Is Parkinson's Disease Genetic? (Yes) (No)
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MDS-0110-224 VOLUME 14, ISSUE 1 • 2 0 1 0 • EDITORS, DR. CARLO COLOSIMO, DR. MARK STACY Is Parkinson’s Disease Genetic? (No) (Yes) — Caroline Tanner, MD, PhD, Director of Clinical Research, The Parkinson’s — Lawrence I. Golbe, MD, Professor of Neurology, UMDNJ-Robert Wood Institute, Sunnyvale, CA, USA Johnson Medical School, New Brunswick, New Jersey, USA More than 16 genetic causes of Consider a malevolent chef designing parkinsonism have been reported, a dinner party with the intent to but most are rare. Mutations in cause PD. Each course can consist of the most common disease-causing any of several dishes, each recipe gene, the leucine-rich repeat kinase includes ingredients that can be 2 (LRRK2) gene, are associated effective in multiple combinations with parkinsonism worldwide. In and no two guests receive exactly the North America, 1-2% of persons same meal. The list of available with apparently idiopathic PD dishes starts with systems for mito- have LRRK2 gene mutations, but chondrial energy production, ubiqui- not all carriers get PD—pen- tin-proteasomal protein disposal and etrance is estimated at 30%-50%.1, the antioxidative response. Other 2 In Asia, single mutations are rare, appealing options are pathways for but several polymorphisms in the the stress response, detoxification, LRRK2 gene are associated with regulation of apoptosis and perhaps greater PD risk.3 Thus, multiple microtubular transport. The basic determinants, likely both environ- ingredients are both genetic and mental and genetic, influence the environmental. development of parkinsonism even In the 1990s, attention was drawn to in those with an identified genetic genetics as a plausible cause of PD by factor. Genome-wide association reports of families with autopsy- studies suggest that most PD is complex in etiology; variation in proven Lewy-body parkinsonism occurring in Mendelian dominant 4 tau and PD-causing genes contributes to risk of sporadic PD. fashion.1,2 Although only about 10% of PD occurs in Mendelian 5 Epigenetic changes may be due non-genetic factors. This evi- patterns and another 10-15% in less-definable familial clusters, dence does not support the hypothesis that PD is “genetic” – that indirect evidence shows that a large fraction of the population’s is, that only genetic factors cause PD. burden of “sporadic” PD is the result of genetic defects. In Iceland, PD is very rarely due to a discrete environmental insult. MPTP- genealogical records show that randomly paired persons with spo- induced parkinsonism, the toxicant-induced form most closely radic PD are, on average, more closely related than random pairs of resembling sporadic PD, affected few people but provided impor- controls.3 Serial fluorodopa PET, presumably a highly sensitive tant mechanistic insights.6 Recently, pathological changes in fetal marker for PD, demonstrates that nearly all of the clinically unaf- tissue—including Lewy body-like inclusions—were observed 14 fected monozygotic co-twins of affected individuals are themselves years after transplantation into the striatum of an individual with subclinically affected, while the same is true for fewer than half of PD.7 Thus, something in the extra-cellular environment caused dizygotic co-twins.4 pathology in the grafted cells, causing the classical pathology of These results demonstrate the subtlety and ubiquity of PD familial PD to develop in the previously normal fetal neurons. These two clustering. The low degree of phenotypic penetrance is probably observations support a non-genetic cause of PD in some. explained by the need for multiple mutations to interact in the Certain non-genetic factors have consistently been associated with individual with one or more exogenous toxin exposures and/or with the risk of PD. While evidence in human populations is strong stochastic factors related to protein conformation. Similarly, perhaps CONTINUED ON PAGE 10 CONTINUED ON PAGE 10 www.movementdisorders.org E d i t o r i a l inside this issue This issue of Moving Along features updates of MDS activities throughout the world, and continues “Controversies” and “Where are They Now.” Professor Roger Duvoisin was kind Controversy enough to share his thoughts about his career, particularly about his mentors, his life with Is Parkinson’s Disease 1 levodopa, and his work searching for genetic linkage in Parkinson’s disease. Throughout the Genetic? conversation, it was apparent that the immense kindness of the man, his warm sense of Editor’s Section humor, and his efforts to promote collegial interaction, were important to the advance of Carlo Colosimo, MD and 2 levodopa as a treatment for PD, and for the collection of clinical and genetic information Mark Stacy, MD leading to the identification of thea -synuclein gene. The Controversies articles feature two Carlo Colosimo, MD President’s Letter investigators who have made major contributions to the epidemiology