Complexity of the Genetics and Clinical Presentation of Spinocerebellar Ataxia 17
Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the TATA-box binding protein gene ( ). The disease has a varied age at onset and clinical presentation. It is distinct from other SCAs for its association with dementia,...
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| Published in: | Frontiers in cellular neuroscience Vol. 12; p. 429 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
Switzerland
Frontiers Research Foundation
23-11-2018
Frontiers Media S.A |
| Subjects: | |
| Online Access: | Get full text |
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| Summary: | Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the TATA-box binding protein gene (
). The disease has a varied age at onset and clinical presentation. It is distinct from other SCAs for its association with dementia, psychiatric symptoms, and some patients presenting with chorea. For this reason, it is also called Huntington's disease-like 4 (HDL-4). Here we examine the distribution of SCA17 allele repeat sizes in a United Kingdom-based cohort with ataxia and find that fully penetrant pathogenic alleles are very rare (5 in 1,316 chromosomes; 0.38%). Phenotype-genotype correlation was performed on 30 individuals and the repeat structure of their
genes was examined. We found a negative linear correlation between total CAG repeat length and age at disease onset and, unlike SCA1, there was no correlation between the longest contiguous CAG tract and age at disease onset. We were unable to identify any particular phenotypic trait that segregated with particular CAG/CAA repeat tract structures or repeat lengths. One individual within the cohort was homozygous for variable penetrance range SCA17 alleles. This patient had a similar age at onset to heterozygotes with the same repeat sizes, but also presented with a rapidly progressive dementia. A pair of monozygotic twins within the cohort presented 3 years apart with the sibling with the earlier onset having a more severe phenotype with dementia and chorea in addition to the ataxia observed in their twin. This appears to be a case of variable expressivity, possibly influenced by other environmental or epigenetic factors. Finally, there was an asymptomatic father with a severely affected child with an age at onset in their twenties. Despite this, they share the same expanded allele repeat sizes and sequences, which would suggest that there is marked difference in the penetrance of this 51-repeat allele. We therefore propose that the variable penetrance range extend from 48 repeats to incorporate this allele. This study shows that there is variability in the presentation and penetrance of the SCA17 phenotype and highlights the complexity of this disorder. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by: Egidio D’Angelo, University of Pavia, Italy Deceased 26th September 2017 Reviewed by: Ryosuke Miyamoto, Tokushima University, Japan; Hakan Gurvit, Istanbul University, Turkey |
| ISSN: | 1662-5102 1662-5102 |
| DOI: | 10.3389/fncel.2018.00429 |