Bergamaschi L.,The Interdisciplinary Center |
Leone M.A.,Ospedale Maggiore and IRCAD |
Fasano M.E.,San Giovanni Battista Hospital |
Guerini F.R.,Foundation Medicine |
And 17 more authors.
Genes and Immunity | Year: 2010
Previous studies reported an association with multiple sclerosis (MS) of distinct HLA-class I markers, namely HLA-A02, HLA-Cw05 and MOG-142L. In this work, we tested the association with MS of A02 and Cw05 in 1273 Italian MS patients and 1075 matched controls, which were previously analyzed for MOG-142, and explored the relationship among these three markers in modulating MS risk. HLA-A02 conferred a statistically robust MS protection (odds ratio, OR0.61; 95% confidence intervals, CI0.51-0.72, P10 9), which was independent of DRB115 and of any other DRB1 allele and remained similar after accounting for the other two analyzed class I markers. Conversely, the protective effect we previously observed for MOG-142L was secondary to its linkage disequilibrium with A02. Cw05 was not associated considering the whole sample, but its presence significantly enhanced the protection in the HLA-A02-positive group, independently of DRB1: the OR conferred by A02 in Cw05-positive individuals (0.22, 95% CI0.13-0.38) was significantly lower than in Cw05-negative individuals (0.69, 95% CI0.58-0.83) with a significant (P4.94 × 10 5) multiplicative interaction between the two markers. In the absence of A02, Cw05 behaved as a risk factor, particularly in combination with DRB103 (OR3.89, P0.0006), indicating that Cw05 might be a marker of protective or risk haplotypes, respectively. © 2010 Macmillan Publishers Limited All rights reserved.
Carmona O.,Multiple Sclerosis Unit |
Carmona O.,Hospital Universitari Of Bellvitge |
Alia P.,Hospital Universitari Of Bellvitge |
Moral E.,Multiple Sclerosis Unit |
And 4 more authors.
European Neurology | Year: 2011
Background: Results for the e4/e2 alleles of the ApoE gene as markers of susceptibility, clinical and radiological progression, and cognitive deterioration in patients with multiple sclerosis (MS) are contradictory. Aim: The usefulness of these markers in predicting the response to interferon-β-1b (IFNβ-1b) was evaluated. Material and Methods: 95 patients with relapsing-remitting MS treated with IFNβ-1b (mean follow-up 7.44 years) were studied. We correlated the e4 and e2 alleles with the time to the first relapse or to a 1-point worsening on the Expanded Disability Status Scale, time to moderate disability, progression index, and treatment discontinuation due to inefficacy. Results: We found no association between the e4 allele and any of the variables. The e2 allele was associated with increased time to moderate disability. Conclusion: The e4 allele of ApoE has no prognostic value for the response to IFNβ-1b. The e2 allele delayed the progression of disability in our MS patient cohort. Copyright © 2011 S. Karger AG, Basel.
Alkhawajah M.M.,University of British Columbia |
Caminero A.B.,Multiple Sclerosis Unit |
Freeman H.J.,University of British Columbia |
Oger J.J.F.,University of British Columbia
Multiple Sclerosis Journal | Year: 2013
Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system (CNS) but the causes have not been defined. The disease process appears to involve interplay between environmental factors and certain susceptibility genes. It is likely that the identification of the exact etiological mechanisms will permit the development of preventive and curative treatments. Evaluation of several diseases found to be more often associated than by chance alone may reveal clues to the etiology of those disorders. An association between MS and inflammatory bowel diseases (IBD) was suggested by the observation of an increased incidence of IBD among MS patients. A problem in the interpretation of the data rests, in part, with the observation that abnormal findings in brain magnetic resonance imaging (MRI) may be reported as MS in IBD patients. Defining the limits between incidental MRI findings and findings compatible with MS has resulted in further exploration of this possible association. © The Author(s) 2012.
Cagliani R.,Scientific Institute Irccs E Medea |
Fumagalli M.,Scientific Institute Irccs E Medea |
Guerini F.R.,Foundation Medicine |
Riva S.,Scientific Institute Irccs E Medea |
And 14 more authors.
Human Genetics | Year: 2012
Contrasting results have been reported concerning the association of a splice-site polymorphism (rs10774671) in OAS1 with multiple sclerosis (MS). We analysed two OAS1 regions encompassing alternatively spliced exons. While the region carrying the splice-site variant is neutrally evolving, a signature of long-standing balancing selection was observed across an alternative exon 7. Analysis of variants in this exon identified an insertion/deletion polymorphism (rs11352835, A/-) that originates predicted products with distinct C termini. This variant is located along the major branch of the haplotype genealogy, suggesting that it may represent the selection target. A case/control study for MS indicated that rs11352835 is associated with disease susceptibility (for an allelic model with the deleted allele predisposing to MS, OR 1.27, 95% CI 1.072-1.513, p = 0.010). No association was found between rs10774671 and MS. As the two SNPs are in linkage disequilibrium in Europeans, the previously reported association between rs10774671 and MS susceptibility might be driven by rs11352835, possibly explaining the contrasting results previously observed for the splice-site polymorphism. Thus, we describe a novel susceptibility variant for MS in OAS1 and show that population genetic analyses can be instrumental to the identification of selection targets and, consequently, of functional polymorphisms with an effect on phenotypic traits. © 2011 Springer-Verlag.
