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

• Published in: Movement disorders Vol. 27; no. 12; pp. 1522 - 1529
• Main Authors: Kilarski, Laura L., Pearson, Justin P., Newsway, Victoria, Majounie, Elisa, Knipe, M. Duleeka W., Misbahuddin, Anjum, Chinnery, Patrick F., Burn, David J., Clarke, Carl E., Marion, Marie-Helene, Lewthwaite, Alistair J., Nicholl, David J., Wood, Nicholas W., Morrison, Karen E., Williams-Gray, Caroline H., Evans, Jonathan R., Sawcer, Stephen J., Barker, Roger A., Wickremaratchi, Mirdhu M., Ben-Shlomo, Yoav, Williams, Nigel M., Morris, Huw R.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.10.2012; Wiley; Wiley Subscription Services, Inc
• Subjects: Biological and medical sciences; Cohort Studies; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DJ-1; DNA Mutational Analysis; early-onset Parkinson's disease; Female; Humans; Intracellular Signaling Peptides and Proteins - genetics; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; LRRK2; Male; Medical sciences; Movement disorders; Mutation - genetics; Neurology; Oncogene Proteins - genetics; PARK2; PARK7; parkin; parkin, DJ‐1; Parkinson Disease - epidemiology; Parkinson Disease - genetics; PINK1; Protein Deglycase DJ-1; Protein Kinases - genetics; Protein Serine-Threonine Kinases - genetics; systematic review; Ubiquitin-Protein Ligases - genetics; United Kingdom - epidemiology; United Kingdom; early-onset Parkinson's disease; Nervous system diseases; LRRK2; Parkinson disease; DJ-1; PARK7; systematic review; PARK2; Cerebral disorder; PINK1; Central nervous system disease; Degenerative disease; Extrapyramidal syndrome; Parkin
• ISSN: 0885-3185; 1531-8257; 1531-8257
• DOI: 10.1002/mds.25132

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.