Assessing the Polygenic Burden of Rare Disruptive Mutations in Parkinson's Disease

Study Overview
=================
Brief Summary
-----------------
The project intends to assess the polygenic burden of rare disruptive mutations in Parkinson's disease (PD) and how they influence the phenotype/pathological heterogeneity of disease.

Detailed Description
-----------------
The investigators intend to extend the genetic analysis to a cohort of 300 PD cases and 300 healthy subjects (wife / husband of the patients) that will be recruited at Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) Neuromed. After signed informed consent patients will be assessed for disease progression (Hoehn and Yahr stadium, Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS), Montreal Cognitive Assessment (MoCA) test, no motor symptoms, therapy and levodopa induced Dyskinesia (LID) occurrence). Each patient and control will be subjected to peripheral blood sampling for the isolation of DNA, RNA, plasma and serum. The investigators will use a disease-specific gene panel including about 100 genes related to Parkinson's Disease, autophagy and levodopa induced Dyskinesia (LID). Bioinformatics analysis will allow to catalog in a database the identified variants/mutations according to their frequency and characteristics. The investigators will specifically assess if the inheritance of multiple rare deleterious variants in Parkinson's Disease genes is predictive of disease risk. The presence of one or more variants will be tested for association with phenotypic manifestation of Parkinson's Disease (motor, non-motor, and cognitive signs, as well as age at onset, LID and neuroimaging changes) to assess the variant burden effect on progression, and prognosis of the disease.

Official Title
-----------------
Assessing the Polygenic Burden of Rare Disruptive Mutations in Parkinson's Disease: a Novel Diagnostic Test to Predict Parkinson's Disease Risk

Conditions
-----------------
Parkinson Disease

Intervention / Treatment
-----------------
* Diagnostic Test: targeted resequencing


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Presence of at least two out the following cardinal signs: resting tremor, cogwheel rigidity, bradykinesia, asymmetrical onset of symptoms and symptomatic response to L-dopa (levodopa). Exclusion Criteria: Previous thalamotomy on the implanted sides; Significant brain atrophy or structural damage seen on CT or MRI; Marked cognitive dysfunction; Active psychiatric symptoms; Concurrent neurological disorders; Other uncontrolled medical disorders.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cases<br>Participants will be assessed for disease progression: Hoehn and Yahr stadium, MDS-UPDRS part III, MoCA test, no motor symptoms, therapy and LID occurrence. Participants will be subjected to peripheral blood sampling for the purification of DNA, RNA, plasma and serum. DNA of each participant will be analysed by targeted resequencing of a disease-specific gene panel including about 100 genes related to Parkinson's Disease, autophagy and levodopa induced Dyskinesia (LID). | Diagnostic Test: targeted resequencing<br>* The investigators will use a disease-specific gene panel including about 100 genes related to Parkinson's Disease, autophagy and levodopa induced Dyskinesia (LID).<br>|
| controls<br>Participants will be assessed for the presence of disease. Participants will be subjected to peripheral blood sampling for the purification of DNA, RNA, plasma and serum. DNA of each participant will be analysed by targeted resequencing of a disease-specific gene panel including about 100 genes related to Parkinson's Disease, autophagy and levodopa induced Dyskinesia (LID). | Diagnostic Test: targeted resequencing<br>* The investigators will use a disease-specific gene panel including about 100 genes related to Parkinson's Disease, autophagy and levodopa induced Dyskinesia (LID).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| clinical evaluation of PD patients and controls | disease progression (Hoehn and Yahr stadium, MDS-UPDRS part III, MoCA test, no motor symptoms, therapy and LID occurrence | three years | 
| identification of variants/mutations | assessing if the inheritance of multiple rare deleterious variants in PD genes is predictive of PD risk. | two years | 
| association with phenotypic manifestation of PD | The presence of one or more variants will be tested for association with phenotypic manifestation of PD (motor, non-motor, and cognitive signs, as well as age at onset, LID and neuroimaging changes) to assess the variant burden effect on progression, and prognosis of the disease. | three years |