Systematic Review and UK‐Based Study of PARK2 (parkin), PINK1, PARK7 (DJ‐1) and LRRK2 in early‐onset Parkinson's disease |
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| Authors: | Laura L Kilarski PhD Justin P Pearson MRCP Victoria Newsway BSc Elisa Majounie PhD M Duleeka W Knipe BSc MPH Anjum Misbahuddin PhD MRCP Patrick F Chinnery PhD FRCP David J Burn MD FRCP Carl E Clarke MD FRCP Marie‐Helene Marion MD Alistair J Lewthwaite MRCP David J Nicholl PhD FRCP Nicholas W Wood PhD FRCP Karen E Morrison DPhil FRCP Caroline H Williams‐Gray PhD MRCP Jonathan R Evans PhD MRCP Stephen J Sawcer PhD FRCP Roger A Barker PhD MRCP Mirdhu M Wickremaratchi PhD MRCP Yoav Ben‐Shlomo PhD FFPH Nigel M Williams PhD Huw R Morris PhD FRCP |
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| Affiliation: | 1. MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom;2. Department of Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom;3. Department of Neurology, Barking, Havering & Redbridge University Hospitals NHS Trust, United Kingdom;4. Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, United Kingdom;5. School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom;6. Sandwell and West Birmingham Hospitals NHS Trust, United Kingdom;7. Department of Neurology, St George's Hospital, London, United Kingdom;8. University Hospitals Birmingham NHS Trust, Birmingham, United Kingdom;9. Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom;10. City Hospital, Birmingham, United Kingdom;11. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's, Hospital, Hills Road, Cambridge, United Kingdom;12. Department of Neurology, Worthing Hospital, Worthing, United Kingdom;13. School of Social and Community Medicine, Bristol University, Bristol, United Kingdom |
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| Abstract: | Approximately 3.6% of patients with Parkinson's disease develop symptoms before age 45. Early‐onset Parkinson's disease (EOPD) patients have a higher familial recurrence risk than late‐onset patients, and 3 main recessive EOPD genes have been described. We aimed to establish the prevalence of mutations in these genes in a UK cohort and in previous studies. We screened 136 EOPD probands from a high‐ascertainment regional and community‐based prevalence study for pathogenic mutations in PARK2 (parkin), PINK1, PARK7 (DJ‐1), and exon 41 of LRRK2. We also carried out a systematic review, calculating the proportion of cases with pathogenic mutations in previously reported studies. We identified 5 patients with pathogenic PARK2, 1 patient with PINK1, and 1 with LRRK2 mutations. The rate of mutations overall was 5.1%. Mutations were more common in patients with age at onset (AAO) < 40 (9.5%), an affected first‐degree relative (6.9%), an affected sibling (28.6%), or parental consanguinity (50%). In our study EOPD mutation carriers were more likely to present with rigidity and dystonia, and 6 of 7 mutation carriers had lower limb symptoms at onset. Our systematic review included information from >5800 unique cases. Overall, the weighted mean proportion of cases with PARK2 (parkin), PINK1, and PARK7 (DJ‐1) mutations was 8.6%, 3.7%, and 0.4%, respectively. PINK1 mutations were more common in Asian subjects. The overall frequency of mutations in known EOPD genes was lower than previously estimated. Our study shows an increased likelihood of mutations in patients with lower AAO, family history, or parental consanguinity. © 2012 Movement Disorder Society. |
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| Keywords: | systematic review PARK2 PINK1 PARK7 LRRK2 early‐onset Parkinson's disease parkin DJ‐1 |
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