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Chio A.,University of Turin | Borghero G.,University of Cagliari | Calvo A.,University of Turin | Capasso M.,University of Turin | And 23 more authors.
Neurology | Year: 2010

Background: 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]). Methods: 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). Results: 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. Conclusions: 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. Copyright © 2010 by AAN Enterprises, Inc. All rights reserved.


PubMed | NEuroMuscular Omnicentre NEMO, University of Milan Bicocca and Medical Genetics
Type: | Journal: Case reports in neurological medicine | Year: 2014

Here we report the case of an ALS patient found to carry both a novel heterozygous change (c.194G>A) within the spastin gene and a homozygous deletion of the SMN2 gene. The patient was started on valproic acid (VPA, 600mg/die per os) considering the capacity of this drug of increasing survival motor neuron through an epigenetic mechanism. Patient clinical course and molecular effects of VPA on skin fibroblasts obtained from the proband are described. This c.194G>A spastin mutation might expand the previously known borders of type 4 spastic paraplegia (SPG4) and we suggest the intriguing possibility that the absence of SMN2 might have acted as a contributory risk factor for starting lower motor neuron damage. Exploring the relationship genocopy-phenocopy in selected ALS patients might represent an interesting strategy for understanding its clinical variability.


PubMed | Instituto Of Ricovero E Cura A Carattere Scientifico Irccs San Camillo, University of Padua, Research Center for Genetic Medicine, NEuroMuscular Omnicentre NEMO and 3 more.
Type: Journal Article | Journal: PloS one | Year: 2015

Dilated cardiomyopathy (DCM) is a major complication and leading cause of death in Duchenne muscular dystrophy (DMD). DCM onset is variable, suggesting modifier effects of genetic or environmental factors. We aimed to determine if polymorphisms previously associated with age at loss of independent ambulation (LoA) in DMD (rs28357094 in the SPP1 promoter, rs10880 and the VTTT/IAAM haplotype in LTBP4) also modify DCM onset.A multicentric cohort of 178 DMD patients was genotyped by TaqMan assays. We performed a time-to-event analysis of DCM onset, with age as time variable, and finding of left ventricular ejection fraction < 50% and/or end diastolic volume > 70 mL/m2 as event (confirmed by a previous normal exam < 12 months prior); DCM-free patients were censored at the age of last echocardiographic follow-up.Patients were followed up to an average age of 15.9 6.7 years. Seventy-one/178 patients developed DCM, and median age at onset was 20.0 years. Glucocorticoid corticosteroid treatment (n = 88 untreated; n = 75 treated; n = 15 unknown) did not have a significant independent effect on DCM onset. Cardiological medications were not administered before DCM onset in this population. We observed trends towards a protective effect of the dominant G allele at SPP1 rs28357094 and recessive T allele at LTBP4 rs10880, which was statistically significant in steroid-treated patients for LTBP4 rs10880 (< 50% T/T patients developing DCM during follow-up [n = 13]; median DCM onset 17.6 years for C/C-C/T, log-rank p = 0.027).We report a putative protective effect of DMD genetic modifiers on the development of cardiac complications, that might aid in risk stratification if confirmed in independent cohorts.


PubMed | Italian Academy of Osteopathic Medicine AIMO, NEuroMuscular Omnicentre NEMO, University of Milan Bicocca, Victoria University of Melbourne and San Raffaele Scientific Institute
Type: | Journal: The open neurology journal | Year: 2016

Current interventions in amyotrophic lateral sclerosis (ALS) are focused on supporting quality of life (QoL) and easing pain with a multidisciplinary approach.Primary aim of this pilot work assessed feasibility, safety, tolerability and satisfaction of osteopathic manual treatment (OMT) in 14 ALS outpatients.Patients were randomized according to an initial single-blind design (12 weeks, T0-T1), in order to receive OMT (weekly for 4 weeks, and fortnightly for the following 8 weeks) versus usual-care (n=7 each group), followed by an OMT open period (T1-T2, once a week for 8 weeks, n=10). Secondary aims included blind osteopathic assessment of somatic dysfunctions (SD) for goal attainment scale (GAS) calculation, Brief Pain Inventory-short form and McGill QoL-16 items.OMT was demonstrated feasible and safe and patients displayed high satisfaction (T1-VAS=8.34 0.46; T2-VAS=8.52 0.60). Considering secondary aims no significant differences emerged. Finally, at study entry (T0), a cervico-dorsal SD was found in 78% of ALS patients versus 28% of healthy matched controls (p<0.01).OMT was found feasible, safe and satisfactory in ALS. The lack of secondary aim differences can be due to the limited sample size. OMT could be an interesting option to explore in ALS.


