A pathogenic progranulin mutation and C9orf72 repeat expansion in a family with frontotemporal dementia. Issue 4 (June 2014)

• Record Type: Journal Article
• Authors: Lashley, Tammaryn; Rohrer, Jonathan D.; Mahoney, Colin; Gordon, Elizabeth; Beck, Jon; Mead, Simon; Warren, Jason; Rossor, Martin; Revesz, Tamas
• Is Part Of: Neuropathology & applied neurobiology. Volume 40:Issue 4(2014)
• Page Start: 502
• Page End: 513
• Publication Date: 2014-06
• Subjects: Nervous system -- Diseases -- Pathology -- Periodicals; Nervous system -- Diseases -- Periodicals; 616.8
• DOI: 10.1111/nan.12100
• Languages: English
• ISSNs: 0305-1846

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="nan12100-sec-0001" sec-type="section"> <title>Aims</title> <p>Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disease and is the second most common form of young onset dementia after Alzheimer's disease (AD). An autosomal dominant pattern of inheritance is present in around 25–50% of FTLD cases indicating a strong genetic component. Major pathogenic mutations of FTLD have been demonstrated independently in the progranulin (<italic>GRN</italic>) gene and the <italic>C9orf72</italic> hexanucleotide expansion repeat. In this study we present a family that have been identified as carrying both a <italic>GRN Cys31fs</italic> mutation and the <italic>C9orf72</italic> hexanucleotide expansion repeat.</p> </sec> <sec id="nan12100-sec-0002" sec-type="section"> <title>Methods</title> <p>In the present study we describe the clinical and genetic details of family members and pathological features of two family members that have come to post‐mortem.</p> </sec> <sec id="nan12100-sec-0003" sec-type="section"> <title>Results</title> <p>The mean age at disease onset was 57 years (48–61 years) and mean duration 4 years (2–7 years). The most common presenting syndrome was behavioural variant frontotemporal dementia. Brain imaging from available cases showed a symmetrical pattern of atrophy particularly affecting the frontal and temporal lobes. Pathologically two cases were classified as FTLD‐TDP type A with TDP‐43 positive inclusions, with additional p62‐positive 'star‐like' inclusions found in the hippocampal formation and cerebellum.</p> </sec> <sec id="nan12100-sec-0004" sec-type="section"> <title>Conclusions</title> <p>The type and distribution of the pathological lesions in these two cases were in keeping with FTLD cases carrying only the <italic>C9orf72</italic> hexanucleotide repeat. However the driving force of the pathological process may be either pathogenic mutation or a combination of both converging on a singular mechanism.</p> </sec> </abstract>