Blumen S.C.,Hillel Yaffe Medical Center |
Blumen S.C.,Technion - Israel Institute of Technology |
Astord S.,University Pierre and Marie Curie |
Robin V.,University Pierre and Marie Curie |
And 15 more authors.
Annals of Neurology | Year: 2012
Objective: Distal hereditary motor neuropathies (dHMN) form a clinically and genetically heterogeneous group of disorders, characterized by muscle weakness and atrophy predominating at the distal part of the limbs, due to the progressive degeneration of motor neurons in the spinal cord. We report here a novel rare variant of dHMN with autosomal recessive inheritance in a large Jewish family originating from Morocco. The disease is characterized by a predominance of paralysis at the lower limbs and an early adulthood onset. We performed a genetic study in this family to identify and characterized the causing mutation. Methods: Homozygosity mapping strategy and sequencing of the candidate genes were performed. Expression studies were made on patient fibroblasts. Functional experiments were performed on a cellular model of motor neuron disease. Results: We mapped the disease to the 2q34-q36.1 chromosomal region and identified a homozygous splice mutation in the gene HSJ1 (DNAJB2) decreasing the expression of the 2 main isoforms HSJ1a and HSJ1b. Overexpression of both HSJ1a and HSJ1b reduced inclusion formation induced by the mutated SOD1-A4V in a neuronal cellular model. Interpretation: HSJ1 is a neuronal enriched member of the HSP40/DNAJ co-chaperone family. Previous studies have shown that HSP40 proteins play a crucial role in protein aggregation and neurodegeneration in several neuronal types, in animal models and human diseases. Interestingly, this mutation causing a loss-of-function of HSJ1 is linked to a pure lower motor neuron disease, strongly suggesting that HSJ1 also plays an important and specific role in motor neurons. Copyright © 2011 American Neurological Association.
Caminero A.,Multiple Sclerosis Unit |
Bartolome M.,Multiple Sclerosis Unit
Journal of the Neurological Sciences | Year: 2011
Objectives: The frequency of sleep disturbances in multiple sclerosis (MS), and their impact on the quality of life of MS patients, have traditionally been underestimated. Here we review the most common sleep disorders seen in this disease, their prevalence, pathophysiology, clinical manifestations and current treatments. Method: We begin with a brief description of epidemiological data on sleep disturbances in MS, explain how these disturbances increase potential associated morbidities, and discuss the bidirectional relationship established between these two comorbid conditions (i.e. MS worsens sleep disturbances and vice versa). We then analyze the main dyssomnias and parasomnias described in MS: insomnia, circadian rhythm disorders, drug-induced sleep disturbances, restless legs syndrome (RLS) and periodic leg movements (PLM), respiratory disorders during sleep, narcolepsy-cataplexy syndrome and REM sleep behavior disorder (RBD). We also review the relationship between sleep disturbances and chronic fatigue syndrome, which is very frequent in MS patients. Conclusion: Sleep disturbances are more common in MS patients than in the general population and limit these patients' quality of life. Therefore, we believe that these disturbances should be a focal point in any multidisciplinary treatment for MS. © 2011 Elsevier B.V. All rights reserved.
Fusco C.,Immunohematology and Transfusion Service |
Guerini F.R.,Foundation Medicine |
Nocera G.,Italian National Cancer Institute |
Ventrella G.,University of Naples Federico II |
And 9 more authors.
Journal of Neuroimmunology | Year: 2010
Killer Immunoglobulin-like Receptor (KIR) genes may affect both resistance and susceptibility to autoimmune disorders, but their role in the pathogenesis of Multiple Sclerosis (MS) is still unclear. To evaluate the involvement of KIRs and their HLA ligands in the development of MS we performed genotyping of HLA -A, -B, -Cw, -DRB1 and KIRs loci in 121 RRMS patients and 103 healthy controls (HC). Results evidenced a possible protective role of the activating KIR2DS1 gene (py=0.001; OR:0.38), enhanced in the presence of its ligand group HLA-C2 (py=0.0001; OR:0.23). Our data suggest that the presence of functional compounds of activating KIR receptors together with their HLA ligands, allowing the immunomodulatory function of NK cells, may have a protective role against the disease. © 2010 Elsevier B.V.
Mancuso R.,Foundation Medicine |
Hernis A.,Foundation Medicine |
Cavarretta R.,Multiple Sclerosis Unit |
Caputo D.,Multiple Sclerosis Unit |
And 7 more authors.
