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Genetic analysis of Mendelian mutations in a large UK population-based Parkinson's disease study.

Tan, MMX; Malek, N; Lawton, MA; Hubbard, L; Pittman, AM; Joseph, T; Hehir, J; Swallow, DMA; Grosset, KA; Marrinan, SL; et al. Tan, MMX; Malek, N; Lawton, MA; Hubbard, L; Pittman, AM; Joseph, T; Hehir, J; Swallow, DMA; Grosset, KA; Marrinan, SL; Bajaj, N; Barker, RA; Burn, DJ; Bresner, C; Foltynie, T; Hardy, J; Wood, N; Ben-Shlomo, Y; Grosset, DG; Williams, NM; Morris, HR (2019) Genetic analysis of Mendelian mutations in a large UK population-based Parkinson's disease study. Brain, 142 (9). pp. 2828-2844. ISSN 1460-2156 https://doi.org/10.1093/brain/awz191
SGUL Authors: Pittman, Alan Michael

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Abstract

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.

Item Type: Article
Additional Information: © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Parkinson’s disease, genetics, heterogeneity, phenotype, prevalence, 11 Medical And Health Sciences, 17 Psychology And Cognitive Sciences, Neurology & Neurosurgery
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Brain
ISSN: 1460-2156
Language: eng
Dates:
DateEvent
September 2019Published
19 July 2019Published Online
28 April 2019Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
J-1101Parkinson's UKhttp://dx.doi.org/10.13039/501100000304
H-1703Parkinson's UKhttp://dx.doi.org/10.13039/501100000304
G1100643Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G-1107Parkinson's UKhttp://dx.doi.org/10.13039/501100000304
PubMed ID: 31324919
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/111060
Publisher's version: https://doi.org/10.1093/brain/awz191

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