scholarly journals CAG Repeat Size Influences the Progression Rate of Spinocerebellar Ataxia Type 3

2020 ◽  
Vol 89 (1) ◽  
pp. 66-73
Author(s):  
Vanessa B. Leotti ◽  
Jeroen J. Vries ◽  
Camila M. Oliveira ◽  
Eduardo P. Mattos ◽  
Gerard J. Te Meerman ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
Progression Rate ◽  
Spinocerebellar Ataxia Type 3 ◽  
Repeat Size ◽  
Type 3

scholarly journals Homozygous spinocerebellar ataxia type 3 in China: a case report

2021 ◽  
Vol 49 (6) ◽  
pp. 030006052110213
Author(s):  
Yuchao Chen ◽  
Dan Li ◽  
Minger Wei ◽  
Menglu Zhou ◽  
Linan Zhang ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Clinical Phenotype ◽  
Gene Dosage ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Spinocerebellar Ataxia Type ◽  
Contraction Pattern ◽  
Spinocerebellar Ataxia Type 3 ◽  
Type 3 ◽  
Stable Transmission

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease caused by a heterozygous CAG repeat expansion in the ataxin 3 gene ( ATXN3). However, patients with homozygous SCA3 carrying expanded CAG repeats in both alleles of ATXN3 are extremely rare. Herein, we present a case of a 50-year-old female who had homozygous SCA3 with expansion of 62/62 repeats. Segregation analysis of the patient’s family showed both a contraction pattern of CAG repeat length and stable transmission. The present case demonstrated an earlier onset and more severe clinical phenotype than that seen in heterozygous individuals, suggesting that the gene dosage enhances disease severity.

scholarly journals Dystonia in Patients with Spinocerebellar Ataxia 3 - Machado-Joseph disease: An Underestimated Diagnosis?

2018 ◽  
Vol 12 (1) ◽  
pp. 41-49 ◽  
Author(s):  
Ligia Maria Perrucci Catai ◽  
Carlos Henrique Ferreira Camargo ◽  
Adriana Moro ◽  
Gustavo Ribas ◽  
Salmo Raskin ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Movement Disorders ◽  
Disease Onset ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 3 ◽  
Generalized Dystonia ◽  
Machado Joseph Disease ◽  
Sca3 Patient ◽  
Type 3

Background:Spinocerebellar Ataxia type 3 (SCA3) or Machado-Joseph Disease (MJD) is characterized by cerebellar, central and peripheral symptoms, including movement disorders. Dystonia can be classified as hereditary and neurodegenerative when present in SCA3.Objective:The objective of this study was to evaluate the dystonia characteristics in patients with MJD.Method:We identified all SCA3 patients with dystonia from the SCA3 HC-UFPR database, between December 2015 and December 2016.Their medical records were reviewed to verify the diagnosis of dystonia and obtain demographic and clinical data. Standardized evaluation was carried out through the classification of Movement Disorders Society of 2013 and Burke Fahn-Marsden scale (BFM).Results:Amongst the presenting some common characteristics, 381 patients with SCA3, 14 (3.7%) subjects presented dystonia: 5 blepharospasm, 1 cervical dystonia, 3 oromandibular, 3 multifocal and 2 generalized dystonia. Regarding dystonia's subtypes, 71.4% had SCA3 subtype I and 28.6% SCA3 subtype II. The average age of the disease onset was 40±10.7 years; the SCA3 disease duration was 11.86± 6.13 years; the CAG repeat lengths ranged from 75 to 78, and the BFM scores ranged from 1.0 to 40. There was no correlation between the dystonia severity and CAG repeat lengths or the SCA3 clinical evolution.Conclusion:Dystonia in SCA3 is frequent and displays highly variable clinical profiles and severity grades. Dystonia is therefore a present symptom in SCA3, which may precede the SCA3 classic symptoms. Dystonia diagnosis is yet to be properly recognized within SCA3 patient.

