A comprehensive in silico analysis of multiple sclerosis related non-synonymous SNPs and their potential effects on protein structure and function.

BACKGROUND: Multiple Sclerosis (MS) is an autoimmune and central nervous system disease characterized by an inflammatory demyelinating process in the brain. Although the exact cause of MS is still unclear, environmental, and genetic factors are known to play a role in the development of disease. New molecular markers must be identified to understand the mechanism of disease formation and progression. We investigated the effects of MS-related non-synonymous single-nucleotide polymorphisms (nsSNPs) on the structure and function of identified proteins in this study. METHODS: Missense variations associated with MS were extracted from the NHGRI-EBI GWAS database. Functional and structural analysis of nsSNPs on mapped genes was performed using g:Profiler, Wikipathway, KEGG, Reactome and Gene ontology programs (p < 0.05 was accepted statistically significant). Amino acid sequence-based analysis was performed to identify deleterious variants by using PROVEAN and PredictSNP tools. Finally, protein structure analyzes were performed on deleterious protein variants by DynaMut, Mutabind2 and Missense3D servers to identify changes in protein stability and flexibility. RESULTS: 10 target nsSNPs were identified. Among these rs34536443, rs10936599, rs2293152, rs11808092, rs1129183 were found deleterious according to amino acid sequence-based analysis. Furthermore, structure-based analyses show that TYK2 (P1104A), MYNN (H6Q), EVI5 (Q612H), and LZTFL1 (D246N) substitutions increase protein stability and decrease structure flexibility, whereas STAT3 (R426G) substitution decreases protein stability and increases structure flexibility. CONCLUSION: We revealed that identified nsSNPs have potential effects on stability and flexibility of the target proteins. The prominent target genes are thought to have significant impacts on the pathogenesis of MS. Further in vitro and in vivo studies are required to validate our in silico results.

Adipokines in Multiple Sclerosis Patients with and without Optic Neuritis as the First Clinical Presentation.

BACKGROUND: Adipocytokines have been implied to be involved in multiple sclerosis (MS) pathogenesis. MS patients whose first clinical episode is optic neuritis (ON) have been reported to display a milder disease course. In this study, we aimed to show whether this milder disease course is related to reduced adipokine production. METHODS: A total of 55 (24 with ON as the first clinical episode) relapsing-remitting MS (RRMS) patients and 40 healthy individuals were recruited. Concentrations of adipokines were measured in sera by ELISA. RESULTS: The levels of adiponectin, leptin, resistin, monocyte chemoattractant protein-1 (MCP-1) and IL-8 were significantly higher in RRMS patients compared with healthy controls. RRMS cases starting with ON had lower expanded disability status scale scores. Serum adiponectin, leptin, resistin and MCP-1 levels were significantly lower in MS patients, whose first clinical episode was ON. CONCLUSIONS: MS patients with ON as the first manifestation display both lower disability scores and reduced serum adipokine levels implying that adipocytokine production is associated with MS progression. Exact mechanisms of this association in MS patients with first episode ON need to be further studied.

Investigation of the prognostic value of adipokines in multiple sclerosis.

BACKGROUND: Adipokines may be involved in multiple sclerosis (MS) as well as other inflammatory diseases. This study aimed to analyze the value of serum adipokine levels as biomarkers in determining the clinical progression of MS. METHODS: A total of 90 subjects including 40 healthy individuals and 50 MS patients [24 with classical clinical course of MS (C-MS), 26 with benign MS (B-MS)] were recruited for this study. The levels of serum adipokines and inflammatory mediators were measured using immunoassay methods. RESULTS: The levels of adiponectin, MCP-1, TNF-α and IL-6 were significantly higher in C-MS patients compared with B-MS patients and healthy controls. Only adiponectin and MCP-1 levels remained significantly high after Bonferroni correction. Adiponectin, MCP-1 and TNF-α levels showed a modest correlation with expanded disability status scale (EDSS) scores, which disappeared after Bonferroni correction. CONCLUSIONS: Our findings suggest the potential role of adipokines in pathogenesis and clinical progression of MS. Adiponectin and MCP-1 might potentially serve as prognostic biomarkers in MS.

