Database : MEDLINE
Search on : Spinocerebellar and Ataxias [Words]
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[PMID]: 28467418
[Au] Autor:Khare S; Nick JA; Zhang Y; Galeano K; Butler B; Khoshbouei H; Rayaprolu S; Hathorn T; Ranum LPW; Smithson L; Golde TE; Paucar M; Morse R; Raff M; Simon J; Nordenskjöld M; Wirdefeldt K; Rincon-Limas DE; Lewis J; Kaczmarek LK; Fernandez-Funez P; Nick HS; Waters MF
[Ad] Address:Department of Neurology, University of Florida, Gainesville, FL, United States of America.
[Ti] Title:A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking.
[So] Source:PLoS One;12(5):e0173565, 2017.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract: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 (Kv3.3). We detail the clinical phenotype of four SCA13 kindreds that confirm causation of the KCNC3R423H allele. The heralding features demonstrate congenital onset with non-progressive, neurodevelopmental cerebellar hypoplasia and lifetime improvement in motor and cognitive function that implicate compensatory neural mechanisms. Targeted expression of human KCNC3R423H in Drosophila triggers aberrant wing veins, maldeveloped eyes, and fused ommatidia consistent with the neurodevelopmental presentation of patients. Furthermore, human KCNC3R423H expression in mammalian cells results in altered glycosylation and aberrant retention of the channel in anterograde and/or endosomal vesicles. Confirmation of the absence of plasma membrane targeting was based on the loss of current conductance in cells expressing the mutant channel. Mechanistically, genetic studies in Drosophila, along with cellular and biophysical studies in mammalian systems, demonstrate the dominant negative effect exerted by the mutant on the wild-type (WT) protein, which explains dominant inheritance. We demonstrate that ocular co-expression of KCNC3R423H with Drosophila epidermal growth factor receptor (dEgfr) results in striking rescue of the eye phenotype, whereas KCNC3R423H expression in mammalian cells results in aberrant intracellular retention of human epidermal growth factor receptor (EGFR). Together, these results indicate that the neurodevelopmental consequences of KCNC3R423H may be mediated through indirect effects on EGFR signaling in the developing cerebellum. Our results therefore confirm the KCNC3R423H allele as causative for SCA13, through a dominant negative effect on KCNC3WT and links with EGFR that account for dominant inheritance, congenital onset, and disease pathology.
[Mh] MeSH terms primary: Receptor, Epidermal Growth Factor/metabolism
Shaw Potassium Channels/genetics
Spinocerebellar Degenerations/genetics
[Mh] MeSH terms secundary: Animals
CHO Cells
Cricetinae
Cricetulus
Drosophila melanogaster
Female
Humans
Male
Pedigree
Protein Transport
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (KCNC3 protein, human); 0 (Shaw Potassium Channels); EC 2.7.10.1 (Receptor, Epidermal Growth Factor)
[Em] Entry month:1709
[Cu] Class update date: 180311
[Lr] Last revision date:180311
[Js] Journal subset:IM
[Da] Date of entry for processing:170504
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0173565

