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

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

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.

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.

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.