Limbic Encephalitis Associated with Sjögren's Syndrome: Report of Three Cases.

Sjögren's syndrome (SS) may be complicated by neurological manifestations. We herein report three women (age range 26-60 years old) who all presented with limbic encephalitis (LE) as the predominant clinical feature 3 months to 15 years after the diagnosis of SS. The 26-year-old patient also developed acute motor axonal neuropathy one week after autoimmune encephalitis. All three patients showed contrast-enhanced MRI lesions and inflammatory cerebrospinal fluid findings, while not displaying any anti-neuronal antibodies and showing a remarkable response to immunotherapy. SS is often overlooked when the symptoms are mild. Therefore, in LE cases with no identifiable cause, serological screening for rheumatologic disorders is recommended.

NMDA receptor encephalitis with cancer of unknown primary origin.

PURPOSE: N-methyl-D-aspartate receptor (NMDAR) encephalitis may present as a paraneoplastic syndrome in young women and is often associated with ovarian teratoma. METHODS: We report 2 male cases of NMDAR encephalitis presenting with metastatic cancer of unknown primary origin. RESULTS: Both patients showed cognitive dysfunction as well as other neurological symptoms, slow waves on EEG, and NMDAR antibodies in sera and CSF. Symptoms were effectively treated by pulse steroid and intravenous immunoglobulin treatment. The patients developed metastatic small cell neuroendocrine carcinoma of the parotid gland and inguinal metastatic squamous cell cancer shortly after their neurological episodes. Follow-up PET studies showed small cell lung cancer in the first patient while no primary origin could be found in the second patient. CONLUSIONS: Our cases imply that NMDAR encephalitis may present with metastatic cancers that display slow progression rates and occur after encephalitis attacks.

Increased complexin-1 and decreased miR-185 expression levels in Behçet's disease with and without neurological involvement.

Although complexin 1 (CPLX1) is not known as an inflammation factor, recent identification of a complexin 1 (CPLX1) polymorphism in Behçet's disease (BD) has sparked an interest in the role of this molecule in autoinflammation. DNA samples were isolated from peripheral blood mononuclear cells (PBMC) of BD and neuro-Behçet's disease (NBD) patients and expression levels of CPLX1 and miR-185, a predicted target miRNA for CPLX1 and an inflammation-related miRNA, were investigated by real time PCR assays. PBMC expression levels of CPLX1 were significantly increased in BD and NBD patients. By contrast, levels of miR-185 were reduced in both patient groups. A moderate inverse correlation was found between levels of CPLX1 and miR-185. No correlation could be found between expression levels and clinical features of patients. Significant expression alterations of CPLX1 in BD and NBD patients suggest that this molecule has a proinflammatory action. The putative role of CPLX1 in BD pathogenesis remains to be further studied.

The association between obesity and oligoclonal band formation in multiple sclerosis patients.

Since some neurological disorders present with increased body-mass index (BMI) and cerebrospinal fluid (CSF) oligoclonal bands (OCB), obesity-induced inflammation has been previously speculated in formation of OCB. We investigated the association between BMI, OCB formation and clinical features of MS in 120 patients with relapsing remitting multiple sclerosis (RRMS), a disease with high OCB positivity incidence. Thirty RRMS patients had BMI≥30 and 100 patients displayed CSF OCB. OCB positive and negative patients had comparable BMI and weight values. Disease duration, annual attack number and EDSS were not correlated with BMI and body weight. Patients with normal and high BMI did not significantly differ by means of OCB positivity, gender, annual attack number, disease duration and EDSS scores. Our results argue against a possible role of obesity in OCB formation. Moreover, obesity does not appear to influence disability and clinical progression of MS patients.

Epigenetics of multiple sclerosis: an updated review.

