 Thank you, Matthew. Parkinson's disease with its characteristic features of tremor, muscle stiffness, and slowness of movement may actually be a group of closely related disorders rather than a single entity. The genes underlying or predisposing to a number of varieties of Parkinson's disease have been determined. Our project aims at delineating another such disorder, FMR1-Grayzone-related Parkinsonism. The Fragile X mental retardation gene, FMR1, on the X chromosome has a repetitive sequence of DNA code, CGG, CGG, CGG, etc. There are normally less than 41 CGG repeats in this sequence. The commonest cause of mental retardation in boys, who unlike girls do not have a second normal X chromosome, is an expansion of this sequence to more than 200 copies. This results in decreased production of the FMR protein. Men and some women, with 55 to 200 CGG repeats, develop a completely different disorder, Fragile X associated tremor-atexia syndrome, or FXTAS, with normal amounts of the FMR protein, but excessive toxic levels of the copied RNA message, that's the code, from the FMR1 DNA sequence. About a third of these FXTAS patients have some features of Parkinsonism. Such premutation expansions can expand further to cause mental retardation in the grandsons of those of FXTAS via their daughters. Grayzone mutations of the FMR1 gene, on the contrary, with between 41 and 54 CGG repeats, produce lesser amounts of this toxic RNA and do not expand to more than 200 copies within two generations. We and others have found, however, that such grayzone FMR1 mutations are over-represented two to three-fold in cohorts of patients with typical Parkinson's disease, both male and female. Our preliminary data on grayzone Parkinson's subjects suggests that there are subtle differences in the clinical and MRI imaging features of the Parkinson's associated with FMR1 grayzone mutations, compared with those without such expansions. Grayzone carriers showing a faster clinical course, more cognitive change and incoordination, less complete responsiveness to Parkinson's medications, and more MRI changes in the deep white matter of the brain. The Brain Foundation gift will be used to extend and verify these findings in a further 20 grayzone Parkinson's patients that we have identified within Parkinson's disease cohorts. Our aim is to produce effective guidelines for FMR1 expansion testing in Parkinson's disease. In a related project not covered by this gift, we are determining the biochemical differences between grayzone Parkinsonism and ordinary Parkinson's disease. Our preliminary results in this aspect show excess activation in a cellular stress-related enzyme, AMPK, in grayzone Parkinsonism, providing a potential therapeutic target for this disorder. Thus, the potential for cascade genetic testing of descendants and the high frequency of grayzone mutations in the population of 1% in males and about 3% in females underlies the significance of this work. My colleagues and I are grateful to the Brain Foundation for their support of our studies.