title: Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson's disease.
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.
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Kilarski
authors.forename: Justin P
authors.initials: JP
authors.lastname: Pearson
authors.forename: Victoria
authors.initials: V
authors.lastname: Newsway
authors.forename: Elisa
authors.initials: E
authors.lastname: Majounie
authors.forename: M Duleeka W
authors.initials: MD
authors.lastname: Knipe
authors.forename: Anjum
authors.initials: A
authors.lastname: Misbahuddin
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.forename: David J
authors.initials: DJ
authors.lastname: Burn
authors.forename: Carl E
authors.initials: CE
authors.lastname: Clarke
authors.forename: Marie-Helene
authors.initials: MH
authors.lastname: Marion
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Lewthwaite
authors.forename: David J
authors.initials: DJ
authors.lastname: Nicholl
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.forename: Karen E
authors.initials: KE
authors.lastname: Morrison
authors.forename: Caroline H
authors.initials: CH
authors.lastname: Williams-Gray
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Evans
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Sawcer
authors.forename: Roger A
authors.initials: RA
authors.lastname: Barker
authors.forename: Mirdhu M
authors.initials: MM
authors.lastname: Wickremaratchi
authors.forename: Yoav
authors.initials: Y
authors.lastname: Ben-Shlomo
authors.forename: Nigel M
authors.initials: NM
authors.lastname: Williams
authors.forename: Huw R
authors.initials: HR
authors.lastname: Morris
mesh_terms: D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D009154:Mutation / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics*; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D006113:United Kingdom / Q000453:epidemiology; D000099202:PTEN-Induced Putative Kinase
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D015513:Oncogene Proteins; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein; C495280:LRRK2 protein, human; C105131:PARK7 protein, human