PubMed | Helmholtz Center Munich, Innsbruck Medical University, Catholic University, Neuromuscular Omnicentre NEMO and 3 more.
Type: | Journal: Movement disorders : official journal of the Movement Disorder Society | Year: 2016

Dystonia is clinically and genetically heterogeneous. Despite being a first-line testing tool for heterogeneous inherited disorders, whole-exome sequencing has not yet been evaluated in dystonia diagnostics. We set up a pilot study to address the yield of whole-exome sequencing for early-onset generalized dystonia, a disease subtype enriched for monogenic causation.Clinical whole-exome sequencing coupled with bioinformatics analysis and detailed phenotyping of mutation carriers was performed on 16 consecutive cases with genetically undefined early-onset generalized dystonia. Candidate pathogenic variants were validated and tested for cosegregation. The whole-exome approach was complemented by analyzing 2 mutated yet unestablished causative genes in another 590 dystonia cases.Whole-exome sequencing detected clinically relevant mutations of known dystonia-related genes in 6 generalized dystonia cases (37.5%), among whom 3 had novel variants. Reflecting locus heterogeneity, identified unique variants were distributed over 5 genes (GCH1, THAP1, TOR1A, ANO3, ADCY5), of which only 1 (ANO3) was mutated recurrently. Three genes (GCH1, THAP1, TOR1A) were associated with isolated generalized dystonia, whereas 2 (ANO3, ADCY5) gave rise to combined dystonia-myoclonus phenotypes. Follow-up screening of ANO3 and ADCY5 revealed a set of distinct variants of interest, the pathogenicity of which was supported by bioinformatics testing and cosegregation work.Our study identified whole-exome sequencing as an effective strategy for molecular diagnosis of early-onset generalized dystonia and offers insights into the heterogeneous genetic architecture of this condition. Furthermore, it provides confirmatory evidence for a dystonia-relevant role of ANO3 and ADCY5, both of which likely associate with a broader spectrum of dystonic expressions than previously thought. 2016 International Parkinson and Movement Disorder Society.


Tremolizzo L.,San Gerardo Hospital | Tremolizzo L.,University of Milan Bicocca | Susani E.,San Gerardo Hospital | Susani E.,University of Milan Bicocca | And 6 more authors.
Journal of Neurology | Year: 2014

Identifying frontal impairment in ALS is an important goal albeit disease-dedicated tools are still scarce. For this reason, we decided to consider primitive reflexes (PRs), variably regarded as correlates of frontal release and/or of upper motor neuron (UMN) impairment, often in the setting of dementias. Specifically, the aims of this work consisted in assessing the exact prevalence of the combination of seven PRs in ALS, trying to clarify their role as putative proxies of cognitive impairment or of UMN dysfunction. In this cross-sectional study, 50 consecutive ALS outpatients were evaluated for the presence of: palmomental (PM), corneomandibular (CM), glabella tap (MY), rooting, sucking, snout, and grasping reflexes. Cognitive screening was performed by the Frontal Assessment Battery (FAB) and the Weigl's Sorting test (WST); UMN dysfunction was concomitantly evaluated. PM, CM and MY were more frequently detected (62, 52, and 44 % of the ALS sample, respectively), while the other reflexes were under-represented. Patients displaying three or more PRs had significantly lower FAB and WST scores. On the other hand, UMN dysfunction was only moderately associated to PRs. In conclusion, PRs' assessment is a promising complementary tool for screening cognitive impairment in ALS; however, further work will be necessary to establish its added value with respect to already existing ALS-dedicated screening tools for cognition. © 2014 Springer-Verlag Berlin Heidelberg.


