Objective/Rationale:
Parkinson’s disease (PD) is a prevalent, heterogeneous disorder with a complex, multifactorial etiology. In Tunisia, North Africa, the burden of genetically-defined LRRK2 G2019S parkinsonism is especially high (Hulihan M et. al., 2008). Within this more homogeneous background, the natural history of parkinsonism, in terms of onset, progression and co-morbidities, may be defined and the contribution of genetic and environmental variables elaborated.
Project Description:
The project will recruit clinical data and blood samples from 258 multi-incident families with LRRK2 G2019S parkinsonism, including 1st – 3rd degree relatives. All aspects of the syndrome will be assessed (including bowel and bladder function, sleep, smell, apathy, depression, cognition and dementia, as well as motor problems - tremor, gait, and postural instability). Lifestyle, occupation and exposures will be documented. ‘Open source’ developments in information technology will support the enterprise. Within pedigrees, the segregation of clinical endophenotypes, environmental and genetic variables will be statistically assessed. Through candidate gene and genome-wide analysis, genetic modifiers of LRRK2 G2019S penetrance and expressivity may be identified.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
James Parkinson (1817) first alluded to the many “motor and non-motor” features of the syndrome that bears his name. An “end-diagnosis” of PD is a gross simplification of the disease process. Nevertheless the symptom components, and “if, when and how” they manifest, has proven difficult to define. Until recently, the underlying molecular etiology of parkinsonism remained elusive. Now, through the study of LRRK2 G2019S carriers who are genetically predisposed, we can address the issues of penetrance (if and when subjects manifest disease) and variable expressivity (what symptoms and signs first and inevitably appear). The information can be used to diagnose PD earlier, to identify other genetic and environmental risk factors and to develop more potent, targeted interventions.
Anticipated Outcome:
The project will build local research capacity, to meet the burden imposed by LRRK2 G2019S parkinsonism on health care in Tunisia. Nevertheless, the insights gained will be of universal benefit. Most immediately, we will define the penetrance and expressivity of PD symptom components, and provide the background for clinical trials of LRRK2-targeted Symptoms & Side Effects and neuroprotective therapies. In addition, analysis of genetic and environmental data may identify additional disease modifiers.