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Mutations in Lysine-Specific Histone Methyltransferase 2B gene (KMT2B) have been reported to be associated with isolated and complex early-onset generalized dystonia. We describe clinico-genetic features on a Greek patient with a novel de novo variant and demonstrate the phenotypic spectrum of KMT2B variants. We performed whole exome sequencing (WES), in a Greek patient with sporadic generalized dystonia. Additionally, we performed a systematic review of all published cases with KMT2B variants. The patient presented with isolated and mild generalized dystonia. We identified a novel splice site variant that was confirmed by Sanger sequencing and was not found in parents. This is the first reported KMT2B variant, in the Greek population. This case report further highlights the growing trend of identifying genetic diseases previously restricted to few cases in many different ethnic groups worldwide via exome sequencing. In the systematic review, we evaluated the mutation pathogenicity in all previously reported cases to investigate possible phenotype-genotype correlations. Greater mutation numbers in different populations will be important and mutation-specific functional studies will be essential to identify the pathogenicity of the various KMT2B variants.

Background Parkinson’s disease (PD) is a neurodegenerative disease, mostly presenting with characteristic motor symptoms. Organochlorines (OC) are a class of widely-used pesticides that have been included among the list of environmental factors incriminated in PD pathogenesis. However, most studies reporting this association are based on questionnaires, and few have reported exposure data. Aim To examine the relationship between OC blood concentrations and PD risk. Methods In the present study, we studied the concentrations of 8 OC compounds (hexachlorobenzene, heptachlor, hepachlor epoxide, c-chlordane, a-chlordane, p,p’-DDE, DDD, DDT) in 104 Greek PD patients and 110 healthy controls. Results All substances studied were present in at least one sample. The most frequently detected (above the level of quantification) pesticides were p,p’-DDE (n = 214, 100 % of both groups) and hexachlorobenzene, HCB (n = 189, cases 46.5 %, controls 53.5 %). Higher levels of DDE were detected among PD patients in comparison to controls by using logistic regression analysis to control for confounders [Odds Ratio, OR (95 % confidence interval, C.I.)]: 2.592,(1.29–5.21)], whilst lower levels of HCB were detect among PD patients [OR,95 %CI:0.176(0.09−0.35)]. Conclusions Our data suggest that exposure to specific OCs is related to the risk of PD. Further studies, using real exposure data, are needed in order to confirm and extend these findings.

A total of 178 consecutive patients with definite sALS without frontotemporal dementia (FTD) were enrolled in this study, after complete clinical evaluation. A Repeat-Primed Polymerase Chain Reacti...

The examination of the risk factors that affect the recurrence of transient global amnesia (TGA) may shed light on the pathophysiological substrate of the disease. A systematic review was performed to identify the factors associated with the recurrence of TGA. MEDLINE, EMBASE, CENTRAL and PsycINFO were meticulously searched. Observational controlled studies involving patients with single (s-TGA) and recurrent TGA (r-TGA) according to Hodges and Warlow’s criteria were retrieved. Differences in the demographic characteristics, personal and family medical history, previous exposure to precipitating events and laboratory findings were examined. Retrieved evidence was assessed in the context of the individual article validity, based on the numerical power and methodological quality of each study. Nine cohort studies with retrospective, prospective or mixed design were retrieved. In total, 1989 patients with TGA were included, 269 of whom suffered from r-TGA (13.5%). R-TGA presented an earlier age of onset. Evidence was suggestive of a relationship between recurrence and a family or personal history of migraine, as well as a personal history of depression. There was weaker evidence that associated recurrence with a positive family history of dementia, a personal history of head injury and hippocampal lesions in diffusion-weighted MRI. On the other hand, no connection was found between recurrence and electroencephalographic abnormalities, impaired jugular venous drainage, cardiovascular risk factors, atrial fibrillation, previous cerebrovascular events, exposure to precipitating events, a positive family history of TGA and hypothyroidism. Important pathophysiological insights that arised from these findings were discussed.

