Frequency of mutations in PRKN, PINK1, and DJ1 in Patients With Early-Onset Parkinson Disease from neighboring countries in Central Europe

Highlights

• Approximately 10% of patients with PD present with early-onset disease.

• PRKN, PINK1, and DJ1 were screened in Czech, German, Polish, and Ukrainian patients.

• PRKN, PINK1, and DJ1 are a rare cause of EOPD in central Europe.

Abstract

Introduction

Approximately 10% of patients with Parkinson disease (PD) present with early-onset disease (EOPD), defined as diagnosis before 50 years of age. Genetic factors are known to contribute to EOPD, with most commonly observed mutations in PRKN, PINK1, and DJ1 genes. The aim of our study was to analyze the frequency of PRKN, PINK1, and DJ1 mutations in an EOPD series from 4 neighboring European countries: Czech Republic, Germany, Poland, and Ukraine.

Methods

Diagnosis of PD was made based on UK Brain Bank diagnostic criteria in departments experienced in movement disorders (1 from Czech Republic, 1 from Germany, 9 from Poland, and 3 from Ukraine). EOPD was defined as onset at or before 50 years of age. Of the 541 patients recruited to the study, 11 were Czech, 38 German, 476 Polish, and 16 Ukrainian. All cohorts were fully screened with Sanger sequencing for PRKN, PINK1, and DJ1 and multiplex ligation-dependent probe amplification for exon dosage.

Results

PRKN homozygous or double heterozygous mutations were identified in 17 patients: 1 Czech (9.1%), 1 German (2.6%), 14 Polish (2.9%), and 1 Ukrainian (6.3%). PINK1 homozygous mutations were only identified in 3 Polish patients (0.6%). There were no homozygous or compound heterozygous DJ1 mutations in analyzed subpopulations. One novel variant in PRKN was identified in the Ukrainian series.

Conclusion

In the analyzed cohorts, mutations in the genes PRKN, PINK1, and DJ1 are not frequently observed.

Introduction

Understanding the genetic basis of monogenic forms of Parkinson disease (PD), representing about 10% of cases, has provided great insight into disease pathophysiology. PD is estimated to affect 1% of the population over the age of 55 years, but 3% over the age of 75 years. Typical onset of PD is at 60–65 years of age; however, between 10% and 15% of patients develop an early-onset form of the disease (EOPD) before 50 years of age [1,2].

The majority of late-onset PD and EOPD cases are sporadic. However, recessive mutations in autosomal inherited genes, such as PRKN, PINK1, and DJ1, are responsible for a high percentage of familial EOPD [1]. With the growing importance of personalized medicine, it is important to establish the frequency of PRKN, PINK1, and DJ1 mutations in EOPD populations. For example, the Michael J. Fox Foundation introduced Parkinson's Research Strategy to Advance Therapeutic Development of PINK1 and PRKN in 2019 [3]; the number of clinical trials will be growing and will likely include specific mutation carriers.

Understanding the genetic landscape of patients with EOPD, especially those in neighboring countries, may help to uncover novel or geographically associated variants that could contribute to further molecular characterization and classification of the disease. Czech Republic, Germany, Poland, and Ukraine are bordering countries in central Europe. Due to historical events, the human migration between these 4 countries may have elevated the frequency of specific mutations, and the presence of gene variants may be similar in these countries.

There were previous studies analyzing PRKN, PINK1 and DJ1 in Czech, German and Polish population (Supplemental Table 1). However, the available data in these countries have mostly been obtained from a small number of case studies, and to our knowledge, the distribution of EOPD gene mutations in bordering countries has never been compared. The aim of our study was to analyze the frequency of PRKN, PINK1, and DJ1 mutations in patients with EOPD from 4 neighboring countries: Czech Republic, Germany, Poland, and Ukraine.