LRRK2 mutations on Crete: R1441H associated with PD evolving to PSP

Mutations of the LRRK2 gene that encodes the protein dardarin occur in Parkinson disease (PD)1 with the G2019S change being the most common cause of hereditary parkinsonism. While the G2019S mutation phenotype is that of typical PD,2 three different amino acid substitutions at residue 1441 (4322G>A: [R1441H], 4321C>T: [R1441C], 4321C>G: [R1441G]) have been associated with pleomorphic phenotypic expressions.3 There is evidence, however, that not all LRRK2 mutations are sufficient to cause PD and that additional genetic or environmental factors may be involved. An oligogenic inheritance for PD has also been suggested in a study of 247 index patients with PD from Crete.4 Here we searched for susceptibility genes to PD in our cohort of 266 cases with PD and 13 patients with progressive supranuclear palsy (PSP) by testing them for LRRK2 mutations. PD was diagnosed by established criteria.4 PSP was diagnosed by the National Institute of Neurologic Disorders and Stroke–SPSP criteria, requiring early postural instability and falls, vertical supranuclear palsy, pseudobulbar palsy, and akinetic-rigid parkinsonism (with prominent axial rigidity) unrelieved by levodopa. Controls (n = 300) were healthy subjects natives of Crete. All patients and controls were analyzed for five LRRK2 …