  2 / 6287 MEDLINE  
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[PMID]: 29440566
[Au] Autor:Zesiewicz TA; Wilmot G; Kuo SH; Perlman S; Greenstein PE; Ying SH; Ashizawa T; Subramony SH; Schmahmann JD; Figueroa KP; Mizusawa H; Schöls L; Shaw JD; Dubinsky RM; Armstrong MJ; Gronseth GS; Sullivan KL
[Ad] Address:From the Department of Neurology (T.A.Z., J.D. Shaw), University of South Florida, Tampa; Department of Neurology (G.W.), Emory University, Atlanta, GA; Department of Neurology (S.-H.K.), Columbia University, New York, NY; Department of Neurology (S.P.), University of California, Los Angeles; Depart
[Ti] Title:Comprehensive systematic review summary: Treatment of cerebellar motor dysfunction and ataxia: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.
[So] Source:Neurology;90(10):464-471, 2018 Mar 06.
[Is] ISSN:1526-632X
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:OBJECTIVE: To systematically review evidence regarding ataxia treatment. METHODS: A comprehensive systematic review was performed according to American Academy of Neurology methodology. CONCLUSIONS: For patients with episodic ataxia type 2, 4-aminopyridine 15 mg/d probably reduces ataxia attack frequency over 3 months (1 Class I study). For patients with ataxia of mixed etiology, riluzole probably improves ataxia signs at 8 weeks (1 Class I study). For patients with Friedreich ataxia or spinocerebellar ataxia (SCA), riluzole probably improves ataxia signs at 12 months (1 Class I study). For patients with SCA type 3, valproic acid 1,200 mg/d possibly improves ataxia at 12 weeks. For patients with spinocerebellar degeneration, thyrotropin-releasing hormone possibly improves some ataxia signs over 10 to 14 days (1 Class II study). For patients with SCA type 3 who are ambulatory, lithium probably does not improve signs of ataxia over 48 weeks (1 Class I study). For patients with Friedreich ataxia, deferiprone possibly worsens ataxia signs over 6 months (1 Class II study). Data are insufficient to support or refute the use of numerous agents. For nonpharmacologic options, in patients with degenerative ataxias, 4-week inpatient rehabilitation probably improves ataxia and function (1 Class I study); transcranial magnetic stimulation possibly improves cerebellar motor signs at 21 days (1 Class II study). For patients with multiple sclerosis-associated ataxia, the addition of pressure splints possibly has no additional benefit compared with neuromuscular rehabilitation alone (1 Class II study). Data are insufficient to support or refute use of stochastic whole-body vibration therapy (1 Class III study).
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180306
[Lr] Last revision date:180306
[St] Status:In-Data-Review
[do] DOI:10.1212/WNL.0000000000005055

  3 / 6287 MEDLINE  
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[PMID]: 29193335
[Au] Autor:Figueroa KP; Gan SR; Perlman S; Wilmot G; Gomez CM; Schmahmann J; Paulson H; Shakkottai VG; Ying SH; Zesiewicz T; Bushara K; Geschwind M; Xia G; Subramony SH; Ashizawa T; Pulst SM; Kuo SH
[Ad] Address:Department of Neurology, University of Utah, Salt Lake City, Utah, USA.
[Ti] Title:C9orf72 repeat expansions as genetic modifiers for depression in spinocerebellar ataxias.
[So] Source:Mov Disord;33(3):497-498, 2018 Mar.
[Is] ISSN:1531-8257
[Cp] Country of publication:United States
[La] Language:eng
[Pt] Publication type:LETTER
[Em] Entry month:1712
[Cu] Class update date: 180306
[Lr] Last revision date:180306
[St] Status:In-Data-Review
[do] DOI:10.1002/mds.27258

  4 / 6287 MEDLINE  
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[PMID]: 29383373
[Au] Autor:Muth CC
[Ti] Title:ASO Therapy: Hope for Genetic Neurological Diseases.
[So] Source:JAMA;319(7):644-646, 2018 Feb 20.
[Is] ISSN:1538-3598
[Cp] Country of publication:United States
[La] Language:eng
[Mh] MeSH terms primary: Muscular Atrophy, Spinal/drug therapy
Neurodegenerative Diseases/drug therapy
Oligonucleotides, Antisense/therapeutic use
[Mh] MeSH terms secundary: Animals
Disease Models, Animal
Humans
Mice
Muscular Atrophy, Spinal/genetics
Muscular Dystrophy, Duchenne/drug therapy
Muscular Dystrophy, Duchenne/genetics
Mutation
Neurodegenerative Diseases/genetics
Spinocerebellar Ataxias/drug therapy
[Pt] Publication type:NEWS
[Nm] Name of substance:0 (Oligonucleotides, Antisense)
[Em] Entry month:1803
[Cu] Class update date: 180302
[Lr] Last revision date:180302
[Js] Journal subset:AIM; IM
[Da] Date of entry for processing:180201
[St] Status:MEDLINE
[do] DOI:10.1001/jama.2017.18665

