reticulum stress plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through altered regulation of proteostasis. Robust preclinical findings demonstrated that guanabenz selectively inhibits endoplasmic reticulum stress-induced eIF2α-phosphatase, allowing misfolded protein clearance, reduces neuronal death and prolongs survival in in vitro and in vivo models. However, its safety and efficacy in patients with ALS are unknown. To address these issues, we conducted a multicentre, randomized, double-blind trial with a futility design. Patients with ALS who had displayed an onset of symptoms within the previous 18 months were randomly assigned in a 1:1:1:1 ratio to receive 64 mg, 32 mg or 16 mg of guanabenz or placebo daily for 6 months as an add-on therapy to riluzole. The purpose of the placebo group blinding was to determine safety but not efficacy. The primary outcome was the proportion of patients progressing to higher stages of disease within 6 months as measured using the ALS Milano-Torino staging system, compared with a historical cohort of 200 patients with ALS. The secondary outcomes were the rate of decline in the total revised ALS functional rating scale score, slow vital capacity change, time to death, tracheotomy or permanent ventilation and serum light neurofilament level at 6 months. The primary assessment of efficacy was performed using intention-to-treat analysis. The treatment arms using 64 mg and 32 mg guanabenz, both alone and combined, reached the primary hypothesis of non-futility, with the proportions of patients who progressed to higher stages of disease at 6 months being significantly lower than that expected under the hypothesis of non-futility and a significantly lower difference in the median rate of change in the total revised ALS functional rating scale score. This effect was driven by patients with bulbar onset, none of whom (0/18) progressed to a higher stage of disease at 6 months compared with those on 16 mg guanabenz (4/8; 50%), the historical cohort alone (21/49; 43%; P = 0.001) or plus placebo (25/60; 42%; P = 0.001). The proportion of patients who experienced at least one adverse event was higher in any guanabenz arm than in the placebo arm, with higher dosing arms having a significantly higher proportion of drug-related side effects and the 64 mg arm a significantly higher drop-out rate. The number of serious adverse events did not significantly differ between the guanabenz arms and the placebo. Our findings indicate that a larger trial with a molecule targeting the unfolded protein response pathway without the alpha-2 adrenergic related side-effect profile of guanabenz is warranted.

4.
Neurol Sci ; 42(6): 2509-2513, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33459893

RESUMO

The Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy with great clinical and genetic heterogeneity. Mutations in DNM2 have been associated with CMT dominant intermediate B (CMTDIB). However, mutations in the same gene are known to induce also axonal CMT (CMT2M) or centronuclear myopathy. Moreover, the ability of effectively and simultaneously sequencing different CMT-related genes by next-generation sequencing approach makes it possible to detect even the presence of modifier genes that sometimes give reason of clinical variability in the context of complex phenotypes. Here, we describe an Italian family with very variable severity of phenotype among members harboring a novel DNM2 gene mutation which caused a prevalent CMT2M phenotype. The contemporary presence of a de novo variant in PRX gene in the most severely affected family member suggests a possible modulator effect of the PRX variant thus highlighting the possible impact of modifier genes in CMT.


Assuntos
Doença de Charcot-Marie-Tooth , Dinamina II , Miopatias Congênitas Estruturais , Doença de Charcot-Marie-Tooth/genética , Dinamina II/genética , Humanos , Itália , Mutação , Fenótipo
5.
Logoped Phoniatr Vocol ; 46(3): 118-125, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32498633

RESUMO

MATERIALS AND METHODS: Between March 2017 and February 2018, 27 newly diagnoses patients (about 2 months) were examined in the ENT Clinic of our University Hospital. The bulbar-onset of ALS was diagnosed by neurologists. RESULTS: According to the endoscopic and clinical results, patients were classified in 4 classes of dysphagia. Laryngology and speech pathology assessment with spectroacuostic analysis of speech using Praat software are fundamental for the proper evaluation of dysphonia of these patients. This study was the first attempt to find a vocal indicator of advancement in swallowing dysfunction in the patient population of ALS. Preliminary findings indicate that the reduction in the maximum fundamental frequency is associated with advancement of dysphagia. CONCLUSIONS: Monitoring the vocal parameters could be useful in order to give an early rehabilitation aid to these patients improving their quality of life and reducing aspiration risks.