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease characterized with autoimmune response against myelin proteins and progressive axonal loss. The heterogeneity of the clinical course and low concordance rates in monozygotic twins have indicated the involvement of complex heritable and environmental factors in MS pathogenesis. MS is more often transmitted to the next generation by mothers than fathers suggesting an epigenetic influence. One of the possible reasons of this parent-of-origin effect might be the human leukocyte antigen-DRB1*15 allele, which is the major risk factor for MS and regulated by epigenetic mechanisms such as DNA methylation and histone deacetylation. Moreover, major environmental risk factors for MS, vitamin D deficiency, smoking and Ebstein-Barr virus are all known to exert epigenetic changes. In the last few decades, compelling evidence implicating the role of epigenetics in MS has accumulated. Increased or decreased acetylation, methylation and citrullination of genes regulating the expression of inflammation and myelination factors appear to be particularly involved in the epigenetics of MS. Although much less is known about epigenetic factors causing neurodegeneration, epigenetic mechanisms regulating axonal loss, apoptosis and mitochondrial dysfunction in MS are in the process of identification. Additionally, expression levels of several microRNAs (miRNAs) (e.g., miR-155 and miR-326) are increased in MS brains and potential mechanisms by which these factors might influence MS pathogenesis have been described. Certain miRNAs may also be potentially used as diagnostic biomarkers in MS. Several reagents, especially histone deacetylase inhibitors have been shown to ameliorate the symptoms of experimental allergic encephalomyelitis. Ongoing efforts in this field are expected to result in characterization of epigenetic factors that can be used in prediction of treatment responsive MS patients, diagnostic screening panels and treatment methods with specific mechanism of action.

Uveitis as a prognostic factor in multiple sclerosis.

Uveitis is occasionally encountered in multiple sclerosis (MS) patients. The objective of this report is to investigate whether uveitis has a prognostic impact on the clinical course of MS. Several clinical and demographic features were compared between 41 MS patients with uveitis and 100 randomly selected MS patients without uveitis. While there were no significant differences by means of gender, age of MS onset, oligoclonal band positivity and disease duration, EDSS and progression index (PI) scores of MS patients with uveitis were significantly lower than those without uveitis (p = 0.004 and <0.001, respectively). Our results suggest that uveitis might be used as a good prognostic factor.

Predictive value of early serum cytokine changes on long-term interferon beta-1a efficacy in multiple sclerosis.

BACKGROUND: In a previous study, we had evaluated short-term effects of interferon beta-1a (IFNB-1a) 44 µg s.c. three times per week treatment on serum levels of IFN-gamma (IFNG), IL-23, IL-17, IL-10, IL-9, IL-4 and TGF-beta (TGFB) and found a reduction only in IL-17 and IL-23 levels after 2 months of treatment. METHODS: Using the same multiple sclerosis (MS) cohort, we assessed the predictive value of early cytokine level changes (difference between 2nd month and baseline levels as measured by ELISA) on the efficacy of long-term IFNB-1a treatment. RESULTS: The alteration in IFNG levels of patients without any relapse was statistically lower than that of patients having one or more relapses (p = 0.019, Student's t-test). When patients with or without expanded disability severity scale (EDSS) progression were compared, none of the cytokine level changes showed a significant difference between groups. IL-17 and IL-23 level changes did not predict relapse and EDSS progression in IFNB-1a-treated MS patients. CONCLUSION: Our results show that the predictive power of early IFNG measurement on relapse occurrence may potentially extend a time span of several years.

Aquaporin-1 antibody in neuromyelitis optical patients.

BACKGROUND/METHODS: To find out the prevalence of aquaporin-antibody (Aqp-Ab) and characterize Aqp-Ab associated clinical features in NMO, Aqp-1 and Aqp-4-Abs were examined using radioimmunoprecipitation and cell-based assays, respectively. RESULTS: Aqp-4 and Aqp-1-Abs were detected in 20/30 and 8/30 NMO patients, respectively. One patient was Aqp-1-Ab single-positive, 13 patients were Aqp-4-Ab single-positive, 7 patients were Aqp-4/Aqp-1-Ab double-positive and 9 patients were seronegative. All double-positive patients had optic neuritis during the first attack. Only 2/29 MS patients and none of the control idiopathic intracranial hypertension patients were Aqp-1-Ab positive. CONCLUSION: Aqp-1-Ab is usually detected in Aqp-4-Ab positive NMO patients and might be involved in optic neuritis pathogenesis.