of PD. Dr. Carlie Philip Thompson, MB, BS, 3 Tanner, at the Parkinson Institute in Sunnyvale, CA, has published extensively concerning PhD, FRACP, President risk factors of PD and related disorders. Topics among her many publications include International Congress 4-5 systematic study of a wide variety of risk factors for the development of PD and Multiple System Atrophy. Dr. Lawrence Golbe worked with Dr. Duvoisin at the School of Medicine Web site 6 and Dentistry at the University of New Jersey and has published manuscripts (mainly on European Section the genetics of PD and on the epidemiology and clinical features of Progressive Supranucle- Alfredo Berardelli, MD, 7-9 ar Palsy). Dr. Duvoisin readily admits that it was Dr. Golbe’s energy and carefulness that MDS-ES Chairman identified many of the subjects in the Contursi kindred, remarking with some amusement, Mark Stacy, MD “he even learned Italian to do the work!” Both have been active in a wide variety of research Asian and Oceanian Section Bhim Singhal, MD, FRCP, 11 activities, and their contributions to this newsletter underscore the convergence of genetic and environmental MDS-AOS Chairman risk factors as a two-hit hypothesis for PD. Dr. Tanner has also provided a picture of the initial DATATOP investigator meeting – the future North American Parkinson Study Group, circa 1985 (see below). While Dr. History 12 Tanner was already positioned in the middle of the group, Dr. Golbe is located at the far right! How many Education 13 others can you identify? Professional Notices 14-17 Please be sure to review the Presi- Upcoming Meetings 18-19 dent’s Letter from Prof. Philip Thompson, highlighting MDS educational programming, as well as updates concerning the 14th Congress in Buenos Aires in June, including Congress registration (May 3), and housing (May 24) deadlines and further details. In addition, an article by Hubert Fernandez and Marcelo Merello describes the various features of the MDS Web site. Also, Members of the Society have been busy in the last half of 2009, and reviews of activities in Mali, Prague, Yerevan, and Boston are summarized. The newsletter also features updates from the Archives committee, and provides notice of the potential changes in the MDS bylaws. Please contact us if you have a photograph, topic or individual to be featured in a future issue of Moving Along! LETTERS TO THE EDITORS Your Comments and Questions Are Always Welcome Editorial Policy Address your communications to: Editor: Moving Along As part of its democratic commitment, MDS welcomes TheMovement Disorder Society the input of all its members about the features and 555 East Wells Street, Suite 1100 articles that appear in this newsletter. Have a comment or Milwaukee, WI 53202-3823 USA question? Each issue will include responses in the “Letters Tel: +1 414-276-2145 to the Editor” section. All materials submitted become the Fax: +1 414-276-3349 property of MDS. E-mail: [email protected] PA G E 2 M o v i n g A l o n g • I s s u e 1 , 2 010 P r E s i d E n t ’ s l E t t E r For this first issue ofMoving Along existing regional neurological meetings. Programs in 2010, I am pleased to look took place in the following countries: back on a highly successful year Asia & Oceanian for The Movement Disorder Cebu City, Philippines, November 2009 Society (MDS). The accomplish- Africa ments of the Society depend Bamako, Republic of Mali, November 2009 heavily on the participation of its MDS Supported Meetings provides support for new membership, which reached an and novel scientific meetings. The following all-time high this year to over 3,000 members from meetings were supported in 2009: more than 80 countries. th 5 International Workshop on Dementia with Lewy OFFICERS This active participation was seen at the 13th Interna- Body and Parkinson’s Disease Dementia. March tional Congress of Parkinson’s Disease and Movement 8-11, 2009, Kassel, Germany. President Disorders held in Paris, France in June 2009, which Psychogenic Movement Disorders & Other Conversion Philip D. Thompson, MB, BS, PhD, FRACP turned out to be one of the most successful, attracting Disorders. April 2- 4, 2009, Washington, DC, USA. a record breaking attendance of over 5,000 attendees. Parkinson Study Group 23rd Annual Symposium on President-Elect Günther Deuschl, MD The success of the Society and the growing enthusi- Etiology, Pathogenesis and Treatment of Parkinson’s asm from members around the world lead the Society Disease and Other Movement Disorders. October 11, Secretary to expand a number of programs this year that 2009, Bethesda, MD, USA. Matthew Stern, MD encourage scientific developments in our field and Looking forward to 2010, I expect this growth in Secretary-Elect enhance physicians’ knowledge of Movement Disor- programming to continue. Our MDS Committees Cynthia Comella, MD ders. Please visit the MDS Web site to learn how to are hard at work and a number of new programs are Treasurer participate during 2010 in the specific programs planned.