The Neurogenetics of Atypical Parkinsonian Disorders

Although classic Parkinson disease is the disorder most commonly associated with the clinical feature of parkinsonism, there is in fact a broader spectrum of disease represented by a collection of phenotypically similar neurodegenerative conditions that mimic many of its core features. These atypical parkinsonian disorders most commonly include progressive supranuclear palsy and corticobasal degeneration, disorders both associated with frontotemporal dementia, as well as multiple system atrophy and dementia with Lewy bodies. Although the clinical distinction of these disorders still remains a challenge to physicians, recent advances in genetics are poised to tease apart the differences. Insights into the molecular etiologies underlying these conditions will improve diagnosis, yield a better understanding of the underlying disease pathology, and ultimately lend stimulation to the development of potential treatments. At the same time, the wide range of phenotypes observed from mutations in a single gene warrants broad testing facilitated by advances in DNA sequencing. These expanding genomic approaches, ranging from the use of next-generation sequencing to identify causative or risk-associated gene variations to the study of epigenetic modification linking human genetics to environmental factors, are poised to lead the field into a new age of discovery.