Non-Motor Symptoms of Essential Tremor Are Independent of Tremor Severity and Have an Impact on Quality of Life

Background: Several publications have focused on accompanying non-motor symptoms (NMS) in essential tremor (ET) patients; however, it remains unclear if NMS are an intrinsic part of the disease or secondary phenomena. We present the results of several neuropsychiatric tests and their impact on quality of life (QoL) in community-dwelling patients with ET. Methods: Participants were recruited via a newspaper article about ET published in the local media and on the internet. All participants completed several standard neuropsychiatric tests, including those that assess QoL. To compare differences between cases and controls, Student’s t-tests with Bonferroni-Holm post hoc tests were performed. Spearman’s correlation coefficients were also calculated. Results: We enrolled 110 patients with definite or probable ET. Highly significant changes were observed for apathy, anxiety, and cognition and negatively impacted QoL. Most aberrations were independent of tremor severity and duration. Discussion: The significant neuropsychiatric deficits and reduced QoL demonstrate a degree of illness that appears to be a non-motor phenotype rather than a secondary effect of ET. In the future, NMS should carefully be explored in ET patients as they may have an impact on QoL and treatment

EIF4G1 in familial Parkinson's disease: pathogenic mutations or rare benign variants?

International audienceMutations in the eukaryotic translation initiation factor 4-gamma (EIF4G1) gene, encoding a component of the eIF4F translation initiation complex, were recently reported as a possible cause for the autosomal dominant form of Parkinson's disease (PD). Here, we describe the screening of all 31 EIF4G1 coding exons in a series of 251 index cases with autosomal dominant PD, mostly of French origin and in 236 European control subjects. We identified 12 rare coding variants (either nonsynonymous amino acid substitutions or in frame deletions/insertions), including 6 variants present only in cases and 3 in controls. Segregation was possible only for 1 variant (p.E462delInsGK) that was found in 2 affected siblings. In addition, we found 2 previously reported pathogenic variants in 2 isolated patients (p.G686C) and in a control subject (p.R1197W). These data do not support the pathogenicity of several EIF4G1 variants in PD, at least in the French population

Clinically approved immunomodulators ameliorate behavioral changes in a mouse model of hereditary spastic paraplegia type 11

We have previously demonstrated that neuroinflammation by the adaptive immune system acts as a robust and targetable disease amplifier in a mouse model of Spastic Paraplegia, type 11 (SPG11), a complicated form of Hereditary Spastic Paraplegia (HSP). While we identified an impact of neuroinflammation on distinct neuropathological changes and gait performance, neuropsychological features, typical and clinically highly relevant symptoms of complicated HSPs, were not addressed. Here we show that the corresponding SPG11 mouse model shows distinct behavioral abnormalities, particularly related to social behavior thus partially reflecting the neuropsychological changes in patients. We provide evidence that some behavioral abnormalities can be mitigated by genetic inactivation of the adaptive immune system. Translating this into a clinically applicable approach, we show that treatment with the established immunomodulators fingolimod or teriflunomide significantly attenuates distinct behavioral abnormalities, with the most striking effect on social behavior. This study links neuroinflammation to behavioral abnormalities in a mouse model of SPG11 and may thus pave the way for using immunomodulators as a treatment approach for SPG11 and possibly other complicated forms of HSP with neuropsychological involvement

