Dominantly inherited olivopontocerebellar atrophy from eastern Cuba

Orozco, Guillermo Hernández; Estrada, Rafael Botella; Perry, Thomas L.; Araña, J.M.Hernandez; Fernandez, Rebecca; González‐Quevedo, Alina; J, Galarraga; Hansen, Shirley

doi:10.1016/0022-510x(89)90159-7

Cited by 167 publications

(141 citation statements)

References 18 publications

Supporting

Mentioning

123

Contrasting

Unclassified

Order By: Relevance

“…In typical patients the gene has the sequence (CAG) 8 (CAA) 1 (CAG) 4 (CAA) 1 (CAG) 8 , coding for 22 consecutive glutamine residues near the N-terminal end of the protein, but in affected individuals the length of the repeat generally surpasses 32 repeats [32]. Neuronal loss is seen in a variety of structures in SCA2, notably the cerebellum [33], thalamus [34], pons [35], medulla [36], midbrain, and cerebral cortex [37].…”

Section: Sca2mentioning

confidence: 99%

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

Chopra

Shakkottai

2014

Neurotherapeutics

View full text Add to dashboard Cite

Polyglutamine diseases are a class of neurodegenerative diseases that share an expansion of a glutamineencoding CAG tract in the respective disease genes as a central hallmark. In all of these diseases there is progressive degeneration in a select subset of neurons, and the mechanisms behind this degeneration remain unclear. Emerging evidence from animal models of disease has identified abnormalities in synaptic signaling and intrinsic excitability in affected neurons, which coincide with the onset of symptoms and precede apparent neuropathology. The appearance of these early changes suggests that altered neuronal activity might be an important component of network dysfunction and that these alterations in network physiology could contribute to symptoms of disease. Here we review abnormalities in neuronal function that have been identified in both animal models and patients, and highlight ways in which these changes in neuronal activity may contribute to disease symptoms. We then review the literature supporting an emerging role for abnormalities in neuronal activity as a driver of neurodegeneration. Finally, we identify common themes that emerge from studies of neuronal dysfunction in polyglutamine disease.

show abstract

Section: Sca2mentioning

confidence: 99%

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

Chopra

Shakkottai

2014

Neurotherapeutics

View full text Add to dashboard Cite

show abstract

“…37, 38 Most reports concern populations with probable founder effects, such as SCA2 in the province of Holguin in Cuba (4/10 000) 39 or SCA3/MJD in the Azores in Portugal (1/4000). 40 The relative frequencies of the different CAG repeat expansions have been determined by molecular typing in several populations.…”

Section: Frequency and Origin Of The Mutationsmentioning

confidence: 99%

Clinical and molecular advances in autosomal dominant cerebellar ataxias: from genotype to phenotype and physiopathology

2000

View full text Add to dashboard Cite

Major advances have been made in the understanding of autosomal dominant cerebellar ataxias since genetic markers came into use in the 1980s. The subsequent mapping of nine genes, six of which have been identified, involved in this clinically diverse group of disorders highlighted their great genetic heterogeneity. Evidence is now accumulating that, except for SCA8, the same molecular and physiopathological processes underlie these diseases and other neurodegenerative disorders sharing the same mutational basis, the expansion of a (CAG)n-polyglutamine coding sequence. The clinical overlap among the different genetic entities makes prediction of the molecular origin impossible in a single patient so that molecular characterisation is necessary. However, extended clinical and neuropathological comparisons have shown that each genetic entity has a characteristic constellation of signs and symptoms that are related to CAG repeat size and disease duration. The combined genetic and clinical information form the basis of a new classification that will aid better understanding of disease evolution, assure follow up and permit genetic counselling by the clinician.

show abstract

“…The epidemiological data available about the prevalence of SCA diseases is limited, and most likely does not represent an accurate occurrence, due to the high degree of variation between difference populations and ethnic backgrounds. Founder effects are seen in Cuba (particularly those of Spanish decent), Portugal and South Africa in SCA2, SCA3 and SCA7, respectively [47,[76][77][78]. Several geographically localised studies have been conducted on the prevalence of ADCAs, with the focus on the six SCA diseases.…”

Section: Prevalence and Incidencementioning

confidence: 99%

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

McIntosh¹,

Htut²,

Fletcher³

et al. 2017

J Genet Syndr Gene Ther

View full text Add to dashboard Cite

Spinocerebellar ataxias are a large group of heterogeneous diseases that all involve selective neuronal degeneration and accompanied cerebellar ataxia. These diseases can be further broken down into discrete groups according to their underlying molecular genetic cause. The most common are the polyglutamine ataxias, of which there are six; Spinocerebellar ataxia type 1, 2, 3, 6, 7 and 17. These diseases are characterised by a pathological expanded cytosine-adenine-guanine (CAG) repeat sequence, in the protein coding region of a given gene. Common clinical features include lack of coordination and gait ataxia, speech and swallowing difficulties, as well as impaired hand and motor functions. The polyglutamine spinocerebellar ataxias are typically late onset diseases that are progressive in nature and often lead to premature death, for which there is currently no known cure or effective treatment strategy. Although caused by the same molecular mechanism, the causative gene and associated protein differ for each disease. The exact mechanism by which disease pathogenesis is caused remains elusive. However, the variable (CAG) n repeats are codons that may be translated to an expanded glutamine tract, leading to conformational changes in the protein, giving it a toxic gain of function. Several pathogenic pathways have been implicated in polyglutamine spinocerebellar ataxia diseases, such as the hallmark feature of neuronal nuclear inclusions, protein misfolding and aggregation, as well as transcriptional dysregulation. These pathways are attractive avenues for potential therapeutic interventions, as the potential to treat more than one disease exists. Research is ongoing, and several promising therapies are currently underway in an attempt to provide relief for this devastating class of diseases.. However, mutations can arise de novo, through errors in DNA replication such that two genetically healthy parents can give rise to an affected child.There are currently six characterised polyQ SCAs (1, 2, 3, 6, 7 and 17) (Table 1), and together with three other diseases, namely Huntington's disease, spinal and bulbar muscular atrophy and dentatorubropallidoluysian atrophy (DRPLA), form a larger category of polyQ diseases [7][8][9][10]. Th ere is little relief for individuals suffering from polyQ SCA disorders, with symptomatic treatments the only available option. Long term pharmacological treatment, although admirable, tends to fall short in an effective management strategy, as unwanted complications and low drug efficacy still exist. In addition, none of these diseases have any treatments that slow the progression of the disease; leaving affected individuals with the daunting reality that time may be a severe limiting factor. Several experimental approaches are currently being assessed to overcome these difficulties. This review will focus on the clinical and molecular features of polyQ SCA diseases (which will be referred to as SCA diseases), as well as highlight several promising and emerging therapeutic strategies...

show abstract

Dominantly inherited olivopontocerebellar atrophy from eastern Cuba

Cited by 167 publications

References 18 publications

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

Clinical and molecular advances in autosomal dominant cerebellar ataxias: from genotype to phenotype and physiopathology

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

Contact Info

Product

Resources

About