Systematic Review and UK-Based Study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson's disease

Laura L. Kilarski PhD¹,  Justin P. Pearson MRCP¹,  Victoria Newsway BSc¹,  Elisa Majounie PhD¹,  M. Duleeka W. Knipe BSc, MPH²,  Anjum Misbahuddin PhD MRCP³, Patrick F. Chinnery PhD, FRCP⁴,  David J. Burn MD, FRCP⁴,  Carl E. Clarke MD, FRCP^5,6,  Marie-Helene Marion MD⁷, Alistair J. Lewthwaite MRCP^5,8,9,  David J. Nicholl PhD, FRCP^5,6,10,  Nicholas W. Wood PhD, FRCP⁹,  Karen E. Morrison DPhil, FRCP^5,8,  Caroline H. Williams-Gray PhD, MRCP¹¹,  Jonathan R. Evans PhD, MRCP¹¹,  Stephen J. Sawcer PhD FRCP¹¹, Roger A. Barker PhD, MRCP¹¹,  Mirdhu M. Wickremaratchi PhD, MRCP¹²,  Yoav Ben-Shlomo PhD, FFPH¹³,  Nigel M. Williams PhD¹,  Huw R. Morris PhD, FRCP^1,*

Movement Disorders Journal. 
DOI: 10.1002/mds.25132Article first published online: 6 SEP 2012

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.