Assuntos
Esclerose Amiotrófica Lateral , Transtornos de Deglutição , Disfonia , Esclerose Amiotrófica Lateral/complicações , Esclerose Amiotrófica Lateral/diagnóstico , Transtornos de Deglutição/diagnóstico , Transtornos de Deglutição/etiologia , Disfonia/diagnóstico , Disfonia/etiologia , Humanos , Qualidade de Vida , Índice de Gravidade de Doença , Qualidade da Voz
6.
J Neurol ; 267(11): 3258-3267, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32556567

RESUMO

OBJECTIVES: The aim of the study is to analyze the ALS disease progression and respiratory function of Italian patients treated with edaravone (EVN), as well as the adherence to, and the effects of, the therapy. METHODS: We performed an observational study of patients treated with EVN from May 2017 to May 2019, in 39 Italian ALS Centers. Taking into account ALS patients with at least 12 months of EVN treatment, we compared the decline of ALSFRS-R and FVC with a group of matched historical controls from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, using both descriptive and survival analysis approaches. RESULTS: A total of 331 ALS Italian patients treated with EVN and 290 matched historical controls were recruited in this study. No significant differences on disease progression or respiratory function were found comparing the two cohorts in both descriptive and survival analyses. The EVN treatment was overall well tolerated. CONCLUSIONS: The study showed that EVN treatment was well tolerated. No significant differences were reported in ALS patients treated and not treated with EVN, in terms of both disease progression and respiratory function. These findings prove that further studies are required to better clarify whether EVN could be considered an effective treatment for ALS disease.


Assuntos
Esclerose Amiotrófica Lateral , Esclerose Amiotrófica Lateral/tratamento farmacológico , Progressão da Doença , Edaravone , Humanos , Itália , Resultado do Tratamento
7.
iScience ; 23(5): 101087, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32371370

RESUMO

Patients with ALS show, in addition to the loss of motor neurons in the spinal cord, brainstem, and cerebral cortex, an abnormal depletion of energy stores alongside hypermetabolism. In this study, we show that bioenergetic defects and muscle remodeling occur in skeletal muscle of the SOD1G93A mouse model of ALS mice prior to disease onset and before the activation of muscle denervation markers, respectively. These changes in muscle physiology were followed by an increase in energy expenditure unrelated to physical activity. Finally, chronic treatment of SOD1G93A mice with Ranolazine, an FDA-approved inhibitor of fatty acid ß-oxidation, led to a decrease in energy expenditure in symptomatic SOD1G93A mice, and this occurred in parallel with a robust, albeit temporary, recovery of the pathological phenotype.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31753915

RESUMO

OBJECTIVE: To assess the prevalence and isotypes of anti-nodal/paranodal antibodies to nodal/paranodal proteins in a large chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) cohort, compare clinical features in seronegative vs seropositive patients, and gather evidence of their isotype-specific pathogenic role. METHODS: Antibodies to neurofascin-155 (Nfasc155), neurofascin-140/186 (Nfasc140/186), contactin-1 (CNTN1), and contactin-associated protein 1 (Caspr1) were detected with ELISA and/or cell-based assay. Antibody pathogenicity was tested by immunohistochemistry on skin biopsy, intraneural injection, and cell aggregation assay. RESULTS: Of 342 patients with CIDP, 19 (5.5%) had antibodies against Nfasc155 (n = 9), Nfasc140/186 and Nfasc155 (n = 1), CNTN1 (n = 3), and Caspr1 (n = 6). Antibodies were absent from healthy and disease controls, including neuropathies of different causes, and were mostly detected in patients with European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite CIDP (n = 18). Predominant antibody isotypes were immunoglobulin G (IgG)4 (n = 13), IgG3 (n = 2), IgG1 (n = 2), or undetectable (n = 2). IgG4 antibody-associated phenotypes included onset before 30 years, severe neuropathy, subacute onset, tremor, sensory ataxia, and poor response to intravenous immunoglobulin (IVIG). Immunosuppressive treatments, including rituximab, cyclophosphamide, and methotrexate, proved effective if started early in IVIG-resistant IgG4-seropositive cases. Five patients with an IgG1, IgG3, or undetectable isotype showed clinical features indistinguishable from seronegative patients, including good response to IVIG. IgG4 autoantibodies were associated with morphological changes at paranodes in patients' skin biopsies. We also provided preliminary evidence from a single patient about the pathogenicity of anti-Caspr1 IgG4, showing their ability to penetrate paranodal regions and disrupt the integrity of the Nfasc155/CNTN1/Caspr1 complex. CONCLUSIONS: Our findings confirm previous data on the tight clinico-serological correlation between antibodies to nodal/paranodal proteins and CIDP. Despite the low prevalence, testing for their presence and isotype could ultimately be part of the diagnostic workup in suspected inflammatory demyelinating neuropathy to improve diagnostic accuracy and guide treatment. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that antibodies to nodal/paranodal proteins identify patients with CIDP (sensitivity 6%, specificity 100%).