Hannu Laaksovirta konsortion jäsenenä. The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Introduction Some case series have suggested that psychotic features could occur even before the onset of motor symptoms of Parkinson's Disease (PD). Our aim was to investigate a possible association between psychotic symptoms and prodromal Parkinson's disease in a population-based cohort, the Hellenic Longitudinal Investigation of Aging and Diet study. Methods This cross-sectional study included participants aged ≥65 years without dementia or PD. We defined psychotic symptoms as the presence of at least one new hallucinatory or delusional feature, assessed with the Neuropsychiatric Inventory scale and the Columbia University Scale for Psychopathology in Alzheimer's Disease, exhibited only at follow-up and not present at baseline visit. We calculated the probability of prodromal PD (pPD) for every participant, according to the 2019 International Parkinson and Movement Disorders Society research criteria for prodromal PD. Results Participants who developed psychotic manifestations over a three-year follow up (20 of 914) had 1.3 times higher probability of pPD score (β [95%CI]: 1.3 [0.9-1.5], p=0.006) compared to non-psychotic subjects. This association was driven mostly by depressive symptoms, constipation and subthreshold parkinsonism (p Conclusion Our data indicate that emerging psychotic features evolve in parallel with the probability of pPD. This is the first study that provides evidence for the presence of psychotic experiences in pPD. The association detected needs to be confirmed in longitudinal studies.

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.

To present the new guidelines and therapeutic options regarding cerebrovascular complications of cancer, mainly ischemic stroke, cerebral venous thrombosis (CVT), and leptomeningeal carcinomatosis (LMC). A temporal trend study (2019) revealed that clinicians are still reluctant to apply thrombolysis to cancer patients, although two new studies (2018) reported no increased mortality. Several clinical trials on direct oral anticoagulants (DOACs) showed their superiority or, at least, non-inferiority compared with low molecular weight heparins in the treatment of venous thromboembolism (VTE) (2018–2019). These trials helped in formulating the new guidelines that are being published and the decisions made for cancer-associated thrombosis (CAT) as a whole. A new DOAC antidote was also officially released (US 2018, Europe 2019). Thrombolysis is safe in a malignancy setting, thus cancer per se should not be considered a contraindication for thrombolysis. Clinical trials assessing the newest DOACs for cancer-associated arterial thrombosis are scarce; however, based on data from VTE studies, the newest DOACs seem to be safe for CAT in patients that are not in high risk of bleeding or suffering from certain malignancies. The treatment should not be ceased after 6 months, but rather continued as long as the cancer remains active. Decompressive craniectomy should maintain its place in patients with CVST in risk of herniation. Last, the future also holds much promise on the role of novel compounds to be used in LMC.

BACKGROUND Helicobacter pylori (H pylori) is a Gram-negative bacterium, considered to trigger autoimmune gastrointestinal disorders. This pathogen has also been linked to the autoimmune sequelae in extra-gastrointestinal diseases and peripheral neuropathies. Guillain-Barre syndrome (GBS) is a serious autoimmune demyelinating disorder of peripheral nerves, usually with a post-infectious onset. About 30% of cases of GBS attributed to by Campylobacter jejuni, so, H pylori, could be also involved. Growing evidence suggests the likely involvement of H pylori infection in the development of GBS. The aim of the current study was to therefore estimate the prevalence of H pylori antibodies in GBS. METHODS A search of the literature was performed, using the PUBMED database, until December 2018. Data were extracted from six case-control studies, and a stratification analysis was conducted according to cerebrospinal fluid (CSF) or serum detection material. RESULTS Among 29 records found, 6 studies met in the inclusion criteria for the meta-analysis. In the CSF subgroup, 105 participants were involved (40 GBS patients and 65 controls), while the serum subgroup included 325 participants (152 GBS and 173 controls). Data were combined using a fixed-effects model. Anti-H pylori IgG were significantly more prevalent in GBS patients compared to controls, in both CSF (95% CI: 9.66-186.56, OR: 42.45, Pz

