26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15–20 July 2017

This work was produced as part of the activities of FAPESP Research,\ud Disseminations and Innovation Center for Neuromathematics (grant\ud 2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud supported by a CNPq fellowship (grant 306251/2014-0)

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Obsahem předkládané práce je série studií v naší populaci pacientů s esenciálním tremorem. Práce se zaměřují na klinické a epidemiologické charakteristiky ET, instrumentální vyšetření kresby a písma a genetické studie. Výsledky vedou к následujícím závěrům: V dotazníkovém šetření byly zmapovány klinické a anamnestické rysy esenciálního tremoru v naší populaci. Základní epidemiologické charakteristiky se výrazněji neodlišují od výsledků obdobných studií publikovaných v zahraniční literatuře, až na pozoruhodně vysoký podíl nemocných v minulosti inadekvátně léčených preparáty levodopa. Dosud blíže nedokumentovaným zjištěním je poměrně vysoké procento pacientů negujících byť jen minimální konzumaci alkoholu. Kresba spirály se jeví jako vhodná pomůcka pro hodnoceni akčního třesu ruky, navržená škála umožňuje intraindividuální kvantifikaci i interindividuální porovnání tíže třesu, avšak s vyšší přesností při posuzování stejným hodnotitelem. Ve studii kvantifikace postižení třesem byl vytvořen algoritmus umožňující použití grafického digitálního tabletu, běžně komerčně dostupného elektronického zařízení, к hodnocení postižení kresby a písma esenciálním tremorem. Byla ověřena praktická využitelnost tohoto zařízení, zjištěna schopnost zavedeného parametru výkonu třesu odlišit patologický třes a také korelace výkonu...Essential tremor (ET) is probably the most common movement disorder with prevalence quoted as ranging in various populations from 0,41 to 3,92% (Louis et al 1998). Despite often given the prefix "benign", many patients are seriously physically, socially or psychologically handicapped. There are sporadic and familial forms with autosomal dominant inheritance with high penetrance. The percentage of patients with a positive family history ranges from 17 to 100%. Etiology and pathogenesis of ET are unknown. Electrophysiological studies have shown the central source of tremorogenic oscillation, the cerebellum and inferior olive are implicated by positron emission tomography studies. Autopsy studies reveal no gross or microscopic abnormalities (Deuschl and Elble 2000). Essential tremor had been for a long time one of the diseases that were not at a primary focus of neurological research (Deuschl and Koller 2000). Now, with the rapid progress of genetic research, the first genes related to ET have been identified (Gulcher et al 1997, Higgins et al 1997). ET is probably not a single disease; several genetic abnormalities appear to exist (Illarioshkin et al 2000, Abbruzzese et al 2001, Kovach et al 2001). High-quality epidemiological studies are needed for the search for genetic abnormalities (Elble 2000). The...Department of Neurology First Faculty of Medicine and General University Hospital in PragueNeurologická klinika 1. LF UK a VFN v PrazeFirst Faculty of Medicine1. lékařská fakult

název v anglickém jazyce není uveden

Essential tremor (ET) is probably the most common movement disorder with prevalence quoted as ranging in various populations from 0,41 to 3,92% (Louis et al 1998). Despite often given the prefix "benign", many patients are seriously physically, socially or psychologically handicapped. There are sporadic and familial forms with autosomal dominant inheritance with high penetrance. The percentage of patients with a positive family history ranges from 17 to 100%. Etiology and pathogenesis of ET are unknown. Electrophysiological studies have shown the central source of tremorogenic oscillation, the cerebellum and inferior olive are implicated by positron emission tomography studies. Autopsy studies reveal no gross or microscopic abnormalities (Deuschl and Elble 2000). Essential tremor had been for a long time one of the diseases that were not at a primary focus of neurological research (Deuschl and Koller 2000). Now, with the rapid progress of genetic research, the first genes related to ET have been identified (Gulcher et al 1997, Higgins et al 1997). ET is probably not a single disease; several genetic abnormalities appear to exist (Illarioshkin et al 2000, Abbruzzese et al 2001, Kovach et al 2001). High-quality epidemiological studies are needed for the search for genetic abnormalities (Elble 2000). The..