M4 Safety and tolerability of BN82451B in huntington’s disease

Background BN82451B is a small, orally active molecule with good CNS penetration. Preclinical studies in tgHD R6/2 mice suggested improved motor function and prolonged survival. In addition antidyskinetic activity was observed in other models. The proposed mechanisms of action (MOA) are (1) antiexcytotoxic due to a sodium channel blocking potential, (2) antioxidant, (3) anti-inflammatory due to a cyclooxygenase (COX) inhibitory potential and (4) mitochondrial protective. Aims The primary objective of this phase 2a study (NCT02231580) is to investigate the safety and tolerability of BN82451B bid versus placebo for 28 days in male HD subjects. Secondary objectives include assessment of pharmacokinetics and of pharmacodynamics via the effects on quantitative motor (Q-Motor) measures. UHDRS subscales are implemented as exploratory measures. Methods Subjects: We intend to recruit 30 male HD subjects. 24 receive BN82451B and 6 placebo. The study is conducted in an inpatient setting at a single phase I unit in Germany. Design A sequential design was chosen to enable dose escalation starting with 40 mg bid with a potential maximum dose of 80 mg bid. Three subsequent cohorts of 10 patients each are randomised with different starting doses. Subjects in group one are treated with 40 mg bid for 14 days and may be increased to 60 mg bid the subsequent 14 days. In group 2, subjects may first receive 60 mg bid with possible increase to 80 mg bid. Group 3 subjects may receive 80 mg bid for 28 days. Dose increases in the consecutive groups are subject to approval by a Data Review Committee (DRC). The decision to increase the dose in individual patient will be based on the investigator’s judgement. Results Results of the study are expected for Q4/2016. Conclusions Recruitment in this trial is difficult as in-patient periods of nearly one month are logistically challenging. Safety data will be available soon and pharmacodynamics readouts such as Q-motor measures may help to guide decisions on the further path of development of BN82451B

PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability

The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T&gt;G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous variant, c.512C&gt;A (p.Ala171Asp), in a Libyan family with a similar phenotype. Both variants co-segregate with disease in the respective families. The affected subjects display juvenile-onset parkinsonism and intellectual disability. The motor symptoms were responsive to treatment with levodopa and deep brain stimulation of the subthalamic nucleus. In overexpression studies, both the PTPA p.Ala171Asp and p.Met298Arg variants were associated with decreased PTPA RNA stability and decreased PTPA protein levels; the p.Ala171Asp variant additionally displayed decreased PTPA protein stability. Crucially, expression of both variants was associated with decreased PP2A complex levels and impaired PP2A phosphatase activation. PTPA orthologue knock-down in Drosophila neurons induced a significant impairment of locomotion in the climbing test. This defect was age-dependent and fully reversed by L-DOPA treatment. We conclude that bi-allelic missense PTPA variants associated with impaired activation of the PP2A phosphatase cause autosomal recessive early-onset parkinsonism with intellectual disability. Our findings might also provide new insights for understanding the role of the PP2A complex in the pathogenesis of more common forms of neurodegeneration.</p

Tiefe Hirnstimulation bei neurologischen und psychiatrischen Erkrankungen

Die invasive Hirnstimulation (tiefe Hirnstimulation [THS], 'deep brain stimulation' [DBS]) ist mittlerweile ein etabliertes Therapieverfahren bei einer Reihe neurologischer Erkrankungen insbesondere Bewegungsstörungen. Die Anzahl der mit einer THS versorgten Patienten steigt stetig, die technische Entwicklung der THS-Systeme schreitet voran und neue Indikationen werden aktuell in Studien überprüft. Im folgenden Beitrag soll ein Überblick über die aktuellen Indikationen und ein Ausblick auf zukünftige Entwicklungen der THS bei Bewegungsstörungen und psychiatrischen Erkrankungen gegeben werden

SARS-CoV-2, COVID-19 and Neurodegeneration

The COVID-19 pandemic continues to affect many areas of our daily life [...

Nichtkompetitive Inhibition der tRNA-Guanin Transglycosylase durch Störung der essentiellen Protein-Protein-Interaktion