Objective The objective of this study was to validate the recently updated research criteria for prodromal Parkinson's disease (pPD) proposed by the International Parkinson's Disease and Movement Disorders Society. Methods A total of 16 of 21 markers of pPD were ascertained in the Hellenic Longitudinal Investigation of Aging and Diet cohort composed of community-dwelling individuals aged ≥65 years. The probability of pPD was calculated for 961 individuals without Parkinson's disease (PD) or dementia with Lewy bodies at baseline who were followed-up for a median of 3 years. The ability of the criteria to predict conversion to PD/dementia with Lewy bodies was assessed by estimating their sensitivity and specificity, plotting receiver operating characteristics curves, and using logistic regression. These analyses were repeated using the original criteria. Results No incident PD/dementia with Lewy bodies case had probable pPD at baseline (ie, ≥80% pPD probability). At cut-offs of 10%, 30%, and 50% probability of pPD, the sensitivity and specificity of the criteria ranged from 4.5% to 27.3%, and 85.7% to 98.3% respectively. The area under the receiver operating characteristics curve was 0.691 (95% confidence intervals, 0.605-0.777). In logistic regression models, the criteria-derived posttest odds of pPD were a significant predictor of conversion at follow-up. The updated criteria performed similarly to the original but showed a slight increase in sensitivity. Conclusions The new criteria demonstrated suboptimal sensitivity in our random sample of community-dwelling individuals. The absence of specialized assessments with high likelihood ratios in our cohort could be hindering the demonstration of higher sensitivities. Such assessments should be a part of future validation attempts. © 2020 International Parkinson and Movement Disorder Society.

Background Amyotrophic lateral sclerosis (ALS) is a devastating disease whose complex pathology has been associated with a strong genetic component in the context of both familial and sporadic disease. Herein, we adopted a next-generation sequencing approach to Greek patients suffering from sporadic ALS (together with their healthy counterparts) in order to explore further the genetic basis of sporadic ALS (sALS). Results Whole-genome sequencing analysis of Greek sALS patients revealed a positive association between FTO and TBC1D1 gene variants and sALS. Further, linkage disequilibrium analyses were suggestive of a specific disease-associated haplotype for FTO gene variants. Genotyping for these variants was performed in Greek, Sardinian, and Turkish sALS patients. A lack of association between FTO and TBC1D1 variants and sALS in patients of Sardinian and Turkish descent may suggest a founder effect in the Greek population. FTO was found to be highly expressed in motor neurons, while in silico analyses predicted an impact on FTO and TBC1D1 mRNA splicing for the genomic variants in question. Conclusions To our knowledge, this is the first study to present a possible association between FTO gene variants and the genetic etiology of sALS. In addition, the next-generation sequencing-based genomics approach coupled with the two-step validation strategy described herein has the potential to be applied to other types of human complex genetic disorders in order to identify variants of clinical significance. Electronic supplementary material The online version of this article (10.1186/s40246-017-0126-2) contains supplementary material, which is available to authorized users.

Helicobacter pylori (H. pylori) induces reactive oxygen species (ROS) production that contribute to pathogenesis of a variety of H. pylori-related gastric diseases, as shown in animal and human studies. Helicobacter pylori infection is also associated with variety of systemic extragastric diseases in which H. pylori-related ROS production might also be involved in the pathogenesis of these systemic conditions. We proposed that Hp-related ROS may play a crucial role in the pathophysiology of Hp-related systemic diseases including Alzheimer's disease, multiple sclerosis, glaucoma and other relative neurodegenerative diseases, thereby suggesting introduction of relative ROS scavengers as therapeutic strategies against these diseases which are among the leading causes of disability and are associated with a large public health global burden. Moreover, we postulated that H. pylori-related ROS might also be involved in the pathogenesis of extragastric common malignancies, thereby suggesting that H. pylori eradication might inhibit the development or delay the progression of aforementioned diseases. However, large-scale future studies are warranted to elucidate the proposed pathophysiological mechanisms, including H. pylori-related ROS, involved in H. pylori-associated systemic and malignant conditions.

