Grant Application Form Please complete the following form for IETF grant applications. This form and all the attachments below must be combined into one document before submitting electronically. Grant submissions will not be accepted otherwise.

Attachments Required1. Specific aims of the proposal (1 page maximum).2. Rationale of the proposal and relevance to essential tremor (1-2 pages maximum).3. Preliminary data, if available should be incorporated into the Rationale/Relevance section. Preliminary data are not required for a proposal. However, if preliminary data are referred to in the proposal rationale, or have been used to formulate the hypotheses to be tested, such information must be formally presented in this section.4. Research methods and procedures (1-2 pages maximum).5. Anticipated results (half-page maximum).6. Detailed budget and justification (1 page maximum).7. Biographic sketch of principal investigator and all professional personnel participating in the project (standard NIH format, including biosketch and other support).8. Copies of relevant abstracts and/or articles that have been published, are in press, or have been submitted for publication.9. Completed conflict of interest questionnaire.

Project Title: ____________________________________________________________________________

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All grant applicants acknowledge that the Board of Directors of the IETF is the only entity authorized to award grants on behalf of the IETF and the amounts of and occasions for awarding such grants, if any shall be awarded at all, shall be wholly within the sole and exclusive discretion of said Board and its judgment shall be final and conclusive and not subject to review for any reason judicial or otherwise.

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PO Box 14005 | Lenexa, Kansas 66285-4005 | USA | 888.387.3667 (toll free) | 913.341.3880 (local) | essentialtremor.org

Mary Ann Thenganatt MD Department of Neurology Baylor College of Medicine 6550 Fannin, Suite 1801 Houston, TX 77030 February 9, 2014

Catherine Rice Executive Director International Essential Tremor Foundation PO Box 14005 Lenexa, KS 66285-4005 Dear Ms. Rice, Please find attached my grant proposal, entitled “Genetics of essential tremor: a study of two kindreds”. Although there is strong evidence for substantial heritability in essential tremor (ET), the responsible genes remain to be elucidated. Here, we propose to determine the gene mutations causing ET in 2 large family pedigrees consistent with an autosomal dominant inheritance. Since our initial submission of this proposal last year, we have made important progress that substantially increases the feasibility of this project. Specifically, we have now completed whole-exome sequencing of 21 familial ET cases, including 2 separate families where we have sequenced 2 affected individuals. In order to identify the most likely responsible mutation from the resulting list of candidates, we will perform comprehensive neurologic examinations of all available family members and collect blood for DNA isolation and genotyping. Following completion of this project, we will be ideally positioned to confirm our findings in our existing collection of ~300 additional familial ET cases, and in other cohorts through collaboration with other centers. Our proposal builds on key institutional strengths at Baylor College of Medicine, including the clinical expertise within the Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology and experience in Mendelian and complex trait genetics within the Department of Molecular and Human Genetics and the Human Genome Sequencing Center. In sum, with the support of the IETF, we hope to make important progress in our understanding of ET genetics, identifying new molecular targets for future advances in ET risk prediction, diagnosis, and possibly treatment. Sincerely,

Mary Ann Thenganatt MD Assistant Professor of Neurology Baylor College of Medicine Parkinson’s Disease Center & Movement Disorders Clinic

1. Specific Aims of the Proposal Essential tremor (ET) is a common and progressive neurologic disorder with evidence for substantial heritability; however, the identification of genetic risk factors has largely remained elusive. Recent advances in sequencing technology are accelerating the identification of genomic variants responsible Mendelian disorders. In the Baylor Parkinson’s Disease Center and Movements Disorders Clinic (PDCMDC), we have evaluated patients from numerous families consistent with autosomal dominantly-inherited ET. In preliminary studies, whole exome sequencing was performed on 21 DNA samples from subjects with familial ET. In 3 separate families, 2 affected relatives were sequenced, identifying numerous shared, deleterious variants that are promising candidate ET-causing mutations. We propose here to follow-up these sequencing analyses in order to refine the list of candidate variants and determine the most likely pathogenic mutation in each family. We specifically plan to execute the following aims: Aim 1: Neurologic phenotyping. In order to confirm and amplify the reported family histories, we will perform standardized neurologic examinations, including videotaping, of all available individuals in 2 selected ET families. Expert clinical diagnoses of ET and standardized tremor rating scales will make possible confident genotype-phenotype correlation. Aim 2: Genotyping and segregation analysis. Blood samples will be obtained from all available family members for DNA isolation and analysis. Based on the available exome sequencing results from 2 members of each family, a selected panel of promising candidate variants will be genotyped in all additional family members. Consistent segregation of candidate mutations with ET affectation status will identify the most likely pathogenic variant in each family. In future studies, we plan to confirm our findings by genotyping the identified mutations in our existing PDCMDC DNA sample collection including ~300 familial ET cases, and we will additionally collaborate with other centers to leverage additional ET cohorts for independent replication. Completion of the proposed investigation will provide foundational data for an NIH career development award to support the continued training of the PI and expand the scope of future efforts to reveal genetic determinants of ET and related movement disorders. 2. Rationale of the proposal and relevance to essential tremor Background and Significance ET is among the most prevalent neurological disorders, with an estimated worldwide prevalence of 0.4% in all age groups and up to 6.3% in those over the age of 60 years.1 In older individuals, the occurrence of ET is therefore similar to that of osteoarthritis, diabetes mellitus and Alzheimer’s disease 2, causing a substantial population burden of disability. From even the earliest comprehensive descriptions of ET, it was recognized that this disorder clusters in families3, and there is now substantial evidence from both familial aggregation and twin studies to support a strong genetic etiology in ET. Although sporadic forms of ET are frequently diagnosed, a family history is reported in about 50-70% of patients.4 Twin studies demonstrated pairwise concordance in monozygotic twins almost twice that seen in dizygotic twins.5 While genetics clearly plays an important role, the specific genes responsible remain to be identified. Linkage analyses of ET pedigrees have led to nomination of three potential ET genetic loci. In 1997, an ET gene was mapped to chromosome 3q13 in 16 Icelandic families and named ETM1.6 Subsequently, a study of 4 unrelated American families with ET mapped the ETM2 gene on chromosome 2p24.1.7 Notably, several of these families were initially evaluated at Baylor College of Medicine at the PDCMDC. A third susceptibility locus on chromosome 6p23 was identified in two North American families.8 Although these suggestive linkage peaks are important leads for identifying genetic determinants of ET, they have been inconsistently replicated and the potentially responsible gene(s) at each locus remain unknown.4 A genome-wide association study in an Icelandic population has identified an ET susceptibility locus at the LINGO1 gene, encoding a protein of still-unknown function.9 Although LINGO1 variants have been confirmed in many—though not all—replication studies 10, this common variant (frequency~0.2) is associated with a relatively modest effect on ET susceptibility (OR=1.55) within the broad population, and does not explain the strong heritability of ET observed in many families, which support the existence of additional, highly-penetrant Mendelian loci. Recent advances in sequencing technology have substantially accelerated the discovery of

genes and variants causing human Mendelian disease.11, 12 Whole-exome sequencing (WES) allows the efficient capture of all variation within the protein-coding sequence of the human genome. In a recent study of a large family affected by ET, WES was successfully employed to identify rare mutations in the FUS gene13

suggesting the value of this new method to advance understanding of ET genetics. In sum, ET is most likely genetically heterogeneous, with multiple contributory genes and variants with a range of effect sizes and penetrance. A comprehensive understanding of the genetic architecture of ET is essential to revealing the molecular mechanisms of this disabling disorder. The elucidation of novel ET genes promises to improve diagnosis and risk prediction and may also reveal new and improved therapeutic strategies. Preliminary Studies in Support of the Proposal In collaboration with the Center for Mendelian Genomics at Baylor College of Medicine, the PDCMDC is participating in efforts to identify the genetic cause of unsolved Mendelian disorders (see Letter of Support from Dr. James Lupski). Over the last year, we selected ~100 patient-derived samples for WES, including 21 familial ET cases, with pedigrees consistent with an autosomal dominant inheritance pattern. In 3 distinct ET families (FIGURE), we sequenced samples from 2 affected family members that have been examined by PDCMDC clinicians. Based on preliminary analyses of WES data from these subjects, a number of promising shared candidate variants were identified as potential causes of ET for further investigation. For example, the two affected brothers from one of the ET families (FIGURE, LEFT), share 7 heterozygous variants predicted to cause damaging protein truncation, either through a frameshift or premature STOP codon. Of this group, 2 genes are definitively linked to other Mendelian disorders, including RP1L1 and GYG1, which are associated with dominant occult macular dystrophy14 and recessive glycogen storage disease15 respectively. Other potential candidates include two genes with high expression in the brain, including MLL3 and CNTNAP3. MLL3 encodes a histone methyltransferase involved in chromatin and epigenomic regulation and has been implicated as a candidate for a neurodevelopmental disorder, Kleefstra syndrome.16 CNTNAP3 encodes a member of the Neurexin family of neuronal cell adhesion molecules and is highly expressed in the cerebellum17, a brain region which has been implicated in ET. Computational analyses of these sequencing data is ongoing, and a final list of the most likely responsible genes/variants will be finalized prior to the start of the proposed work. These results will inform selection of the 2 families that will be the focus of our initial investigations.