Assuntos
Autoanticorpos/sangue , Moléculas de Adesão Celular Neuronais/imunologia , Moléculas de Adesão Celular/imunologia , Contactina 1/imunologia , Imunoglobulina G/classificação , Fatores de Crescimento Neural/imunologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/sangue , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/imunologia , Adulto , Feminino , Humanos , Masculino
10.
Neurol Sci ; 41(2): 365-372, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31654362

RESUMO

OBJECTIVES: Anti-myelin-associated glycoprotein (MAG) antibody is associated with clinically heterogeneous polyneuropathies. Our purpose was to compare neuropathy phenotypes identified by different anti-MAG tests' results. METHODS: Cohort study: Sera from 40 neuropathy anti-MAG EIA positive patients were tested for anti-MAG by Western blot (WB), for anti-peripheral nerve myelin (PNM) on monkey nerve by immunofluorescence assay (IFA), and for anti-HNK1 on rat CNS slices by IFA. Anti-sulfatide antibodies, for comparison, were also tested by EIA. RESULTS: Among 40 anti-MAG EIA positive sera, 85% also had anti-PNM IFA reactivity and 67.5% bind HNK1 on rat CNS. Anti-HNK1 positive patients had the classical predominantly distal acquired demyelinating symmetric (DADS) neuropathy with a benign course, while anti-PNM positive but anti-HNK1 negative patients had predominantly axonal neuropathy with a high frequency of anti-sulfatide reactivity and the worst long-term prognosis. Anti-MAG EIA positive patients without anti-PNM or anti-HNK1 IFA reactivity had a CIDP-like polyneuropathy. CONCLUSION: Different methods to test for anti-MAG antibodies identify different clinical and electrophysiological findings, as well as long-term outcome. HNK1 reactivity is the strongest marker of DADS.


Assuntos
Autoanticorpos/sangue , Imunoglobulina M/imunologia , Glicoproteína Associada a Mielina/metabolismo , Doenças do Sistema Nervoso Periférico/imunologia , Adolescente , Animais , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Bainha de Mielina/imunologia , Glicoproteína Associada a Mielina/imunologia , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Polineuropatias/imunologia , Ratos , Adulto Jovem
11.
Neurol Genet ; 5(5): e352, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31517061

RESUMO

Objective: Next-generation sequencing (NGS) was applied in molecularly undiagnosed asymptomatic or paucisymptomatic hyperCKemia to investigate whether this technique might allow detection of the genetic basis of the condition. Methods: Sixty-six patients with undiagnosed asymptomatic or paucisymptomatic hyperCKemia, referred to tertiary neuromuscular centers over an approximately 2-year period, were analyzed using a customized, targeted sequencing panel able to investigate the coding exons and flanking intronic regions of 78 genes associated with limb-girdle muscular dystrophies, rhabdomyolysis, and metabolic and distal myopathies. Results: A molecular diagnosis was reached in 33 cases, corresponding to a positive diagnostic yield of 50%. Variants of unknown significance were found in 17 patients (26%), whereas 16 cases (24%) remained molecularly undefined. The major features of the diagnosed cases were mild proximal muscle weakness (found in 27%) and myalgia (in 24%). Fourteen patients with a molecular diagnosis and mild myopathic features on muscle biopsy remained asymptomatic at a 24-month follow-up. Conclusions: This study of patients with undiagnosed hyperCKemia, highlighting the advantages of NGS used as a first-tier diagnostic approach in genetically heterogeneous conditions, illustrates the ongoing evolution of molecular diagnosis in the field of clinical neurology. Isolated hyperCKemia can be the sole feature alerting to a progressive muscular disorder requiring careful surveillance.