A 67-year-old male photographer who used traditional cameras that necessitated monocular focusing developed intermittent blepharospasms, evident only during and shortly after the voluntary contraction of the left eyelids while using the camera, a form of a task-specific blepharospasm. The spasms gradually progressed to involve the entire hemiface resulting in a task-specific hemifacial spasm that eventually evolved into a persistent hemifacial spasm. Our case report highlights the fact that focal dystonia may also develop in the facial muscles following chronic and repetitive muscle contractions, such as those performed by an older photographer who used traditional cameras that necessitated monocular focusing. To our knowledge, hemifacial spasm has not yet been recognized as a form of focal, task-specific dystonia. Moreover, occupational, focal dystonia has not been described in photographers.

Background To investigate the association between frailty, Parkinson’s disease (PD), and the probability of prodromal Parkinson’s disease (prodromal PD) in Greek community-dwelling older individuals. Methods Parkinson’s disease diagnosis was reached through standard clinical research procedures. Probability of prodromal PD was calculated according to the International Parkinson and Movement Disorder Society’s research criteria for PD-free participants. Frailty was evaluated according to definitions of the phenotypic and multidomain approach. Logistic and linear regression models were performed to investigate associations between frailty (predictor) and the probability of prodromal PD, either continuous or dichotomous (≥30% probability score), or PD (outcome). Results Data from 1765 participants aged 65 and older were included in the present analysis. Parkinson’s disease and prodromal PD prevalence were 1.9% and 3.0%, respectively. Compared to nonfrail participants, those who were frail, as identified with either the Fried frailty phenotype or Frailty Index had approximately 4 (odds ratio [OR] 4.09, 95% confidence interval [CI] 1.54–10.89) and 12 times (OR 12.16, 95% CI 5.46–27.09) higher odds of having a PD diagnosis, respectively. Moreover, compared to the nonfrail, frail participants as identified with either the Fried frailty phenotype or Frailty Index had 2.8 (OR 2.83, 95% CI 1.09–7.37) and 8.3 times (OR 8.39, 95% CI 4.56–15.42) higher odds of having possible/probable prodromal PD, respectively. Conclusions Frailty status was associated with prodromal PD and PD, suggesting common characteristics or underlying mechanisms of these conditions. Although prospective studies are warranted, acknowledging the possible association of frailty, PD, and prodromal PD may improve their clinical management.

Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0–49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2–5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1–46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an ‘AP-4 deficiency syndrome’. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.

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.

Introduction Fahr’s syndrome due to hypoparathyroidism refers to bilateral basal ganglia (BG) calcifications and manifests with movement disorders, seizures, cognitive and behavioral symptoms. Case presentation We report a case of a 74-year-old woman, who presented with parkinsonism due to post-surgical hypoparathyroidism and normal DaT scan, despite extensive calcifications of the BG, periventricular white matter, and cerebellum. Methods A comprehensive literature review of all reported cases of Fahr’s syndrome due to hypoparathyroidism was conducted in the electronic databases PubMed and Web of science. Moreover, demographic and clinical characteristics of the patients overall were calculated and associated with radiological findings. Results We reviewed a total of 223 cases with Fahr’s syndrome due to hypoparathyroidism (124 female, 99 male). Mean age on presentation was 44.6 ± 17.7 years. Thirty nine percent of patients had idiopathic hypoparathyroidism, 35.4 % acquired and 25.6 % pseudohypoparathyroidism. Almost half of the patients had tetany, seizures or a movement disorder and approximately 40 % neuropsychiatric symptoms. The patients with a movement disorder had a 2.23 likelihood of having neuropsychiatric symptoms as well (OR 2.23, 95 % CI 1.29–3.87). Moreover, there was a statistically significant association between the phenotype severity (i.e. the presence of more than one symptom) and the extent of brain calcifications (χ2 = 32.383, p = 0.009). Conclusion Fahr’s syndrome is a rare disorder, which nonetheless manifests with several neurological symptoms. A head CT should be considered for patients with hypoparathyroidism and neurological symptoms. More studies using DaT scan are needed to elucidate the effects of calcifications on the dopaminergic function of the BG.