FIGURE: Representative ET families selected for WES analysis. Proband patients evaluated by the PDCMDC indicated with arrows. (LEFT) Proband is a 73-year old man with essential tremor. DNA was also collected on his 72 year-old brother with essential tremor and cervical dystonia (asterisk). (RIGHT) Proband is a 45-year old woman with essential tremor as well as orthostatic tremor and history of seizures. DNA was also collected on her affected mother (asterisk). Besides the 3 initial families selected for WES analysis, the PDCMDC has collected genetic samples from an additional ~340 patients with ET, of which the majority (~290) have a documented family history. WES has already been completed on 15 additional familial ET cases, and these data will be available to enhance our studies. Though outside of the scope of the current proposal, additional samples are being considered for WES, and the full cohort will be available for replication genotyping. Our progress to date demonstrates the overall feasibility of our approach to leverage WES for the genetic dissection for ET and other familial movement disorders. We have also established collaborations with other investigators to support confirmation of our anticipated findings in independent ET cohorts (See letter of support from Dr. Elan Louis). 4. Research methods and procedures Aim 1. Neurologic Phenotyping. Our goal is to perform comprehensive neurologic examinations on as many individuals as possible, within the two families selected for this study. With the help of the proband, family

members will be contacted to arrange a family get-together at a convenient location and time. We will assist family members with the cost of travel, and will provide meals as well as an informational seminar on ET and genetics. We anticipate approximately 30 individuals at each family gathering. Every effort will be made to organize the events for maximal attendance, but in the case of family members unable to attend but willing to participate in our study, we will interview and perform examinations by video conferencing. Examinations will be performed by a study team from the Baylor PDCMDC, including Dr. Mary Ann Thenganatt (PI), Dr. Joshua Shulman (Co-I), and Christine Hunter, RN (PDCMDC Research Nurse). A phlebotomist will also attend this event, for collection of blood from each family member. In the case of study participants unable to attend the family event for in person evaluation and blood draws, we will mail saliva collection kits for DNA sampling (Oragene OR-500, DNA Genotek). All study participants will sign informed consent before they are interviewed, examined and videotaped. Participants will complete a detailed questionnaire obtaining information about demographics, medical history, and medications. Detailed questions about tremor mode of onset, anatomical distribution, exacerbating and relieving factors, response to alcohol and pharmacological therapy will be obtained. The clinicians will systematically examine each family member, both affected and unaffected, and videotape the examination. Patients will be videotaped according to a standardized protocol developed at the PDCMDC to evaluate tremor at rest, during maintenance of posture with arms in front of the body, in wing-beating position, and during the finger-to-nose-maneuver. We will also observe the patients during writing, drawing of Archimedes’ spirals, dot approximation and pouring water. Subjects will be evaluated for rigidity, bradykinesia and will be observed walking. Severity of tremor will be evaluated using The Essential Tremor Rating Assessment Scale (TETRAS) which has been demonstrated to be a reliable scale for evaluating the severity of tremor.18 TETRAS contains 9 performance items rating action tremor in the head, face, voice, limbs and trunk. All examinations and collected data will subsequently be reviewed during the PDCMDC video rounds, where the study team, including the PI (Dr. Thenganatt), and Co-Is (Dr. Shulman and Dr. Jankovic) will make a consensus determination of ET diagnosis, based on the criteria proposed by the Movement Disorders Society in 1998 with specific inclusion and exclusion criteria.19 Aim 2. Genotyping and segregation analysis. In order to identify the mutation most likely responsible for ET in each pedigree, we plan to genotype all examined family members based on the panel of candidate variants identified from WES. DNA preparation and genotyping will be performed in Dr. Shulman’s laboratory based in the Jan and Dan Duncan Neurological Research Institute (NRI) at Baylor College of Medicine (see letter of support from Dr. Shulman). Blood and saliva samples will be processed for DNA by Dr. Shulman’s research assistant using standard protocols (Qiagen Puregene). TaqMan multiplex PCR assays (Applied Biosystems) will be developed to genotype all individuals. Each candidate variant will be assessed for segregation with ET phenotype, such that affected individuals should be carriers and unaffecteds are non-carriers. We will also consider a series of models allowing for incomplete and age-dependent penetrance (i.e. some younger individuals without ET manifestations may carry pathogenic variants). All samples will additionally be genotyped for the common LINGO1 polymorphism (rs9652490), in order to evaluate for interactions between rare and common variants in determining ET pathogenesis. 5. Anticipated results Following completion of the proposed aims, we will have substantially refined the list of candidate mutations responsible for ET in two large pedigrees. We are hopeful that our findings will provide evidence to support a unique mutation as causative of ET in each family; however, it is possible that additional studies will be required to differentiate between a number of equally plausible candidate variants. In this case, we will be strongly positioned to carry out the required studies. We plan to genotype any remaining candidate variants in our PDCMDC cohort of nearly 300 familial ET cases, and collaboration with other investigators should allow replication in an even larger number of samples (see letter of support from Dr. Louis). We will additionally consider targeted re-sequencing of the implicated gene(s) in these patient cohorts, in order to identify potential allelic heterogeneity (i.e. multiple mutations in the same gene). Replication of our findings in independent cohorts will be essential to definitively establish any finding(s) of a novel genetic risk locus for ET. In other future planned studies, we will pursue WES in additional, large ET pedigrees within the PDCMDC database, and these results can be integrated with analyses from the families studied in this project. Lastly, we will strongly consider pursuing functional investigation of any promising ET gene candidates, and this work will be

facilitated by the involvement of Dr. Shulman in this project, whose laboratory has substantial experience in using simple model organisms, such as fruit flies, to study neurologic disorders, including movement disorders such as Parkinson’s Disease. In sum, completion of the proposed study promises important advances in our understanding of ET genetics. Identifying the gene mutations responsible for ET in 2 large families will define novel mechanisms of disease pathogenesis, and may ultimately point to new therapeutic strategies. Literature Cited 1. Louis ED, Ferreira JJ. How common is the most common adult movement disorder? Update on the worldwide

prevalence of essential tremor. Movement disorders : official journal of the Movement Disorder Society 2010;25:534-541.

2. Louis ED. Etiology of essential tremor: should we be searching for environmental causes? Movement disorders : official journal of the Movement Disorder Society 2001;16:822-829.

3. CL D. Hereditary tremor, a hitherto undescribed form of motor neurosis. Am J Med Sci 1887;94:386-389. 4. Deng H, Le W, Jankovic J. Genetics of essential tremor. Brain : a journal of neurology 2007;130:1456-1464. 5. Tanner CM, Goldman SM, Lyons KE, et al. Essential tremor in twins: an assessment of genetic vs environmental

determinants of etiology. Neurology 2001;57:1389-1391. 6. Gulcher JR, Jonsson P, Kong A, et al. Mapping of a familial essential tremor gene, FET1, to chromosome 3q13.

Nature genetics 1997;17:84-87. 7. Higgins JJ, Loveless JM, Jankovic J, Patel PI. Evidence that a gene for essential tremor maps to chromosome 2p in

four families. Movement disorders : official journal of the Movement Disorder Society 1998;13:972-977. 8. Shatunov A, Sambuughin N, Jankovic J, et al. Genomewide scans in North American families reveal genetic linkage

of essential tremor to a region on chromosome 6p23. Brain : a journal of neurology 2006;129:2318-2331. 9. Stefansson H, Steinberg S, Petursson H, et al. Variant in the sequence of the LINGO1 gene confers risk of essential

tremor. Nature genetics 2009;41:277-279. 10. Deng H, Gu S, Jankovic J. LINGO1 variants in essential tremor and Parkinson's disease. Acta neurologica

Scandinavica 2012;125:1-7. 11. Bamshad MJ, Ng SB, Bigham AW, et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nature

reviews Genetics 2011;12:745-755. 12. Bamshad MJ, Shendure JA, Valle D, et al. The Centers for Mendelian Genomics: a new large-scale initiative to

identify the genes underlying rare Mendelian conditions. American journal of medical genetics Part A 2012;158A:1523-1525.

