Genetic analysis of age at onset variation in spinocerebellar ataxia type 2

Figueroa, Karla P.; Coon, Hilary; Santos, Nieves; Velázquez, Luís; Mederos, Luis Almaguer; Pulst, Stefan M.

doi:10.1212/nxg.0000000000000155

Cited by 39 publications

(35 citation statements)

References 20 publications

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“…This is particularly well illustrated for the CAG/polyglutamine diseases, nine disorders in which relatively modest CAG repeat expansions encode abnormally long stretches of glutamine in the respective disease proteins. In all nine CAG/polyglutamine diseases, there is a strong inverse correlation between repeat length and age of symptom onset: longer repeats cause earlier disease that usually has more profound signs and symptoms (3,36,40,59,62,66,70,75,108,115,122,126,129). The size of the expanded CAG repeat is itself the key determinant for age of onset, accounting for 45% to 70% of the effect, depending on the specific disease.…”

Section: Introductionmentioning

confidence: 99%

Repeat expansion diseases

Paulson

2018

Handbook of Clinical Neurology

325

286

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More than 40 diseases, most of which primarily affect the nervous system, are caused by expansions of simple sequence repeats dispersed throughout the human genome. Expanded trinucleotide repeat diseases were discovered first and remain the most frequent. More recently tetra-, penta-, hexa-, and even dodeca-nucleotide repeat expansions have been identified as the cause of human disease, including some of the most common genetic disorders seen by neurologists. Repeat expansion diseases include both causes of myotonic dystrophy (DM1 and DM2), the most common genetic cause of amyotrophic lateral sclerosis/frontotemporal dementia (C9ORF72), Huntington disease, and eight other polyglutamine disorders, including the most common forms of dominantly inherited ataxia, the most common recessive ataxia (Friedreich ataxia), and the most common heritable mental retardation (fragile X syndrome). Here I review distinctive features of this group of diseases that stem from the unusual, dynamic nature of the underlying mutations. These features include marked clinical heterogeneity and the phenomenon of clinical anticipation. I then discuss the diverse molecular mechanisms driving disease pathogenesis, which vary depending on the repeat sequence, size, and location within the disease gene, and whether the repeat is translated into protein. I conclude with a brief clinical and genetic description of individual repeat expansion diseases that are most relevant to neurologists.

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Section: Introductionmentioning

confidence: 99%

Repeat expansion diseases

Paulson

2018

Handbook of Clinical Neurology

325

286

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“…This relationship varies between diseases and the difference in age at onset is not accounted for solely by the TNR repeat length. A substantial portion of this residual variance is heritable [3,24].…”

Section: Autosomal Dominant Cerebellar Ataxiamentioning

confidence: 99%

“…The length of TNR expansion above the disease threshold is inversely proportional to the age of onset [22,23]. A substantial portion of this residual variance is heritable [3,24]. A substantial portion of this residual variance is heritable [3,24].…”

Section: Introductionmentioning

confidence: 99%

DNA repair in trinucleotide repeat ataxias

et al. 2018

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The inherited cerebellar ataxias comprise of a genetic heterogeneous group of disorders. Pathogenic expansions of cytosine-adenine-guanine (CAG) encoding polyglutamine tracts account for the largest proportion of autosomal dominant cerebellar ataxias, while GAA expansion in the first introns of frataxin gene is the commonest cause of autosomal recessive cerebellar ataxias. Currently, there is no available treatment to alter the disease trajectory, with devastating consequences for affected individuals. Inter- and Intrafamily phenotypic variability suggest the existence of genetic modifiers, which may become targets amendable to treatment. Recent studies have demonstrated the importance of DNA repair pathways in modifying spinocerebellar ataxia with CAG repeat expansions. In this review, we discuss the mechanisms in which DNA repair pathways, epigenetics and other genetic factors may act as modifiers in cerebellar ataxias due to trinucleotide repeat expansions.

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“…Once the length of the CAG repeat has been accounted for, the residual AOO variance can be considered as a heritable trait, implying the existence of genetic modifiers. 51,52 A recent study identified non-pathological repeat lengths in other CAG-containing disease loci, that act in trans with wildtype alleles (SCA1, SCA6, SCA7), as modifiers of disease onset in 1255 patients from the EUROSCA cohort. 53 These findings were partly replicated by other studies in smaller cohorts.…”

Section: Modifiers Of Aoomentioning

confidence: 99%

Advances in the understanding of hereditary ataxia – implications for future patients

Zeitlberger¹,

Ging²,

Nethisinghe³

et al. 2018

Expert Opinion on Orphan Drugs

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Introduction: Hereditary ataxias are caused by mutations in a plethora of different genes. Advances in sequencing technologies have led to an exponential increase in novel gene discoveries, highlighted the genetic overlap with other neurological diseases and improved our understanding of genotype-phenotype relationships. Together, these developments allowed the identification of new therapeutic targets that are subsequently making their way into clinical trials. Areas covered: This review focuses on the shared genetic characteristics and the latest insights into the molecular cause of the most prevalent hereditary ataxias. Furthermore, conventional genetic diagnosis and the gradual implementation of next-generation sequencing (NGS) approaches in clinical practice is discussed. Finally, the latest investigated disease-modifying therapeutic agents are reviewed. A literature search was performed in PubMed and the Cochrane Library. Additional information on previous and ongoing trials was obtained from the ClinicalTrials.gov website. Expert opinion: The implementation of NGS in clinical practice has led to an increase in detected sequence variants of unknown clinical significance. Determining their pathogenicity is an expensive and time-consuming process. However, misinterpretation of these variants can have far-reaching consequences for the patient and their relatives. In accordance with the progresses in genetics, there is a need for the simultaneous definition of novel biomarkers and functional assays that can assist in the interpretation of genetic tests. Moreover, the identification of biomarkers that are relevant to specific diseases has the potential to improve clinical trial design.

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Genetic analysis of age at onset variation in spinocerebellar ataxia type 2

Cited by 39 publications

References 20 publications

Repeat expansion diseases

Repeat expansion diseases

DNA repair in trinucleotide repeat ataxias

Advances in the understanding of hereditary ataxia – implications for future patients

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