It is critical that Randomized Controlled Trials(RCTs) present complete and transparent reporting. The present study aims to determine the reporting quality of double-blind RCTs for medicinal interventions in patients with ischemic stroke, based on the 2010 CONSORT-statement.MEDLINE was comprehensively searched. The CONSORT period was demarcated between 2000 and 2019, while compliance ≥75 was defined as good-adequate. Possible determinants were univariately and multivariately examined for associations.Overall, 197 articles were considered eligible, 143 published after and 54 before 2000. CONSORT compliance was 68.11% ± 11.56% (standard deviation) and 55.65% ± 11.57% respectively. Among retrieved articles 56/143(39.16%) and 1/54(1.85%) were rated as of good reporting quality correspondingly [p .001, OR = 34.115, 95%CI = (4.586, 253.762)]. McNemar's test was indicative of consistency regarding the adequately/inadequately reported items before and after the 2010 CONSORT-revision (p = 1.00). Univariate analysis revealed two significant associations with the reporting quality: high impact factor(IF) [high vs. moderate; p = .007, OR = 3.521, 95%CI = (1.396, 8.879), high vs. low; p .001, OR = 7.583, 95%CI = (3.063, 18.762), moderate vs. low; p = .078, OR = 2.154, 95%CI = (0.911, 5.093)] and sample size [p .001, OR = 4.297, 95%CI = (2.081, 8.874)]. Publication period (p = .742) and funding (p = .280) were not significantly associated. Multivariate analysis attenuated the impact of sample size providing insignificant results, whereas the effect of high IF remained significant [moderate vs. high; p = .029, OR = 0.337, 95%CI = (0.127, 0.895), low vs. high; p = .012, OR = 0.199, 95%CI = (0.057, 0.699)]. An exploratory analysis demonstrated significant, weak to moderate, positive linear correlation between reporting quality and IF [Pearson's r = 0.418, p .001].Adherence to the CONSORT-statement needs to be further endorsed and incorporated in every journal's instructions-to-authors.

ObjectiveThe aim of this study was to evaluate the correlation between the various NOTCH3 mutations and their clinical and genetic profile, along with the presentation of a novel mutation in a patient.MethodsHere, 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 NOTCH3 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.ResultsOur patient harbored a novel mutation in the NOTCH3 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.ConclusionsThe collection and analysis of these scarce data published since the identification of NOTCH3 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.

Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurodegenerative disorder. Two forms are recognized, familial (FALS) that accounts for 5-10% of ALS cases, and sporadic (SALS) that accounts for the rest. Early diagnosis of ALS is important because it improves their therapeutic efficacy. Current diagnosis is based on clinical assessment and requires approximately 12 months, leading to a significant delay in drug administration. Therefore, new methods are required for the earlier diagnosis of ALS. Screening for pathogenic variants in known ALS-associated genes is already exploited as a diagnostic tool in ALS but cannot be applied for population-based screening. New circulating biomarkers (proteins or small molecules) are needed for initial screening, whereas specific diagnostic methods can be applied to confirm the presence of pathogenic variants in the selected population subgroup. Lipids appear as promising biomarkers for population-based screening and for monitoring disease progression. Genetic analysis can also assist in the prediction of disease progression by analyzing disease-modifying genes, for example, EPHA4 and CHGB. Furthermore, molecular diagnosis will aid the stratification of ALS patients for improved pharmacological approaches. Here, we discuss current and novel diagnostic strategies and how they can be applied to revolutionize the field of ALS molecular diagnosis.

