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https://www.readbyqxmd.com/read/28529475/fragile-x-associated-tremor-ataxia-syndrome-from-molecular-pathogenesis-to-development-of-therapeutics
#1
REVIEW
Ha Eun Kong, Juan Zhao, Shunliang Xu, Peng Jin, Yan Jin
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a premutation CGG repeat expansion (55-200 repeats) within the 5' UTR of the fragile X gene (FMR1). FXTAS is characterized by intension tremor, cerebellar ataxia, progressive neurodegeneration, parkinsonism and cognitive decline. The development of transgenic mouse and Drosophila melanogaster models carrying an expanded CGG repeat has yielded valuable insight into the pathophysiology of FXTAS. To date, we know of two main molecular mechanisms of this disorder: (1) a toxic gain of function of the expanded CGG-repeat FMR1 mRNA, which results in the binding/sequestration of the CGG-binding proteins; and (2) CGG repeat-associated non-AUG-initiated (RAN) translation, which generates a polyglycine peptide toxic to cells...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28518055/a-positive-feedback-loop-linking-enhanced-mglur-function-and-basal-calcium-in-spinocerebellar-ataxia-type-2
#2
Pratap Meera, Stefan Pulst, Thomas Otis
Metabotropic glutamate receptor 1 (mGluR1) function in Purkinje neurons (PNs) is essential for cerebellar development and for motor learning and altered mGluR1 signaling causes ataxia. Downstream of mGluR1, dysregulation of calcium homeostasis has been hypothesized as a key pathological event in genetic forms of ataxia but the underlying mechanisms remain unclear. We find in a spinocerebellar ataxia type 2 (SCA2) mouse model that calcium homeostasis in PNs is disturbed across a broad range of physiological conditions...
May 18, 2017: ELife
https://www.readbyqxmd.com/read/28508084/clinicopathologic-and-molecular-spectrum-of-rnaseh1-related-mitochondrial-disease
#3
Enrico Bugiardini, Olivia V Poole, Andreea Manole, Alan M Pittman, Alejandro Horga, Iain Hargreaves, Cathy E Woodward, Mary G Sweeney, Janice L Holton, Jan-Willem Taanman, Gordon T Plant, Joanna Poulton, Massimo Zeviani, Daniele Ghezzi, John Taylor, Conrad Smith, Carl Fratter, Meena A Kanikannan, Arumugam Paramasivam, Kumarasamy Thangaraj, Antonella Spinazzola, Ian J Holt, Henry Houlden, Michael G Hanna, Robert D S Pitceathly
OBJECTIVE: Pathologic ribonuclease H1 (RNase H1) causes aberrant mitochondrial DNA (mtDNA) segregation and is associated with multiple mtDNA deletions. We aimed to determine the prevalence of RNase H1 gene (RNASEH1) mutations among patients with mitochondrial disease and establish clinically meaningful genotype-phenotype correlations. METHODS: RNASEH1 was analyzed in patients with (1) multiple deletions/depletion of muscle mtDNA and (2) mendelian progressive external ophthalmoplegia (PEO) with neuropathologic evidence of mitochondrial dysfunction, but no detectable multiple deletions/depletion of muscle mtDNA...
June 2017: Neurology. Genetics
https://www.readbyqxmd.com/read/28498095/risk-factors-for-development-of-postoperative-cerebellar-mutism-syndrome-in-children-after-medulloblastoma-surgery
#4
San Y C V Pols, Marie Lise C van Veelen, Femke K Aarsen, Antonia Gonzalez Candel, Coriene E Catsman-Berrevoets
OBJECTIVE Postoperative cerebellar mutism syndrome (pCMS) occurs in 7%-50% of children after cerebellar tumor surgery. Typical features include a latent onset of 1-2 days after surgery, transient mutism, emotional lability, and a wide variety of motor and neurobehavioral abnormalities. Sequelae of this syndrome usually persist long term. The principal causal factor is bilateral surgical damage (regardless of tumor location) to any component of the proximal efferent cerebellar pathway, which leads to temporary dysfunction of cerebral cortical regions as a result of diaschisis...
May 12, 2017: Journal of Neurosurgery. Pediatrics
https://www.readbyqxmd.com/read/28481932/unmasking-adrenoleukodystrophy-in-a-cohort-of-cerebellar-ataxia
#5
Ying-Hao Chen, Yi-Chung Lee, Yu-Shuen Tsai, Yuh-Cherng Guo, Cheng-Tsung Hsiao, Pei-Chien Tsai, Jin-An Huang, Yi-Chu Liao, Bing-Wen Soong
Adrenoleukodystrophy (ALD) is a rare and progressive neurogenetic disease that may manifest disparate symptoms. The present study aims at investigating the role of ataxic variant of ALD (AVALD) in patients with adult-onset cerebellar ataxia, as well as characterizing their clinical features that distinguish AVALD from other cerebellar ataxias. Mutations in the ATP binding cassette subfamily D member 1 gene (ABCD1) were ascertained in 516 unrelated patients with ataxia. The patients were categorized into three groups: molecularly unassigned hereditary ataxia (n = 118), sporadic ataxia with autonomic dysfunctions (n = 296), and sporadic ataxia without autonomic dysfunctions (n = 102)...