Journal of Medical Virology | Year: 2010
The role of viruses in the pathogenesis of multiple sclerosis (MS) is a subject of heated debate. The presence of six different neurotropic viruses was sought, including JC virus (JCV), varicella zoster virus (VZV), human herpesvirus 6 (HHV-6), and Epstein-Barr virus (EBV), in cerebrospinal fluid (CSF) samples collected from 51 patients with MS and 30 patients with other neurological diseases. Cell-free or cell-associated viral DNA in CSF samples was detected by real-time PCR, and viral loads were determined. Magnetic resonance imaging (MRI) examinations were also performed to look for active lesions. Cell-associated JCV DNA was detected in 3 of the 51 patients with MS and in 2 of the 30 patients with other neurological disease. Cell-free JCV DNA was detected in one additional patient with MS. Cell-free VZV DNA was detected in one patient without MS, cell-free HHV-6 was detected in one patient with MS, and cell-free EBV was detected in one patient with MS. All other study patients had no detectable viral DNA in CSF samples and no double infections were found. The small percentage of patients with detectable viral DNA in CSF samples was comparable between patients with MS and those with other neurological disease, and presence of viral DNA was not a predictor of brain lesions. Additional observations suggest that cell trafficking from the periphery, rather than leakage through the blood-brain barrier, results in the transport of viruses to the CNS, where local immunosurveillance can control viral replication in immunocompetent individuals. © 2010 Wiley-Liss, Inc.
PubMed | Fondazione Italiana Sclerosi Multipla FISM, Foundation Irccs Neurological Institute C Besta, FARO, University of Chieti Pescara and 2 more.
Type: Journal Article | Journal: Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation | Year: 2016
Individualized quality of life (QoL) measures differ from traditional inventories in that QoL domains/weights are not predetermined, but identified by the individual. We assessed practicability of the Schedule for the Evaluation of Individual QoL-Direct Weighting (SEIQoL-DW) interview in severely affected multiple sclerosis (MS) patients; the key QoL dimensions identified; and the correlation of the SEIQoL-DW index score with standard patient-reported outcome measures (PROMs).Participants were people with severe MS who performed the baseline visit of the PeNSAMI trial (ISRCTN73082124). The SEIQoL-DW was administered at the patients home by a trained examiner. Patients then received the following PROMs: the Core-Palliative care Outcome Scale (Core-POS), the Palliative care Outcome Scale-Symptoms-MS (POS-S-MS), the European Quality of Life Five Dimensions-3L (EQ-5D-3L), and the Hospital Anxiety and Depression Scale (HADS).Of 59 enrolled patients, 11 (19%) did not receive the SEIQoL-DW (and the other PROMs) because of severe cognitive compromise or inability to communicate. SEIQoL-DW administration was completed and deemed valid in all 48 cases (mean age 60years, 58% women, median Expanded Disability Status Scale score 8.5). Mean SEIQoL-DW index score was 59.1 (SD 25.5). The most commonly nominated SEIQoL-DW areas were family (94% of the patients), relationships, and leisure activities (both 65%). Core-POS and POS-S-MS contained 70% of the SEIQoL-DW-nominated areas. Nevertheless, correlations between SEIQoL-DW index, Core-POS, and POS-S-MS (and the other PROMs) were negligible.Individualized QoL can be assessed in severely affected MS patients, providing information that is not tracked by the standard inventories Core-POS, POS-S-MS, EQ-5D-3L, and HADS.
PubMed | Foundation Irccs Neurological Institute C Besta, University of Chieti Pescara, Multiple Sclerosis Unit, University of Turin and 2 more.
Type: Journal Article | Journal: PloS one | Year: 2016
The Multiple Sclerosis Quality of Life-54 (MSQOL-54, 52 items grouped in 12 subscales plus two single items) is the most used MS specific health related quality of life inventory.To develop a shortened version of the MSQOL-54.MSQOL-54 dimensionality and metric properties were investigated by confirmatory factor analysis (CFA) and Rasch modelling (Partial Credit Model, PCM) on MSQOL-54s completed by 473 MS patients. Their mean age was 41 years, 65% were women, and median Expanded Disability Status Scale (EDSS) score was 2.0 (range 0-9.5). Differential item functioning (DIF) was evaluated for gender, age and EDSS. Dimensionality of the resulting short version was assessed by exploratory factor analysis (EFA) and CFA. Cognitive debriefing of the short instrument (vs. the original) was then performed on 12 MS patients.CFA of MSQOL-54 subscales showed that the data fitted the overall model well. Two subscales (Role Limitations--Physical, Role Limitations--Emotional) did not fit the PCM, and were removed; two other subscales (Health Perceptions, Social Function) did not fit the model, but were retained as single items. Sexual Satisfaction (single-item subscale) was also removed. The resulting MSQOL-29 consisted of 25 items grouped in 7 subscales, plus 4 single items. PCM fit statistics were within the acceptability range for all MSQOL-29 items except one which had significant DIF by age. EFA and CFA indicated adequate fit to the original two-factor (Physical and Mental Health Composites) hypothesis. Cognitive debriefing confirmed that MSQOL-29 was acceptable and had lost no key items.The proposed MSQOL-29 is 50% shorter than MSQOL-54, yet preserves key quality of life dimensions. Prospective validation on a large, independent MS patient sample is ongoing.