13. Merner ND, Girard, S., Catoire, H, et al. Exome sequencing identifies FUS mutations as a cause of essential tremor. Am J Hum Genet 2012; 91(2), 313–319.

14. Akahori M, Tsunoda K, Miyake Y, et al. Dominant Mutations in RP1L1 Are Responsible for Occult Macular Dystrophy. Am J Hum Genet 2010;87(3), 424–429.

15. Moslemi AR, Lindberg C, Nilsson J, et al. Glycogenin-1 deficiency and inactivated priming of glycogen synthesis. N Engl J Med 2010; 362(13), 1203–1210.

16. Kleefstra T, Kramer JM, Neveling K, et al. Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability. Am J Hum Genet 2012; 91(1), 73–82.

17. Spiegel I, Salomon D, Erne B, et al. Caspr3 and caspr4, two novel members of the caspr family are expressed in the nervous system and interact with PDZ domains. Mol Cell Neurosci. 2002; 20(2), 283–297.

18. Elble R, Comella C, Fahn S, et al. Reliability of a new scale for essential tremor. Movement disorders : official journal of the Movement Disorder Society 2012;27:1567-1569.

19. Deuschl G, Bain P, Brin M. Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee. Movement disorders : official journal of the Movement Disorder Society 1998;13 Suppl 3:2-23.

BUDGET JUSTIFICATION

Personnel Mary Ann Thenganatt, MD (PI, 20% effort) is faculty at The Parkinson’s Disease Center and Movement Disorders Clinic at Baylor College of Medicine and Assistant Professor of Neurology. Dr. Thenganatt will be responsible for the design and supervision of clinical data acquisition, analysis and interpretation and the writing of the manuscripts. The PI, along with the co-investigators and clinical research nurse will conduct neurologic evaluation of all study participants. No salary support is requested; Dr. Thenganatt has existing support for protected time to cover her research and academic activities, including her effort on this project. Joseph Jankovic , MD (Co-I, 5% effort) is Professor of Neurology and Distinguished Chair in Movement Disorders, Director of the Parkinson’s Disease Center and Movement Disorders Clinic at Baylor College of Medicine. Dr. Jankovic will assist in study design, interpretation of the data, assignment of consensus ET diagnoses, and review of the manuscript. No salary is requested. Joshua M. Shulman, M.D. Ph.D. (Co-I, 5% effort) is an Assistant Professor of Neurology and Molecular and Human Genetics at Baylor College of Medicine and Investigator in the Jan and Dan Duncan Neurological Research Institute. Dr. Shulman will be involved in study design, data analysis, interpretation, and revision of manuscripts. Dr. Shulman will also assist with neurologic evaluations of study participants. No salary is requested. Christine Hunter, RN, CCRD (Research Nurse, 5% effort) is Instructor of Neurology at The Parkinson’s Disease Center and Movement Disorders Clinic at Baylor College of Medicine. The research nurse will conduct neurological examinations of study participants. No salary is requested. Paula Porter (Research Technician, 10% effort) will perform DNA preps from blood or saliva, and will also perform the genotyping experiments. (salary + fringe = $5,000) Family Reunion We are requesting $10,000 to organize a family reunion to systematically perform neurological examinations and collect blood samples for DNA analysis. This amount will cover travel for family members from various parts of the country, staff travel, and phlebotomy supplies. Supplies and Consumables We are requesting a total amount of $10,000 to cover saliva collection kits, laboratory reagents, and consumables for DNA preparation from blood or saliva, and PCR reactions for subject genotyping.

 

Program Director/Principal Investigator (Last, First, Middle):

PHS 398/2590 (Rev. 06/09) Page Biographical Sketch Format Page

BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors in the order listed on Form Page 2.

Follow this format for each person. DO NOT EXCEED FOUR PAGES.

NAME Thenganatt, Mary Ann

POSITION TITLE Assistant Professor, Baylor College of Medicine

eRA COMMONS USER NAME (credential, e.g., agency login) EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable.)

INSTITUTION AND LOCATION DEGREE (if applicable) MM/YY FIELD OF STUDY

Boston University, Boston, MA BA 5/2002 Medical Science Boston University School of Medicine, MA MD 5/2006 Medicine UCLA School of Medicine, Los Angeles, CA Internship 6/2007 Internal Medicine Columbia University Medical Center, NY, NY Residency 6/2010 Neurology Columbia University Medical Center, NY, NY Fellowship 6/2012 Movement Disorders

A. PERSONAL STATEMENT Dr. Mary Ann Thenganatt is Assistant Professor of Neurology at Baylor College of Medicine in Houston, Texas. After obtaining her medical degree from Boston University, she completed internship in internal medicine at UCLA Medical Center in Los Angeles, California. She subsequently completed residency in neurology and fellowship in movement disorders at The Neurological Institute of New York at Columbia University Medical Center. Dr. Thenganatt is certified by the American Board of Psychiatry and Neurology and practices at The Parkinson’s Disease Center and Movement Disorders Clinic at Baylor College of Medicine. She specializes in the evaluation and management of various movement disorders and has a particular interest in essential tremor genetics. B. POSITIONS AND HONORS Positions 2012- Assistant Professor of Neurology, Parkinson’s Disease Center & Movement Disorders Clinic, Baylor College of Medicine Professional Societies 2013- F1000 Prime, Associate Faculty Member 2013- The Houston Neurological Society 2012- American Academy of Neurology 2012- Movement Disorders Society Honors 2012 Annual Meeting Fellow Scholarship, American Academy of Neurology 2012 Movement Disorders Society Meeting Travel Award 2011 Movement Disorders Society Meeting Travel Award 2006 Robert G. Feldman Prize in Neurology, Boston University School of Medicine 2005 Alpha Omega Alpha, Boston University School of Medicine 2002 Phi Beta Kappa, Boston University

Program Director/Principal Investigator (Last, First, Middle):

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C. SELECTED PUBLICATIONS 2014 Thenganatt MA, Jankovic J. Parkinson Disease Subtypes. JAMA Neurol. 2014 Feb 10. [Epub ahead of print] 2013 Virmani T, Thenganatt MA, Goldman JS, Kubisch C, Greene PE, Alcalay RN. Oculogyric crises induced by levodopa in PLA2G6 parkinsonism-dystonia. Parkinsonism Relat Disord. 2014 Feb;20(2):245-7 2013 Thenganatt MA, Jankovic J. Treatment of dystonia. Neurotherapeutics. 2014 Jan;11(1):139-52. 2013 Thenganatt MA. Tauopathies with dementia and parkinsonism. In Gilman S, editor. Neurology- Medlink. Arbor Publishing, La Jolla, CA; 2013. Annual update 2013. 2013 Thenganatt MA, Jankovic J. Tardive Dyskinesia. In Gilman S, editor. Neurology-Medlink. Arbor

Publishing, La Jolla, CA; 2013. Annual update 2013. 2013 Thenganatt MA, Jankovic J. Idiopathic torsion dystonia. In Gilman S, editor. Neurology-

Medlink. Arbor Publishing, La Jolla, CA; 2013. Annual update 2013. 2013 Thenganatt MA, Jankovic J. Cervical dystonia. In Gilman S, editor. Neurology-Medlink. Arbor

Publishing, La Jolla, CA; 2013. Annual update 2013. 2012 Thenganatt MA, Alcalay RN, Vonsattel JPG, Greene PE. Somatic mitochondrial DNA

mutations and parkinsonism. Ann Neurol. 2012 2012 Nov;72(5):823. 2012 Thenganatt MA, Fahn S. Botulinum toxin for the treatment of movement Disorders. Curr Neurol

Neurosci Rep. 2012 Aug;12(4):399-409. 2012 Thenganatt MA, Louis ED. Personality profile in essential tremor: A case-control study.

Parkinsonism Relat Disord. 2012 Jun 13. 2012 Thenganatt MA, Louis ED. Distinguishing essential tremor from Parkinson's disease: bedside

tests and laboratory evaluations. Expert Rev Neurother. 2012 Jun;12(6):687-96. 2012 Thenganatt MA, Waters C. Combined dopaminergic and nondopaminergic therapies.

Advances in Parkinson’s Disease Management. London : Future Medicine Ltd, 2012. p. 54-62. 2011 Thenganatt MA, Frucht SJ. Treatment Options for Sleep Dysfunction in Parkinson’s Disease.