2017: PloS One
https://www.readbyqxmd.com/read/28476762/white-matter-microstructure-cognition-and-molecular-markers-in-fragile-x-premutation-females
#6
Annie L Shelton, Kim M Cornish, David Godler, Quang Minh Bui, Scott Kolbe, Joanne Fielding
OBJECTIVE: To examine the interrelationships between fragile X mental retardation 1 (FMR1) mRNA and the FMR1 exon 1/intron 1 boundary methylation, white matter microstructure, and executive function, in women with a FMR1 premutation expansion (PM; 55-199 CGG repeats) and controls (CGG < 44). METHODS: Twenty women with PM without fragile X-associated tremor/ataxia syndrome (FXTAS) and 20 control women between 22 and 54 years of age completed this study. FMR1 mRNA and methylation levels for 9 CpG sites within the FMR1 exon 1/intron 1 boundary from peripheral blood samples were analyzed...
May 5, 2017: Neurology
https://www.readbyqxmd.com/read/28467418/a-kcnc3-mutation-causes-a-neurodevelopmental-non-progressive-sca13-subtype-associated-with-dominant-negative-effects-and-aberrant-egfr-trafficking
#7
Swati Khare, Jerelyn A Nick, Yalan Zhang, Kira Galeano, Brittany Butler, Habibeh Khoshbouei, Sruti Rayaprolu, Tyisha Hathorn, Laura P W Ranum, Lisa Smithson, Todd E Golde, Martin Paucar, Richard Morse, Michael Raff, Julie Simon, Magnus Nordenskjöld, Karin Wirdefeldt, Diego E Rincon-Limas, Jada Lewis, Leonard K Kaczmarek, Pedro Fernandez-Funez, Harry S Nick, Michael F Waters
The autosomal dominant spinocerebellar ataxias (SCAs) are a diverse group of neurological disorders anchored by the phenotypes of motor incoordination and cerebellar atrophy. Disease heterogeneity is appreciated through varying comorbidities: dysarthria, dysphagia, oculomotor and/or retinal abnormalities, motor neuron pathology, epilepsy, cognitive impairment, autonomic dysfunction, and psychiatric manifestations. Our study focuses on SCA13, which is caused by several allelic variants in the voltage-gated potassium channel KCNC3 (Kv3...
2017: PloS One
https://www.readbyqxmd.com/read/28463998/plasma-metabolomics-reveals-a-diagnostic-metabolic-fingerprint-for-mitochondrial-aconitase-aco2-deficiency
#8
Lucia Abela, Ronen Spiegel, Lisa M Crowther, Andrea Klein, Katharina Steindl, Sorina Mihaela Papuc, Pascal Joset, Yoav Zehavi, Anita Rauch, Barbara Plecko, Thomas Luke Simmons
Mitochondrial respiratory chain dysfunction has been identified in a number of neurodegenerative disorders. Infantile cerebellar-retinal degeneration associated with mutations in the mitochondrial aconitase 2 gene (ACO2) has been recently described as a neurodegenerative disease of autosomal recessive inheritance. To date there is no biomarker for ACO2 deficiency and diagnosis relies on genetic analysis. Here we report global metabolic profiling in eight patients with ACO2 deficiency. Using an LC-MS-based metabolomics platform we have identified several metabolites with affected plasma concentrations including the tricarboxylic acid cycle metabolites cis-aconitate, isocitrate and alpha-ketoglutarate, as well as phosphoenolpyruvate and hydroxybutyrate...
2017: PloS One
https://www.readbyqxmd.com/read/28463835/neurodegeneration-and-the-cerebellum
#9
Margot Samson, Daniel O Claassen
BACKGROUND: The cerebellum modulates diverse neuronal networks, regulating motor, cognitive, behavioral, and limbic circuits. Structural and functional changes to the cerebellum that occur with neurodegenerative conditions have not been systematically reviewed. OBJECTIVE: We synthesize the current understanding of cerebellar somatotopy and function with previously described cerebellar changes in neurodegenerative diseases not associated with primary cerebellar pathology...
