scholarly journals Clinical Characteristics and Possible Drug Targets in Autosomal Dominant Spinocerebellar Ataxias

2019 ◽  
Vol 18 (4) ◽  
pp. 279-293 ◽  
Author(s):  
Laszlo Szpisjak ◽  
Denes Zadori ◽  
Peter Klivenyi ◽  
Laszlo Vecsei
Keyword(s):  
Drug Targets ◽  
Autosomal Dominant ◽  
Scientific Progress ◽  
Cag Repeat ◽  
Motor Dysfunction ◽  
Spinocerebellar Ataxias ◽  
Coding Region ◽  
Causative Gene ◽  
Gene Therapies ◽  
Repeat Expansions

Background & Objective: The autosomal dominant spinocerebellar ataxias (SCAs) belong to a large and expanding group of neurodegenerative disorders. SCAs comprise more than 40 subtypes characterized by progressive ataxia as a common feature. The most prevalent diseases among SCAs are caused by CAG repeat expansions in the coding-region of the causative gene resulting in polyglutamine (polyQ) tract formation in the encoded protein. Unfortunately, there is no approved therapy to treat cerebellar motor dysfunction in SCA patients. In recent years, several studies have been conducted to recognize the clinical and pathophysiological aspects of the polyQ SCAs more accurately. This scientific progress has provided new opportunities to develop promising gene therapies, including RNA interference and antisense oligonucleotides. Conclusion: The aim of the current work is to give a brief summary of the clinical features of SCAs and to review the cardinal points of pathomechanisms of the most common polyQ SCAs. In addition, we review the last few year’s promising gene suppression therapies of the most frequent polyQ SCAs in animal models, on the basis of which human trials may be initiated in the near future.

scholarly journals Current Status of Gene Therapy Research in Polyglutamine Spinocerebellar Ataxias

2021 ◽  
Vol 22 (8) ◽  
pp. 4249
Author(s):  
Ricardo Afonso-Reis ◽  
Inês T. Afonso ◽  
Clévio Nóbrega
Keyword(s):  
Gene Therapy ◽  
Cag Repeat ◽  
Current Status ◽  
Clinical Feature ◽  
Spinocerebellar Ataxias ◽  
Coding Region ◽  
Causative Gene ◽  
Gene Therapies ◽  
Progressive Ataxia ◽  
Near Future

Polyglutamine spinocerebellar ataxias (PolyQ SCAs) are a group of 6 rare autosomal dominant diseases, which arise from an abnormal CAG repeat expansion in the coding region of their causative gene. These neurodegenerative ataxic disorders are characterized by progressive cerebellar degeneration, which translates into progressive ataxia, the main clinical feature, often accompanied by oculomotor deficits and dysarthria. Currently, PolyQ SCAs treatment is limited only to symptomatic mitigation, and no therapy is available to stop or delay the disease progression, which culminates with death. Over the last years, many promising gene therapy approaches were investigated in preclinical studies and could lead to a future treatment to stop or delay the disease development. Here, we summed up the most promising of these therapies, categorizing them in gene augmentation therapy, gene silencing strategies, and gene edition approaches. While several of the reviewed strategies are promising, there is still a gap from the preclinical results obtained and their translation to clinical studies. However, there is an increase in the number of approved gene therapies, as well as a constant development in their safety and efficacy profiles. Thus, it is expected that in a near future some of the promising strategies reviewed here could be tested in a clinical setting and if successful provide hope for SCAs patients.

scholarly journals Twenty-five years since the identification of the first SCA gene: history, clinical features and perspectives for SCA1

2018 ◽  
Vol 76 (8) ◽  
pp. 555-562 ◽  
Author(s):  
Carlos Roberto Martins Junior ◽  
Fabrício Castro de Borba ◽  
Alberto Rolim Muro Martinez ◽  
Thiago Junqueira Ribeiro de Rezende ◽  
Iscia Lopes Cendes ◽  
...  
Keyword(s):  
Clinical Features ◽  
Autosomal Dominant ◽  
Trinucleotide Repeat ◽  
Point Of View ◽  
Spinocerebellar Ataxias ◽  
Coding Region ◽  
The Past ◽  
Monogenic Diseases ◽  
Repeat Expansions ◽  
Core Features

ABSTRACT Spinocerebellar ataxias (SCA) are a clinically and genetically heterogeneous group of monogenic diseases that share ataxia and autosomal dominant inheritance as the core features. An important proportion of SCAs are caused by CAG trinucleotide repeat expansions in the coding region of different genes. In addition to genetic heterogeneity, clinical features transcend motor symptoms, including cognitive, electrophysiological and imaging aspects. Despite all the progress in the past 25 years, the mechanisms that determine how neuronal death is mediated by these unstable expansions are still unclear. The aim of this article is to review, from an historical point of view, the first CAG-related ataxia to be genetically described: SCA 1.