Human papillomavirus (HPV) infection alone is not sufficient to explain the development of cervical cancer. Genetic variants have been linked to the development of precancerous lesions and cervical cancer. In this study, we aimed to evaluate the association of 10 single nucleotide polymorphisms (SNPs) of the Fas cell surface death receptor (FAS), trinucleotide repeat containing 6C (TNRC6C), transmembrane channel like 8 (TMC8), DNA meiotic recombinase 1 (DMC1), deoxyuridine triphosphatase (DUT), sulfatase 1 (SULF1), 2′-5-oligoadenylate synthetase 3 (OAS3), general transcription factor IIH subunit 4 (GTF2H4) and interferon gamma (IFNG) genes with susceptibility to precancerous lesions and cervical cancer. In total, 608 female participants, consisting of 199 patients with persistent low-grade precancerous lesions (CIN1), 100 with high-grade precancerous lesions (CIN2/3), 17 patients with cervical cancer and 292 healthy controls, were enrolled in this study. SNPs were tested for associations with each of the above-mentioned cervical group lesions or when considering an overall patient group. A significant difference for rs4737999 was observed between the controls and the overall patient group considering the recessive mode of inheritance [odds ratio (OR), 0.48; 95% confidence interval (CI), 0.24–0.96; P=0.033]. This effect was even stronger on the risk of CIN1 lesions. Carriers of the rs4737999 AA genotype were almost 3-fold less likely of having low grade lesions compared to the other genotypes. On the whole, this study provides evidence of an influence of the SULF1 gene rs4737999 SNP in the development of precancerous lesions/cervical cancer.

Background Thyrotoxic periodic paralysis (TPP) is an uncommon complication of Graves' disease, characterized by the triad of acute hypokalemia without total body potassium deficit, episodic muscle paralysis, and thyrotoxicosis. Graves' encephalopathy is an extremely rare form of encephalopathy associated with autoimmune thyroid disease (EAATD), characterized by neuropsychiatric symptoms, increased antithyroid antibodies and cerebrospinal fluid protein concentration, nonspecific electroencephalogram abnormalities, and cortico-responsiveness. Coexistence of both these complications in the same patient has not been reported before. Case report We herein present a 48-year-old white male patient with TPP and encephalopathy as initial presentations of Graves' disease. Flaccid tetraparesis was reversed a few hours after potassium level correction and the patient did not suffer any relapse with the successful pharmaceutical management of the thyroid function. One month later, the patient presented with dizziness and behavioral symptoms, such as inappropriate laughter and anger. Brain magnetic resonance imaging revealed meningeal enhancement and cerebrospinal fluid analysis showed a mild protein increase, with a blood-brain barrier disruption. With the suspicion of EAATD, the patient was treated with high doses of corticosteroids and improved dramatically. Conclusions To our knowledge this is the first reported coexistence of potentially treatable TPP and EAATD as initial neurological manifestations of Graves' disease, thereby underscoring the necessity of suspicion of possible underlying Graves' disease in patients with acute paralysis and encephalopathy of unclear origin.

A recent study MacLeod et al. has shown that an interaction between variants at the LRRK2 and PARK16 loci influences risk of development of Parkinson's disease (PD). Our study examines the proposed interaction between LRRK2 and PARK16 variants in modifying PD risk using a large multicenter series of PD patients (7715) and controls (8261) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Our data does not support a strong direct interaction between LRRK2 and PARK16 variants; however, given the role of retromer and lysosomal pathways in PD, further studies are warranted. (C) 2016 Elsevier Inc. All rights reserved.

THAP1 mutations have been shown to be the cause of DYT6. A number of different mutation types and locations in the THAP1 gene have been associated with a range of severity and dystonia phenotypes, but, as yet, it has been difficult to identify clear genotype phenotype patterns. Here, we screened the THAP1 gene in a further series of dystonia cases and evaluated the mutation pathogenicity in this series as well as previously reported mutations to investigate possible phenotype-genotype correlations. THAP1 mutations have been identified throughout the coding region of the gene, with the greatest concentration of variants localized to the THAP1 domain. In the additional cases analyzed here, a further two mutations were found. No obvious, indisputable genotype-phenotype correlation emerged from these data. However, we managed to find a correlation between the pathogenicity of mutations, distribution, and age of onset of dystonia. THAP1 mutations are an important cause of dystonia, but, as yet, no clear genotype-phenotype correlations have been identified. Greater mutation numbers in different populations will be important and mutation-specific functional studies will be essential to identify the pathogenicity of the various THAP1 mutations. © 2012 Movement Disorder Society.

