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Nomenclature of Genetic Movement Disorders: Recommendations of the International Parkinson and Movement Disorder Society Task Force

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Nomenclature of Genetic Movement Disorders: Recommendations of the International Parkinson and Movement Disorder Society Task Force GENETICS SERIES: REVIEW CME Nomenclature of Genetic Movement Disorders: Recommendations of the International Parkinson and Movement Disorder Society Task Force Connie Marras, MD, PhD,1 Anthony Lang, MD,1 Bart P. van de Warrenburg, MD, PhD,2 Carolyn M. Sue, MBBS, PhD,3 Sarah J. Tabrizi, MBChB, PhD,4 Lars Bertram, MD,5,6 Saadet Mercimek-Mahmutoglu, MD, PhD,7 Darius Ebrahimi-Fakhari, MD,8,9 Thomas T. Warner, BMBCh, PhD,10 Alexandra Durr, MD, PhD,11 Birgit Assmann, MD,12 Katja Lohmann, PhD,13 Vladimir Kostic, MD, PhD,14 and Christine Klein, MD13* 1Toronto Western Hospital Morton, Gloria Shulman Movement Disorders Centre, and the Edmond J. Safra Program in Parkinson’s Disease, University of Toronto, Toronto, Canada 2Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands 3Department of Neurology, Royal North Shore Hospital and Kolling Institute of Medical Research, University of Sydney, St. Leonards, New South Wales, Australia 4Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK 5Lubeck€ Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Integrative and Experimental Genomics, University of Lubeck,€ Lubeck,€ Germany 6School of Public Health, Faculty of Medicine, Imperial College, London, UK 7Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada 8Division of Pediatric Neurology and Inborn Errors of Metabolism, Department of Pediatrics, Heidelberg University Hospital, Ruprecht-Karls- University Heidelberg, Heidelberg, Germany 9Department of Neurology & F. M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, Massachusetts, USA 10Reta Lila Weston Institute of Neurological Studies, Department of Molecular Neurosciences, UCL Institute of Neurology, London, UK 11Sorbonne Universite, UPMC, Inserm and Hopital^ de la Salpetrie^ ` re, Departement de Gen etique et Cytogen etique, Paris, France 12Division of Pediatric Neurology, Department of Pediatrics I, Heidelberg University Hospital, Ruprecht-Karls-University Heidelberg 13Institute of Neurogenetics, University of Lubeck,€ Lubeck,€ Germany 14Institute of Neurology, School of Medicine University of Belgrade, Belgrade, Serbia ABSTRACT: The system of assigning locus symbols demonstrate how the system would be applied to cur- to specify chromosomal regions that are associated with rently known genetically determined parkinsonism, dys- a familial disorder has a number of problems when used tonia, dominantly inherited ataxia, spastic paraparesis, as a reference list of genetically determined disorders,in- chorea, paroxysmal movement disorders, neurodegener- cluding (I) erroneously assigned loci, (II) duplicated loci, ation with brain iron accumulation, and primary familial (III) missing symbols or loci, (IV) unconfirmed loci and brain calcifications. This system provides a resource for genes, (V) a combination of causative genes and risk clinicians and researchers that, unlike the previous sys- factor genes in the same list, and (VI) discordance tem, can be considered an accurate and criterion-based between phenotype and list assignment. In this article, list of confirmed genetically determined movement dis- we report on the recommendations of the International orders at the time it was last updated. VC 2016 Interna- Parkinson and Movement Disorder Society Task Force tional Parkinson and Movement Disorder Society for Nomenclature of Genetic Movement Disorders and present a system for naming genetically determined Key Words: genetics; movement disorders; movement disorders that addresses these problems. We nomenclature ------------------------------------------------------------ *Correspondence to: Christine Klein, Institute of Neurogenetics, Univer- sity of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany, Introduction E-mail: [email protected] Funding agencies: This research received no specific grant from any The system of locus symbols (eg, DYT1) was origi- funding agency. nally established to specify chromosomal regions that Relevant conflicts of interest/financial disclosures: Nothing to report. had been linked to a familial disorder where the gene Full financial disclosures and author roles may be found in the online ver- was yet unknown.1 This system has been adopted by sion of this article. Received: 12 May 2015; Revised: 21 October 2015; Accepted: 22 clinicians and researchers to provide names for a con- November 2015 dition as well as the chromosomal region, and the use Published online in Wiley Online Library of these names is commonplace in medical parlance, (wileyonlinelibrary.com). DOI: 10.1002/mds.26527 particularly in the field of movement disorders. 