SCIENTIFIC COMMENTARIES One complex world of mitochondrial parkinsonism

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 in POLG patients. In humans, POLG is found on chromosome 15q25 and codes for the only DNA polymerase found in mitochondria, polymerase gamma (Copeland, 2010). The first pathogenic mutations in POLG were described in 2001 in several Belgian families with adult-onset autosomal chronic progressive external ophthalmoplegia (Van Goethem et al., 2001): two had a clear dominant disorder, and one appeared to be recessive, but both were associated with the presence of multiple deletions of mitochondrial DNA in skeletal muscle biopsies. Subsequent candidate gene analysis revealed recessive POLG mutations in the majority of children with the often fatal Alpers-Huttenlocher syndrome (Naviaux and Nguyen, 2004), a totally different disease presenting in infancy with encephalopathy and liver failure, the latter often precipitated by sodium valproate. However, in Alpers-Huttenlocher syndrome, the POLG mutations were associated with loss (or depletion) of mitochondrial DNA in affected tissues. Even more curiously, recessive POLG mutations were then seen in adults presenting with sensory and cerebellar ataxia, leading to overlapping acronyms, including sensory ataxic neuropathy with dysarthria and opthalmoparesis (SANDO, Van Goethem et al., 2003); and mitochondrial recessive ataxia syndrome (MIRAS, Hakonen et al., 2005), both linked to multiple deletions of mitochondrial DNA. As the number of patients increased, the boundaries between these apparently distinct syndromes became increasingly blurred, revealing a spectrum of POLG phenotypes presenting from ‘the cradle to the grave’ (Horvath et al., 2006). It remains unclear why often the very same POLG mutations can cause very different phenotypes. This topic was the subject of a recent paper in Brain from Rita Horvath et al. (Neeve et al., 2012). Shortly after the first description, Anu Suomalainen and colleagues noted the surprisingly high frequency of parkinsonian features in the elderly relatives of patients with classical autosomal dominant progressive external ophthalmoplegia (Luoma et al., 2004). The parkinsonism segregated with POLG mutations in these, and other families (Hudson et al., 2007). At around the same time, several laboratories described mitochondrial defects in the substantia nigra neurons of post-mortem brains from patients with idiopathic Parkinson’s disease, linked to the high levels of somatic mitochondrial DNA deletions (Bender et al., 2006; Kraytsberg et al., 2006). Thus, the circumstantial evidence suggested that mitochondrial DNA mutations in single cells contributed to the pathogenesis of parkinsonism—the idea being that de novo mitochondrial DNA deletions were generated within neurons during life, and that these ‘clonally expanded’, eventually replacing wild-type (normal) mitochondrial DNA within the cell. The mitochondrial DNA deletions removed genes that were critically important for intra-mitochondrial protein synthesis, leading to a defect of mitochondrial respiration and bioenergetic failure. In the short term, the biochemical defect would lead to neuronal dysfunction, but in the longer term, this was thought to cause neurodegeneration in the substantia nigra pars compacta, the Brain 2013: 136; 2336–2341 | 2336