Inherited Ataxias

2015 ◽  
Author(s):  
Susan Perlman
Keyword(s):  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Friedreich Ataxia ◽  
Spinocerebellar Ataxias ◽  
Recessive Ataxia ◽  
Internet Resources ◽  
Genetic Abnormalities ◽  
Repeat Expansions ◽  
The Common ◽  
Inherited Ataxias

The inherited ataxias are disorders that cause progressive imbalance as a result of pathology in the cerebellum and its various connecting pathways. Autosomal recessive ataxias include Friedreich ataxia, ataxia with isolated vitamin E deficiency, ataxia-telangiectasia, and autosomal recessive ataxia of Charlevoix-Saguenay, among others. A discussion of autosomal dominant ataxias covers spinocerebellar ataxias (SCA) types 1 through 14, dentatorubral pallidoluysian atrophy (DRPLA), and episodic ataxia (EA) syndromes. Clinical features, laboratory studies, differential diagnosis, and management of inherited ataxias are discussed. Tables describe both autosomal recessive ataxias and autosomal dominant ataxias (with known gene loci), childhood– or young adult–onset ataxias with ill-defined genetic abnormalities, phenotypic features that may indicate a specific genotype in the common autosomal dominant ataxias, and normal and expanded ranges of various repetitive nucleotide sequences in inherited ataxias. Figures include a diagrammatic representation of the type of repeat expansions associated with ataxias, aggregates of ataxin 3, a schematic of some of the proposed pathogenic mechanisms in the polyglutamine ataxias, and dystonia in a patient with SCA3. A sidebar offers selected Internet resources for information on ataxias. This chapter contains 64 references.

scholarly journals Polyglutamine Ataxias: Our Current Molecular Understanding and What the Future Holds for Antisense Therapies

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1499
Author(s):  
Craig S. McIntosh ◽  
Dunhui Li ◽  
Steve D. Wilton ◽  
May T. Aung-Htut
Keyword(s):  
Trinucleotide Repeat ◽  
Spinocerebellar Ataxias ◽  
Coding Region ◽  
Causative Gene ◽  
Polyglutamine Disorders ◽  
Heterogenous Group ◽  
Clinical Presentations ◽  
Progressive Ataxia ◽  
Swallowing Difficulties ◽  
The Common

Polyglutamine (polyQ) ataxias are a heterogenous group of neurological disorders all caused by an expanded CAG trinucleotide repeat located in the coding region of each unique causative gene. To date, polyQ ataxias encompass six disorders: spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17 and account for a larger group of disorders simply known as polyglutamine disorders, which also includes Huntington’s disease. These diseases are typically characterised by progressive ataxia, speech and swallowing difficulties, lack of coordination and gait, and are unfortunately fatal in nature, with the exception of SCA6. All the polyQ spinocerebellar ataxias have a hallmark feature of neuronal aggregations and share many common pathogenic mechanisms, such as mitochondrial dysfunction, impaired proteasomal function, and autophagy impairment. Currently, therapeutic options are limited, with no available treatments that slow or halt disease progression. Here, we discuss the common molecular and clinical presentations of polyQ spinocerebellar ataxias. We will also discuss the promising antisense oligonucleotide therapeutics being developed as treatments for these devastating diseases. With recent advancements and therapeutic approvals of various antisense therapies, it is envisioned that some of the studies reviewed may progress into clinical trials and beyond.

scholarly journals Frequency of the different mutations causing spinocerebellar ataxia (SCA1, SCA2, MJD/SCA3 and DRPLA) in a large group of Brazilian patients

1997 ◽  
Vol 55 (3B) ◽  
pp. 519-529 ◽  
Author(s):  
Iscia Lopes-Cendesi ◽  
Hélio G.A. Teive ◽  
Maria E Calcagnotto ◽  
Jaderson C. da Costa ◽  
Francisco Cardoso ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Autosomal Dominant ◽  
Late Onset ◽  
Geographic Origin ◽  
Autosomal Dominant Inheritance ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
Dominant Inheritance ◽  
Coding Region ◽  
Spinocerebellar Ataxia Type 3

