Publications by authors named "Antonios Provatas"

9 Publications

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Screening for the C9ORF72 expansion in Greek Huntington Disease phenocopies and controls and meta-analysis of current data.

Tremor Other Hyperkinet Mov (N Y) 2020 06 12;10. Epub 2020 Jun 12.

University of Thessaly, University Hospital of Larissa, Neurology Department, Larissa, GR.

Background: Several European studies examined the role of C9orf72 repeat expansion in patients with Huntington-disease like phenotypes (HD-L). The scope of our study is to investigate the expansion frequency in a Greek HD-L cohort and the meta-analysis of all published cases. This will be of use in genetic counseling of these cases.

Methods: A cohort of 74 patients with HD-L and 67 healthy controls were screened for the C9orf72 expansion status. Case-controls comparison was assessed with the Pearson's chi-square statistic for a 2 × 2 table.A systematic database search was conducted and seven studies, including the current study, were considered eligible for inclusion in a meta-analysis considering a total of 812 patients with HD phenocopies. Pooled mutation frequency was calculated using a Random Effects model or the Mantel-Haezsel fixed effects model, depending on the observed heterogeneity.

Results: In our cohort, one patient was found to have a pathologic expansion of C9orf72, and none from the control group (chi-square: 0.91, p-value: 0.34). Pooled mutation frequency was found at 2% (CI: 1-3%) with low heterogeneity (I:15%).

Discussion: Based on this meta-analysis the recommendation for genetic testing for C9orf72 expansions is further solidified.
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http://dx.doi.org/10.5334/tohm.61DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394208PMC
June 2020

Recurrent episodes of syncope requiring pacemaker implantation as an initial presentation of neuromyelitis optica spectrum disorder.

Mult Scler Relat Disord 2020 Oct 25;45:102423. Epub 2020 Jul 25.

Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece. Electronic address:

Neuromyelitis Optica Spectrum Disorders (NMOSD) can manifest with a variety of heterogeneous symptoms, mainly encompassing optic neuritis, acute myelitis and area postrema syndrome (hiccups, nausea, and vomiting). Syncopal episodes have rarely been described as an initial manifestation of NMOSD. Here, we report a case of a 42-year-old male who was diagnosed with NMOSD after initially presenting with intractable hiccups and recurrent episodes of syncope. This report is of particular interest, as it suggests that NMOSD should be included in the differential diagnosis of patients with intractable hiccups and heart rhythm disorders.
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http://dx.doi.org/10.1016/j.msard.2020.102423DOI Listing
October 2020

Posterior reversible encephalopathy in a GT1a positive oculopharyngeal variant of Guillain-Barré syndrome: A case-report and review of the literature.

Clin Neurol Neurosurg 2020 Sep 22;196:106037. Epub 2020 Jun 22.

Department of Neurology, University Hospital of Larissa, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece.

Guillain-Barre syndrome (GBS) is the most common cause of acute flaccid paralysis and its incidence increases with age, although all age groups can be affected. The cranial subtypes of GBS account for approximately 5% of cases. Posterior reversible encephalopathy syndrome (PRES) is an acute neurological disorder, mostly reversible but with increased morbidity with permanent neurological sequelae in severe cases. The coexistence of these two syndromes is very rare and underdiagnosed. To the best of our knowledge, there are several dozen cases reported in the literature including ours with the coexistence of these two syndromes in adult patients. We present a rare case of oculopharyngeal type of GBS followed by PRES syndrome. Based on the reviewed cases we discuss various pathogenic mechanisms that support the association between these two entities. This review illustrates the importance of detecting PRES syndrome in the context of acute inflammatory immune-mediated polyneuropathies especially when the patients present early dysautonomia. We also discuss the importance of early administration of immunoglobulin (IVIG) treatment but the possible risks that poses to the occurrence of PRES syndrome as well.
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http://dx.doi.org/10.1016/j.clineuro.2020.106037DOI Listing
September 2020

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy revisited: Genotype-phenotype correlations of all published cases.

Neurol Genet 2020 Jun 11;6(3):e434. Epub 2020 May 11.

Department of Neurology (G.X., C.M., D.G., A.P., M.S., G.M.H.), University Hospital of Larissa, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece; Second Department of Neurology (C.Z., A.T., P.Z., A.B., K.V., G.T.), "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece; Department of Neurology (G.M.H.), Medical School, University of Cyprus, Nicosia, Cyprus; Department of Hygiene and Epidemiology (K.D., C.H.), Faculty of Medicine, University of Thessaly, Larissa, Greece; Department of Medical Oncology (P.N.), University Hospital of Ioannina, Ioannina, Greece; Department of Neurology (P.S.), Mediterraneo Hospital, Glyfada, Athens, Greece; Histopathological Department (C.N., S.S.), Hippokration General Hospital Thessaloniki; and Department of Neurology (G.P.P.), School of Medicine, National and Kapodistrian University of Athens, Eginition Hospital, Athens, Greece.