  5 / 6287 MEDLINE  
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[PMID]: 29463856
[Au] Autor:Rabenstein M; Peter F; Rolfs A; Frech MJ
[Ad] Address:Albrecht-Kossel-Institute for Neuroregeneration (AKos), University Medicine Rostock, Gehlsheimer Straße 20, D-18147, Rostock, Germany.
[Ti] Title:Impact of Reduced Cerebellar EAAT Expression on Purkinje Cell Firing Pattern of NPC1-deficient Mice.
[So] Source:Sci Rep;8(1):3318, 2018 Feb 20.
[Is] ISSN:2045-2322
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Niemann-Pick disease Type C1 (NPC1) is a rare hereditary neurodegenerative disease. NPC1-patients suffer, amongst others, from ataxia, based on a loss of cerebellar Purkinje cells (PCs). Impaired expression/function of excitatory amino acid transporters (EAATs) are suspected of contributing to PC-degeneration in hereditary spinocerebellar ataxias (SCAs). Thus, we studied EAAT-expression and its impact to PC-activity in NPC1 mice. Western blot revealed reduced EAAT1, EAAT2, EAAT4, and ßIII-spectrin levels in NPC1 mice. EAATs play a crucial role in synaptic transmission, thus we were interested in the impact of the reduced EAAT-expression on the function of PCs. Patch-clamp recordings of PCs showed no differences in the firing patterns of NPC1 and NPC1 mice using a low internal chloride concentration. Because EAAT4 also comprises a chloride permeable ion pore, we perturbed the chloride homeostasis using a high internal chloride concentration. We observed differences in the firing patterns of NPC1 and NPC1 mice, suggesting an impact of the altered EAAT4-expression. Additionally, the EAAT-antagonist DL-TBOA acts differently in NPC1 and NPC1 mice. Our data support the line of evidence that an altered EAAT-expression/function is involved in neurodegeneration of PCs observed in SCAs. Thus, we suggest that similar pathogenic mechanisms contribute the loss of PCs in NPC1.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180227
[Lr] Last revision date:180227
[St] Status:In-Data-Review
[do] DOI:10.1038/s41598-018-21805-z

  6 / 6287 MEDLINE  
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[PMID]: 29419417
[Au] Autor:Massey TH; Jones L
[Ad] Address:Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Hadyn Ellis Building, Cardiff University, Cardiff, CF24 4HQ, UK.
[Ti] Title:The central role of DNA damage and repair in CAG repeat diseases.
[So] Source:Dis Model Mech;11(1), 2018 Jan 30.
[Is] ISSN:1754-8411
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Diseases such as Huntington's disease and certain spinocerebellar ataxias are caused by the expansion of genomic cytosine-adenine-guanine (CAG) trinucleotide repeats beyond a specific threshold. These diseases are all characterised by neurological symptoms and central neurodegeneration, but our understanding of how expanded repeats drive neuronal loss is incomplete. Recent human genetic evidence implicates DNA repair pathways, especially mismatch repair, in modifying the onset and progression of CAG repeat diseases. Repair pathways might operate directly on repeat sequences by licensing or inhibiting repeat expansion in neurons. Alternatively, or in addition, because many of the genes containing pathogenic CAG repeats encode proteins that themselves have roles in the DNA damage response, it is possible that repeat expansions impair specific DNA repair pathways. DNA damage could then accrue in neurons, leading to further expansion at repeat loci, thus setting up a vicious cycle of pathology. In this review, we consider DNA damage and repair pathways in postmitotic neurons in the context of disease-causing CAG repeats. Investigating and understanding these pathways, which are clearly relevant in promoting and ameliorating disease in humans, is a research priority, as they are known to modify disease and therefore constitute prevalidated drug targets.
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Em] Entry month:1802
[Cu] Class update date: 180227
[Lr] Last revision date:180227
[St] Status:In-Data-Review

