The clinical diagnosis of progressive supranuclear palsy(PSP) relies on the id entification of characteristic signsand symptoms. A proportion of pathologically diagnosed cases do not develop these classic features, prove difficult to diagn ose during life and are considered as atypical PSP. The aim of this study was to examine the apparent clinical dichotomy between typical and atypical PSP, and t o compare the biochemical and genetic characteristics of these groups. In 103 co nsecutive cases of pathologically confirmed PSP, we have identified two clinical phenotypes by factor analysis which we have named Richardson’s syndrome (RS) a nd PSP-parkinsonism (PSP-P). Cases of RS syndrome made up 54%of all cases, an d were characterized by the early onset of postural instability and falls, supra nuclear vertical gaze palsy and cognitive dysfunction. A second group of 33 (32 %) were characterized by asymmetric onset, tremor, a moderate initial therapeut ic response to levodopa and were frequently confused with Parkinson’s disease ( PSP-P). Fourteen cases (14%)-could not be separated according to these criter ia. In RS, two-thirds of cases were men, whereas the sex distribution in PSP-P was even. Disease duration in RS was significantly shorter (5.9 versus 9.1 year s, P < 0.001)-and age at death earlier (72.1 versus 75.5 years, P=0.01) than in PSP-P. The isoform composition of insoluble tangle-tau isolated from the basa l pons also differed significantly. In RS, the mean four-repeat: three-repeat tau ratio was 2.84 and in PSP-P it was 1.63 (P< 0.003). The effect of the H1,H1 PSP susceptibility genotype appeared stronger in RS than in PSP-P (odds ratio 13.2 versus 4.5). The difference in genotype frequencies between the clinical su bgroups was not significant. There were no differences in apolipoprotein E genot ypes. The classic clinical description of PSP, which includes supranuclear gaze palsy, early falls and dementia, does not adequately describe one-third of case s in this series of pathologically confirmed cases. We propose that PSP-P repre sents a second discrete clinical phenotype that needs to be clinically distingui shed from classical PSP (RS). The different tau isoformdeposition in the basal p ons suggests that this may ultimately prove to be a discrete nosological entity.
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