Our objective was to define the prevalence and clinical features of genetic Parkinson’s disease in a large UK population-based cohort, the largest multicentre prospective clinico-genetic incident study in the world. We collected demographic data, Movement Disorder Society Unified Parkinson’s Disease Rating Scale scores, and Montreal Cognitive Assessment scores. We analysed mutations in PRKN (parkin), PINK1, LRRK2 and SNCA in relation to age at symptom onset, family history and clinical features. Of the 2262 participants recruited to the Tracking Parkinson’s study, 424 had young-onset Parkinson’s disease (age at onset ≤ 50) and 1799 had late onset Parkinson’s disease. A range of methods were used to genotype 2005 patients: 302 young-onset patients were fully genotyped with multiplex ligation-dependent probe amplification and either Sanger and/or exome sequencing; and 1701 late-onset patients were genotyped with the LRRK2 ‘Kompetitive’ allele-specific polymerase chain reaction assay and/or exome sequencing (two patients had missing age at onset). We identified 29 (1.4%) patients carrying pathogenic mutations. Eighteen patients carried the G2019S or R1441C mutations in LRRK2, and one patient carried a heterozygous duplication in SNCA. In PRKN, we identified patients carrying deletions of exons 1, 4 and 5, and P113Xfs, R275W, G430D and R33X. In PINK1, two patients carried deletions in exon 1 and 5, and the W90Xfs point mutation. Eighteen per cent of patients with age at onset ≤30 and 7.4% of patients from large dominant families carried pathogenic Mendelian gene mutations. Of all young-onset patients, 10 (3.3%) carried biallelic mutations in PRKN or PINK1. Across the whole cohort, 18 patients (0.9%) carried pathogenic LRRK2 mutations and one (0.05%) carried an SNCA duplication. There is a significant burden of LRRK2 G2019S in patients with both apparently sporadic and familial disease. In young-onset patients, dominant and recessive mutations were equally common. There were no differences in clinical features between LRRK2 carriers and non-carriers. However, we did find that PRKN and PINK1 mutation carriers have distinctive clinical features compared to young-onset non-carriers, with more postural symptoms at diagnosis and less cognitive impairment, after adjusting for age and disease duration. This supports the idea that there is a distinct clinical profile of PRKN and PINK1-related Parkinson’s disease. We estimate that there are approaching 1000 patients with a known genetic aetiology in the UK Parkinson’s disease population. A small but significant number of patients carry causal variants in LRRK2, SNCA, PRKN and PINK1 that could potentially be targeted by new therapies, such as LRRK2 inhibitors.

Background Hyposmia can develop with age and in neurodegenerative conditions, including Parkinson’s disease (PD). The University of Pennsylvania Smell Identification Test (UPSIT) is a 40-item smell test widely used for assessing hyposmia. However, in a number of situations, such as identifying hyposmic individuals in large populations, shorter tests are preferable. Methods We assessed the ability of shorter UPSIT subsets to detect hyposmia in 891 healthy participants from the PREDICT-PD study. Shorter subsets included Versions A and B of the 4-item Pocket Smell Test (PST) and 12-item Brief Smell Identification Test (BSIT). Using a data-driven approach, we evaluated screening performances of 23,231,378 combinations of 1–7 smell items from the full UPSIT to derive “winning” subsets, and validated findings separately in another 191 healthy individuals. We then compared discriminatory UPSIT smells between PREDICT-PD participants and 40 PD patients, and assessed the performance of “winning” subsets containing discriminatory smells in PD patients. Results PST Versions A and B achieved sensitivity/specificity of 76.8%/64.9% and 86.6%/45.9%, respectively, while BSIT Versions A and B achieved 83.1%/79.5% and 96.5%/51.8%. From the data-driven analysis, 2 “winning” 7-item subsets surpassed the screening performance of 12-item BSITs (validation sensitivity/specificity of 88.2%/85.4% and 100%/53.5%), while a “winning” 4-item subset had higher sensitivity than PST-A, -B, and even BSIT-A (validation sensitivity 91.2%). Interestingly, several discriminatory smells featured within “winning” subsets, and demonstrated high-screening performances for identifying hyposmic PD patients. Conclusion Using abbreviated smell tests could provide a cost-effective means of large-scale hyposmia screening, allowing more targeted UPSIT administration in general and PD-related settings. Electronic supplementary material The online version of this article (10.1007/s00415-019-09340-x) contains supplementary material, which is available to authorized users.

Biallelic PRKN (Parkin) mutations cause autosomal recessive Parkinson’s (PD); however, the role of monoallelic PRKN mutations as a risk factor for PD remains unclear. We investigated the role of single heterozygous PRKN mutations in three large independent case–control cohorts totalling 10 858 PD cases and 8328 controls. Overall, after exclusion of biallelic carriers, single PRKN mutations were more common in PD than controls conferring a > 1.5-fold increase in risk of PD (P = 0.035), with meta-analysis (19 574 PD cases and 468 488 controls) confirming increased risk (OR = 1.65, P = 3.69E-07). Carriers were shown to have significantly younger ages at onset compared to non-carriers (NeuroX: 56.4 vs. 61.4 years; Exome: 38.5 vs. 43.1 years). Stratifying by mutation type, we provide preliminary evidence for a more pathogenic risk profile for single PRKN copy number variant (CNV) carriers compared to single nucleotide variant carriers. Studies that did not assess biallelic PRKN mutations or consist of predominantly early-onset cases may be biasing these estimates, and removal of these resulted in a loss of association (OR = 1.23, P = 0.614; n = 4). Importantly, when we looked for additional CNVs in 30% of PD cases with apparent monoallellic PRKN mutations we found that 44% had biallelic mutations suggesting that previous estimates may be influenced by cryptic biallelic mutation status. While this study supports the association of single PRKN mutations with PD, it highlights confounding effects therefore caution is needed when interpreting current risk estimates. Together, we demonstrate that comprehensive assessment of biallelic mutation status is essential when elucidating PD risk associated with monoallelic PRKN mutations.

Biallelic PARK2 (Parkin) mutations cause autosomal recessive Parkinson's (PD); however, the role of monoallelic PARK2 mutations as a risk factor for PD remains unclear. We investigated the role of single heterozygous PARK2 mutations in three large independent case-control cohorts totalling 10,858 PD cases and 8,328 controls. Overall, after exclusion of biallelic carriers, single PARK2 mutations were more common in PD than controls conferring a >1.5-fold increase in risk of PD (P=0.035), with meta-analysis (19,574 PD cases and 468,488 controls) confirming increased risk (OR=1.65, P=3.69E-07). Carriers were shown to have significantly younger ages at onset compared to non-carriers (NeuroX: 56.4 vs. 61.4 years; Exome: 38.5 vs. 43.1 years). Stratifying by mutation type, we provide preliminary evidence for a more pathogenic risk profile for single PARK2 copy number variant (CNV) carriers compared to single nucleotide variant carriers. Studies that did not assess biallelic PARK2 mutations or consist of predominantly early-onset cases may be biasing these estimates, and removal of these resulted in a loss of association (OR=1.23, P=0.614; n=4). Importantly, when we looked for additional CNVs in 30% of PD cases with apparent monoallellic PARK2 mutations we found that 44% had biallelic mutations suggesting that previous estimates may be influenced by cryptic biallelic mutation status. While this study supports the association of single PARK2 mutations with PD, it highlights confounding effects therefore caution is needed when interpreting current risk estimates. Together, we demonstrate that comprehensive assessment of biallelic mutation status is essential when elucidating PD risk associated with monoallelic PARK2 mutations.