Pagnini F.,University of Milan | Lunetta C.,NEuroMuscular Omnicentre NEMO | Banfi P.,NEuroMuscular Omnicentre NEMO | Rossi G.,NEuroMuscular Omnicentre NEMO | And 7 more authors.
Neurological Sciences | Year: 2012

Pain in Amyotrophic Lateral Sclerosis is often underestimated and untreated by clinicians and few studies have investigated its specific features and impact. Pain experience was investigated with the Italian Questionnaire of Pain, together with the McGill Quality of Life Questionnaire for quality of life (QoL), at a baseline and at a 4-month follow-up. About half of ALS patients reported pain, described as nagging, sore, annoying, boring and exhausting, with periodic but enduring episodes. Pain was related with QoL and its intensity was able to predict QoL worsening. Obtained results indicate the importance of clinical investigation of pain in ALS patients and of the intervention with anti-pain treatment whenever necessary. © Springer-Verlag 2012.


Pagnini F.,University of Milan | Pagnini F.,University of Bergamo | Rossi G.,NEuroMuscular Omnicentre NEMO | Lunetta C.,NEuroMuscular Omnicentre NEMO | And 4 more authors.
Psychology, Health and Medicine | Year: 2010

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease caused by the degeneration of motor neurons. The burden for ALS caregivers is quite high. There are still few studies that have investigated the emotional impact of ALS care. We conducted a cross-sectional study among 40 ALS caregivers, assessing general worries, burden of care, depression, anxiety, perception of social support, and patients' severity of disease. Caregiver burden, depression, and anxiety were positively related with each other, and all these variables had a negative relation with social support. Patient's loss of physical functions was positively related with caregiver burden, anxiety, and somatic expression of depression. Caregivers expressed worries for their own health conditions. Given these results, we consider the hypothesis of an emotional-somatic impact of ALS care. The implications and limitations are discussed. © 2010 Taylor & Francis.


Pagnini F.,University of Milan | Simmons Z.,Pennsylvania State University | Corbo M.,NEuroMuscular Omnicentre NEMO | Molinari E.,University of Milan | Molinari E.,San Giuseppe Hospital
Amyotrophic Lateral Sclerosis | Year: 2012

The literature on psychological aspects of amyotrophic lateral sclerosis (ALS) has explored quality of life, depression, anxiety, spirituality, hopelessness, and other constructs in an attempt to understand the patient's grief and other psychological responses to the disease. However, there is a lack of research on the efficacy of psychological interventions. We believe it is important to develop 'best practices' for the improvement of quality of life and the reduction of psychological distress related to ALS. © 2012 Informa Healthcare.


Pagnini F.,Catholic University of the Sacred Heart | Pagnini F.,University of Bergamo | Lunetta C.,NEuroMuscular Omnicentre NEMO | Rossi G.,NEuroMuscular Omnicentre NEMO | And 8 more authors.
Amyotrophic Lateral Sclerosis | Year: 2011

Existential well-being (EWB) and spirituality issues are important factors in determining quality of life (QoL) in amyotrophic lateral sclerosis (ALS) patients. No conclusive data among the relation between patient's EWB, their spirituality and caregivers QoL are available. In the mainframe of a longitudinal study, we performed a cross-sectional analysis aimed to investigate EWB and spirituality issues in sporadic ALS (SALS) patients and the relations with caregivers psychological features. Thirty-seven SALS patients, together with their caregivers, consecutively recruited at NEuroMuscular Omnicentre, in Milan, were included in this study. EWB and spirituality questions were administrated to patients and caregivers. Caregivers also completed questionnaires about quality of life (MQoL-SI), care burden (ZBI), depression (BDI) and anxiety (STAI). Both EWBs and questions about spirituality of SALS patients showed a positive correlation with MQoL-SI and EWBs in their caregivers. Conversely, SALS patients EWB and spirituality were negatively correlated with caregivers STAI, BDI and ZBI scores. In conclusion, existential well-being, as well as spirituality issues, perceived by SALS patients seems to be directly related with quality of life, severity of mood disturbance and burden experienced by their caregivers. © 2011 Informa Healthcare.

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