General and selective brain connectivity alterations in essential tremor: A resting state fMRI study

Although essential tremor is the most common movement disorder, there is little knowledge about the pathophysiological mechanisms of this disease. Therefore, we explored brain connectivity based on slow spontaneous fluctuations of blood oxygenation level dependent (BOLD) signal in patients with essential tremor (ET). A cohort of 19 ET patients and 23 healthy individuals were scanned in resting condition using functional magnetic resonance imaging (fMRI). General connectivity was assessed by eigenvector centrality (EC) mapping. Selective connectivity was analyzed by correlations of the BOLD signal between the preselected seed regions and all the other brain areas. These measures were then correlated with the tremor severity evaluated by the Fahn-Tolosa-Marin Tremor Rating Scale (FTMTS). Compared to healthy subjects, ET patients were found to have lower EC in the cerebellar hemispheres and higher EC in the anterior cingulate and in the primary motor cortices bilaterally. In patients, the FTMTS score correlated positively with the EC in the putamen. In addition, the FTMTS score correlated positively with selective connectivity between the thalamus and other structures (putamen, pre-supplementary motor area (pre-SMA), parietal cortex), and between the pre-SMA and the putamen. We observed a selective coupling between a number of areas in the sensorimotor network including the basal ganglia and the ventral intermediate nucleus of thalamus, which is widely used as neurosurgical target for tremor treatment. Finally, ET was marked by suppression of general connectivity in the cerebellum, which is in agreement with the concept of ET as a disorder with cerebellar damage. Keywords: Essential tremor, Magnetic resonance imaging, fMRI, Brain connectivity, Eigenvector centrality, Fahn-Tolosa-Marin Tremor Rating Scal

Changes of Retina Are Not Involved in the Genesis of Visual Hallucinations in Parkinson’s Disease

Parkinson’s disease (PD) is characterized by motor and nonmotor symptoms. Nonmotor symptoms include primarily visual hallucinations (VH). The aim of our study was to establish whether patients with PD and visual hallucinations (PDH+) have structural changes of retina detected by an optical coherence tomography (OCT) in comparison with PD patients without visual hallucinations (PDH−). We examined 52 PD patients (18 with VH, 34 without VH) and 15 age and sex matched healthy controls. Retinal nerve fiber layer (RNFL) thickness and macular thickness and volume were assessed by OCT. Functional impairment of retina was assessed using 2.5% contrast sensitivity test. For OCT outcomes we analyzed 15 PDH+ and 15 PDH− subjects matched for age, gender, and PD duration. For contrast sensitivity we analyzed 8 pairs of patients matched for age, gender, and visual acuity. There was no significant difference in RNFL thickness and macular thickness and macular volume between 15 PDH+ and 15 PDH− subjects, and also between a group of 44 PD patients (both PDH+ and PDH−) and 15 age and gender matched healthy controls. No significant difference was found for 2.5% contrast sensitivity test values between PDH+ and PDH− subjects. Therefore we conclude that functional and structural changes in retina play no role in genesis of VH in PD

Pseudodominant Nanophthalmos in a Roma Family Caused by a Novel PRSS56 Variant

Background. The aim of the study was to identify the molecular genetic cause of two different Mendelian traits with ocular involvement present in the members of a single consanguineous Czech Roma family. Methods. We have performed ocular examination and review of medical records in two individuals diagnosed with nanophthalmos (proband and her father) and one individual followed for bilateral congenital cataract and microcornea (uncle of the proband). DNA of subjects with nanophthalmos was analysed by exome sequencing. Sanger sequencing was applied for targeted screening of potentially pathogenic variants and to follow segregation of identified variants within the family. Results. A homozygous variant c.1509G>C; p.(Met503Ile), in PRSS56 was found in the two individuals affected with nanophthalmos. The change was absent from the gnomAD dataset, but two out of 118 control Roma individuals were also shown to be heterozygous carriers. Analysis of single nucleotide polymorphisms in linkage disequilibrium with the c.1509G>C in PRSS56 suggested a shared chromosomal segment. The nanophthalmos phenotype, characterized in detail in the younger individual, encompassed bilateral corneal steepening, retinal folds, buried optic head drusen, and restricted visual fields, but no signs of retinal dystrophy. A known pathogenic founder CTDP1 variant c.863+389C>T in a homozygous state was identified in the other family member confirming the suspected diagnosis of congenital cataracts, facial dysmorphism, and demyelinating neuropathy syndrome. Conclusions. Herein, we report the first occurrence of nanophthalmos in the Roma population. We have identified pseudodominant inheritance for this phenotype caused by a novel variant in PRSS56, representing a possible founder effect. Despite advances in genetic technologies such as exome sequencing, careful phenotype evaluation in patients from an isolated population, along with an awareness of population-specific founder effects, is necessary to ensure that accurate molecular diagnoses are made

Monogenic variants in dystonia: an exome-wide sequencing study

Background Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. Methods For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow. Findings We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism. Interpretation In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations. Funding Else Kröner-Fresenius-Stiftung, Technische Universität München, Helmholtz Zentrum München, Medizinische Universität Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency

Monogenic variants in dystonia: an exome-wide sequencing study

Background Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. Methods For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow. Findings We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism. Interpretation In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations