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Daniel R Scoles, Stefan M Pulst
Therapeutics that directly target RNAs are promising for a broad spectrum of disorders, including the neurodegenerative diseases. This is exemplified by the FDA approval of Nusinersen, an antisense oligonucleotide (ASO) therapeutic for spinal muscular atrophy (SMA). RNA targeting therapeutics are currently under development for amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and spinocerebellar ataxias. We have used an ASO approach toward developing a treatment for spinocerebellar ataxia type 2 (SCA2), for targeting the causative gene ATXN2...
March 21, 2018: RNA Biology
David D Bushart, Ravi Chopra, Vikrant Singh, Geoffrey G Murphy, Heike Wulff, Vikram G Shakkottai
Objective: Purkinje neuron dysfunction is associated with cerebellar ataxia. In a mouse model of spinocerebellar ataxia type 1 (SCA1), reduced potassium channel function contributes to altered membrane excitability resulting in impaired Purkinje neuron spiking. We sought to determine the relationship between altered membrane excitability and motor dysfunction in SCA1 mice. Methods: Patch-clamp recordings in acute cerebellar slices and motor phenotype testing were used to identify pharmacologic agents which improve Purkinje neuron physiology and motor performance in SCA1 mice...
March 2018: Annals of Clinical and Translational Neurology
Alhassane Diallo, Heike Jacobi, Arron Cook, Robyn Labrum, Alexandra Durr, Alexis Brice, Perrine Charles, Cecilia Marelli, Caterina Mariotti, Lorenzo Nanetti, Marta Panzeri, Maria Rakowicz, Anna Sobanska, Anna Sulek, Tanja Schmitz-Hübsch, Ludger Schöls, Holger Hengel, Bela Melegh, Alessandro Filla, Antonella Antenora, Jon Infante, José Berciano, Bart P van de Warrenburg, Dagmar Timmann, Sylvia Boesch, Massimo Pandolfo, Jörg B Schulz, Peter Bauer, Paola Giunti, Jun-Suk Kang, Thomas Klockgether, Sophie Tezenas du Montcel
BACKGROUND: Spinocerebellar ataxias are dominantly inherited progressive ataxia disorders that can lead to premature death. We aimed to study the overall survival of patients with the most common spinocerebellar ataxias (SCA1, SCA2, SCA3, and SCA6) and to identify the strongest contributing predictors that affect survival. METHODS: In this longitudinal cohort study (EUROSCA), we enrolled men and women, aged 18 years or older, from 17 ataxia referral centres in ten European countries; participants had positive genetic test results for SCA1, SCA2, SCA3, or SCA6 and progressive, otherwise unexplained, ataxias...
April 2018: Lancet Neurology
Tetsuo Ashizawa
No abstract text is available yet for this article.
April 2018: Lancet Neurology
Luis Velázquez-Pérez, Roberto Rodríguez-Labrada, Reidenis Torres-Vega, Ricardo Ortega-Sánchez, Jacqueline Medrano-Montero, Rigoberto González-Piña, Yaimeé Vázquez-Mojena, Georg Auburger, Ulf Ziemann
OBJECTIVE: Corticospinal tract (CST) dysfunction is common in the pre-ataxic stage of spinocerebellar ataxia type 2 (SCA2) but quantitative assessment of its progression over time has not been explored. The aim of this study was to quantify the progression of CST dysfunction in pre-ataxic SCA2 using transcranial magnetic stimulation (TMS). METHODS: Thirty-three pre-ataxic SCA2 mutation carriers and a 33 age- and gender-matched healthy controls were tested at baseline and 2-years follow-up by standardized clinical exams, validated clinical scales, and TMS...
March 15, 2018: Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology
Jorge C Kattah
Background: Previous series of bilateral vestibular loss (BVL) identified numerous etiologies, but surprisingly, a cause in a significant number of cases remains unknown. In an effort to understand possible etiology and management strategies, a global effort is currently in progress. Here, I contribute my 10-year experience with both acute and chronic BVL during the 2007-2017 decade. Methods: This is a retrospective review of the charts and EMR of patients diagnosed with BVL in the last 10 years...
2018: Frontiers in Neurology
Stefania Squadrone, Paola Brizio, Cecilia Mancini, Maria Cesarina Abete, Alfredo Brusco
Spinocerebellar ataxia type 2 (SCA2) is a neurological disorder characterized by cerebellar dysfunction. The possible association between metals and neurodegenerative diseases is under constant investigation, with particular focus on their involvement in oxidative stress and their potential role as biomarkers of these pathologies. Whole blood samples of SCA2 patients and of healthy individuals were subjected to multi-elemental analysis by inductively coupled plasma-mass spectrometry (ICP-MS). Reduced levels of manganese and copper were found in SCA2 patients, while zinc and vanadium concentrations were significantly higher in patients compared to controls...
May 2018: Journal of Trace Elements in Medicine and Biology
Michael H Parkinson, Ana P Bartmann, Lisa M S Clayton, Suran Nethisinghe, Rolph Pfundt, J Paul Chapple, Mary M Reilly, Hadi Manji, Nicholas J Wood, Fion Bremner, Paola Giunti
Autosomal recessive spastic ataxia of Charlevoix-Saguenay is a rare neurodegenerative disorder caused by mutations in the SACS gene. Thickened retinal nerve fibres visible on fundoscopy have previously been described in these patients; however, thickening of the retinal nerve fibre layer as demonstrated by optical coherence tomography appears to be a more sensitive and specific feature. To test this observation, we assessed 292 individuals (191 patients with ataxia and 101 control subjects) by peripapillary time-domain optical coherence tomography...
March 12, 2018: Brain: a Journal of Neurology
Laura Alice Santos de Oliveira, Camilla Polonini Martins, Carlos Henrique Ramos Horsczaruk, Débora Cristina Lima da Silva, Luiz Felipe Vasconcellos, Agnaldo José Lopes, Míriam Raquel Meira Mainenti, Erika de Carvalho Rodrigues
Background and Purpose: The motor impairments related to gait and balance have a huge impact on the life of individuals with spinocerebellar ataxia (SCA). Here, the aim was to assess the possibility of retraining gait, improving cardiopulmonary capacity, and challenging balance during gait in SCA using a partial body weight support (BWS) and a treadmill. Also, the effects of this training over functionality and quality of life were investigated. Methods: Eight SCA patients were engaged in the first stage of the study that focused on gait training and cardiovascular conditioning...
2018: Rehabilitation Research and Practice
Chandrakanth Reddy Edamakanti, Jeehaeh Do, Alessandro Didonna, Marco Martina, Puneet Opal
Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disease caused by a polyglutamine expansion in the protein ATXN1, which is involved in transcriptional regulation. Although symptoms appear relatively late in life, primarily from cerebellar dysfunction, pathogenesis begins early, with brain-wide transcriptional changes detectable as early as a week after birth in SCA1 knock-in mice. Given the importance of this postnatal period for cerebellar development, we asked whether this region might be developmentally altered by mutant ATXN1...
March 13, 2018: Journal of Clinical Investigation
Martin Paucar, Åsa Bergendal, Peter Gustavsson, Magnus Nordenskjöld, José Laffita-Mesa, Irina Savitcheva, Per Svenningsson
Spinocerebellar ataxia type 19 (SCA19), allelic with spinocerebellar ataxia type 22 (SCA22), is a rare syndrome caused by mutations in the KCND3 gene which encodes the potassium channel Kv4.3. Only 18 SCA19/22 families and sporadic cases of different ethnic backgrounds have been previously reported. As in other SCAs, the SCA19/22 phenotype is variable and usually consists of adult-onset slowly progressive ataxia and cognitive impairment; myoclonus and seizures; mild Parkinsonism occurs in some cases. Here we describe a Swedish SCA19/22 family spanning five generations and harboring the T377M mutation in KCND3...
March 12, 2018: Cerebellum
Maxime W C Rousseaux, Tyler Tschumperlin, Hsiang-Chih Lu, Elizabeth P Lackey, Vitaliy V Bondar, Ying-Wooi Wan, Qiumin Tan, Carolyn J Adamski, Jillian Friedrich, Kirk Twaroski, Weili Chen, Jakub Tolar, Christine Henzler, Ajay Sharma, Aleksandar Bajić, Tao Lin, Lisa Duvick, Zhandong Liu, Roy V Sillitoe, Huda Y Zoghbi, Harry T Orr
Polyglutamine (polyQ) diseases are caused by expansion of translated CAG repeats in distinct genes leading to altered protein function. In spinocerebellar ataxia type 1 (SCA1), a gain of function of polyQ-expanded ataxin-1 (ATXN1) contributes to cerebellar pathology. The extent to which cerebellar toxicity depends on its cognate partner capicua (CIC), versus other interactors, remains unclear. It is also not established whether loss of the ATXN1-CIC complex in the cerebellum contributes to disease pathogenesis...
March 7, 2018: Neuron
Hirokazu Hirai, Masanobu Kano
Neurodegenerative diseases such as spinocerebellar ataxias and autoantibody-associated disorders of the central nervous system often affect the cerebellum, resulting in motor deficits. Recent studies have revealed that most of these disorders impair type 1 metabotropic glutamate receptor (mGluR1) and/or the closely associated signaling molecules in cerebellar Purkinje cell. Since the signaling pathway triggered by mGluR1 activation in Purkinje cell plays a pivotal role in coordinated movements and motor learning, pharmacological repair of aberrant mGluR1 signaling in Purkinje cell is critical for mitigation of cerebellar symptoms...