Curr Treat Options Neurol. 2011 Oct;13(5):473-87. 2010 Thenganatt MA, Frucht SJ. Myoclonus. In: Katie K, Leo Verhagen M, eds. Encyclopedia of

Movement Disorders. Oxford: Academic Press, 2010: 234-241. 2010 Thenganatt MA, Frucht SJ. Dystonia, Task-specific. In: Katie K, Leo Verhagen M, eds.

Encyclopedia of Movement Disorders. Oxford: Academic Press, 2010: 386-389. Dr. Thenganatt is co-PI on the following projects A Phase IIIb, Multicentre, Randomised, Double-Blind, Placebo-Controlled Study Evaluating The Efficacy And

Safety Of Dysport Using 2ml Dilution In Adults With Cervical Dystonia. IPSEN

Program Director/Principal Investigator (Last, First, Middle):

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A Phase IIIb, Prospective, Multicentre, Open-Label Extension Study To Assess Long Term Safety And Effectiveness Of Dysport Using 2ml Dilution In Adults With Cervical Dystonia. IPSEN

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating The Safety And Efficacy Of

Fixed-Dose Once-Daily Oral Aripiprazole In Children And Adolescents With Tourette’s Disorder. OTSUKA Enroll-HD: A Prospective Registry Study Of Global Huntington's Disease CHDI CD Flex: An Open-Label, Non-Inferiority Study Evaluating The Efficacy And Safety Of Two Injection Schedules

Of Xeomin® (Incobotulinumtoxina) [Short Flex Vs. Long Flex] In Subjects With Cervical Dystonia < 10 Weeks Of Benefit From Onabotulinumtoxina Treatment). MERZ

The Parkinson’s Progression Markers Initiative (PPMI). Michael J. Fox Foundation National Parkinson Foundation Patient Registry (Phase II Protocol). NPF An Open Label, Multicenter Study, Evaluating The Safety And Efficacy Of 18f-AV-133 Pet Imaging To Identify

Subjects With Dopaminergic Degeneration Among Subjects Presenting To A Movement Disorders Specialty Clinic With An Uncertain Diagnosis (AVID)

Jankovic, Joseph M.D.

BIOGRAPHICAL SKETCH DO NOT EXCEED FOUR PAGES.

NAME Joseph Jankovic, M.D.

POSITION TITLE Professor of Neurology, Distinguished Chair in Movement Disorders, Director, Parkinson’s Disease Center and Movement Disorders Clinic

eRA COMMONS USER NAME Baylor College of Medicine EDUCATION/TRAINING Phoenix College (1966-67), Arizona State University (1967-69)

INSTITUTION AND LOCATION DEGREE (if applicable)

MM/YY FIELD OF STUDY

University of Arizona, College of Medicine Tucson, Arizona M.D. 1973 Medicine

PERSONAL STATEMENT Dr. Jankovic, past president of the International Parkinson and Movement Disorder Society, has served as the principal investigator on over hundred clinical trials in Parkinson disease and other movement disorders, and his pioneering research on drugs such as botulinum toxin and tetrabenazine has led to their approval by the Food and Drug Administration. Dr. Jankovic has published over 900 original articles and chapters, and edited or co-edited over 50 books and volumes, including several standard textbooks such as “Neurology in Clinical Practice” (NICP.com) and “Principles and Practice of Movement Disorders”. A co-director the annual course “A Comprehensive Review of Movement Disorders”, in Aspen, Colorado since 1991, Dr. Jankovic has mentored numerous fellows and other trainees, including training of clinician-scientists and non-clinician scientists, many of whom have become leaders in the field of neurology and movement disorders. He is current or past member of many scientific and medical advisory boards of national foundations and has also served on the executive scientific advisory boards of the Michael J. Fox Foundation for Parkinson’s Research and the National Parkinson Foundation. He has been a member of many editorial boards including Neurology, Journal of Neurology Neurosurgery and Psychiatry, Movement Disorders, Journal of Neurological Sciences, and Neurology Medlink (for further information visit www.jankovic.org). PROFESSIONAL EXPERIENCE 1973-74 Straight Medicine Intern, Baylor College of Medicine (BCM), Houston, Texas 1974-77 Resident in Neurology (Chief resident 1976-77), The Neurological Institute, Columbia University, NYC 1977-Present Director, Parkinson’s Disease Center and Movement Disorders Clinic, BCM 1977-84 Assistant Professor of Neurology, BCM 1984-88 Associate Professor of Neurology (Tenured), BCM 1988-Present Professor of Neurology (Tenured), BCM 2007-Endowed Distinguished Chair in Movement Disorders HONORS Selected awards: American Academy of Neurology Movement Disorders Research Award, Guthrie Family Humanitarian Award presented by the Huntington’s Disease Society of America, Lifetime Achievement Award by the Tourette Syndrome Association; Dystonia Medical Research Foundation Distinguished Service Award; Baylor College of Medicine Alumni Association Distinguished Faculty Award, and the Fulbright & Jaworski Faculty Excellence Award. Selected honorary memberships: American Neurological Association, Australian Association of Neurologists, French Neurological Society, Movement Disorders Society; “Great Teacher” selection by the National Institute of Health; Listed in Highly Cited Researcher (ISIHighlyCited.com).

Jankovic, Joseph M.D.

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SELECTED PEER-REVIEW PUBLICATIONS (Since 2011 out of total >900 since 1979)

• Wu Y, Le W, Jankovic J. Preclinical biomarkers of Parkinson’s disease. Arch Neurol 2011;68:22-30. • Baizabal Carvallo JB, Simpson R, Jankovic J. Diagnosis and treatment of complications related to deep

brain stimulation hardware. Mov Disord 2011;26:1398-1406. • Fekete R, Jankovic J. Revisiting the relationship between essential tremor and Parkinson’s disease.

Mov Disord 2011;26:391-8. • Pan T, Li X, Jankovic J. The association between Parkinson’s disease and melanoma. International J

Cancer 2011;128:2251-60. • Yaltho TC, Jankovic J. The many faces of hemifacial spasm: Differential diagnosis of unilateral facial

spasms. Mov Disord 2011;26:1582-92. • Jankovic J, Kurlan R. Tourette Syndrome: Evolving concepts. Mov Disord 2011;26:1149-56. • Rascol O, et al (Jankovic). A double-blind, delayed-start trial of rasagiline in Parkinson's disease (the

ADAGIO study): Prespecified and post-hoc analyses of the need for additional therapies, changes in UPDRS scores, and non-motor outcomes. Lancet Neurol. 2011;10:415-23.

• Deng H, Gao K, Jankovic J. The genetics of Tourette syndrome. Nat Rev Neurol. 2012 Mar 13;8(4):203-13. • Ha AD, Jankovic J. Pain in Parkinson's disease. Mov Disord 2012;27:485-91. • Jankovic J, Poewe W. Therapies in Parkinson's disease. Curr Opin Neurol. 2012 Aug;25(4):433-47. • Poewe W, Mahlknecht P, Jankovic J. Emerging therapies for Parkinson's disease. Curr Opin Neurol.

2012 Aug;25(4):448-59. • Baizabal-Carvallo JF, Jankovic J. Movement disorders in autoimmune diseases. Mov Disord.

2012 Jul;27(8):935-46. • Pan T, Zhu J, Hwu WJ, Jankovic J. The role of alpha-synuclein in melanin synthesis in melanoma

and dopaminergic neuronal cells. PLoS One 20127(9): e45183. • Deng H, Liang H, Jankovic J. F-Box Only Protein 7 Gene in Parkinsonian-Pyramidal Disease. Arch

Neurol. 2012 Oct 1:1-5. • Elble R, Comella C, Fahn S, Hallett M, Jankovic J, Juncos JL, Lewitt P, Lyons K, Ondo W, Pahwa R,

Sethi K, Stover N, Tarsy D, Testa C, Tintner R, Watts R, Zesiewicz T. Reliability of a new scale for essential tremor. Mov Disord 2012;27(12):1567-9.

• Okun MS, Gallo BV, Mandybur G, Jagid J, Foote KD, Revilla FJ, Alterman R, Jankovic J, et al. Subthalamic deep brain stimulation with a constant-current device in Parkinson's disease: an open-label randomised controlled trial. Lancet Neurol. 2012 Feb;11(2):140-9.

