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.

Verbal adynamia in parkinsonian syndromes: behavioral correlates and neuroanatomical substrate.

Verbal adynamia (impaired language generation, as during conversation) has not been assessed systematically in parkinsonian disorders. We addressed this in patients with Parkinson's dementia, progressive supranuclear palsy and corticobasal degeneration. All disease groups showed impaired verbal fluency and sentence generation versus healthy age-matched controls, after adjusting for general linguistic and executive factors. Dopaminergic stimulation in the Parkinson's group selectively improved verbal generation versus other cognitive functions. Voxel-based morphometry identified left inferior frontal and posterior superior temporal cortical correlates of verbal generation performance. Verbal adynamia warrants further evaluation as an index of language network dysfunction and dopaminergic state in parkinsonian disorders.

Deletions at 22q11.2 in idiopathic Parkinson's disease: a combined analysis of genome-wide association data.

BACKGROUND: Parkinson's disease has been reported in a small number of patients with chromosome 22q11.2 deletion syndrome. In this study, we screened a series of large, independent Parkinson's disease case-control studies for deletions at 22q11.2. METHODS: We used data on deletions spanning the 22q11.2 locus from four independent case-control Parkinson's disease studies (UK Wellcome Trust Case Control Consortium 2, Dutch Parkinson's Disease Genetics Consortium, US National Institute on Aging, and International Parkinson's Disease Genomics Consortium studies), which were independent of the original reports of chromosome 22q11.2 deletion syndrome. We did case-control association analysis to compare the proportion of 22q11.2 deletions found, using the Fisher's exact test for the independent case-control studies and the Mantel-Haenszel test for the meta-analyses. We retrieved clinical details of patients with Parkinson's disease who had 22q11.2 deletions from the medical records of these patients. FINDINGS: We included array-based copy number variation data from 9387 patients with Parkinson's disease and 13 863 controls. Eight patients with Parkinson's disease and none of the controls had 22q11.2 deletions (p=0·00082). In the 8451 patients for whom age at onset data were available, deletions at 22q11.2 were associated with Parkinson's disease age at onset (Mann-Whitney U test p=0·001). Age at onset of Parkinson's disease was lower in patients carrying a 22q11.2 deletion (median 37 years, 95% CI 32·0-55·5; mean 42·1 years [SD 11·9]) than in those who did not carry a deletion (median 61 years, 95% CI 60·5-61·0; mean 60·3 years [SD 12·8]). A 22q11.2 deletion was present in more patients with early-onset (p<0·0001) and late-onset Parkinson's disease (p=0·016) than in controls, and in more patients with early-onset than late-onset Parkinson's disease (p=0·005). INTERPRETATION: Clinicians should be alert to the possibility of 22q11.2 deletions in patients with Parkinson's disease who have early presentation or features associated with the chromosome 22q11.2 deletion syndrome, or both. FUNDING: UK Medical Research Council, UK Wellcome Trust, Parkinson's UK, Patrick Berthoud Trust, National Institutes of Health, "Investissements d'Avenir" ANR-10-IAIHU-06, Dutch Parkinson Foundation (Parkinson Vereniging), Neuroscience Campus Amsterdam, National Institute for Health Research, National Institute on Aging, National Institutes of Health.

DRD1 rare variants associated with tardive-like dystonia: a pilot pathway sequencing study in dystonia.

The dystonias are a clinical heterogeneous group with a complex genetic background. To gain more insight in genetic risk factors in dystonia we used a pathway sequence approach in patients with an extreme dystonia phenotype (n = 26). We assessed all coding and non-coding variants in candidate genes in D1-like subclass of dopamine receptor genes (DRD1, DRD5) and the synaptic vesicle pathway linked to torsinA (TOR1A, STON2, SNAPIN, KLC1 and THAP1), spanning 96 Kb. Two rare missense variants in DRD1 were found: c.68G>A(p.Arg23His) in the screening group and c.776C>A(p.Ser259Tyr) in an additional screen of 15 selected dystonia patients. Genetic burden analysis of DRD1 rare variants in patients (4.8%) versus European American controls from ESP (0.72%) reveals an OR 5.35 (95% CI 1.29-23.1). No rare missense SNVs in the synaptic vesicle pathway were found. Sequencing of TOR1A showed variant enrichment in haplotype 2, possibly accountable for contradictive results in previous association studies. Two new rare SNVs were detected in THAP1, including a nonsense mutation (p.Gln167Ter) and a splice site variant (c.72-1G>A). Screening for rare SNV of candidate pathways in a phenotype extreme population appears to be a promising alternative method to identify genetic risk factors in complex disorders like primary torsion dystonia. These findings indicate a role for rare genetic variation in dopamine processing genes in dystonia pathophysiology.

Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration.

The hereditary spastic paraplegias (HSPs) are a genetically and clinically heterogeneous group of upper-motor-neuron degenerative diseases characterized by selective axonal loss in the corticospinal tracts and dorsal columns. Although numerous mechanisms involving defective subcellular transportation, mitochondrial malfunction, and increased oxidative stress have been proposed, the pathogenic basis underlying the neuronal loss is unknown. We have performed linkage analysis to refine the extent of the SPG5 disease locus and conducted sequence analysis of the genes located within this region. This identified sequence alterations in the cytochrome P450-7B1 (CYP7B1) associated with this pure form of HSP. In the liver, CYP7B1 offers an alternative pathway for cholesterol degradation and also provides the primary metabolic route for the modification of dehydroepiandrosterone neurosteroids in the brain. These findings provide the first direct evidence of a pivotal role of altered cholesterol metabolism in the pathogenesis of motor-neuron degenerative disease and identify a potential for therapeutic intervention in this form of HSP.