436 Movement Disorders, Vol. 31, No. 4, 2016 NOMENCLATURE OF GENETIC MOVEMENT DISORDERS However, as our techniques of genetic research and feedback was solicited. The recommendations were our knowledge have evolved, a number of problems also shared with representatives from GeneReviews, a have developed with the system of designating locus compendium of genetic phenotypes for commentary symbols and with its use. These problems have been and suggestions. Suggestions from both sources were described elsewhere2 but briefly they include (1) an considered before finalizing our recommendations and inability to distinguish disease-causing genes from tables. A summary of MDS membership feedback and weaker genetic risk factors, (2) an inconsistent rela- the task force’s responses can be found in the supple- tionship between list membership and movement dis- mentary material and on the task force’s page on the order phenotype, (3) failure of some established MDS website at XXX. genetic movement disorders to be assigned a locus symbol, (4) more than one symbol being assigned for Recommendations the same disorder, (5) unconfirmed associations between a gene or locus and a movement disorder, (6) 1. Include Only Genes Where Genetic erroneous labels resulting from laboratory errors or Testing Is Possible mistakes of phenotypic assignment, and (7) symbol Originally, locus symbols represented chromosomal designation in the absence of any known locus or regions. However, if we know only the chromosomal gene. Together these problems make the locus symbols region associated with a particular phenotype there unsuitable as a reference list of genetically determined are no direct implications for diagnostic testing or for movement disorders. Unfortunately, it is currently (basic) research applications. Therefore, a disorder used as such. This lack of a reference list was the justi- should only be listed once the causative gene is found. fication for the International Parkinson and Movement The exception to this is when a founder haplotype is Disorder Society (MDS) Task Force for Nomenclature diagnostic, as in the case of X-linked dystonia parkin- of Genetic Movement Disorders to present a recom- sonism (“Lubag”). In this case, the disorder should be mendation for a new system for naming genetically a member of the list. determined movement disorders. 2. Assign Appropriate Phenotype-Prefix The Task Force and Its Mandate Relationships The MDS Task Force for the Nomenclature of For a gene to be assigned a movement disorder pre- Genetic Movement Disorders first convened in May fix, the phenotype (eg, dystonia in the case of DYTs) 2012. The mandate of the task force was to generate should be a prominent feature of the disease linked to recommendations for revising the naming system of mutations in that gene in a majority of cases. When genetic movement disorders, addressing the problems more than one movement disorder is a prominent fea- summarized previously. The task force included clini- ture and these movement disorders generally coexist in cal neurologists and genetic experts covering the spec- an individual, a double prefix would be assigned trum of movement disorders as well as a metabolic (eg, DYT/PARK-ATP1A3) and the symbol would geneticist (S.M.-M.). Input was sought from experts in belong to more than one list. Disorders that may less medical fields other than movement disorders, where commonly present with an alternative movement dis- naming systems for genetically determined disorders order as the predominant manifestation would appear were in place (eg, epilepsy). Editors of general medical cross-referenced to the list of the alternative phenotype and neurology journals were also queried regarding (eg, SCA17 occasionally presents as a choreic disorder, their requirements from authors for assigning names thus it is cross-referenced to the chorea list), but the for newly discovered genetic conditions or their associ- prefix would reflect the phenotype that is consistent ated genes. With this background, the task force with the majority of cases. When a genetic mutation agreed on a set of rules that should govern the naming can unusually manifest with a movement disorder as based on a set of previously published recommenda- the predominant manifestation but the usual pheno- tions authored by several members of the task force.2 type is not a movement disorder (eg, C9orf72 muta- These previously published recommendations were tions presenting as a predominantly choreic disorder developed into more concrete rules. We then pro- instead of the usual dementia-predominant syndrome), ceeded to apply the rules to classes of genetically we have included these disorders on the lists
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