38 were infrequent and when present, they were typically limited to mild rigidity or intermittent hyperkinesias. Only one patient (1/30, 3%) showed classical parkinsonism. The three FTLD-UPS cases all had an initial diagnosis of bvFTD. Very little clinical information was available, but apathy was common to two of these cases as was parkinsonism. Discussion This study describes the ﬁrst comprehensive collection of the aFTLD-U subtype of FTLD-FUS. We show that aFTLD-U has a distinct clinical phenotype characterised by the behavioural variant FTD syndrome, a young onset of disease, a high prevalence of psychotic symptoms and a low prevalence of motor symptoms. FUS pathology accounted for 92% of cases with ubiquitin-positive, tau- and TDP-43-negative FTLD showing that it deﬁnes the vast majority of such cases. However, we identiﬁed three FTLD-UPS cases without CHMP2B mutation showing that while such cases are rare, the FTLD-UPS classiﬁcation has not been completely subsumed by CHMP2B mutation cases or FTLD-FUS. Of all of the FTLD subtypes, bvFTD is pathologically the most heterogeneous making it difﬁcult to predict the under- lying pathology from clinical features in life. This cohort similarly has an overlapping range of symptoms with other sporadic and genetic causes of bvFTD. However, psychotic symptoms are rarely described in other cases of bvFTD [22], and the presence of delusions and hallucinations in a sub- stantial proportion of this cohort may help to distinguish them from other patients. The very low frequency of motor symptoms may also help deﬁne this group of patients. The mean age of onset of 41.2 years for the aFTLD-U cases is much lower than that of a previously reported sporadic FTLD cohort (60.5 years) [4], and therefore, may help distinguish them from other sporadic FTLD cases. 15/ 34 aFTLD-U cases came from two contributing centres, therefore, it is possible that the results have been biassed by these cases, which were previously reported to have a low age of onset [29, 42]. However, the age of onset of these cases is not signiﬁcantly different from the other 19 cases in the study (t test, ns). Furthermore, psychotic symptoms are evenly distributed between cases from these two cen- tres (3/7, 42%) and cases from other centres (5/15, 33%) (Fisher’s exact test, ns). Only one aFTLD-U case (3%, 1/34) had a positive family history for FTD: this patient was one of nine sib- lings, and had one brother who was diagnosed clinically with ‘Pick’s disease’ at 61 years of age and died at 64 years of age without autopsy. Another brother was reported to show ‘cognitive changes’ at the age of 64 years. 123 Acta Neuropathol (2010) 120:33–41 The patient was negative for FUS mutation, suggesting that there may be other genetic causes of FTLD-FUS. While aFTLD-U cases have a distinctive and consistent clinico- pathological phenotype, FTLD appears to occur sporadi- cally in the majority of cases. Of the three FTLD-UPS cases, two had a family history, and one had at least two relatives affected with the same disease [43]. These cases were negative for CHMP2B mutations, which suggests other genetic causes of FTLD-UPS and the possibility of at least one other unidentiﬁed ubiquitinated protein associated with FTLD. No gender bias was found in any of the groups studied. A female preponderance was previously reported in an analysis of a subset of aFTLD-U cases [29]; however, this was not conﬁrmed in wider analysis. It has recently been shown that two rare subtypes of FTLD, NIFID and BIBD have extensive FUS pathology [34, 38]. We did not include NIFID and BIBD cases in this study as they have been described to have distinct clinical features to aFTLD-U cases, particularly prominent motor symptoms [3, 18, 19, 34, 51, 58]. In order to allow comparison of FTLD-FUS to other FTLD cases, we focussed on one subtype of FTLD-FUS (aFTLD-U), as it is possible that FTLD-FUS comprises a clinically heterogeneous group. However, now that NIFID, BIBD and aFTLD-U have been shown to have a common underlying pathology, it will be interesting to directly compare these different FUS entities in future studies. FUS pathology is also found in polyglu- tamine expansion diseases including Huntington’s disease [57], showing that it is not limited to the FTLD-MND spectrum of diseases. This is similar to tau and TDP-43 pathology, which are pathological hallmarks of different FTLD subtypes but are also observed in a wide range of other neurodegenerative diseases. Within the clinical syn- drome of FTLD, FUS pathology will be an extremely important tool for the classiﬁcation of cases which are tau- and TDP-43- negative, and wider analysis of FTLD-FUS cases may reveal further subtypes. In conclusion, the vast majority of cases with tau- and TDP-43 negative inclusions have FUS pathology, sug- gesting that FTLD-FUS is an important FTLD subtype. The opportunity to analyse a large series of aFTLD-U cases has only been possible through a large multi-centre col- laboration, with all centres contributing a relatively small number of cases. This collaborative effort has provided new insights into the genetic and clinicopathological spectrum of FTLD-FUS and FTLD-UPS. Conﬂict of interest statement The authors report no conﬂicts of interest. 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