May 3, 2017: Neuro-degenerative Diseases
https://www.readbyqxmd.com/read/28461060/gray-matter-structural-variability-in-the-human-cerebellum-lobule-specific-differences-across-sex-and-hemisphere
#10
REVIEW
Christopher J Steele, M Mallar Chakravarty
Though commonly thought of as a "motor structure", we now know that the cerebellum's reciprocal connections to the cerebral cortex underlie contributions to both motor and non-motor behavior. Further, recent research has shown that cerebellar dysfunction may contribute to a wide range of neuropsychiatric disorders. However, there has been little characterization of normative variability at the level of cerebellar structure that can facilitate and further our understanding of disease biomarkers. In this manuscript we examine normative variation of the cerebellum using data from the Human Connectome Project (HCP)...
April 28, 2017: NeuroImage
https://www.readbyqxmd.com/read/28446490/complicated-acute-cerebellitis-with-obstructive-hydrocephalus-and-tonsillar-herniation-in-a-child
#11
Manchikanti Venkatesh, Sunitha Vellathussery Chakkalakkoombil, Manju Bashini Duraipandi, Reena Gulati
Acute cerebellitis (AC) is a rare inflammatory syndrome presenting as cerebellar dysfunction, seen more frequently in children. AC can have a variable course with features of cerebellar dysfunction, raised intracranial pressure and neurological deficits, and can sometimes even be potentially fatal due to complications such as obstructive hydrocephalus and brainstem compression, warranting surgical intervention. We report a case of a 12-year-old boy who presented with raised intracranial pressure and ataxia...
April 26, 2017: BMJ Case Reports
https://www.readbyqxmd.com/read/28439961/involvement-of-the-cerebellum-in-parkinson-s-disease-and-dementia-with-lewy-bodies
#12
K Seidel, M Bouzrou, N Heidemann, R Krüger, L Schöls, Wfa den Dunnen, H-W Korf, U Rüb
Patient brains with Parkinson's disease or Dementia with Lewy bodies show aggregation of alpha-synuclein in pre-cerebellar brainstem structures. Furthermore, patients exhibit resting tremor, unstable gait and impaired balance which may be associated with cerebellar dysfunction. Therefore, we screened the cerebella of 12 patients with alpha-synucleinopathies for neuropathological changes. Cerebellar nuclei and neighboring white matter displayed numerous aggregates, while lobules were mildly affected. Cerebellar aggregation pathology may suggest a prion-like spread originating from affected precerebellar structures and the high homogeneity between patients with Dementia with Lewy bodies and Parkinson's disease shows that both diseases likely belong to the same neuropathological spectrum...
April 25, 2017: Annals of Neurology
https://www.readbyqxmd.com/read/28435670/type-1-metabotropic-glutamate-receptor-signaling-in-cerebellar-purkinje-cells-in-health-and-disease
#13
REVIEW
Masanobu Kano, Takaki Watanabe
The cerebellum is a brain structure involved in coordination, control, and learning of movements, as well as certain aspects of cognitive function. Purkinje cells are the sole output neurons from the cerebellar cortex and therefore play crucial roles in the overall function of the cerebellum. The type-1 metabotropic glutamate receptor (mGluR1) is a key "hub" molecule that is critically involved in the regulation of synaptic wiring, excitability, synaptic response, and synaptic plasticity of Purkinje cells. In this review, we aim to highlight how mGluR1 controls these events in Purkinje cells...
2017: F1000Research
https://www.readbyqxmd.com/read/28431605/global-brain-atrophy-and-metabolic-dysfunction-in-lgi1-encephalitis-a-prospective-multimodal-mri-study
#14
Monika Szots, Morten Blaabjerg, Gergely Orsi, Pernille Iversen, Daniel Kondziella, Camilla G Madsen, Ellen Garde, Peter O Magnusson, Peter Barsi, Ferenc Nagy, Hartwig R Siebner, Zsolt Illes
BACKGROUND: Chronic cognitive deficits are frequent in leucin-rich glioma-inactivated 1 protein (LGI1) encephalitis. We examined structural and metabolic brain abnormalities following LGI1 encephalitis and correlated findings with acute and follow-up clinical outcomes. METHODS: Nine patients underwent prospective multimodal 3 Tesla MRI 33.1±18months after disease onset, including automated volumetry, diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS)...
May 15, 2017: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/28415165/progressive-supranuclear-gaze-palsy-with-predominant-cerebellar-ataxia-a-case-series-with-videos
#15
Zheyu Xu, Tchoyoson C C Lim, Wing Lok Au, Louis C S Tan
Progressive supranuclear palsy (PSP) with predominant cerebellar ataxia (PSP-C) is a rare phenotype of PSP. The clinical and radiological features of this disorder remain poorly characterized. Through a retrospective case series, we aim to characterize the clinical and radiological features of PSP-C. Four patients with PSP-C were identified: patients who presented with prominent cerebellar dysfunction that disappeared with the progression of the disease. Supranuclear gaze palsy occurred at a mean of 2.0 ± 2...