• Dusek P, Jankovic J, Le W. Iron dysregulation in movement disorders. Neurobiol Dis. 2012;46(1):1-18. • Squitieri F, Jankovic J. Huntington's disease: How intermediate are intermediate repeat lengths? Mov

Disord. 2012 Dec;27(14):1714-7. • Baizabal-Carvallo JF, Jankovic J. Movement disorders in autoimmune diseases. Mov Disord. 2012

Jul;27(8):935-46. • Jankovic J. Medical treatment of dystonia. Mov Disord. 2013 Jun15;28(7):1001-12. • Deng H, Gao K, Jankovic J. The VPS35 gene and Parkinson's disease. Mov Disord.2013 May;28(5):569-

75. • Ramirez-Castaneda J, Jankovic J, Comella C, Dashtipour K, Fernandez HH, Mari Z. Diffusion, spread, and

migration of botulinum toxin. Mov Disord. 2013 Nov;28(13):1775-83. • Killoran A, Biglan KM, Jankovic J, Eberly S, Kayson E, Oakes D, Young AB, Shoulson I. Characterization

of the Huntington intermediate CAG repeat expansion phenotype in PHAROS. Neurology. 2013 May 28;80(22):2022-7.

• Mehanna R, Jankovic J. Movement disorders in cerebrovascular disease. LancetNeurol. 2013 Jun;12(6):597-608.

• Patel N, Jankovic J, Hallett M. Sensory aspects of movement disorders. Lancet Neurol 2014;13:100-112. • Le W, Sayana P, Jankovic J. Animal models of Parkinson's disease: A gateway to therapeutics?

Neurotherapeutics. 2014 (in press). • Thenganatt MA, Jankovic J. Parkinson’s disease subtypes. JAMA Neurol 2014 (in press).

Jankovic, Joseph M.D.

PHS 398/2590 (Rev. 06/09) Page 3 Continuation Format Page

RESEARCH SUPPORT For New and Renewal Applications (PHS 398) – DO NOT SUBMIT UNLESS REQUESTED For Non-competing Progress Reports (PHS 2590) – Submit only Active Support for Key Personnel

PHS 398/2590 OTHER SUPPORT Dr. Jankovic is the PI or co-PI on the following projects (selected out of >50 studies): Ceregene, Inc./MJFF/Sangamo (Site PI: Jankovic) 2/1/10-1/31/16 A phase 1/2 trial assessing the safety and efficacy of bilateral intraputaminal and intranigral administration of CERE-120 (adeno-associated virus serotype 2 [AAV2]-neurturin [NTN]) in subjects with idiopathic Parkinson’s disease. (Protocol CERE-120-09).

Michael J. Fox Foundation (Site PI: Jankovic) 7/13/10-7/12/20 The Parkinson’s Progression Markers Initiative (PPMI). The goal is to identify biomarkers for PD disease progression.

St. Jude Medical/ANS (Site PI: JANKOVIC) 12/22/09-9/30/14 A long-term follow-up study of the patients who underwent unilateral or bilateral stimulation of the (VIM) using the LIBRA deep brain stimulation system for the suppression of tremor in the upper extremities of patients with essential tremor. St. Jude Medical/ANS (Site PI: Jankovic) 12/22/09-9/30/14 A long-term follow-up study of the patients who underwent bilateral stimulation of the STN using the LIBRA/LIBRA XP deep brain stimulation system as adjunctive treatment for reducing some of the symptoms of advanced, levodopa-responsive Parkinson's disease (PROTOCOL C-06-04). Merz Pharmaceuticals, LLC (Site PI: Jankovic) 10/20/12 – 9/16/16 CD-FLEX: An open label study evaluating Xeomin in cervical dystonia Massachusetts General Hospital/Huntington Study Group (Site PI: Jankovic) 5/14/07-5/13/15 Coenzyme Q10 (COQ) in Huntington’s disease (2CARE). The goal is to examine the safety and efficacy of CoQ10 in HD. National Parkinson Foundation (Site PI: Jankovic) 2/10/10 – 2/9/15 National Parkinson Foundation Patient Outcomes Study (Phase II protocol). The goal is to collect and follow patients with PD and examine outcomes variables. Huntington Study Group/ Auspex Pharmaceuticals (Site PI: Jankovic) 4/28/13-4/29/15 A randomized, double blind, placebo controlled study of SD-809 extended release for the treatment of chorea associated with Huntington disease (FIRST-HD). Ipsen (Site PI: Jankovic) 2/12/13-2/11/15 A phase IIIB, multicentre, randomised, double-blind, placebo-controlled study evaluating the efficacy and safety of Dysport using 2ml dilution in adults with cervical dystonia. Great Lakes Neurotechnologies Inc. (Site PI: Jankovic) 2/10/12-2/9/15 Et Sense: Adaptive, Portable Essential Tremor Monitor, Phase II Huntington Study Group/Auspex Pharmaceuticals (Site PI: Jankovic) 10/14/2013 – 10/13/2016 An open-label, long-term, safety study of SD-809 ER in patients with chorea associated with HD. (ARC-HD) Protocol SD-809-16)

Jankovic, Joseph M.D.

PHS 398/2590 (Rev. 06/09) Page 4 Continuation Format Page

Kyowa Hakko Kirin Pharma, Inc. (Site PI: Jankovic) 8/15/13- 8/14/2016 A Phase 3, 12-week, Double-Blind, Placebo-Controlled, Randomized, Multicenter Study to Evaluate the Efficacy of Oral Istradefylline 20 and 40 mg/day as Treatment for Subjects with Moderate to Severe Parkinson's Disease. (Protocol 6002-14) Chelsea Therapeutics (Site PI: Jankovic) 12/31/13- 1/1/2016 PHOENIX: A clinical study of Patients with symptomatic neurogenic orthostatic hypotension to assess sustained effects of droxidopa therapy. Omeros Corporation (Site PI: Jankovic) 12/18/13- 12/17/2016 Phase 2 Randomized, Double-Blind, Placebo-Controlled, Sequential Cohort Study to Evaluate Safety and Efficacy of OMS643762 in Subjects with Huntington's Disease. Completed research support

National Institutes of Health (NIH) (Site PI: Jankovic) 7/26/06-1/19/12 A longitudinal observational follow-up of the precept study cohort (POSTCEPT)

Allon therapeutics, Inc (Site PI: Jankovic) A phase 2, randomized, double-blind, placebo-controlled, study to evaluate the safety and efficacy of davunetide for the treatment of progressive supranuclear palsy (PSP).

EMD Serono, Inc (Site PI: Jankovic) 12/9/10- 4/16/12 (Settle- Protocol # 27919) a phase iii, double-blind, placebo controlled, randomised trial to determine the efficacy and safety of a dose range of 50 to 100 mg/day of safinamide, as add-on therapy, in subjects with idiopathic parkinson’s disease with motor fluctuations, treated with a stable dose of levodopa and who may be receiving concomitant treatment with stable doses of a dopamine agonist, an anticholinergic and/or amantadine. Synosia Therapeutics, Inc. (Site PI: Jankovic) 5/3/11- 12/11/12 A double-blind, randomized, placebo-controlled study of the safety and efficacy of SYN115 as adjunctive therapy in levodopa-treated Parkinson’s subjects with end of dose wearing off. (PROTOCOL NUMBER: SYN115-CL02) Atlantic Research Group (Site PI: Jankovic) 11/10/10 – 3/12/13 A multi-center, one-year open-label study to assess the long-term safety of droxidopa in subjects with primary autonomic failure, dopamine beta hydroxylase deficiency or non-diabetic neuropathy and symptomatic neurogenic orthostatic hypotension. (Droxidopa-304) Ceregene, Inc./MJFF (Site PI: Jankovic) 1 2/4/08-7/1/13 Extended observation study to assess the safety and efficacy of idiopathic parkinson’s disease patients treated with cere-120 (adeno-associated virus serotype 2 [aav2]-neurturin [ntn]) (CERE-120-03). NIH 5R01HD051844-03 (Site PI: Jankovic) 4/12/07-5/29/13 Gait and step training to prevent falls in Parkinson’s disease. NINDS 5U10NS044441-10 (NET-PD) (Site PI: Jankovic) 8/29/06 – 11/30/13 Clinical center for the study of neuroprotection from PD. The goal is to develop infrastructure for neuroprotective therapy testing in PD.

BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors in the order listed on Form Page 2.

Follow this format for each person. DO NOT EXCEED FOUR PAGES. NAME SHULMAN, JOSHUA M.

POSITION TITLE Assistant Professor, Baylor College of Medicine

eRA COMMONS USER NAME (credential, e.g., agency login) JSHULMAN562 EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable.)

