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Front. Cell. Neurosci. | doi: 10.3389/fncel.2018.00429

Complexity of the genetics and clinical presentation of spinocerebellar ataxia 17

 Suran Nethisinghe1,  Wei N. Lim1,  Heather Ging1,  Anna M. Zeitlberger1,  Rosella Abeti1, Sally Pemble2, Mary G. Sweeney2,  Robyn W. Labrum2, Charisse Cervera2,  Henry Houlden1, Elisabeth Rosser3,  Patricia Limousin1, Angus Kennedy4, Michael Lunn1,  Kailash P. Bhatia1, Nicholas W. Wood1,  John Hardy1, 5, James M. Polke2,  Liana Veneziano6,  Alfredo Brusco7, 8,  Mary B. Davis1 and  Paola Giunti1*
  • 1Ataxia Centre, Department of Clinical and Movement Neurosciences, Institute of Neurology, University College London, United Kingdom
  • 2Neurogenetics Unit, National Hospital for Neurology and Neurosurgery (NHNN), United Kingdom
  • 3Department of Clinical Genetics, Great Ormond Street Hospital, United Kingdom
  • 4Chelsea and Westminster Hospital NHS Foundation Trust, United Kingdom
  • 5The Reta Lila Weston Institute of Neurological Studies, United Kingdom
  • 6Istituto di Farmacologia Traslazionale (IFT), Italy
  • 7Medical Genetics Unit, A.O.U. Citta della Salute e della Scienza di Torino, Italy
  • 8Department of Medical Sciences, Università degli Studi di Torino, Italy

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 (TBP). 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 UK-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 TBP 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.

Keywords: PolyQ, Ataxia, CAG repeat expansions, SCA17, neurodegeneration, Genetic counselling

Received: 30 Jul 2018; Accepted: 30 Oct 2018.

Edited by:

Egidio D‘Angelo, University of Pavia, Italy

Reviewed by:

Hakan Gurvit, Istanbul University, Turkey
Ryosuke Miyamoto, Tokushima University, Japan  

Copyright: © 2018 Nethisinghe, Lim, Ging, Zeitlberger, Abeti, Pemble, Sweeney, Labrum, Cervera, Houlden, Rosser, Limousin, Kennedy, Lunn, Bhatia, Wood, Hardy, Polke, Veneziano, Brusco, Davis and Giunti. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Paola Giunti, Institute of Neurology, University College London, Ataxia Centre, Department of Clinical and Movement Neurosciences, London, United Kingdom,