12.
J Peripher Nerv Syst ; 24(3): 276-282, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31397934

RESUMO

In this study, we assessed the modifications over time of daily activities and quality of life (QoL) in 32 subjects with anti-myelin-glycoprotein (MAG) antibody neuropathy. A widespread panel including clinical scores and patient-reported questionnaires, in compliance of the terms by the International Classification of Functioning, Disability, and Health (ICF) of the World Health Organization (WHO), was employed at enrollment (T0) and at follow-up evaluation (T1) after a mean interval of 15.4 ± 5.7 months. The Sensory Modality Sum score (SMS) at four limbs showed a significant worsening over time (mean score 27.2 ± 3.9 at T0 vs 25.7 ± 3 at T1 at upper limbs, P = .03; 20.5 ± 4.8 at T0 vs 18.6 ± 5.9 at T1 at lower limbs, P = .04). The Visual Analogue Scale (VAS) for pain significantly worsened at upper limbs at T1 (mean values 0.84 ± 1.95 at T0 vs 1.78 ± 2.6 at T1, P = .03). All the other tests did not show significant differences between T0 and T1. In the subgroup who underwent rituximab (15/32 treated before T0, 3/32 patients treated between T0 and T1 with median interval of 1 year), no significant differences were observed between T0 and T1. Despite the quite long follow-up, statistical significance was not achieved either for the limited number of patients or for the lack of sensitive outcome measures. In our cohort, the significant worsening of the SMS and VAS after a median of 14 months can be considered as a reliable expression of the natural history of the disease, and suggest that these scales might represent possible outcome measures in anti-MAG antibody neuropathy.


Assuntos
Atividades Cotidianas/psicologia , Glicoproteína Associada a Mielina/imunologia , Polineuropatias/psicologia , Qualidade de Vida/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Avaliação da Deficiência , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polineuropatias/tratamento farmacológico , Polineuropatias/imunologia , Rituximab/uso terapêutico , Resultado do Tratamento
13.
Artigo em Inglês | MEDLINE | ID: mdl-31170830

RESUMO

Objective: To describe the phenotypic and genotypic features of two unrelated Italian amyotrophic lateral sclerosis (ALS) patients, a FALS case and an apparently sporadic case, carrying the same D124G SOD1 mutation. Since this mutation is very rare, previously reported in only one patient of unknown geographical origin, to look for a founder effect. Methods: Cases were classified based on the El Escorial revised criteria. Genomic DNA was isolated from whole blood samples and the coding region of the SOD1 gene was analyzed by polymerase chain reaction (PCR) and sequencing. For the haplotype analysis, genotyping was carried out using eight polymorphic markers flanking the SOD1 gene. Results: Both patients had a spinal onset in the lower limbs and progressive muscular atrophy (PMA) phenotype. The progression of the disease in our cases differed from that reported for PMA patients, characterized by a longer survival than the majority of ALS phenotypes, being more aggressive, in particular in the sporadic case (survival less than 1 year). Genotyping showed a shared haplotype for the D124G allele and the estimate of the mutation dating revealed that the mutation originated approximately 400 years ago. Conclusions: We have defined for the first time the clinical profile associated with the D124G mutation in SOD1 gene and provided evidence that this mutation in Italy originates from a common founder.