Objective: The aim of this study was to evaluate the correlation between the various mutations and their clinical and genetic profile, along with the presentation of a novel mutation in a patient.

Methods: Here, we describe the phenotype of a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) harboring a novel mutation. We also performed an extensive literature research for mutations published since the identification of the gene and performed a systematic review of all published cases with NOTCH3 mutations. We evaluated the mutation pathogenicity in a great number of patients with detailed clinical and genetic evaluation and investigated the possible phenotype-genotype correlations.

Results: Our patient harbored a novel mutation in the gene, the c.3084 G > C, corresponding to the aminoacidic substitution p.Trp1028Cys, presenting with seizures as the first neurologic manifestation. We managed to find a correlation between the pathogenicity of mutations, severity of the phenotype, and age at onset of CADASIL. Significant differences were also identified between men and women regarding the phenotype severity.

Conclusions: The collection and analysis of these scarce data published since the identification of qualitatively by means of a systematic review and quantitatively regarding genetic profile and pathogenicity scores, highlight the significance of the ongoing trend of investigating phenotypic genotypic correlations.
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http://dx.doi.org/10.1212/NXG.0000000000000434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238894PMC
June 2020

Pesticides, cognitive functions and dementia: A review.

Toxicol Lett 2020 Jun 4;326:31-51. Epub 2020 Mar 4.

Department of Neurology, Laboratory of Neurogenetics, University Hospital of Larissa, Greece; Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece. Electronic address:

Pesticides are widely-used chemicals commonly applied in agriculture for the protection of crops from pests. Depending on the class of pesticides, the specific substances may have a specific set of adverse effects on humans, especially in cases of acute poisoning. In past years, evidence regarding sequelae of chronic, low-level exposure has been accumulating. Cognitive impairment and dementia heavily affect a person's quality of life and scientific data has been hinting towards an association between them and antecedent chronic pesticide exposure. Here, we reviewed animal and human studies exploring the association between pesticide exposure, cognition and dementia. Additionally, we present potential mechanisms through which pesticides may act neurotoxically and lead to neurodegeneration. Study designs rarely presented homogeneity and the estimation of the exposure to pesticides has been most frequently performed without measuring the synergic effects and the possible interactions between the toxicants within mixtures, and also overlooking low exposures to environmental toxicants. It is possible that a Real-Life Risk Simulation approach would represent a robust alternative for future studies, so that the safe exposure limits and the net risk that pesticides confer to impaired cognitive function can be examined. Previous studies that evaluated the effect of low dose chronic exposure to mixtures of pesticides and other chemicals intending to simulate real life exposure scenarios showed that hormetic neurobehavioral effects can appear after mixture exposure at doses considered safe for individual compounds and these effects can be exacerbated by a coexistence with specific conditions such as vitamin deficiency. However, there is an overall indication, derived from both epidemiologic and laboratory evidence, supporting an association between exposure to neurotoxic pesticides and cognitive dysfunction, dementia and Alzheimer's disease.
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http://dx.doi.org/10.1016/j.toxlet.2020.03.005DOI Listing
June 2020

A novel homozygous SACS mutation identified by whole exome sequencing-genotype phenotype correlations of all published cases.

J Mol Neurosci 2020 Jan 7;70(1):131-141. Epub 2019 Nov 7.

Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece.

ARSACS is an autosomal recessive disorder characterized by ataxia, spasticity, and polyneuropathy. A plethora of worldwide distributed mutations have been described so far. Here, we report two brothers, born to non-consanguineous parents, presenting with cerebellar ataxia and peripheral neuropathy. Whole-exome sequencing revealed the presence of a novel homozygous variant in the SACS gene. The variant was confirmed by Sanger sequencing and found at heterozygous state in both parents. This is the first reported mutation in this gene, in Greek population. This case report further highlights the growing trend of identifying genetic diseases previously restricted to single, ethnically isolated regions in many different ethnic groups worldwide. Additionally, we performed a systematic review of all published cases with SACs mutations. ARSACS seems to be an important cause of ataxia and many different types of mutations have been identified, mainly located in exon 10. We evaluated the mutation pathogenicity in all previously reported cases to investigate possible phenotype-genotype correlations. We managed to find a correlation between the pathogenicity of mutations, severity of the phenotype, and age of onset of ARSACS. Greater mutation numbers in different populations will be important and mutation-specific functional studies will be essential to identify the pathogenicity of the various ARSACS variants.
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http://dx.doi.org/10.1007/s12031-019-01410-zDOI Listing
January 2020

Body mass index in patients with Multiple Sclerosis: a meta-analysis.

Neurol Res 2019 Sep 31;41(9):836-846. Epub 2019 May 31.

Department of Neurology, University Hospital of Larissa, University of Thessaly , Larissa , Greece.

