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FTLD-ALS of TDP-43 type and SCA2 in a family with a full ataxin-2 polyglutamine expansion

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Abstract

Polyglutamine expansions in the ataxin-2 gene (ATXN2) cause autosomal dominant spinocerebellar ataxia type 2 (SCA2), but have recently also been associated with amyotrophic lateral sclerosis (ALS). We present clinical and pathological features of a family in which a pathological ATXN2 expansion led to frontotemporal lobar degeneration with ALS (FTLD-ALS) in the index case, but typical SCA2 in a son, and compare the neuropathology with a case of typical SCA2. The index case shares the molecular signature of SCA2 with prominent polyglutamine and p62-positive intranuclear neuronal inclusions mainly in the pontine nuclei, while harbouring more pronounced neocortical and spinal TDP-43 pathology. We conclude that ATXN2 mutations can cause not only ALS, but also a neuropathological overlap syndrome of SCA2 and FTLD presenting clinically as pure FTLD-ALS without ataxia. The cause of the phenotypic heterogeneity remains unexplained, but the presence of a CAA-interrupted CAG repeat in the FTLD case in this family suggests that one potential mechanism may be variation in repeat tract composition between members of the same family.

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Acknowledgments

We are indebted to the family of the index case for supporting this research and their provision of DNA samples. In addition, we are grateful to the department of Clinical Genetics, Churchill Hospital, Oxford, for technical support. We acknowledge the Oxford Brain Bank, supported by the Medical Research Council (MRC), Brains for Dementia Research (BDR) and the NIHR Oxford Biomedical Research Centre. DB is funded by an Oxfordshire Health Services Research Committee (OHSRC)/Nuffield Oxford Hospitals Fund (NOHF)/BRC Fellowship. The Oxford Brain Bank is supported by the Medical Research Council (OA) and Brains for Dementia Research (OA). SE and OA are supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and University of Oxford.

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  1. Department of Neuropathology, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford, OX3 9DU, UK

    Dirk Bäumer, Simon Z. East, Bing Tseu & Olaf Ansorge

  2. Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford, OX3 9DU, UK

    Dirk Bäumer, Kevin Talbot & Olaf Ansorge

  3. University of Exeter Medical School, St Luke’s Campus, Magdalen Road, Exeter, EX1 2LU, UK

    Adam Zeman

  4. Department of Cellular and Anatomical Pathology, Derriford Hospital, Plymouth, PL6 8DH, UK

    David Hilton

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Correspondence to Olaf Ansorge.

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Bäumer, D., East, S.Z., Tseu, B. et al. FTLD-ALS of TDP-43 type and SCA2 in a family with a full ataxin-2 polyglutamine expansion. Acta Neuropathol 128, 597–604 (2014). https://doi.org/10.1007/s00401-014-1277-z

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