The genetic and clinico‐pathological profile of early‐onset progressive supranuclear palsy

BACKGROUND: Studies on early‐onset presentations of progressive supranuclear palsy (PSP) have been limited to those where a rare monogenic cause has been identified. Here, we have defined early‐onset PSP (EOPSP) and investigated its genetic and clinico‐pathological profile in comparison with late‐onset PSP (LOPSP) and Parkinson's disease (PD). METHODS: We included subjects from the Queen Square Brain Bank, PROSPECT‐UK study, and Tracking Parkinson's study. Group comparisons of data were made using Welch's t‐test and Kruskal‐Wallis analysis of variance. EOPSP was defined as the youngest decile of motor age at onset (≤55 years) in the Queen Square Brain Bank PSP case series. RESULTS: We identified 33 EOPSP, 328 LOPSP, and 2000 PD subjects. The early clinical features of EOPSP usually involve limb parkinsonism and gait freezing, with 50% of cases initially misdiagnosed as having PD. We found that an initial clinical diagnosis of EOPSP had lower diagnostic sensitivity (33%) and positive predictive value (38%) in comparison with LOPSP (80% and 76%) using a postmortem diagnosis of PSP as the gold standard. 3/33 (9%) of the EOPSP group had an underlying monogenic cause. Using a PSP genetic risk score (GRS), we showed that the genetic risk burden in the EOPSP (mean z‐score, 0.59) and LOPSP (mean z‐score, 0.48) groups was significantly higher (P < 0.05) when compared with the PD group (mean z‐score, −0.08). CONCLUSIONS: The initial clinical profile of EOPSP is often PD‐like. At the group level, a PSP GRS was able to differentiate EOPSP from PD, and this may be helpful in future diagnostic algorithms. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.