Assuntos
Esclerose Amiotrófica Lateral/genética , Estudos de Associação Genética , Mutação/genética , Superóxido Dismutase-1/genética , Superóxido Dismutase/genética , Genótipo , Haplótipos/genética , Humanos , Itália , Linhagem , Fenótipo
14.
Medicine (Baltimore) ; 98(13): e15052, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30921233

RESUMO

RATIONALE: Aromatase inhibitors (AIs) are a class of drugs widely used in the treatment of estrogen sensitive breast and ovarian cancer which convert testosterone to estradiol and androstenedione to estrogen. The AIs of third generation, including anastrazole, letrozole and exemestane, have actually become the standard of care of estrogen-receptor-positive breast cancer in menopausal women and are recommended as adjuvant treatment after surgery in place of/or following tamoxifen. Their main side-effects include reduction in bone mineral density, occurrence of menopausal manifestations and development of musculoskeletal symptoms which are, usually, transient, but sometimes evolve into a typical form of arthritis, such as rheumatoid arthritis (RA). Recently, a pathogenic linkage with other autoimmunity diseases, such as Sjogren syndrome (SjS), anti-synthetase antibody syndrome (ASAS), systemic sclerosis (SS) and subacute cutaneous lupus erythematosus (SCLE), was also described. PATIENT CONCERNS: Here, we report the first case of a patient with primary antiphospholipid syndrome (APS) developed during treatment with anastrazole. DIAGNOSIS: The patient developed a sudden onset of speech disturbance and disorientation, due to ischemic lesions, after 6 months of AIs therapy and the laboratory examination showed the positivity of anti-Cardiolipin antibodies, anti-ß2 Glycoprotein 1 antibodies and Lupus Anticoagulant, so a certain diagnosis of APS was achieved. INTERVENTIONS: The patient was treated with warfarin associated to hydroxychloroquine and monthly cycles of low doses intravenous immunoglobulins. OUTCOMES: A good control of the disease was obtained despite the continuation of anastrazole; the patient's clinical and laboratory situation remained not modified after AIs withdrawal. LESSONS: We discussed the possible role of anastrazole treatment in inducing APS in our patient, reporting the available literature data about the association between AIs treatment and autoimmune diseases. Furthermore, we analyzed the mechanism of action of estrogens in the pathophysiology of autoimmune rheumatic disorders.


Assuntos
Anastrozol/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Síndrome Antifosfolipídica/induzido quimicamente , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Pessoa de Meia-Idade
15.
AACE Clin Case Rep ; 5(2): e132-e137, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31967018

RESUMO

Objective: Myotonic dystrophy (DM) is a monogenic disorder. It is caused by expansion of a cytosine-thymineguanine triplet in the DMPK gene which encodes for myotonic dystrophy protein kinase (DMPK). Methods: A 24-year-old man with DM and the DMPK mutation presented with elevated adrenocorticotropic hormone (ACTH) levels twice (152 and 185 pg/mL; normal value is 10 to 52 pg/mL) with normal cortisol levels (134.6 and 113.0 ng/mL, or 371.3 and 311.7 nmol/L; normal values are 67 to 226 ng/mL or 184.8 to 623.5 nmol/L). ACTH, corticotropin-releasing hormone (CRH) and insulin tolerance test (ITT) demonstrated normal cortisol response to ACTH and partial response to CRH and ITT tests, and ACTH hyperresponse to CRH and ITT. We suspected ACTH and/or ACTH receptor (ACTHR) mutations and evaluated the genetic profile for pro-opiomelanocortin (POMC), melanocortin 2 receptor (MC2R) and follicle-stimulating hormone receptor (FSHR) genes. Results: No mutations were found in either the MC2R or FSHR genes. The patient was heterozygous for the c.614A>G mutation corresponding to a p.53D>G substitution with a glycine instead of an aspartate in position 53 in POMC gene. This mutation was outside the sequence for ACTH (which spans amino acids 138 to 176) but was included in the part originating the N-terminal peptide of pro-opiomelanocortin (also called pro-γ-melanocyte stimulating hormone) which spans amino acids 27 to 102 and is involved in the regulation of adrenal steroidogenesis. Conclusion: The pathologic expansion of the cytosine-thymine-guanine triplet repeat in the 3' noncoding region of DMPK could explain the hyperresponse of ACTH typical of DM. The mutation of pro-γ-melanocyte-stimulating hormone could be associated with the abnormal response of cortisol, compatible with a partial adrenal insufficiency. Other studies are necessary to demonstrate this hypothesis.