INSTITUTION AND LOCATION DEGREE (if applicable) MM/YY FIELD OF STUDY

Harvard College, Cambridge, MA A.B. 6/1997 Biochemical Sciences University of Cambridge, Cambridge, England M.Phil. 6/1998 Biological Science University of Cambridge, Cambridge, England Ph.D. 6/2000 Genetics Harvard Medical School, Boston, MA M.D. 6/2005 Medicine Massachusetts General Hospital, Boston, MA Internship 6/2006 Medicine Brigham and Women's Hospital & Massachusetts General Hospital, Boston, MA Residency 6/2009 Neurology

Fellowship 6/2010 Movement Disorders Harvard Medical School, Boston, MA M.M.Sc. 5/2011 Clinical Investigation

A. PERSONAL STATEMENT For the proposed project, I will supervise preparation of ET patient and family member DNA samples and genotyping of candidate variants. I am a board-certified neurologist and geneticist with sub-specialty training in movement disorders, having expertise in the genetics, pathogenesis, diagnosis and clinical management of movement disorders. The Baylor Parkinson Disease Center and Movement Disorders Clinic (PDCMDC) has greater than 3,000 annual unique PD patient encounters, and we have extensive experience with the recruitment and collection of patient blood samples for research cohorts. I am PI on a NIH project (K08 AG034290) investigating the genetics of cognitive decline and Alzheimer's disease neuropathology (Shulman et al., Am. J. Human Genet. 2011; Shulman et al. JAMA Neurol. 2013). More recently, I have developed successful complementary projects exploring PD-related clinical and neuropathological phenotypes (Buchman, Shulman et al., Annals Neurol. 2012; Shulman et al. JAMA Neurol. in press), leading to funding from the Parkinson's Study Group/Parkinson’s Disease Foundation and the Burroughs Wellcome Fund to study the genetics of these traits, and to perform functional studies of implicated genes. B. POSITIONS AND HONORS Positions 2009-2011 Fellow, Clinical Investigator Training Program, Harvard Medical School/M.I.T. 2009-2012 Instructor in Neurology, Harvard Medical School, Boston, MA 2009-2012 Associate Neurologist, Brigham & Women’s Hospital, Boston, MA 2012 Assistant Professor of Neurology, Harvard Medical School, Boston, MA 2012- Assistant Professor of Neurology and Molecular and Human Genetics Baylor College of Medicine, Houston, TX 2012- Investigator, Jan and Dan Duncan Neurological Research Institute, Houston, TX Professional Societies / Other Experience 2005-2012 Member, Massachusetts Medical Society 2006- Member, American Academy of Neurology 2009 Workshop on the Genetics of Complex Disorders, Doris Duke Foundation and Broad Institute 2010- Member, Movement Disorders Society 2010 Genetics of Complex Human Diseases, Cold Spring Harbor Laboratory Course 2011- Member, Parkinson's Study Group 2011- Member, American Society of Human Genetics

Honors 1997 L. J. Henderson Prize, recognizing Harvard thesis 1997 Thomas Temple Hoopes Prize, recognizing Harvard thesis 1997 A.B., summa cum laude in Biochemical Sciences, Harvard 1997-1998 Herchel Smith Harvard Scholar, fellowship for Cambridge University 1998-1999 Emmanuel College Research Studentship Award 1999 British Society for Developmental Biology Travel Award 2001-2002 Harvard Medical School Summer Research Fellowship 2004 American Neurological Association Medical Student Travel Award 2005 American Academy of Neurology Medical Student Prize 2005 Dr. Sirgay Sanger Award for excellence in research at Harvard Medical School 2006 M.D., summa cum laude, Harvard Medical School 2008 Harvard Medical School excellence in teaching award 2009 American Academy of Neurology Alzheimer’s Disease Research Fellowship 2009 Allergan Travel Fellowship, Aspen movement disorders course 2011 Alzheimer's Association International Conference Travel Fellowship 2011 C.W. Cotterman Award, American Society of Human Genetics C. SELECTED PUBLICATIONS (15 of 45) 1. Shulman, JM, Benton, R., and St Johnston, D. A Drosophila homolog of C. elegans PAR-1 organizes the

oocyte cytoskeleton and directs oskar mRNA localization to the posterior pole. Cell 2000; 101:377-388. 2. Wittman, CW, Wszolek, MF, Shulman, JM, Salvaterra, PM, Lewis, J, Hutton, M., Feany, MB. Tauopathy in

Drosophila: Neurodegeneration without neurofibrillary tangles. Science 2001; 293:711-714. 3. Tree, DRP, Shulman, JM, Gubb, D, and Axelrod, JD. Prickle mediates feedback amplification to generate

asymmetric planar cell polarity signaling. Cell 2002; 109:371-381. 4. Shulman, JM and Feany, MB. Genetic modifiers of tauopathy in Drosophila. Genetics 2003; 165:1233-

1242. PMCID: PMC1462852 5. Shulman, JM, Chibnik, LB, Aubin, C, Schneider, J, De Jager, P, and Bennett, D. Intermediate phenotypes

identify divergent pathways to Alzheimer’s disease. PLoS ONE 2010; 5(6): e11244. PMCID: PMC2888589 6. Shulman, JM, Chipendo, PC, Aubin, C, Tran, D, Kramer, P, Schneider, J.A., Bennett, DA, Feany, MB, De

Jager, PL. Functional screening of Alzheimer's pathology genome-wide association signals in Drosophila. American Journal of Human Genetics. 2011; 88:232-238. PMCID: PMC3035702

7. Chibnik, LB, Shulman, JM, et al. The Alzheimer’s susceptibility locus CR1 is associated with increased amyloid plaque burden and age-related cognitive decline. Annals of Neurology. 2011; 69:560-569.

8. Treusch, S, Hamamichi, S, Goodman, JL, Matlack, KES, Chung, CY, Baru, V, Shulman, JM, et al. A yeast model establishes a functional connection between Aβ Toxicity and endocytic trafficking and Alzheimer’s Disease risk factors. Science. 2011; 334:1241-1245.

9. Buchman, AS, Shulman, JM, Nag, S, Leurgans, SE, Schneider, JA, and Bennett, DA. Nigral Pathology and Parkinsonian Signs in Elders without Parkinson's Disease. Annals of Neurology. 2012; 71:258-266. PMCID: PMC3367476.

10. De Jager, PL*, Shulman, JM*, Chibnik, LB*, Keenan, BT, Raj, T, Wilson, RS, Yu, L, Leurgans, SE, Tran, D, Aubin, C, Corneveaux, JJ, Huentelman, MJ, ADNI, Myers, AJ, Hardy, JA, Reiman, EM, Bennett, DA, and Evans, DA. A genome-wide scan for common variants affecting rate of age-related cognitive decline. Neurobiology of Aging. 2012; 33: 1017.e1-1017.e15. *Equal authorship. PMCID: PMC3307898.

11. Keenan, BT, Shulman, JM, Chibnik, LB, Raj, T, Tran, D, Sabuncu, MR, ADNI, Allen, A, Myers, AJ, Hardy, JA, Huentelman, MJ, Reiman, EM, Evans, DA, Bennett, DA, De Jager, PL. Functional fine-mapping of the CR1 locus identifies a causal variant. Human Molecular Genetics. 2012; 21:2377-2388. PMCID: PMC3335317.

12. Raj, T, Shulman, JM, Keenan, BT, Chibnik, LB, Evans, DA, Bennett, DA, Stranger, BE, and De Jager, PL. Alzheimer’s disease susceptibility: evidence for a protein network under natural selection. American Journal of Human Genetics. 2012; 90:720-726. PMCID: PMC3322230.

13. Bis*, JC, DeCarli*, C, Smith*, AV, van der Lijn*, F, Crivello*, F, Fornage*, M, Debette*, S, Shulman, JM et

al. Genome-wide association studies implicate loci on Chromosome 12 in hippocampal volume. Nature Genetics. 2012; 44:545-551. *Equal authorship. PMCID: PMC3427729.

14. Cruchaga, C, Kauwe, JSK, Harari, O, Jin, SC, Shulman, JM, et al. A genome-wide association study for

cerebrospinal fluid tau and phospho-tau levels identifies new candidate variants implicated in risk for Alzheimer’s Disease. Neuron. 2013; 78:256-268. PMCID: PMC3664945

15. Shulman, JM, Chen, K, Keenan, BT, Chibnik, LB, Thiyyagura, P, Liu, X, Roontive, A, Yu, L, Aubin, C,

Corneveaux, JJ, Huentelman, MJ, ADNI, Evans, DA, Schneider, JA, Reimain, EM, De Jager, PL, Bennett, DA. Genetic susceptibility for Alzheimer’s Disease neuritic plaque pathology. JAMA Neurology. 2013; 70:1150-7. PMCID: PMC3773291.

