Rare neurological diseases are back in the spotlight (Rohn, 2013). Technological advances linked to massively parallel ‘second generation’ sequencing have catalysed an upsurge of interest in monogenic disorders (Singleton, 2011), leading to an unexpected and unprecedented explosion in disease gene discovery (over 20/month in the early part of 2013, of which Brain has published its fair share). These advances are clearly important for the families and patients concerned, providing a clear diagnosis culminating years, and sometimes decades of investigation. This new knowledge enables reliable prognostic and genetic counselling, and disease prevention through prenatal diagnosis. However, there is now additional excitement based on the realization that, in many instances, discovering a new gene responsible for an esoteric familial disorder can have much greater significance, casting light on a disease mechanism relevant for the common diseases seen in general neurological practice. These observations have not escaped the attention of the pharmaceutical industry and Governments (Rohn, 2013). Both now recognize the importance of the common phenotypes seen as part of a rare disease. The precision offered by a molecular diagnosis allows the assembly of near homogenous patient cohorts. When deeply phenotyped over time, these cohorts provide an ideal test bed for novel treatments targeting the known mechanism. If successful, this provides the rationale for much more expensive randomized controlled trials manipulating the same biochemical pathway in patients with a more common disorder sharing some of the clinical characteristics of the rare disease. Although discovered in the ‘pre-exome’ era, mutations in POLG raise just this possibility. POLG mutations are a rare cause of neurological disease, but the tantalizing observation of l-DOPA responsive parkinsonism in some patients (Luoma et al. , 2004) rekindled interest in the role of the mitochondria in idiopathic Parkinson’s disease, and raised the possibility of testing new mitochondria-enhancing antiparkinsonian drugs …