Genotypic and phenotypic characteristics of Dutch patients with early onset Parkinson's disease

Abstract

Early onset Parkinson's disease (EOPD) has been associated with mutations in the Parkin, DJ-1, PINK1, LRRK2, and SNCA genes. The aim of this study is to assess the contribution of these genes in a Dutch EOPD cohort and the phenotypic characteristics of the mutation carriers. A total of 187 unrelated Dutch EOPD patients (age at onset < or = 50 years) were phenotyped and screened for mutations in all exons of Parkin, DJ-1, and PINK1 by direct sequencing and gene dosage analysis. Additionally, analysis of the A30P mutation and exon dosage of SNCA and sequencing of exons 19,31,35,38,41, and 48 of LRRK2 was performed. Pathogenic variations could explain disease in 4% (7 of 187) of the patients including five patients carrying homozygous or compound heterozygous mutations in Parkin, one with a novel homozygous deletion in DJ-1 (P158Del) and one with a heterozygous mutation in LRRK2 (T2356I). We found seven novel mutations. The phenotypic characteristics of mutation carriers varied widely, comparable to the variability seen in sporadic EOPD. Parkin is the most frequently mutated gene in this EOPD cohort, followed by DJ-1, PINK1 and LRRK2. The low overall mutation frequency indicates that the extrapolation of mutation frequencies from other populations should be applied with caution.

Analysis of Leucine-rich repeat kinase 2 (LRRK2) and Parkinson protein 2 (parkin, PARK2) genes mutations in Slovak Parkinson disease patients

“…This result of the case doesn´t differ from the studies which were made with other European populations: Austria, Poland, Holland, Belgium, or from Africa: Niger, or from Asia: Taiwan, Singapore, South Korea (Calne et al 1992;Bialecka et al 2005;Lu et al 2005;Mata et al 2005;Tan et al 2005;Fung et al 2006;Farrer et al 2007;Cho et al 2007;Haubenberger et al 2007;Choi et al 2008;Lin et al 2008;Nuytemans et al 2008;Okubadejo et al 2008;Macedo et al 2009). …”

Phenotype analysis in patients with early onset Parkinson’s disease with and without parkin mutations

“…A previous study found that the frequent and early occurrence of levodopainduced dyskinesia was a characteristic of patients with parkin mutations [35]. However, more recent studies have found that levodopa-induced dyskinesia and motor fluctuation are not more frequent in EOPD with parkin mutations [8,10,14]. Only a small number of studies have investigated the latency of levodopa-induced motor complications.…”

“…However, while several studies have found that parkin disease is more likely to have atypical features of EOPD [7,[11][12][13], other studies showed that the phenotype of EOPD patients with parkin mutations may be indistinguishable from that of parkin noncarriers [9,14,15]. Most of the previous studies on parkin mutations and phenotypes recruited patients with an AAO of younger than 45-50 years [7,10,11,[13][14][15][16][17][18][19]. Since the incidence of parkin mutations is very low in patients with an AAO of [40 years [14,19], previous studies have unfairly compared the phenotypes of two EOPD groups with different AAOs (patients with parkin mutations with a younger AAO and parkin noncarriers with an older AAO).…”

“…The most common genetic causes of EOPD are parkin mutations, which have been reported to account for 6-37% of cases [7][8][9][10]. The frequency of parkin mutations was found to be strongly correlated with a low AAO and a positive family history [10].…”

Genetics of Parkinson’s Disease: The Role of Copy Number Variations

“…Further heterozygous CNVs (both deletions and duplication) involving the exons of DJ-1 gene have been published so far [93,[100][101][102], although they do not completely explain the recessive pattern of the PD phenotype.…”