D. SUPPORT Ongoing K08 AG034290 (Shulman) 8/1/09 - 7/30/14 NIH/NIA Exploring the Genetics of Alzheimer’s Disease in Humans and Drosophila The major goal of this project is to discover susceptibility genes for Alzheimer’s disease based on a genome-wide association study for neuropathologic intermediate phenotypes, and functional validation using a Drosophila disease model. Role: Principal Investigator Career Award for Medical Scientists (Shulman) 9/1/11-8/31/16 Burroughs Wellcome Fund Exploring the Genetics of Parkinson's Disease in Humans and Drosophila The goal of this proposal is to discover susceptibility genes for Parkinson's disease based on a genome-wide association study for PD neuropathology, and perform functional validation using a Drosophila disease model. Role: Principal Investigator R01 NS078009 (A. Buchman, Rush University) 9/15/12-9/14/17 NIH/NINDS The Clinical Profile of Parkinson’s Disease (PD) Pathology The overall goal is to characterize the clinical profile of PD pathology in older persons without a diagnosis of PD. Role: Co-Investigator Caroline Wiess Law Fund for Research in Molecular Medicine (Shulman) 7/1/13-6/30/14 Catalyzing Studies of Parkinson's Disease Genetics at BCM The goal is to discover new susceptibility genes for Parkinson’s disease through exome sequencing of familial cases, in collaboration with the Center for Mendelian Genomics. Role: Principal Investigator

New Investigator Research Grant 3/1/14-2/28/16 Alzheimer’s Association Genome instability as a novel link between aging and AD The goal is to investigate retrotransposon mobilization as a potential mechanism for the interaction between aging and neurodgeneration in Alzheimer’s disease, using studies in human Drosophila. Role: PI R01 AG033193 (S. Seshadri, Boston University) 8/15/14-5/31/17 NIH/NIA AD Gene Discovery: Exome Chip, New Endophenotypes & Functional Studies in CHARGE The overall goal is to identify low-frequency and rare variant causes of Alzheimer’s disease and related endophenotypes. Dr. Shulman will lead functional investigation of the most promising, conserved novel susceptibility gene leads using Drosophila models relevant to Alzheimer’s disease. Role: Co-Investigator Completed Neurodegenerative Disease Pilot Study Grant (Shulman) 4/1/11- 3/31/12 Harvard Neurodiscovery Center / Massachusetts Alzheimer's Disease Research Center Functional Validation of Genome-wide Association Signals in Alzheimer's Disease The goal of this proposal is to use a Drosophila disease model to perform functional validation of top results from Alzheimer's disease genome-wide association study consortia. Mentored Clinical Research Award (Shulman) 7/1/11-6/30/13 The Parkinson's Study Group (PSG) / Parkinson's Disease Foundation (PDF) Genetic and Transcriptional Analysis of Susceptibility for Parkinson's Disease Neuropathology The goal is to discover susceptibility genes for Parkinson's disease based on associations with Lewy body pathology and transcriptional analysis in postmortem brain.

Program Director/Principal Investigator (Last, First, Middle):

PHS 398/2590 (Rev. 06/09) Page Biographical Sketch Format Page

BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors in the order listed on Form Page 2.

Follow this format for each person. DO NOT EXCEED FOUR PAGES.

NAME : Christine Hunter

POSITION TITLE Instructor, Baylor College of Medicine Parkinson Disease Center and Movement Disorders Clinic

eRA COMMONS USER NAME (credential, e.g., agency login) EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable.)

INSTITUTION AND LOCATION DEGREE (if applicable) MM/YY FIELD OF STUDY

University of Texas, Arlington Houston Community College

BSN

ADN

2011

1992

Nursing Nursing

NOTE: The Biographical Sketch may not exceed four pages. Follow the formats and instructions below. A. Personal Statement: Christine Hunter, RN, BSN has been the Center Nurse and Research Manager of the Parkinson’s Disease Center and Movement Disorders Clinic (PDCMDC) at Baylor College of Medicine in Houston, Texas for 18 years. She has coordinated many clinical trials for all movement disorders including many with the Parkinson Study Group as well as other pharmaceutical studies during this time period. She has been an active participant in the Parkinson Disease Foundation Clinical Research Learning Institute (CRLI) and the liaison with the NPF for the Center of Excellence here at Baylor. Baylor College of Medicine, PDCMDC is a Center of Excellence for the National Parkinson Foundation (NPF). She has also served as the Facilitator for the Movement Disorders Special Focus Group of the American Association of Neuroscience Nurses and remains active in the organization as well as the Movement Disorders Society. B. Positions and Honors: 1996-2014 Baylor College of Medicine, Instructor Parkinson Disease Center and Movement Disorders Clinic, Houston, Texas 1995-1996 Memorial Hermann Hospital, Case Management Department, Houston, Texas 1981-1995 Baylor College of Medicine, Research Nurse/Research Coordinator Hypertension Section, Department of Medicine, Houston, Texas

Parkinson Study Group (PSG) Executive Committee, 2006-2008, PSG Credentials Committee, 2008-2010, Huntington Study Group (HSG) Executive Committee 2010-2012, HSG Credentials Committee 2011-2013; Finance Committee PSG 2007-2010; Member NINDS Common Data Elements Project, 2011.

C. Selected Peer-reviewed Publications

Pulliam CL, Eichenseer SR, Goetz CG, Waln O, Hunter CB, Jankovic J, et al. Continuous in-home monitoring of essential tremor. Parkinsonism Relat Disord. 2014;20(1):37-40. [View journal article]

Program Director/Principal Investigator (Last, First, Middle):

PHS 398/2590 (Rev. 06/09) Page 2 Biographical Sketch Format Page

Mehanna R, Hunter C, Davidson A, Jimenez-Shahed J, Jankovic J. Analysis of CYP2D6 genotype and response to tetrabenazine. Mov Disord. 2013;28(2):210-5. Shen V, Clarence-Smith K, Hunter C, Jankovic J. Safety and Efficacy of Tetrabenazine and Use of Concomitant Medications During Long-Term, Open-Label Treatment of Chorea Associated with Huntington's and Other Diseases. Tremor Other Hyperkinet Mov (N Y). 2013;3:. [View journal article] Ondo WG, Hunter C, Ferrara JM, Mostile G. Apomorphine injections: predictors of initial common adverse events and long term tolerability. Parkinsonism Relat Disord. 2012;18(5):619-22. Ondo WG, Kenney C, Sullivan K, Davidson A, Hunter C, Jahan I, et al. Placebo-controlled trial of lubiprostone for constipation associated with Parkinson disease. Neurology. 2012;78(21):1650-4. Ondo WG, Hunter C, Isaacson SH, Silver DE, Stewart RM, Tetrud JW, et al. Tolerability and efficacy of switching from oral selegiline to Zydis selegiline in patients with Parkinson's disease. Parkinsonism Relat Disord. 2011;17(2):117-8. Ferrara J, Diamond A, Hunter C, Davidson A, Almaguer M, Jankovic J. Impact of STN-DBS on life and health satisfaction in patients with Parkinson's disease. J Neurol Neurosurg Psychiatry. 2010;81(3):315-9. Quaid KA, Swenson MM, Sims SL, Harrison JM, Moskowitz C, Stepanov N, et al. What were you thinking?: individuals at risk for Huntington Disease talk about having children. J Genet Couns. 2010;19(6):606-17. Paulsen JS, Nopoulos PC, Aylward E, Ross CA, Johnson H, Magnotta VA, et al. Striatal and white matter predictors of estimated diagnosis for Huntington disease. Brain Res Bull. 2009;82(3-4):201-7. Frank S, Ondo W, Fahn S, Hunter C, Oakes D, Plumb S, et al. A study of chorea after tetrabenazine withdrawal in patients with Huntington disease. Clin Neuropharmacol. 2008;31(3):127-33. Book Chapters and Other Publications Jankovic J, Hunter C. Psychogenic parkinsonism. In: Hallett M, Cloninger CR, Fahn S, Halligan P, Jankovic J, Lang AE, Voon V, editors. Psychogenic movement disorders and other conversion disorders. Cambridge, UK: 2011. p. 14-19. Poster and Platform Presentations (Selected out of 49) Pulliam CL, Eichenseer S, Goetz C, Waln O, Hunter C, Jankovic J, et al. Continuous home monitoring of essential tremor using motion sensors. Neurology. 2013;80(Meeting Abstracts 1):P05.035. Baizabal Carvallo JF, Suresh K, Hunter C, Jankovic J. Flu-like and systemic symptoms following treatment with botulinum toxins. Mov Disord. 2012;27(Suppl 1):S422. Mehanna R, Hunter C, Davidson A, Ondo W, Jimenez-Shahed J, Jankovic J. Analysis of CYP2D6 genotype and response to tetrabenazine. Mov Disord. 2012;27(Suppl 1):S457. Shen V, Clarence-Smith K, Hunter C, Jankovic J. Concomitant use of antidepressants and neuroleptics with tetrabenazine during treatment of Huntington's disease. Mov Disord. 2012;27(Suppl

