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Published on: November 3, 2016
The genetic and clinico-pathological profile of early-onset progressive supranuclear palsy
Edwin Jabbari1,2, John Woodside1,2, Manuela M X Tan1,2
1Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom.
Insights
Early-onset progressive supranuclear palsy (PSP) often mimics Parkinson's disease (PD), leading to misdiagnosis. A PSP genetic risk score (GRS) can help differentiate EOPSP from PD, improving diagnostic accuracy.
Area of Science:
- Neuroscience
- Genetics
- Neurology
Background:
- Limited studies exist on early-onset progressive supranuclear palsy (PSP), primarily focusing on rare monogenic causes.
- This study defines early-onset PSP (EOPSP) and compares its genetic and clinico-pathological profile with late-onset PSP (LOPSP) and Parkinson's disease (PD).
Purpose of the Study:
- To define and characterize early-onset PSP (EOPSP).
- To investigate the genetic and clinico-pathological differences between EOPSP, LOPSP, and PD.
- To assess the diagnostic utility of a PSP genetic risk score (GRS) in differentiating these conditions.
Main Methods:
- Defined EOPSP as the youngest decile of motor age at onset (≤55 years) using data from the Queen Square Brain Bank, PROSPECT-UK, and Tracking Parkinson's studies.
- Compared clinical and genetic data between 33 EOPSP, 328 LOPSP, and 2000 PD subjects.
- Utilized Welch's t-test and Kruskal-Wallis analysis of variance for group comparisons and calculated PSP genetic risk scores (GRS).
Main Results:
- EOPSP often presents with limb parkinsonism and gait freezing, with 50% initially misdiagnosed as PD.
- EOPSP showed lower diagnostic sensitivity (33%) and positive predictive value (38%) compared to LOPSP (80%, 76%) when diagnosed clinically.
- A PSP GRS was significantly higher in both EOPSP (0.59) and LOPSP (0.48) groups compared to the PD group (-0.08), with 9% of EOPSP cases having a monogenic cause.
Conclusions:
- The initial clinical presentation of EOPSP frequently resembles PD, complicating early diagnosis.
- A PSP genetic risk score (GRS) can distinguish EOPSP from PD at a group level.
- The findings suggest that a PSP GRS may be a valuable tool for future diagnostic algorithms in differentiating EOPSP from PD.
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.
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