In their review Licinio et al.1 concluded that, despite mostly experimental clues for an association between Helicobacter pylori (Hp) and portal hypertension (PH) have been shown, the relationship ...

Nasu-hakola disease (NHD) is a rare disease characterized by bone cysts and fractures, frontal lobe syndrome, and progressive presenile dementia. NHD may be the prototype of primary microglial disorders of the CNS or, as they have been coined, "microgliopathies". Mutations in TREM2 and TYROBP genes are known to cause NHD. Interestingly, recent evidence-associated rare genetic variants of TREM2 gene with increased risk of Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, and Parkinson's disease. Here, we report a 33-year-old Greek female with phenotype suggestive of NHD. Full gene sequencing of the TREM2 and TYROBP genes revealed a novel mutation in exon 2 of TREM2 gene, namely c.244G>T (p.W50C) and heterozygosity in the parents and her brother. This report extends the range of TREM2 mutations that cause NHD phenotype. In addition, we provide a comprehensive review of all reported in the literature TREM2 gene mutations and the respective wide spectrum of clinical manifestations that highlights the importance of considering TREM2 gene mutations in a variety of neurodegenerative phenotypes.

An increasing number of clinical, neuropathological and experimental evidence linking Gaucher disease and a spectrum of synucleinopathies, including Parkinson's disease (PD) has emerged over the last decade. In particular, several studies, despite individual differences, have shown that mutations in the β-glucocerebrosidase gene (GBA) are a risk factor for PD. Recently a study from Northern Greece has shown a significant overrepresentation of such mutations only in patients with early onset PD. In the present study 8 different GBA mutations covering 87% of the mutations identified in Gaucher disease patients diagnosed in Greece were investigated in two ethnic Greek cohorts of patients with sporadic Parkinson's disease. Cohort A included patients residing and originating from Thessaly, Central Greece (n=100) and cohort B included patients residing and/or originating from the greater area of Athens (n=105). Age-gender-ethnicity matched healthy individuals from the same areas were included as controls (n=206). In patients of cohort A 11 carriers of GBA mutations were identified (5/11:N370S, 2/11:L444P, 2/11: D409H;H255Q, 1/11:H255Q, 1/11D409H) as opposed to 3 in the controls (n=105) (1/3:N370S, 1/3:H255Q, 1/3:Y108C) (p=0.021, OR 4.2, 95% CI=1.14-15.54). In patients of cohort B 10 carriers of GBA mutations were identified (4/10:L444P, 4/10:D409H;H255Q, 1/10:N370S, 1/10:IVS10-1G→A) as opposed to 4 in controls (n=101) (3/4:N370S, 1/4:L444P). However the difference was not statistically significant (p=0.113, OR 2.5, 95% CI=0.77-8.42). In both cohorts, patients with PD harboring a GBA mutation had an earlier onset of symptoms than non-carriers (p=0.034, p=0.004). The overall difference in the number of carriers identified in PD patients and controls was statistically significant (p=0.006; OR 3.24; 95% CI=1.35-7.81). The association was reinforced in the early onset PD patients (EOPD; n=28, p=0.000, OR 11.37; 95% CI=3.73-34.6). In conclusion GBA mutations were identified with increased frequency in both geographical cohorts of patients with sporadic PD studied compared to control individuals, with the difference being statistically significant only in cohort A. An impressive association with EOPD was found and one third of the EOPD patients examined harbored a GBA mutation. Qualitative differences regarding the type of mutations and/or their relative frequencies were observed between cohorts A and B of PD patients. Genetic and/or environmental factors may account for the observed differences.