Protein-Protein-Kontakte stellen eine reiche Vielfalt an Interaktionsmöglichkeiten der Polypeptide mit regulatorischen Funktionen innerhalb lebender Organismen dar. Das homodimere Enzym tRNA-Guanin Transglykosylase(TGT) katalysiert z. B. eine Basenaustauschreaktion, die essentiell für die Pathogenität der Shigella Bakterien ist. Durch einen geeigneten Liganden, der an die Kontaktfläche der beiden Monomere bindet, könnte die Ausbildung des aktiven Komplexes unterdrückt werden. In dieser Arbeit wurde deshalb zunächst das Interface mittels Molekulardynamik-Simulationen ausführlich und eingehend charakterisiert. So konnte ein zentraler Hot-Spot, bestehend aus den aromatischen Aminosäuren Trp326, Tyr330, His 333 und Phe92‘, identifiziert werden. Sie stehen am Interface durch Stacking miteinander in Kontakt und bilden zusätzlich ein Netzwerk von Wasserstoffbrückenbindungen zu Akzeptorfunktionalitäten am Dimerpartner aus. Durch umfassende Mutagenesestudien konnte gezeigt werden, dass Veränderungen innerhalb dieses Clusters zur Monomerisierung des sonst permanenten, obligaten Homodimers führen. Die Aufklärung mittels Röntgenstrukturbestimmung ließ, bei stabiler Tertiärstruktur, einen klaren Trend zum Erhalt eines kristallographischen Dimers in analoger Weise zum Wildtypprotein erkennen (RG C2). Durch eine Disulfidbrücke C330-C330‘ konnte die Variante TGT Y330C jedoch auch in einer geänderten geometrischen Anordnung kristallisiert werden (RG P6(5)22). In allen Strukturen zeigte sich ein am Interface beteiligter Loop (AS 46-52) als besonders flexibel, wobei sich nach ersten Analysen durch verschiedene Konformationen Bindetaschen mit der Möglichkeiten zur Interaktion von geeigneten Protein-Protein-Interface-Liganden öffnen. Hier könnte ein Schlüsselmechanismus für einen möglichen Wirkstoff gefunden worden sein. Erste Versuche, einen potentiellen Liganden zu platzieren, bedienten sich in silico der Molekulardynamik und des Dockings, in vitro eines MS-gekoppelten Fragment-Tetherings. Weitere, vertiefende Experimente könnten den Durchbruch für einen neuen Protein-Protein-Interface-Inhibitor am Homodimer der TGT bedeuten

Clinical and genetic heterogeneity in hereditary spastic paraplegias: From SPG1 to SPG72 and still counting

International audienceHereditary spastic paraplegias (HSPs) are genetically determined neurodegenerative disorders characterized by progressive weakness and spasticity of lower limbs, and are among the most clinically and genetically heterogeneous human diseases. All modes of inheritance have been described, and the recent technological revolution in molecular genetics has led to the identification of 76 different spastic gait disease-loci with 59 corresponding spastic paraplegia genes. Autosomal recessive HSP are usually associated with diverse additional features (referred to as complicated forms), contrary to autosomal dominant HSP, which are mostly pure. However, the identification of additional mutations and families has considerably enlarged the clinical spectra, and has revealed a huge clinical variability for almost all HSP; complicated forms have also been described for primary pure HSP subtypes, adding further complexity to the genotype-phenotype correlations. In addition, the introduction of next generation sequencing in clinical practice has revealed a genetic and phenotypic overlap with other neurodegenerative disorders (amyotrophic lateral sclerosis, neuropathies, cerebellar ataxias, etc.) and neurodevelopmental disorders, including intellectual disability. This review aims to describe the most recent advances in the field and to provide genotype-phenotype correlations that could help clinical diagnoses of this heterogeneous group of disorders.Les paraplégies spastiques héréditaires (PSH) sont des maladies neurodégénératives, d’origine génétique, caractérisées par une spasticité progressive et une faiblesse des membres inférieurs. Les PSH font partie des affections les plus hétérogènes d’un point de vue clinique mais également génétique, avec plus de 76 loci différents et 59 gènes connus rapportés dans la littérature, dont les mutations se transmettent selon tous les modes de transmissions connus. Les PSH autosomiques récessives sont généralement des formes complexes, i.e. associant d’autres symptômes neurologiques ou extra-neurologiques, contrairement aux formes autosomiques dominantes qui ont été décrites comme des formes habituellement pures. Toutefois, un élargissement phénotypique s’est opéré avec la description de familles et mutations additionnelles pour quasiment tous les sous-types de PSH et des formes complexes ont été décrites également dans les formes initialement pures, compliquant ainsi considérablement la visibilité des différentes entités cliniques pour les cliniciens. Par ailleurs, l’introduction du séquençage de nouvelle génération dans la pratique clinique a récemment révélé un chevauchement génétique et phénotypique important entre les PSH et d’autres types de maladies neurodégénératives comme la sclérose latérale amyotrophique, les neuropathies héréditaires, ou encore les ataxies cérébelleuses. Ce chevauchement s’est étendu également à des maladies neuro-développementales comme la déficience intellectuelle. Dans ce contexte, cette revue a pour but de décrire les avancées les plus récentes du domaine et de fournir aux cliniciens un aperçu des corrélations génotype-phénotypes qui peuvent aider à établir un diagnostic moléculaire dans ce groupe de pathologies hétérogènes