16.
J Neurol ; 265(12): 2927-2933, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30306264

RESUMO

Although anti-myelin-associated glycoprotein (MAG) antibody neuropathy is reported as a slowly progressive disease, it can lead to significant disability and impairment of health-related quality of life (HR-QoL) and social participation. The aim of this cross-sectional study was to evaluate the functioning and HR-QoL determinants in 67 patients with anti-MAG neuropathy in terms of the International Classification of Functioning, Disability, and Health (ICF). Evaluations included: Medical Research Council (MRC) sum score, Sensory Modality Sum score (SMS), Berg balance scale (BBS), Fatigue Severity Scale (FSS), Visual Analogue Scale (VAS) for pain, 9-Hole Peg Test (9-HPT), 6-min Walk Distance (6MWD), Impact on Participation and Autonomy (IPA) and the physical component score (PCS) and mental component score (MCS) of the short-form-36 health status scale (SF-36) HR-QoL measure. In the regression models, 6MWD was the most reliable predictor of PCS, explaining the 52% of its variance, while the strongest determinants of 6MWD were BBS and FSS, explaining the 41% of its variance. Consistently, VAS and BBS were good predictor of PCS, explaining together 54% of its variance. FSS was the most reliable determinant of MCS, explaining 25% of its variance. SMS and MRC were not QoL determinants. The results of our study suggest that 6MWD and FSS might be considered as potential meaningful outcome measures in future clinical trials. Furthermore, neurorehabilitation interventions aimed at improving balance and walking performance, fatigue management, and specific pain relief therapy should be considered to ameliorate participation in social life and HR-QoL in anti-MAG neuropathy patients.


Assuntos
Autoanticorpos/metabolismo , Glicoproteína Associada a Mielina/imunologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/fisiopatologia , Idoso , Estudos Transversais , Fadiga , Feminino , Humanos , Masculino , Dor , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/psicologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/reabilitação , Equilíbrio Postural , Qualidade de Vida , Comportamento Social , Caminhada
17.
BMJ Open ; 7(8): e015434, 2017 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-28801400

RESUMO

INTRODUCTION: Recent studies suggest that endoplasmic reticulum stress may play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through an altered regulation of the proteostasis, the cellular pathway-balancing protein synthesis and degradation. A key mechanism is thought to be the dephosphorylation of eIF2α, a factor involved in the initiation of protein translation. Guanabenz is an alpha-2-adrenergic receptor agonist safely used in past to treat mild hypertension and is now an orphan drug. A pharmacological action recently discovered is its ability to modulate the synthesis of proteins by the activation of translational factors preventing misfolded protein accumulation and endoplasmic reticulum overload. Guanabenz proved to rescue motoneurons from misfolding protein stress both in in vitro and in vivo ALS models, making it a potential disease-modifying drug in patients. It is conceivable investigating whether its neuroprotective effects based on the inhibition of eIF2α dephosphorylation can change the progression of ALS. METHODS AND ANALYSES: Protocolised Management In Sepsis is a multicentre, randomised, double-blind, placebo-controlled phase II clinical trial with futility design. We will investigate clinical outcomes, safety, tolerability and biomarkers of neurodegeneration in patients with ALS treated with guanabenz or riluzole alone for 6 months. The primary aim is to test if guanabenz can reduce the proportion of patients progressed to a higher stage of disease at 6 months compared with their baseline stage as measured by the ALS Milano-Torino Staging (ALS-MITOS) system and to the placebo group. Secondary aims are safety, tolerability and change in at least one biomarker of neurodegeneration in the guanabenz arm compared with the placebo group. Findings will provide reliable data on the likelihood that guanabenz can slow the course of ALS in a phase III trial. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of IRCCS 'Carlo Besta Foundation' of Milan (Eudract no. 2014-005367-32 Pre-results) based on the Helsinki declaration.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Esclerose Amiotrófica Lateral/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Guanabenzo/farmacologia , Deficiências na Proteostase/tratamento farmacológico , Idade de Início , Esclerose Amiotrófica Lateral/fisiopatologia , Progressão da Doença , Método Duplo-Cego , Humanos , Itália , Futilidade Médica , Fármacos Neuroprotetores , Deficiências na Proteostase/fisiopatologia
18.
Neurol Sci ; 38(4): 563-570, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28130605