  7 / 6287 MEDLINE  
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[PMID]: 29421540
[Au] Autor:Huang M; Verbeek DS
[Ad] Address:University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
[Ti] Title:Why do so many genetic insults lead to Purkinje Cell degeneration and spinocerebellar ataxia?
[So] Source:Neurosci Lett;, 2018 Feb 05.
[Is] ISSN:1872-7972
[Cp] Country of publication:Ireland
[La] Language:eng
[Ab] Abstract:The genetically heterozygous spinocerebellar ataxias are all characterized by cerebellar atrophy and pervasive Purkinje Cell degeneration. Up to date, more than 35 functionally diverse spinocerebellar ataxia genes have been identified. The main question that remains yet unsolved is why do some many genetic insults lead to Purkinje Cell degeneration and spinocerebellar ataxia? To address this question it is important to identify intrinsic pathways important for Purkinje Cell function and survival. In this review, we discuss the current consensus on shared mechanisms underlying the pervasive Purkinje Cell loss in spinocerebellar ataxia. Additionally, using recently published cell type specific expression data, we identified several Purkinje Cell-specific genes and discuss how the corresponding pathways might underlie the vulnerability of Purkinje Cells in response to the diverse genetic insults causing spinocerebellar ataxia.
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Em] Entry month:1802
[Cu] Class update date: 180225
[Lr] Last revision date:180225
[St] Status:Publisher

  8 / 6287 MEDLINE  
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[PMID]: 29462666
[Au] Autor:Cagnoli C; Brussino A; Mancini C; Ferrone M; Orsi L; Salmin P; Pappi P; Giorgio E; Pozzi E; Cavalieri S; Di Gregorio E; Ferrero M; Filla A; De Michele G; Gellera C; Mariotti C; Nethisinghe S; Giunti P; Stevanin G; Brusco A
[Ad] Address:Department of Medical Sciences, University of Turin, Turin, Italy.
[Ti] Title:SCA Tethering-PCR: A Rapid Genetic Test for the Diagnosis of SCA1-3, 6, and 7 by PCR and Capillary Electrophoresis.
[So] Source:J Mol Diagn;, 2018 Feb 17.
[Is] ISSN:1943-7811
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Spinocerebellar ataxias (SCA) type 1, 2, 3, 6, and 7, associated with a (CAG)n repeat expansion in coding sequences, are the most prevalent autosomal dominant ataxias worldwide (approximately 60% of the cases). In addition, the phenotype of SCA2 expansions has been now extended to Parkinson's disease and amyotrophic lateral sclerosis. Their diagnosis is presently based on a PCR to identify small expanded alleles, followed by a second-level test whenever the suspect of false normal homozygous, or a CAT interruption in SCA1 needs to be verified. Next-generation sequencing still does not allow efficient detection of these repeats. Here, we show the efficacy of a novel, rapid, and cost-effective method to identify and size pathogenic expansions in SCA1-3, 6, and 7 and recognize large alleles or interruptions without a second-level test. Twenty-five healthy controls and 33 expansion carriers were analyzed: alleles migrated consistently in different PCRs/capillary runs, and homozygous subjects were always distinguishable from heterozygous carriers of both common and large (>100 repeats) pathogenic CAG expansions. Repeat number could be calculated counting the number of peaks, except for the largest SCA2 and SCA7 alleles. Interruptions in SCA1 were always visible. Overall, our method allows a simpler, cost-effective, and sensibly faster SCA diagnostic protocol compared to the standard technique and to the still unadapted next-generation sequencing.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180220
[Lr] Last revision date:180220
[St] Status:Publisher