May 2017: Journal of Movement Disorders
https://www.readbyqxmd.com/read/28405024/antisense-oligonucleotide-therapy-for-spinocerebellar-ataxia-type-2
#16
Daniel R Scoles, Pratap Meera, Matthew D Schneider, Sharan Paul, Warunee Dansithong, Karla P Figueroa, Gene Hung, Frank Rigo, C Frank Bennett, Thomas S Otis, Stefan M Pulst
There are no disease-modifying treatments for adult human neurodegenerative diseases. Here we test RNA-targeted therapies in two mouse models of spinocerebellar ataxia type 2 (SCA2), an autosomal dominant polyglutamine disease. Both models recreate the progressive adult-onset dysfunction and degeneration of a neuronal network that are seen in patients, including decreased firing frequency of cerebellar Purkinje cells and a decline in motor function. We developed a potential therapy directed at the ATXN2 gene by screening 152 antisense oligonucleotides (ASOs)...
April 20, 2017: Nature
https://www.readbyqxmd.com/read/28401768/primary-progressive-multiple-sclerosis-presenting-with-severe-predominant-cognitive-impairment-and-psychiatric-symptoms-a-challenging-case
#17
Alberto Andrea Zambon, Giordano Cecchetti, Francesca Caso, Roberto Santangelo, Cristina Baldoli, Maria Grazia Natali Sora, Giancarlo Comi, Giuseppe Magnani, Vittorio Martinelli
Severe cognitive dysfunction is a frequent feature of multiple sclerosis (MS), normally associated with later stages of the disease in adult population. Nevertheless, progressive cognitive and neuropsychiatric disturbances might rarely be the presenting and predominant symptom. In order to better characterize this peculiar phenotype of MS, we report on the case of a 38-year-old man who referred to our hospital with the suspect of hereditary leukodystrophy after 5 years of behavioral and mood abnormalities, global cognitive dysfunction, clumsiness, and very mild pyramidal and cerebellar signs...
April 1, 2017: Multiple Sclerosis: Clinical and Laboratory Research
https://www.readbyqxmd.com/read/28394027/changes-in-the-cell-population-in-brain-white-matter-in-multiple-system-atrophy
#18
Charlotte Havelund Nykjaer, Tomasz Brudek, Lisette Salvesen, Bente Pakkenberg
BACKGROUND: Multiple system atrophy (MSA) is a sporadic progressive neurodegenerative disorder with adult onset and unknown etiology. Clinically it is characterized by autonomic failure, cerebellar ataxia, parkinsonism, and corticospinal dysfunction in any combination and with varying severity. OBJECTIVES AND METHODS: To establish the extent of involvement of the white matter in the disease, we have used stereology to quantify the total number of neurons and glial cells (oligodendrocytes, astrocytes, and microglia) in the brains from 10 MSA patients and 11 controls...
April 10, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28393013/neural-substrates-of-motor-and-cognitive-dysfunctions-in-sca2-patients-a-network-based-statistics-analysis
#19
G Olivito, M Cercignani, M Lupo, C Iacobacci, S Clausi, S Romano, M Masciullo, M Molinari, M Bozzali, M Leggio
Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease characterized by a progressive cerebellar syndrome, which can be isolated or associated with extracerebellar signs. It has been shown that patients affected by SCA2 present also cognitive impairments and psychiatric symptoms. The cerebellum is known to modulate cortical activity and to contribute to distinct functional networks related to higher-level functions beyond motor control. It is therefore conceivable that one or more networks, rather than isolated regions, may be dysfunctional in cerebellar degenerative diseases and that an abnormal connectivity within specific cerebello-cortical regions might explain the widespread deficits typically observed in patients...
2017: NeuroImage: Clinical
https://www.readbyqxmd.com/read/28385189/suppression-of-nk-and-cd8-t-cells-reduces-astrogliosis-but-accelerates-cerebellar-dysfunction-and-shortens-life-span-in-a-mouse-model-of-sandhoff-disease
#20
Elizabeth J White, Bernardo L Trigatti, Suleiman A Igdoura
Sandhoff disease is an inherited lysosomal storage disease, resulting from the deficiency of lysosomal β-hexosaminidase A and B enzyme activity. The Hexb-/- mouse model recapitulates human disease and leads to fatal neurodegeneration and neuroinflammation. IL-15 is important for the proliferation of NK, NK T, and CD8(+) cytotoxic/memory T cells. In order to determine how changes to IL-15-dependent immune cell populations would alter the course of Sandhoff disease in mice, we generated a Hexb-/-Il-15-/- double knockout mouse and used motor behaviour tests, analyzed peripheral blood and brain leukocyte immunophenotypes, cytokine secretion, as well as examined markers of microgliosis, astrogliosis and apoptosis...
May 15, 2017: Journal of Neuroimmunology
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