RESUMO

POLG gene encodes the catalytic subunit of DNA polymerase gamma, essential for mitochondrial DNA (mtDNA) replication and repair. Mutations in POLG have been linked to a spectrum of clinical phenotypes, resulting in autosomal recessive or dominant mitochondrial diseases. These mutations have been associated with heterogeneous phenotypes, presenting with varying severity and at different ages of onset, ranging from the neonatal period to late adult life. We screened 13 patients for POLG mutations. All patients underwent a complete neurological examination, and in most of cases, muscle biopsy was performed. We detected 15 different variations in 13 unrelated Italian patients. Two mutations were novel and mapped in the pol domain (p.Thr989dup and p.Ala847Thr) of the enzyme. We also report new cases carrying controversial variations previously described as incompletely penetrant or a variant of unknown significance. Our study increases the range of clinical presentations associated with mutations in POLG gene, underlining some peculiar clinical features, such as PEO associated with corneal edema, and epilepsy, severe neuropathy with achalasia. The addition of two new substitutions, including the second report of an in-frame duplication, to the growing list of defects increases the value of POLG genetic diagnosis in a range of neurological presentations.


Assuntos
DNA Polimerase Dirigida por DNA/genética , Doenças Mitocondriais/genética , Mutação , Fenótipo , Adolescente , Adulto , Idoso , Análise Mutacional de DNA , DNA Polimerase gama , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/patologia , Doenças Mitocondriais/fisiopatologia , Músculo Esquelético/patologia , Exame Neurológico , Adulto Jovem
19.
Cochrane Database Syst Rev ; 11: CD006839, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27845501

RESUMO

BACKGROUND: Ulnar neuropathy at the elbow (UNE) is the second most common entrapment neuropathy after carpal tunnel syndrome. Treatment may be conservative or surgical, but optimal management remains controversial. This is an update of a review first published in 2010 and previously updated in 2012. OBJECTIVES: To determine the effectiveness and safety of conservative and surgical treatment in ulnar neuropathy at the elbow (UNE). We intended to test whether:- surgical treatment is effective in reducing symptoms and signs and in increasing nerve function;- conservative treatment is effective in reducing symptoms and signs and in increasing nerve function;- it is possible to identify the best treatment on the basis of clinical, neurophysiological, or nerve imaging assessment. SEARCH METHODS: On 31 May 2016 we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, AMED, CINAHL Plus, and LILACS. We also searched PEDro (14 October 2016), and the papers cited in relevant reviews. On 4 July 2016 we searched trials registries for ongoing or unpublished trials. SELECTION CRITERIA: The review included only randomised controlled clinical trials (RCTs) or quasi-RCTs evaluating people with clinical symptoms suggesting the presence of UNE. We included trials evaluating all forms of surgical and conservative treatments. We considered studies regarding therapy of UNE with or without neurophysiological evidence of entrapment. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed titles and abstracts of references retrieved from the searches and selected all potentially relevant studies. The review authors independently extracted data from included trials and assessed trial quality. We contacted trial investigators for any missing information. MAIN RESULTS: We identified nine RCTs (587 participants) for inclusion in the review, of which three studies were found at this update. The sequence generation was inadequate in one study and not described in three studies. We performed two meta-analyses to evaluate the clinical (3 trials, 261 participants) and neurophysiological (2 trials, 101 participants) outcomes of simple decompression versus decompression with submuscular or subcutaneous transposition; four trials in total examined this comparison.We found no difference between simple decompression and transposition of the ulnar nerve for both clinical improvement (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.80 to 1.08; moderate-quality evidence) and neurophysiological improvement (mean difference (in m/s) 1.47, 95% CI -0.94 to 3.87). The number of participants to clinically improve was 91 out of 131 in the simple decompression group and 97 out of 130 in the transposition group. Transposition showed a higher number of wound infections (RR 0.32, 95% CI 0.12 to 0.85; moderate-quality evidence).In one trial (47 participants), the authors compared medial epicondylectomy with anterior transposition and found no difference in clinical and neurophysiological outcomes.In one trial (48 participants), the investigators compared subcutaneous transposition with submuscular transposition and found no difference in clinical outcomes.In one trial (54 participants for 56 nerves treated), the authors found no difference between endoscopic and open decompression in improving clinical function.One trial (51 participants) assessed conservative treatment in clinically mild or moderate UNE. Based on low-quality evidence, the trial authors found that information on avoiding prolonged movements or positions was effective in improving subjective discomfort. Night splinting and nerve gliding exercises in addition to information provision did not result in further improvement.One trial (55 participants) assessed the effectiveness of corticosteroid injection and found no difference versus placebo in improving symptoms at three months' follow-up. AUTHORS' CONCLUSIONS: We found only two studies of treatment of ulnar neuropathy using conservative treatment as the comparator. The available comparative treatment evidence is not sufficient to support a multiple treatment meta-analysis to identify the best treatment for idiopathic UNE on the basis of clinical, neurophysiological, and imaging characteristics. We do not know when to treat a person with this condition conservatively or surgically. Moderate-quality evidence indicates that simple decompression and decompression with transposition are equally effective in idiopathic UNE, including when the nerve impairment is severe. Decompression with transposition is associated with more deep and superficial wound infections than simple decompression, also based on moderate-quality evidence. People undergoing endoscopic surgery were more likely to have a haematoma. Evidence from one small RCT of conservative treatment showed that in mild cases, information on movements or positions to avoid may reduce subjective discomfort.