scholarly journals Polyglutamine-expanded ataxin-3: a target engagement marker for Spinocerebellar ataxia type 3 in peripheral blood

2021 ◽  
Author(s):  
Jeannette Huebener-Schmid ◽  
Kirsten Kuhlbrodt ◽  
Julien Peladan ◽  
Jennifer Faber ◽  
Magda M Santana ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
Clinical Parameters ◽  
Target Engagement ◽  
Spinocerebellar Ataxia Type 3 ◽  
Curative Therapy ◽  
Cag Repeat Expansion ◽  
Type 3

Abstract Spinocerebellar ataxia type 3 is a rare neurodegenerative disease, caused by a CAG repeat expansion leading to polyglutamine elongation in the ataxin-3 protein. While no curative therapy is yet available, preclinical gene silencing approaches to reduce polyglutamine-toxicity demonstrate promising results. In view of upcoming clinical trials, quantitative and easily accessible molecular markers are of critical importance as pharmacodynamic and particularly as target engagement markers. We developed a novel ultrasensitive immunoassay to measure specifically polyQ-expanded ataxin-3 in plasma and cerebrospinal fluid. Statistical analyses revealed a correlation with clinical parameters and a stability of polyglutamine-expanded ataxin-3 during conversion from the pre-ataxic to the ataxic phase.

scholarly journals CAG repeat length does not associate with the rate of cerebellar degeneration in spinocerebellar ataxia type 3

2017 ◽  
Vol 13 ◽  
pp. 97-105 ◽  
Author(s):  
Shang-Ran Huang ◽  
Yu-Te Wu ◽  
Chii-Wen Jao ◽  
Bing-Wen Soong ◽  
Jiing-Feng Lirng ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Cerebellar Degeneration ◽  
Repeat Length ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 3 ◽  
Type 3

scholarly journals DNAzyme Cleavage of CAG Repeat RNA in Polyglutamine Diseases

2021 ◽  
Author(s):  
Nan Zhang ◽  
Brittani Bewick ◽  
Jason Schultz ◽  
Anjana Tiwari ◽  
Robert Krencik ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 3 ◽  
Therapeutic Value ◽  
Expanded Allele ◽  
Allele Specific ◽  
Aggresome Formation ◽  
Polyq Diseases ◽  
Type 3

AbstractCAG repeat expansion is the genetic cause of nine incurable polyglutamine (polyQ) diseases with neurodegenerative features. Silencing repeat RNA holds great therapeutic value. Here, we developed a repeat-based RNA-cleaving DNAzyme that catalyzes the destruction of expanded CAG repeat RNA of six polyQ diseases with high potency. DNAzyme preferentially cleaved the expanded allele in spinocerebellar ataxia type 1 (SCA1) cells. While cleavage was non-allele-specific for spinocerebellar ataxia type 3 (SCA3) cells, treatment of DNAzyme leads to improved cell viability without affecting mitochondrial metabolism or p62-dependent aggresome formation. DNAzyme appears to be stable in mouse brain for at least 1 month, and an intermediate dosage of DNAzyme in a SCA3 mouse model leads to a significant reduction of high molecular weight ATXN3 proteins. Our data suggest that DNAzyme is an effective RNA silencing molecule for potential treatment of multiple polyQ diseases.

scholarly journals Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3

2020 ◽  
Vol 12 (566) ◽  
pp. eabb7086 ◽  
Author(s):  
Mercedes Prudencio ◽  
Hector Garcia-Moreno ◽  
Karen R. Jansen-West ◽  
Rana Hanna AL-Shaikh ◽  
Tania F. Gendron ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Gene Silencing ◽  
Spinocerebellar Ataxia ◽  
Biological Fluids ◽  
Human Fibroblasts ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 3 ◽  
Targeting Therapy ◽  
Type 3

Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.