March 8, 2018: Current Opinion in Pharmacology
Diana A Olszewska, Terri McVeigh, Emer M Fallon, Gregory M Pastores, Tim Lynch
Genetics is the backbone of Neurology, where a number of disorders have a genetic aetiology and are complex, requiring a dedicated Neurogenetics clinic. Genetics in the Republic of Ireland is under-resourced, with the lowest number of consultants per million of population in Europe. In November 2014, we established the monthly adult Neurogenetics clinic in Ireland, staffed by 2 consultants and 2 registrars from each speciality. We see patients with complex rare neurological conditions that may potentially have an underlying genetic basis, in the presence or absence of a family history...
March 9, 2018: Irish Journal of Medical Science
Hok Khim Fam, Kunho Choi, Lauren Fougner, Chinten James Lim, Cornelius F Boerkoel
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a nuclear and mitochondrial protein that in nuclei and in vitro repairs blocked 3' DNA termini such as 3' phosphotyrosine conjugates resulting from stalling of topoisomerase I-DNA intermediates. Its mutation also causes spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1). Because Tdp1 colocalizes with mitochondria following oxidative stress, we hypothesized that Tdp1 repairs mitochondrial DNA (mtDNA) and that mtDNA damage mediates entry of Tdp1 into the mitochondria...
March 9, 2018: Scientific Reports
Stephanie E Wallace, Thomas D Bird
Purpose of review: Because of extensive clinical overlap among many forms of hereditary ataxia, molecular genetic testing is often required to establish a diagnosis. Interrogation of multiple genes has become a popular diagnostic approach as the cost of sequence analysis has decreased and the number of genes associated with overlapping phenotypes has increased. We describe the benefits and limitations of molecular genetic tests commonly used to determine the etiology of hereditary ataxia...
February 2018: Neurology. Clinical Practice
Jodie Stephenson, Erik Nutma, Paul van der Valk, Sandra Amor
Neurodegenerative diseases, the leading cause of morbidity and disability is gaining increased attention as it imposes a considerable socioeconomic impact, due in part to the ageing community. Neuronal damage is a pathological hallmark of Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxia and multiple sclerosis, although such damage is also observed following neurotropic viral infections, stroke, genetic white matter diseases and paraneoplastic disorders...
March 7, 2018: Immunology
X Zhou, C Wang, D Ding, Z Chen, Y Peng, H Peng, X Hou, P Wang, X Hou, W Ye, T Li, H Yang, R Qiu, K Xia, J Sequeiros, B Tang, H Jiang
Multiple system atrophy (MSA) is a complex and multifactorial neurodegenerative disease, and its pathogenesis remains uncertain. Patients with MSA or spinocerebellar ataxia (SCA) show overlapping clinical phenotypes. Previous studies have reported that intermediate or long CAG expansions in SCA genes have been associated with other neurodegenerative disease. In this study, we screened for the number of CAG repeats in ATXN1, 2 and 3 in 200 patients with MSA and 314 healthy controls to evaluate possible associations between (CAG)n in these three polyQ-related genes and MSA...
March 1, 2018: Scientific Reports
Koji Abe
The present review focuses an early history of Japanese amyotrophic lateral sclerosis (ALS)-related diseases and the current development. In relation to foreign previous reports, five topics are introduced and discussed on ALS with dementia, ALS/Parkinsonism dementia complex (ALS/PDC), familial ALS (FALS), spinal bulbar muscular atrophy (SBMA), and multisystem involvement especially in cerebellar system of ALS including ALS/SCA (spinocerebellar ataxia) crossroad mutation Asidan. This review found the great contribution of Japanese reports on the above five topics, and confirmed the great development of ALS-related diseases over the past 120 years...
February 28, 2018: Rinshō Shinkeigaku, Clinical Neurology
Jin-Shan Yang, Ping-Ping Chen, Min-Ting Lin, Mei-Zhen Qian, Hui-Xia Lin, Xiao-Ping Chen, Xian-Jin Shang, Dan-Ni Wang, Yu-Chao Chen, Bin Jiang, Yi-Jun Chen, Ning Wang, Wan-Jin Chen, Shi-Rui Gan
Spinocerebellar ataxia type 3 (SCA3), the most common subtype of SCA worldwide, is caused by mutation of CAG repeats expansion in ATXN3. Body mass index (BMI) is an important modulatory factor in the progression of neurodegenerative disorders such as Huntington disease and amyotrophic lateral sclerosis. However, its relevance in SCA3 is not well understood. In this study, BMI was investigated in 134 molecularly confirmed SCA3 patients and 136 healthy controls from China. The multivariable linear regression models were performed to establish the putative risk factors for BMI, and whether BMI could affect the severity of ataxia...
February 23, 2018: Cerebellum
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