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Frontotemporal lobar degeneration (FTLD) is genetically and pathologically heterogeneous. Until recently, two main pathological subtypes were recognised, defined by the presence of tau positive or tau negative, ubiquitin positive neuronal inclusions. However, the identification of TDP-43 as a major constituent of ubiquitinated inclusions led to descriptions of a smaller subgroup of patients with ubiquitin positive but TDP-43 negative pathology. Recently, the major constituent of the inclusions in such cases has been identified as FUS (‘fused-in sarcoma’) protein, implicated in RNA processing.1
We retrospectively reviewed all cases ascertained via a tertiary level cognitive disorders clinic between 1992 and 2009 with a clinical diagnosis of FTLD and neuropathological confirmation (post mortem or brain biopsy during life). Five of 100 patients were found to have FUS pathology (FUS1 with neuronal intermediate filament inclusion disease and four other cases with atypical FTLD with ubiquitin-positive inclusions).
FUS1 was previously described as having young onset sporadic Pick's disease.2 The patient presented with an 18 month history of progressive behavioural change with apathy, social withdrawal, reduced speech and fatuous giggling. The patient had also developed increased difficulty using their hands for everyday tasks. On examination the patient was distractible with impoverished, dysarthric speech and bilateral limb apraxia but no other neurological signs. Neuropsychometry demonstrated executive impairment and dyscalculia but normal naming and visuoperceptual skills. The patient was unable to perform tests of episodic memory. The condition deteriorated over the next 3 months with worsening apathy, development of urinary incontinence and falls. The patient was subsequently lost to follow-up. …
Funding This work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. The Dementia Research Centre is an Alzheimer's Research Trust Coordinating Centre. This work was also funded by the Medical Research Council UK. JW has received research support from the Wellcome Trust (Intermediate Clinical Fellowship).
Competing interests None.
Patient consent Obtained.
Ethics approval This study was conducted with the approval of the National Hospital for Neurology and Neurosurgery local ethics committee.
Provenance and peer review Not commissioned; externally peer reviewed.