Somatic mosaicism of the CAG repeat expansion in spinocerebellar ataxia type 3/Machado-Joseph disease

1998 ◽  
Vol 11 (1) ◽  
pp. 23-27 ◽  
Author(s):  
Géraldine Cancel ◽  
Isabelle Gourfinkel-An ◽  
Giovanni Stevanin ◽  
Olivier Didierjean ◽  
Nacer Abbas ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Somatic Mosaicism ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 3 ◽  
Cag Repeat Expansion ◽  
Machado Joseph Disease ◽  
Type 3

An insight into advances in the pathogenesis and therapeutic strategies of spinocerebellar ataxia type 3

2015 ◽  
Vol 26 (1) ◽  
Author(s):  
Yan Wu ◽  
Ying Peng ◽  
Yidong Wang
Keyword(s):  
Spinocerebellar Ataxia ◽  
Symptom Relief ◽  
Cellular Protein ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 3 ◽  
Repeat Expansions ◽  
Type 3 ◽  
Neural Signaling ◽  
And Oxidative Stress

AbstractSpinocerebellar ataxia type 3 (SCA3) is the most common type of spinocerebellar ataxia, which are inherited neurodegenerative diseases. CAG repeat expansions that translate into an abnormal length of glutamine residues are considered to be the disease-causing mutation. The pathological mechanisms of SCA3 are not fully elucidated but may include aggregate or inclusion formation, imbalance of cellular protein homeostasis, axonal transportation dysfunction, translation dysregulation, mitochondrial damage and oxidative stress, abnormal neural signaling pathways, etc. Currently, symptom relief is the only available therapeutic route; however, promising therapeutic targets have been discovered, such as decreasing the mutant protein through RNA interference (RNAi) and antisense oligonucleotides (AONs) and replacement therapy using stem cell transplantation. Other potential targets can inhibit the previously mentioned pathological mechanisms. However, additional efforts are necessary before these strategies can be used clinically.

scholarly journals A Novel Calpain Inhibitor Compound Has Protective Effects on a Zebrafish Model of Spinocerebellar Ataxia Type 3

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2592
Author(s):  
Katherine J. Robinson ◽  
Kristy Yuan ◽  
Stuart K. Plenderleith ◽  
Maxinne Watchon ◽  
Angela S. Laird
Keyword(s):  
Spinocerebellar Ataxia ◽  
Protein Aggregates ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
Calpain Inhibitor ◽  
Repeat Region ◽  
Zebrafish Model ◽  
Spinocerebellar Ataxia Type 3 ◽  
Zebrafish Larvae ◽  
Type 3

Spinocerebellar ataxia type 3 (SCA3) is a hereditary ataxia caused by inheritance of a mutated form of the human ATXN3 gene containing an expanded CAG repeat region, encoding a human ataxin-3 protein with a long polyglutamine (polyQ) repeat region. Previous studies have demonstrated that ataxin-3 containing a long polyQ length is highly aggregation prone. Cleavage of the ataxin-3 protein by calpain proteases has been demonstrated to be enhanced in SCA3 models, leading to an increase in the aggregation propensity of the protein. Here, we tested the therapeutic potential of a novel calpain inhibitor BLD-2736 for the treatment of SCA3 by testing its efficacy on a transgenic zebrafish model of SCA3. We found that treatment with BLD-2736 from 1 to 6 days post-fertilisation (dpf) improves the swimming of SCA3 zebrafish larvae and decreases the presence of insoluble protein aggregates. Furthermore, delaying the commencement of treatment with BLD-2736, until a timepoint when protein aggregates were already known to be present in the zebrafish larvae, was still successful at removing enhanced green fluorescent protein (EGFP) fused-ataxin-3 aggregates and improving the zebrafish swimming. Finally, we demonstrate that treatment with BLD-2736 increased the synthesis of LC3II, increasing the activity of the autophagy protein quality control pathway. Together, these findings suggest that BLD-2736 warrants further investigation as a treatment for SCA3 and related neurodegenerative diseases.

Sign in / Sign up

Export Citation Format

Share Document