Assuntos
Síndromes de Compressão do Nervo Ulnar/terapia , Nervo Ulnar/cirurgia , Descompressão Cirúrgica/métodos , Cotovelo , Terapia por Exercício/métodos , Humanos , Transferência de Nervo/métodos , Educação de Pacientes como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Contenções , Ulna/cirurgia , Síndromes de Compressão do Nervo Ulnar/cirurgia
20.
J Neurol Sci ; 368: 359-68, 2016 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-27538665

RESUMO

BACKGROUND: POLG-related disorders are a group of heterogeneous diseases characterized by an overlapping clinical presentations and associated with mutations in the POLG gene. POLG codes for the catalytic subunit of mitochondrial polymerase gamma (POLG), essential for mitochondrial DNA (mtDNA) replication and repair. Studies on mutator POLG mice showed an increase in oxidative stress and apoptosis. In this regard we analysed the involvement of POLG mutations in the apoptotic regulation, evaluating apoptosis in peripheral blood lymphocytes (PBLs) from patients with POLG-related diseases. METHODS: Cells were cultured under basal conditions and with 2-deoxy-d-ribose (dRib), a reducing sugar that induces apoptosis by oxidative stress. Apoptosis rate was assessed by flow cytometry. Phosphatidylserine translocation, mitochondrial membrane depolarization and caspase 3 activation were also analysed. RESULTS: Our data showed higher percentages of apoptosis after dRib treatment in patients with POLG mutations than in controls, while under basal culture conditions, apoptosis levels were similar in the two groups. CONCLUSIONS: Cells with POLG mutations are more sensitive than control cells to oxidative stress-induced apoptosis, confirming that mtDNA mutations may have a role in mitochondrial apoptosis pathway. We also suggest that redox state homeostasis may play a crucial role in phenotypic expression of POLG-related diseases.


Assuntos
Apoptose/genética , DNA Polimerase Dirigida por DNA/genética , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Linfócitos/patologia , Mutação/genética , Estresse Oxidativo/fisiologia , Adulto , Idoso , Estudos de Casos e Controles , Caspase 3 , Células Cultivadas , DNA Polimerase gama , Desoxirribose/farmacologia , Feminino , Citometria de Fluxo , Humanos , Linfócitos/metabolismo , Masculino , Potencial da Membrana Mitocondrial/genética , Pessoa de Meia-Idade , Fatores de Tempo
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