  9 / 6287 MEDLINE  
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[PMID]: 29458753
[Au] Autor:Seshagiri DV; Sasidharan A; Kumar G; Pal PK; Jain S; Kutty BM; Yadav R
[Ad] Address:Department of Neurology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India.
[Ti] Title:Challenges in sleep stage R scoring in patients with autosomal dominant spinocerebellar ataxias (SCA1, SCA2 and SCA3) and oculomotor abnormalities: a whole night polysomnographic evaluation.
[So] Source:Sleep Med;42:97-102, 2018 Feb.
[Is] ISSN:1878-5506
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:OBJECTIVES: Spinocerebellar ataxias are progressive neurodegenerative disorders characterized by progressive cerebellar features with additional neuro-axis involvement. Oculomotor abnormality is one of the most frequent manifestations. This study was done to assess the polysomnographic abnormalities in patients with Spinocerebellar ataxia (SCA1, SCA2 and SCA3) and also to evaluate whether oculomotor abnormalities interfere with sleep stage R scoring. METHODS: The study was carried out using 36 genetically positive SCA patients. All patients underwent neurological examination with special focus on oculomotor function (optokinetic nystagmus-OKN and extraocular movement restriction-EOM). The sleep quality was measured with Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). Disease severity was assessed with International Cooperative Ataxia Rating Scale (ICARS). All the patients underwent over-night video-polysomnography (VPSG). RESULTS: Out of 36 patients studied, the data of 34 patients [SCA1 (n = 12), SCA2 (n = 13), SCA3 (n = 9)] were used for final analysis. Patients from SCA1, SCA2, and SCA3 category did not show significant differences in age and diseases severity (ICARS). All patients had vertical OKN impairment. Oculomotor impairment was higher in SCA2 patients. Sleep macro-architecture analysis showed absent stage R sleep, predominantly in SCA2 (69%) followed by SCA3 (44%) and SCA1 (8%). Patients showed a strong negative correlation of stage R sleep percentage with disease severity and oculomotor dysfunction. CONCLUSION: Voluntary saccadic eye movement velocity and rapid eye movements (REMs) in sleep are strongly correlated. The more severe the saccadic velocity impairment, the less likely was it to generate REMs (rapid eye movements) during stage R. Accordingly 69% of SCA2 patients with severe occulomotor impairments showed absent stage R as per the AASM sleep scoring. We presume that the impaired REMs generation in sleep could be due to oculomotor abnormality and has resulted in spuriously low or absent stage R sleep percentage in SCA patients with conventional VPSG scoring rules. The present study recommends the modification of AASM scoring rules for stage R in patients with oculomotor abnormalities.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180220
[Lr] Last revision date:180220
[St] Status:In-Data-Review

  10 / 6287 MEDLINE  
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[PMID]: 29355955
[Au] Autor:Thomas EA; D'Mello SR
[Ad] Address:Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, 92037.
[Ti] Title:Complex neuroprotective and neurotoxic effects of histone deacetylases.
[So] Source:J Neurochem;, 2018 Jan 22.
[Is] ISSN:1471-4159
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:By their ability to shatter quality of life for both patients and caregivers, neurodegenerative diseases are the most devastating of human disorders. Unfortunately, there are no effective or long-terms treatments capable of slowing down the relentless loss of neurons in any of these diseases. One impediment is the lack of detailed knowledge of the molecular mechanisms underlying the processes of neurodegeneration. While some neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and Amyotrophic lateral sclerosis, are mostly sporadic in nature, driven by both environment and genetic susceptibility, many others, including Huntington's disease, Spinocerebellar ataxias and Spinal-bulbar muscular atrophy, are genetically inherited disorders. Surprisingly, given their different roots and etiologies, both sporadic and genetic neurodegenerative disorders have been linked to disease mechanisms involving histone deacetylase (HDAC) proteins, which consists of 18 family members with diverse functions. While most studies have implicated certain HDAC subtypes in promoting neurodegeneration, a substantial body of literature suggests that other HDAC proteins can preserve neuronal viability. Of particular interest, however, is the recent realization that a single HDAC subtype can have both neuroprotective and neurotoxic effects. Diverse mechanisms, beyond transcriptional regulation have been linked to these effects, including deacetylation of non-histone proteins, protein-protein interactions, post-translational modifications of the HDAC proteins themselves and direct interactions with disease proteins. The roles of these HDACs in both sporadic and genetic neurodegenerative diseases will be discussed in the current review. This article is protected by copyright. All rights reserved.
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Em] Entry month:1801
[Cu] Class update date: 180217
[Lr] Last revision date:180217
[St] Status:Publisher
[do] DOI:10.1111/jnc.14309


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