TY - JOUR
T1 - Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ-1)and LRRK2 in early-onset Parkinson's disease
AU - Kilarski, Laura L.
AU - Pearson, Justin P.
AU - Newsway, Victoria
AU - Majounie, Elisa
AU - Knipe, M. Duleeka W.
AU - Misbahuddin, Anjum
AU - Chinnery, Patrick F.
AU - Burn, David J.
AU - Clarke, Carl E.
AU - Marion, Marie-Helene
AU - Lewthwaite, Alistair J.
AU - Nicholl, David J.
AU - Wood, Nicholas W.
AU - Morrison, Karen E.
AU - Williams-Gray, Caroline H.
AU - Evans, Jonathan R.
AU - Sawcer, Stephen J.
AU - Barker, Roger A.
AU - Wickremaratchi, Mirdhu M.
AU - Ben-Shlomo, Yoav
AU - Williams, Nigel M.
AU - Morris, Huw R.
PY - 2012/10/1
Y1 - 2012/10/1
N2 - 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.
AB - 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.
KW - Cohort Studies
KW - DNA Mutational Analysis
KW - Female
KW - Humans
KW - Intracellular Signaling Peptides and Proteins/genetics
KW - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
KW - Male
KW - Mutation/genetics
KW - Oncogene Proteins/genetics
KW - Parkinson Disease/epidemiology
KW - Protein Deglycase DJ-1
KW - Protein Kinases/genetics
KW - Protein Serine-Threonine Kinases/genetics
KW - Ubiquitin-Protein Ligases/genetics
KW - United Kingdom/epidemiology
U2 - 10.1002/mds.25132
DO - 10.1002/mds.25132
M3 - Review article
C2 - 22956510
SN - 0885-3185
VL - 27
SP - 1522
EP - 1529
JO - Movement Disorders
JF - Movement Disorders
IS - 12
ER -