: The impact of nutrition and diet on the etiology of Multiple Sclerosis (MS) has been evaluated through a number of studies. Only a limited number reported findings on the association between body mass index (BMI) and MS. We systematically assessed whether BMI differs between MS patients and healthy individuals. : The PubMed database was searched for available studies assessing the relationship between BMI and MS until April 2018. Random effects models were applied for evaluating the association of mean BMI between MS, relapsing-remitting MS (RRMS) patients, females, or males with MS, and their respective healthy control groups. : We included 25 studies. The mean BMI of MS patients during the course of the disease and RRMS patients was significantly different from the mean BMI of their healthy counterpart individuals [standardized mean difference (SMD) (95% confidence interval (CI)): -0.25 (-0.44, -0.06), P = 0.01 and SMD (95%): -0.27 (-0.54, -0.01), P = 0.04, respectively]. The mean BMI of females with MS was significantly differentfrom that of corresponding healthy females [SMD (95% CI): -0.52 (-0.96, -0.07), P = 0.02]. Moreover, the mean BMI was significantly different between males with MS and healthy males [SMD (95% CI): -0.75 (-1.33, -0.18), P = 0.01]. : Statistically significantly lower mean BMI was revealed in the overall MS patients' group during the MS course than in healthy controls. The same difference was revealed in all parts of the meta-analysis demonstrating a significantly lower BMI in patients with RRMS, in females, and in males with MS, when compared to their respective healthy individuals.
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http://dx.doi.org/10.1080/01616412.2019.1622873DOI Listing
September 2019

The role of C9orf72 in neurodegenerative disorders: a systematic review, an updated meta-analysis, and the creation of an online database.

Neurobiol Aging 2019 12 24;84:238.e25-238.e34. Epub 2019 Apr 24.

Department of Neurology, University of Thessaly, University Hospital of Larissa, Larissa, Greece. Electronic address:

A pathologic expansion of a noncoding GGGGCC hexanucleotide repeat of the C9orf72 gene has been strongly associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) cases predominantly in Caucasian populations. In the last decade, scientific interest had been drawn to this gene and many studies conducted have shown a possible correlation with other neurodegenerative diseases as well. We performed an extensive literature search for C9orf72 mutation and its frequency in various neurological and psychiatric diseases. In addition, we performed a meta-analysis of the data related to ALS and familial ALS. An online cloud-based database and an interactive map were developed. The overall mutation frequency of C9orf72 is 20% for familial FTD, 16% for familial ALS and around 6%-8% for sporadic ALS and FTD. The updated meta-analysis that we performed showed that the pooled frequency of C9orf72 repeat expansion in patients with familial ALS was 23% (CI: 18%-28%) and in patients with sporadic ALS 3% (CI: 3%-4%). The subgroup analysis regarding the origin of the population revealed significant differences between Caucasian and Asian patients. Our analysis supports the direct causal relation of the C9orf72 expansion in ALS and FTD. On the contrary, the role of C9orf72 in other neurodegenerative disorders remains controversial. The system that we developed-the online database and the interactive map-is hopefully a stepping stone for an ever-growing platform that will aid scientists from all over the world in contributing to the meta-analysis of C9orf72-related publications.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.04.012DOI Listing
December 2019

Gene variants of adhesion molecules act as modifiers of disease severity in MS.

Neurol Neuroimmunol Neuroinflamm 2017 Jul 24;4(4):e350. Epub 2017 Apr 24.

The Cyprus Institute of Neurology and Genetics (E.D., E.P., K.C., A.H., M.P., T.K.), Nicosia, Cyprus; Department of Neurology (E.D., A.P., G.M.H.), Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa; Head of Research and Developments (A.A.), Stremble Ventures LTD, Limassol, Cyprus; and 2nd Department of Neurology (A.L., N.G.), AHEPA University Hospital, Aristotle University of Thessaloniki, Greece.

Objective: To assess the potential effect of variants in genes encoding molecules that are implicated in leukocyte trafficking into the CNS on the clinical phenotype of multiple sclerosis (MS).

Methods: A total of 389 Greek MS cases and 336 controls were recruited in 3 MS centers from Cyprus and Greece. We genotyped 147 tagging single nucleotide polymorphisms (SNPs) in 9 genes encoding for P-selectin (), integrins (, , and ), adhesion molecules (, , and ), fibronectin 1 (), and osteopontin () involved in lymphocyte adhesion and trafficking into the CNS. Clinical end points of the study were age at MS onset and MS severity as measured by the Multiple Sclerosis Severity Score. Permutation testing was applied to all analyses.

Results: SNPs rs6721763 of the and rs6532040 of the were found to significantly influence disease severity (permutation values: 3.00e-06 and 0.009884, respectively). SNP rs1250249 of the had a dose-dependent effect on age at disease onset (permutation value: 0.0002).

Conclusions: This study provides evidence implicating variants encoding adhesion molecules, responsible for lymphocyte adhesion and trafficking within the CNS, as modifiers of MS disease severity. These genetic biomarkers, which can be available at the time of diagnosis, may be used to assess the biological aggressiveness of the disease and thus guide decisions on treatment.
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http://dx.doi.org/10.1212/NXI.0000000000000350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405760PMC
July 2017