Genetic classification of Parkinson's disease (PD) subtypes may become the preferred diagnostic tool for neurologists. Herein we compare clinical features from a large cohort of patients with familial PD of unknown aetiology or attributable to distinct genetic forms. Comprehensive neurological examinations were performed in 231 familial PD patients from Tunisia. Analysis was previously performed to screen for mutations in leucine rich repeat kinase 2 (LRRK2), PTEN induced kinase 1 (PINK1) and parkin (PRKN). Clinical features were compared between patients with genetically undefined PD (n=107) and those with LRRK2 (n=73) and PINK1 (n=42) mutations using regression analyses adjusted for gender, age of onset and disease duration. PRKN cases (n=9) were too few for meaningful statistical analysis. In comparison with genetically undefined patients, LRRK2 mutation carriers had more severe motor symptoms (median Unified Parkinson's Disease Rating Scale scores ∼1.6 times higher, p<0.001), a higher rate of dyskinesia (OR 4.21, p=0.002) and use of dopamine agonists (OR 3.64, p<0.001), and less postural tremor (OR 0.21, p<0.001). PINK1 mutation carriers presented an increased rate of drug induced dyskinesia (OR 3.81, p=0.007) and a lower rate of postural tremor (OR 0.16, p<0.001) than genetically undefined patients. As expected, PINK1 patients had younger ages and ages at disease onset, and a longer disease duration compared with LRRK2 mutation carriers and genetically undefined patients. Clinical differences between LRRK2, PINK1 and genetically undefined familial PD appear more pronounced than previously appreciated, and may prove useful in clinical practice. As future therapies are targeted to specific protein abnormalities, identifying the genetic causes and associated clinical and pathological features will determine diagnosis, preventative medicine and drug intervention strategies.
- Parkinson's Disease
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Funding GlaxoSmithKline financially supported the patient recruitment and clinical data collection. Statistical analysis was supported by the Neurogenetic Core of a Morris K Udall Center, National Institute of Neurological Disorders and Stroke P50 NS40256. KN was supported by an Eli-Lilly scholarship and Herb Geist gift for Lewy body research. CW was supported by the Swiss National Science Foundation (PASMP3-123 268/1).
Competing interests MJF reports (a) International Publication Number WO 2006/045392 A2; (b) International Publication Number WO 2006/068492 A1; (c) US Patent Number 7,544,786; and (d) Norwegian patent 323 175, appertaining to Lrrk2. MJF reports salary and royalty payments from the pharmaceutical industry for sponsored research on Lrrk2 biology and mouse model characterisation. As of August 2009, Mayo and MJF have received royalties from the licensing of these technologies of greater than $10 000, the US federal threshold for significant financial interest.
Ethics approval This study was conducted with the approval of the Institut National de Neurologie, Tunis, Tunisia.
Provenance and peer review Not commissioned; externally peer reviewed.