Parkinsonism in neurodegenerative diseases predominantly presenting with ataxia.

Abstract

The number of molecularly defined degenerative ataxia diseases is rapidly increasing, many of them involving complex multisystemic presentations including parkinsonism. The increasing number of novel ataxia genes -with most of them being ultra-rare - often makes it difficult for clinicians and scientists to identify the molecular diagnosis underlying these ataxia-parkinsonism syndromes. Here we aim to provide an overview on the most frequent diseases and molecular causes underlying ataxia-parkinsonism, focusing both on novel aspects of well-known causes of ataxia-parkinsonism (MSA-C, PSP-C, FXTAS, repeat-expansion spinocerebellar ataxias [SCAs], conventional mutation SCAs) as well as on more recently identified rare genetic causes of ataxia-parkinsonism (AT, POLG, SPG7). We demonstrate that frequency data and phenotype characteristics help to guide diagnostics in patients with unexplained ataxia-parkinsonism, while the newly identified rare genetic causes of ataxia-parkinsonism provide novel insights into molecular key pathways underlying the shared vulnerability of cerebellar and basal ganglia neurons.