Spinocerebellar ataxia type 1 (SCA1), spinocerebellar ataxia type 2 (SCA2) and Machado-Joseph disease or spinocerebellar ataxia type 3 (MJD/SCA3) are three distinctive forms of autosomal dominant spinocerebellar ataxia (SCA) caused by expansions of an unstable CAG repeat localized in the coding region of the causative genes. Another related disease, dentatorubropallidoluysian atrophy (DRPLA) is also caused by an unstable triplet repeat and can present as SCA in late onset patients. We investigated the frequency of the SCA1, SCA2, MJD/SCA3 and DRPLA mutations in 328 Brazilian patients with SCA, belonging to 90 unrelated families with various patterns of inheritance and originating in different geographic regions of Brazil. We found mutations in 35 families (39%), 32 of them with a clear autosomal dominant inheritance. The frequency of the SCA1 mutation was 3% of all patients; and 6 % in the dominantly inherited SCAs. We identified the SCA2 mutation in 6% of all families and in 9% of the families with autosomal dominant inheritance. The MJD/SCA3 mutation was detected in 30 % of all patients; and in the 44% of the dominantly inherited cases. We found no DRPLA mutation. In addition, we observed variability in the frequency of the different mutations according to geographic origin of the patients, which is probably related to the distinct colonization of different parts of Brazil. These results suggest that SCA may be occasionally caused by the SCA1 and SCA2 mutations in the Brazilian population, and that the MJD/SCA3 mutation is the most common cause of dominantly inherited SCA in Brazil.

scholarly journals Clinical and molecular characteristics of a Brazilian family with spinocerebellar ataxia type 1

1996 ◽  
Vol 54 (3) ◽  
pp. 412-418 ◽  
Author(s):  
Iscia Lopes-Cendes ◽  
Carlos E. Steiner ◽  
Isabel Silveira ◽  
Walter Pinto-Junior ◽  
Jayme A. Maciel ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Late Onset ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
Molecular Characteristics ◽  
Spinocerebellar Ataxias ◽  
Dominant Type ◽  
Expanded Allele ◽  
Mean Size ◽  
Autosomal Dominant Type

The spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of late onset neurodegenerative disorders. To date, seven different genes causing autosomal dominant SCA have been mapped: SCA1, SCA2, Machado-Joseph disease (MJD)/SCA3, SCA4, SCA5, SCA7 and dentatorubropallidoluysian atrophy (DRPLA). Expansions of an unstable trinucleotide CAG repeat cause three of these disorders: SCA1, MJD/SCA3 and DRPLA. We studied one Brazilian family segregating an autosomal dominant type of SCA. A total of ten individuals were examined and tested for the presence of the SCA1, MJD and DRPLA mutations. Three individuals, one male and two females, were considered affected based on neurological examination; ages at onset were: 32, 36 and 41 years. The first complaint in all three patients was gait ataxia which progressed slowly over the years. Six individuals showed one allele containing an expanded CAG repeat in the SCA1 gene. The mean size of the expanded allele was 48.2 CAG units. Instability of the expanded CAG tract was seen in the two transmissions that were observed in this family. In both occasions there was a contraction of the CAG tract. Our study demonstrates that SCA1 occurs in the Brazilian population. In addition, our results stress the importance of molecular studies in the confirmation of diagnosis and for pre-symptomatic testing in SCAs.

scholarly journals Hypospadiasis előfordulása öt fivérben

2015 ◽  
Vol 156 (33) ◽  
pp. 1348-1352
Author(s):  
Stelios Mavrogenis ◽  
Endre Czeizel
Keyword(s):  
Androgen Receptor ◽  
Receptor Gene ◽  
Androgen Receptor Gene ◽  
Androgen Insensitivity Syndrome ◽  
Cag Repeat ◽  
Coding Region ◽  
Mild Form ◽  
Normal Range ◽  
Familial Cluster ◽  
Genetic Institute

The healthy couple had five sons with hypospadias (glandular 1, coronal 4) without other child. Similar familial cluster has not reported in the sons of European parents without consanguinity. Mild form androgen insensitivity syndrome was expected in these 5 boys because of the X-linked androgen receptor gene, however, sequencing of the entire coding region (exons 1-8) and all intron-exon boundaries of the androgen receptor gene did not reveal abnormality and the CAG repeat was found in the normal range (21 repeats). This extreme familial cluster may help us to elucidate gene polymorphisms in the polygenic background of the multifactorial origin of isolated hypospadias. Therefore, the authors collaborate with a genetic institute in Pittsburg, USA to perform whole genome sequencing in these probands and their parents. Orv. Hetil., 2015, 156(33), 1348–1352.

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