Search for Genetic Factors in Parkinson*s disease

The recent discovery of genetic mutations causing Mendelian forms of
Parkinson*s disease (PD), such as those in the α-synuclein, parkin, DJ-1,
PINK1, and the LRRK2 gene, have provided novel clues into the mechanisms of
this disease. However, none of these mutations is common in the Dutch
population, and the etiology of the disease remains here almost totally
unknown. Recent large-scale genome-wide association studies (GWA) highlighted
the role of common variants in the α-synuclein and tau gene as risk factors for
the sporadic forms of this disease in the population of European ancestry.
However, these variants possess very low penetrance, and while they only
account for a portion of the disease heritability at the population level, they
do not explain the familial aggregation of PD, present in up to 25% of cases.
Taken together, these data suggest that most of the genetic determinants of PD
remain to be identified in several populations including the Dutch one, and
particularly, additional highly-penetrant mutations remain to be discovered in
one or several PD-causing genes. The identification of further PD-causing genes
is urgently needed by the research community at large, as these genes might
provide further important clues for the dissection of the disease pathogenesis,
and for the identification of biomarkers and of innovative therapeutic targets.
In the post-GWA era, the focus on families with PD, likely harboring
high-penetrance mutations is therefore gaining novel momentum. The Dutch
population appears very suitable for family-based genetic studies, because
large families are still frequently observed, family relationships are kept
strong, and excellent genealogical records are available to researchers.

The aims of this study are the ascertainment, characterization, and
longitudinal follow-up of a large cohort of Dutch families segregating
Parkinson*s disease, including affected and unaffected first-degree relatives.
The cohort will be characterized clinically and genealogically. Moreover, a
bank of biological samples (DNA, RNA, plasma, serum, blood cells, fibroblasts)
will be established. The cohort, together with the clinical-genealogical
database and the biological bank will represent an important resource for a
number of molecular genetic studies aimed at the identification of novel
genetics determinants of PD.
The cohort will also be suitable for monitoring early, pre-clinical disease
stages and for biomarker discovery (e.g. using serum proteomics and
metabolomics, gene expression profiling, functional imaging, smell-testing,
neuropsychological testing). Last, the cohort of non-manifesting at-risk
relatives will constitute an ideal population for testing neuroprotective
strategies, as soon as they become available.

Written informed consent is obtained from every participating subject and the
project has been submitted to the Medical Ethic Committee of the Erasmus MC
Rotterdam. From each subject we plan to collect detailed clinical and
genealogical data and a blood sample (20 cc) for the isolation and storage of
serum, plasma, genomic DNA and total RNA. An aliquot of freshly collected blood
will also be stored in adequate medium for future generation of
Epstein-Barr-virus transformed lymphoblastoid cell lines.
From critical individuals, such as patients from very large families or very
interesting phenotypes, we will also collect skin biopsies and establish
primary fibroblasts lines. These lines might be used in the future for the
preparation of induced pluripotent (stem-like) cells (iPC), which in turn, can
be differentiated into dopaminergic neurons for modelling the disease in vitro.
The clinical diagnosis of Parkinson*s disease will be established according to
the UK Brain Bank criteria, and the disease severity assessed using the Unified
Parkinson*s disease rating scale, the SCOPA-COG, FAB and the Hoehn-Yahr
staging.

We expect no serious adverse events in this study. Peripheral venous blood
sampling (max. 20 mL) is a routine minimally-invasive procedure which will be
performed only by highly experienced and certified nurses or physicians.
Further, our neurologic and neuropsychological assessments are highly
structured and have been extensively tested, without any known serious adverse
events.

Adverse events may include minor bruising or local tenderness at the site of
venous blood sampling. All patients will be monitored to ensure proper
hemostasis.
A selection of patients and family members will be asked to give consent for a
skin biopsy. This is a minimally invasive procedure that is not very painful
but might produces some discomfort. Prior to the biospy, the skin is treated
with a creme as a local anesthetic. Some scar tissue could form and there is a
small chance to develop an infection.
During interviews and neuropsychological testing, the patient will be fully
aware of his/her right to terminate the testing at any time and for any reason.