Solving the puzzle of dystonia
By Pedro Gonzalez-Alegre, MD
Department of Neurology, Division of Movement Disorders
Carver College of Medicine at the University of Iowa
Special to The Movement Disorder Society
Dystonia, whether referring to the symptom or syndrome, represents one of the most complex phenomena faced by neurologists and neuroscientists. Among the major achievements on this field in the second half of last century were its recognition as a neurological disorder, the creation of clinics devoted to the care of dystonia patients, laboratories aimed at unraveling the mysteries of this group of disorders and philanthropic foundations to promote the awareness and research, and the therapeutic revolution represented by the use botulinum toxin. All these changes, triggered by the initial efforts of a limited number of people, laid the foundation for a new generation of pro-active patients, devoted scientists and caring physicians with the shared goal of finding a cure. One of the most remarkable results of this combined effort has been a significant advance on our understanding of the molecular genetic mechanisms underlying inherited forms of dystonia.
Advances in dystonia genetics
The hereditary bases for many forms of dystonia have long been recognized. The information provided by sequencing the human genome, the study of human genetic variations through the HapMap Project and the improvements in the tools available for genetic research have facilitated the identification of a growing number of causative genes for monogenic dystonias. Since the landmark discoveries of the dopa-responsive dystonia (GCH1) and DYT1 (TOR1A) genes in 1994 and 1997, respectively, 6 additional genetic defects linked to mendelian forms of dystonia have been identified. Furthermore, genetic association studies have gone beyond the analysis of monogenic disorders and have identified loci that confer risk for the more common forms of dystonia. Interestingly, two polymorphisms in close to TOR1A, the causative gene in DYT1, are strongly associated with "sporadic" focal dystonia.
Having this increasing number of apparently unrelated genes in hand, which represent different pieces of the complex puzzle of dystonia, neurobiologists now face the exciting but challenging task of assembling those pieces together to finally visualize the underpinnings of the pathogenic process underlying this hyperkinetic disorder. To start connecting the dots, these genes are being used to model biological abnormalities linked to dystonia in test tubes, cultured cells or different animal species, leading to the identification of biological events implicated in dystonia pathogenesis and triggering the development of potential therapeutic interventions.
The example of DYT1 dystonia
DYT1 serves as a good example of how advances in the genetics front can impact clinical care and advance research efforts. The availability of molecular testing for the DYT1 mutation has allowed clinicians to refine the DYT1 phenotype, ascertain the penetrance of the mutation and has significantly improved our ability to provide appropriate genetic counseling to families afflicted by this disorder. In the clinical research arena, "DYT1 gene status" is now included in many therapeutic trials for idiopathic dystonia. For instance, patients harboring this mutation have been found to exhibit a relatively good outcome after GPi deep brain stimulation. On the basic research front, laboratories have focused their efforts on understanding the biological function of torsinA, the protein mutated in DYT1, and how its dysfunction leads to disease. Initial cell-based studies demonstrated that torsinA normally localizes in the endoplasmic reticulum, whereas the mutant form redistributes to the nuclear envelope, "sequestering" the wild type protein expressed from the non-mutated allele and leading to a total loss of torsinA function. This information has led to the exploration of therapeutic RNA interference (RNAi) as a potential "gene-therapy" modality for DYT1. In RNAi, small double stranded RNAs suppress expression of genes with remarkable specificity. Using this approach, scientists have been able to "silence" the mutated TOR1A allele while preserving expression of the non-mutated one, restoring its distribution to the endoplasmic reticulum. Ongoing pre-clinical trials in different animal models will help establish whether this therapeutic modality will advance as a viable option for DYT1. In addition, the availability of different animal models of DYT1, from worms to flies or mice, have provided scientists with valuable tools to perform screenings aiming to identify potential therapeutic compounds.
Although much remains to be done, in the last few years we have witnessed significant advances in our understanding of the neurobiology of dystonia. The future seems even brighter, and the increasing recognition of genes and biological pathways implicated in dystonia pathogenesis should translate in the identification of biological targets for therapeutic development.
About Dr. Pedro Gonzalez-Allegre
Dr. Gonzalez-Allegre is currently an Assistant Professor at the University of Iowa School of Medicine. He graduated from Medical School at the University of Málaga in Spain. He did his Neurology Residency Training and Fellowship at the University of Iowa. He is a recipient of several awards including the Junior Award of Excellence in Basic Science Research given by The Movement Disorder Society and the S. Weir Mitchell Award by the American Academy of Neurology. He is a member of the Scientific Advisory Board of the Dystonia Medical Research Foundation and has several grants and devoted much of his career looking into the application of RNA interference for dystonia.