Sorcin antibody as a possible predictive factor in conversion from radiologically isolated syndrome to multiple sclerosis: a preliminary study.

OBJECTIVE: To identify an antibody biomarker for prediction of conversion from radiologically isolated syndrome (RIS) to relapsing remitting multiple sclerosis (RRMS). METHODS: Sera of 13 RIS patients were screened by a protein macroarray derived from human fetal brain cDNA library. RESULTS: Sequencing of a clone with the highest signal intensity revealed sorcin as a potential target autoantigen in RIS patients. ELISA studies showed high-titer sorcin-antibodies in 3 of 4 RIS patients who converted to RRMS in a 5-year follow-up period and 13 of 23 control RRMS patients. CONCLUSION: The value of sorcin antibody as a predictor of conversion from RIS to RRMS requires to be tested in larger prospective studies.

Evaluation of incidence and clinical features of antibody-associated autoimmune encephalitis mimicking dementia.

BACKGROUND: Anti-neuronal autoimmunity may cause cognitive impairment that meets the criteria for dementia. Objective. Our aim was to detect the incidence and clinical features of autoimmune encephalitis imitating clinical findings of primary dementia disorders and to delineate the validity of anti-neuronal antibody screening in dementia patients. METHODS: Fifty consecutive patients fulfilling the clinical criteria for primary dementia, 130 control patients, and 50 healthy controls were included. Their sera were investigated for several ion channel and glutamic acid decarboxylase (GAD) antibodies by a cell-based assay, radioimmunoassay, and ELISA, as required. RESULTS: Sixteen patients satisfying dementia criteria had atypical findings or findings suggestive of autoimmune encephalitis. N-methyl-D-aspartate receptor (NMDAR) antibody was detected in a patient with dementia, Parkinsonism, and REM sleep behavior disorder (RBD) fulfilling the criteria for dementia with Lewy bodies (DLB). One control patient with bipolar disease displayed low anti-GAD antibody levels. CONCLUSIONS: Our study showed for the first time the presence of parkinsonism and RBD in an anti-NMDAR encephalitis patient mimicking DLB. Although autoimmune encephalitis patients may occasionally present with cognitive decline, most dementia patients do not exhibit anti-neuronal antibodies, suggesting that routine analysis of these antibodies in dementia is not mandatory, even though they display atypical features.

Switch-associated protein 70 antibodies in multiple sclerosis: possible association with disease progression.

OBJECTIVE: This study was conducted to identify a biomarker for multiple sclerosis (MS) that can be used as a predictor of relapse and disability. MATERIALS AND METHODS: Sera of 26 consecutive relapsing-remitting MS (RRMS) patients were screened for switch-associated protein 70 (SWAP-70) antibody, which was previously identified by protein macroarray. The serum levels of several cytokines, chemokines and soluble adhesion molecules related to MS attacks were measured by enzyme-linked immunosorbent assay (ELISA). A possible correlation was sought among levels of SWAP-70 antibody, measured humoral factors and disability scores. RESULTS: ELISA studies showed high-titre SWAP-70 antibodies in 16 (61.5%) RRMS sera obtained during the attack period and 9 (34.6%) sera obtained during remission. There was a significant inverse correlation between SWAP-70 antibody levels and expanded disability status scale scores, CXCL10, soluble VCAM-1, CXCL13 and soluble VLA-4 levels. CONCLUSION: Our results showed that SWAP-70 antibodies could potentially be utilized as relapse and prognostic biomarkers in MS. Whether or not SWAP-70 antibodies have any effect on disease mechanisms requires further investigation.

Glycine receptor and myelin oligodendrocyte glycoprotein antibodies in Turkish patients with neuromyelitis optica.

