Hereditary dystonia and parkinsonism: two sides of the same coin?

and thalamic resting-state functional connectivity is altered in childhood absence epilepsy. system hyperconnectivity in juvenile myoclonic epilepsy: a cognitive functional magnetic resonance imaging study. Duncan JS, et al. Motor co-activation in siblings of juvenile myoclonic epilepsy patients: an imaging endophenotype? Hereditary dystonia and parkinsonism: two sides of the same coin? This scientific commentary refers to 'Parkinson's disease in GTP cyclohydrolase 1 mutation carriers', by Mencacci et al. (doi:10/ 1093/brain/awu179). A number of inherited disorders are marked by combined dystonia and parkinsonism, and the genetic basis of many of these has now been identified. They include putative 'neurofunctional' conditions with dystonia-parkinsonism, such as DOPA-responsive dystonia caused by mutations in the GTP cyclohydrolase 1 (GCH1) gene, as well as neurodegenerative diseases that present with predominant parkinsonism, frequently accompanied by dystonic features, i.e. 'parkinsonism-dystonia', as seen in carriers of parkin (PARK2) and PINK1 mutations. Because dystonia can be the presenting sign in parkinsonism-dystonias (Grü newald et al., 2013) and, conversely , patients with DOPA-responsive dystonia can present with isolated parkinsonism (Grimes et al., 2002; Tadic et al., 2012), it can be difficult to categorize individual patients solely on clinical grounds. The boundaries between dystonia and parkin-sonism may thus be less well defined than previously thought, and this calls for detailed longitudinal phenotyping of patients. Indeed, despite the advent of next-generation sequencing and increased availability of diagnostic testing—resulting in a wealth of genetic data—systematic genotype–phenotype evaluations lag behind advances in genetics and have largely yet to be translated into clinical practice (Grü newald et al., 2013). In this issue of Brain, Mencacci et al. elegantly address the phenomenon of prominent parkinsonism in carriers of GCH1 mutations (Mencacci et al., 2014). Prompted by their observation that relatives of patients with DOPA-responsive dystonia can present with pure 'Parkinson's disease', they systematically collected and examined four such unrelated pedigrees harbouring GCH1 mutations and reviewed the literature for similar reports. This resulted in a total of eight cases from different ethnic backgrounds with predominant parkinsonism, all of whom had a mostly asymmetrical reduction in dopamine transporter density or fluorodopa uptake, in keeping with degeneration of dopaminergic neurons (Mencacci et al., 2014). Based on this finding, the authors hypothesized that sporadic Parkinson's disease can also be caused by mutations in GCH1. To test this idea, they evaluated in-house whole exome data from 1318 patients with Parkinson's disease and 1635 controls, as well as 4300 additional control data sets from …