Analysis of concordancy rates in monozygotic and dizygotic twins with Parkinson's disease (PD) has been an important subject for research into the disorder1 and discordancy between twins has traditionally been interpreted as evidence against a genetic etiology of disease. Discordancy in late-onset diseases such as PD is complicated by the possibility that the disease onset may vary considerably between twins, and cases with up to 20 years of discordance have been reported.2 Leucine-rich repeat-kinase type 2 (LRRK2) mutations are the most common Mendelian cause of PD,3, 4 with the G2109S mutation occurring in 1% to 2% of idiopathic cases in the UK.5 Here we report the identification of a pair of identical twins with this mutation who are discordant by more than 10 years.

Susceptibility to sporadic Parkinson's disease (PD) is thought to be influenced by both genetic and environmental factors and their interaction with each other. Statistical models including multiple variants in axon guidance pathway genes have recently been purported to be capable of predicting PD risk, survival free of the disease and age at disease onset; however the specific models have not undergone independent validation. Here we tested the best proposed risk panel of 23 single nucleotide polymorphisms (SNPs) in two PD sample sets, with a total of 525 cases and 518 controls. By single marker analysis, only one marker was significantly associated with PD risk in one of our sample sets (rs6692804: P = 0.03). Multi-marker analysis using the reported model found a mild association in one sample set (two sided P = 0.049, odds ratio for each score change = 1.07) but no significance in the other (two sided P = 0.98, odds ratio = 1), a stark contrast to the reported strong association with PD risk (P = 4.64x10(-38), odds ratio as high as 90.8). Following a procedure similar to that used to build the reported model, simulated multi-marker models containing SNPs from randomly chosen genes in a genome wide PD dataset produced P-values that were highly significant and indistinguishable from similar models where disease status was permuted (3.13x10(-23) to 4.90x10(-64)), demonstrating the potential for overfitting in the model building process. Together, these results challenge the robustness of the reported panel of genetic markers to predict PD risk in particular and a role of the axon guidance pathway in PD genetics in general.

Leucine-rich repeat kinase 2 (LRRK2) mutation is the most common cause of genetic-related parkinsonism and is usually associated with Lewy body pathology; however, tau, α-synuclein, and ubiquitin pathologies have also been reported. We report the case of a patient carrying the LRRK2 G2019S mutation and a novel heterozygous variant c.370C>G, p.Q124E in exon 4 of the microtubule-associated protein tau (MAPT). The patient developed parkinsonism with good levodopa response in her 70s. Neuropathological analysis revealed nigral degeneration and Alzheimer-type tau pathology without Lewy bodies. Immunohistochemical staining using phospho-TDP-43 antibodies identified occasional TDP-43 pathology in the hippocampus, temporal neocortex, striatum, and substantia nigra. However, TDP-43 pathology was not identified in another 4 archival LRRK2 G2019S cases with Lewy body pathology available in the Queen Square Brain Bank. Among other published cases of patients carrying LRRK2 G2019S mutation, only 3 were reportedly evaluated for TDP-43 pathology, and the results were negative. The role of the MAPT variant in the clinical and pathological manifestation in LRRK2 cases remains to be determined.

Microtubule-associated protein tau (MAPT) mutations have been shown to underlie frontotemporal dementia and a variety of additional sporadic tauopathies. We identified a rare p.A152T variant in MAPT exon 7 in two (of eight) patients with clinical presentation of parkinsonism and postmortem finding of neurofibrillary tangle pathology. Two siblings of one patient also carried the p.A152T variant, and both have progressive cognitive impairment. Further screening identified the variant in two other cases: one with pathologically confirmed corticobasal degeneration and another with the diagnosis of Parkinson's disease with dementia. The balance of evidence suggests this variant is associated with disease, but the very varied phenotype of the cases with the mutation is not consistent with it being a fully penetrant pathogenic mutation. Interestingly, this variation results in the creation of a new phosphorylation site that could cause reduced microtubule binding. We suggest that the A152T variant is a risk factor associated with the development of atypical neurodegenerative conditions with abnormal tau accumulation.