BACKGROUND: Seronegative NMO is highly prevalent in non-Western countries implying the presence of as yet unknown antibodies (Ab). We investigated potential novel Ab in aquaporin-4 Ab (AQP-4-Ab) positive and negative NMO patients. METHODS: Sera of 20 NMO patients were examined for AQP-4, myelin oligodendrocyte glycoprotein (MOG) and glycine receptor (GlyR) Ab by cell-based assays. RESULTS: AQP-4-Ab was identified in 10 NMO patients, MOG-Ab was detected only in one AQP-4-Ab positive patient and GlyR-Ab was detected in two AQP-4-Ab negative patients. GlyR-Ab positive patients displayed simultaneous optic neuritis and transverse myelitis attacks and relatively low disability, whereas MOG and AQP-4-Ab double positive patient had a significantly increased disability. CONCLUSION: This study showed for the first time the presence of GlyR-Ab in Turkish NMO patients. In contrast with previous reports, MOG Ab does not appear to be a distinctive marker for Turkish AQP-4-Ab negative NMO patients.

Reduced orexin-A levels in frontotemporal dementia: possible association with sleep disturbance.

Sleep disturbances including excessive daytime sleepiness (EDS) are encountered in frontotemporal dementia (FTD). To investigate the relationship between the plasma orexin-A levels and sleep disturbance patterns, we measured the plasma orexin-A levels and performed sleep studies in patients with FTD. The orexin-A levels were measured in 10 consecutive patients with FTD and controls by enzyme-linked immunosorbent assay. Nocturnal polysomnography (PSG) and Multiple Sleep Latency Test (MSLT) were performed in 2 patients with FTD. The orexin-A levels were significantly lower in patients with FTD compared to controls. The PSG revealed increased rapid eye movement (REM) latency in patients, whether or not they reported EDS. Mean sleep latency in MSLT was less than 10 minutes in both the patients, being shorter in patient without EDS, but none of them had REM sleep onset. Some patients with FTD may develop narcolepsy-like involuntary sleep attacks, even without complaining of EDS. Involvement of hypothalamus and a subsequent alteration in the orexin levels might be one of the determining factors in this sleep disturbance.

[Migraine with prolonged atypical aura: report of two cases]. / Uzamis atipik aurali migren: Iki olgu sunumu.

If migraine does not manifest itself in the form of headache but in some other atypical symptoms with a headache, it is labeled a Migraine Variant. Many migraine variants have been redefined and included in the 2004 International Classification of Headache Disorders classification. These include hemiplegic migraine, basilar-type migraine, childhood periodic syndromes, retinal migraine, complicated migraine, ophthalmoplegic migraine and vertiginous migraine. In this study, we report two patients in different age groups who display basilar-type migraine with symptoms of prolonged atypical aura. Migraine Variants are important to recognize in clinical practice. Most variants respond well to treatment with antimigraine prophylaxis. If diagnosed correctly, treatment response is always satisfying.

Serum anti-neuronal antibodies in amyotrophic lateral sclerosis.

We aimed to investigate various anti-neuronal antibodies in sera of amyotrophic lateral sclerosis (ALS) patients to detect possible autoimmune encephalitis patients imitating ALS findings and to delineate the validity of routine screening of well-characterized anti-neuronal antibodies in ALS. The patients fulfilling the revised El Escorial diagnostic criteria for definite ALS were included. Their serum samples were investigated for antiganglioside (IgM/IgG) and onconeural (IgG) antibodies by immunoblotting, for ion channel antibodies (IgG) by a cell-based assay and for IgG binding patterns to the rat brain by indirect immunohistochemistry. Thirty-five patients with definite ALS and 30 healthy individuals were included. Ganglioside antibodies were detected in 2 out of 35 (5.7%) patients with ALS. The onconeural and ion channel antibodies were negative in our series. Varied serum IgG binding patterns were identified in eight (22.9%) patients. Although autoimmune encephalitis patients may occasionally present with atypical motor neuron disease findings, definite ALS patients do not appear to exhibit onconeural or ion channel antibodies, suggesting that routine analysis of these antibodies in typical ALS is not mandatory. By contrast, some ALS patients display anti-neuronal antibodies against undetermined target antigens, prompting investigation of these novel antibodies with more advanced methods.