Program Director/Principal Investigator (Last, First, Middle):

PHS 398/2590 (Rev. 06/09) Page 3 Biographical Sketch Format Page

1):S59-60. Shen V, Clarence-Smith K, Hunter C, Jankovic J. Long-term safety and efficacy of tetrabenazine in the treatment of chorea associated with Huntington's disease. Mov Disord. 2012;27(Suppl 1):S60. Shen V, Clarence-Smith K, Hunter C, Jankovic J. Tetrabenazine for moderate vs. severe/disabling chorea associated with Huntington's disease. Mov Disord. 2012;27(Suppl 1):S60. York MK, Marsh L, Jimenez-Shahed J, Okun M, Moro E, Hunter C, et al. Parkinson's Study Group Neurosurgical Working Group (PSG-NSWG) deep brain stimulation (DBS) non-motor symptoms (NMS) survey: Real world pre-operative practice patterns. Mov Disord. 2012;27(Suppl 1):S172. York MK, Marsh L, Jimenez-Shahed J, Okun M, Moro E, Hunter C, et al. Parkinson's Study Group Neurosurgical Working Group (PSG-NSWG) deep brain stimulation (DBS) non-motor symptoms (NMS) survey: Real world pre-operative practice patterns. Mov Disord. 2012;27(4):e12. [View poster] Clarence-Smith K, Shen V, Hunter C, Jankovic J. Concomitant use of antidepressants and neuroleptics with tetrabenazine during treatment of Huntington's disease (HD). Neurology. 2012;78(Meeting Abstracts 1):P06.039. Meunier C, Jennings D, Hunter C, Sherer T. Fox Trial Finder: An innovative web-based trial matching tool to facilitate clinical trial recruitment. Neurology. 2012;78(Meeting Abstracts 1):P02.241.

February 20, 2014

Catherine Rice Executive Director International Essential Tremor Foundation PO Box 14005, Lenexa, KS 66285-4005 Dear Ms. Rice: It is with great pleasure that I write this letter of support for Dr. Mary Ann Thenganatt and her grant proposal for the International Essential Tremor Foundation. Her exciting project promises to identify candidate rare variants responsible for autosomal dominant inherited essential tremor in several large families. In am co-principal investigator of the Baylor Hopkins Center for Mendelian Genomics (BHCMG) at Baylor College of Medicine. Together with John Hopkins, we are funded by the National Institutes of Health to perform whole exome sequencing in thousands of subjects, with the goal of identifying genes and mutations responsible for as many unsolved Mendelian disorders as possible. This effort is made possible through collaboration with our clinical partners, and we have already initiated sequencing studies of approximately ~100 DNA samples from patients submitted by Dr. Thengenatt and her colleagues in the Baylor Parkinson’s Disease Center and Movement Disorders Clinic. Among these cases, we recently finalized high-quality, whole-exome sequencing of 21 familial essential tremor (ET) cases. This group includes 3 distinct families with whole-exome sequence data available from 2 affected relatives each, in which we have already identified a number of highly promising candidate causal variants. A senior analyst in my group has been assigned to assist with the interpretation of these data, and selection of the most promising variants for further study. These computational analyses are being performed in collaboration with Dr. Joshua Shulman and Dr. Thenganatt, and will be completed well in advance of the earliest possible start of this award. Dr. Thenganatt proposes to follow up the identified leads by performing comprehensive neurologic assessments and collecting blood samples for as many additional family members as possible in each pedigree. Next, DNA will be isolated, and the panel of candidate genetic variants (identified from our sequencing analysis) will be genotyped in each individual. This will allow Dr. Thenganatt to further refine the responsible genetic variant. Given the large size of these pedigrees, we believe there is an excellent chance of successfully identifying the responsible gene. For definitive replication, Dr. Thenganatt will also be able to genotype the most promising genetic variant(s) in her large, existing Baylor collection of DNA samples from other subjects with familial essential tremor, and she is also wisely developing collaborations with other investigators to support even broader replication efforts in the future. My colleagues and I will be available to serve as genetic consultants for Dr. Thengenatt’s project, and she will

also have the expert support and guidance from Dr. Shulman, who has joint affiliations with the Departments of Neurology and Molecular and Human Genetics at Baylor. Given the strong evidence for heritability and the relatively little known about the responsible genes, essential tremor is a perfect target for our Center for Mendelian Genomics. In fact, based on the results of Dr. Thenganatt’s proposed followup studies, we have the capability and existing resources to perform whole-exome sequencing on many more ET subjects and/or families in the coming years, as part of our center’s mandate. I am excited to team with Dr. Thengenatt to tackle this important problem and she has our strong support in her application for an International Essential Tremor Foundation Grant.

Most sincerely,

James R. Lupski, M.D., Ph.D., D.Sc. (hon), FAAP, FACMG, FAAAS, FAAS Cullen Professor and Vice Chair Department of Molecular and Human Genetics and Professor of Pediatrics Member, Human Genome Sequencing Center (HGSC)

Joshua M. Shulman, M.D., Ph.D. Assistant Professor in Neurology and Molecular & Human Genetics Jan and Dan Duncan Neurological Research Institute 1250 Moursund Street, Suite N.1150 Houston, Texas 77030 Tel: 832-824-8976 Fax: 832-825-1270 Joshua.Shulman@bcm.edu

February 25, 2014 Mary Ann Thenganatt, MD Department of Neurology Baylor College of Medicine Re: Letter of Collaboration for Dr. Mary Ann Thenganatt Dear Mary Ann, I am writing this letter to enthusiastically confirm my collaboration and support of your grant proposal. Essential tremor (ET) is a highly heritable and potentially disabling neurologic disorder; however, we yet know surprisingly little about the genetic risk factors involved. Through identifying the genes responsible for ET in several large family pedigrees, this project has the potential to make important contributions to genetic risk prediction, diagnosis and ultimately, treatment of ET. My research is focused on understanding genetic mechanisms of neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease. My interest in ET grows out of my clinical activities in movement disorders, as well as the intriguing potential for mechanistic overlaps with neurodegenerative disease, including Parkinson’s disease. For your project, I will participate in the experimental design, implementation, and interpretation of the planned genetic analyses, and I will also join you to assist with the neurologic evaluation of recruited families. My laboratory is located in the Jan and Dan Duncan Neurological Research Institute (NRI), a 13-floor, 350,000 sq. ft., state-of-the-art facility dedicated to basic and translational investigation of neurological disorders. My space on the NRI 11th floor consists of 1,500 sq. ft., including wet-lab benches and adjoining desk space / write-up stations for 12 individuals. The laboratory is fully-equipped with all the necessary reagents and equipment to complete the proposed work. We also have access to excellent core facilities, both within the NRI, and within the broader Baylor College of Medicine community. For this project, we will utilize quantitative PCR (qPCR) machines for genotyping assays, three of which will be available at the NRI, and we may additionally leverage the Baylor genomic and RNA profiling core. My research technicians, will be responsible for preparation of DNA samples from blood or saliva, and they will additionally assist with implementation of the qPCR genotyping assays. A major goal of my laboratory is to follow-up human genetic studies with functional investigation in simple model organisms, such as the fruit fly Drosophila melanogaster, amenable to rapid and powerful genetic manipulation. As our work in ET genetics achieves success, I anticipate that we may be able to study the functions of any identified genes in flies. We will have opportunity to discuss our progress during weekly interactions at the Baylor Parkinson’s Disease Center and Movement Disorders Clinic (PDCMDC), and will also formally review progress during our monthly PDCMDC genetics working group meetings, which I lead. Given my joint appointment at Baylor as faculty in both Neurology and in Molecular and Human Genetics, we have a fantastic opportunity with this project to integrate the vast clinical expertise within the PDCMDC and the substantial strengths in both Mendelian and complex genetics within the Baylor Department of Molecular and Human Genetics. Part of my role in the project will be to facilitate communication with our other genetics collaborators, including Dr. James Lupski, who

directs the Baylor Center for Mendelian Genomics. Besides the substantial Mendelian project, Baylor hosts one of only three NIH-funded genome centers in the country. Thus, Baylor is an ideal institutional environment to initiate a substantial effort to probe the genetic mechanisms of ET. With the support of International Essential Tremor Foundation grant, we will have all the resources necessary to complete the proposed genetic analyses. I have substantial and flexible laboratory start-up funds available that I can also commit to supplement and enhance our efforts. Following completion of this work, I anticipate we will be well positioned to apply for additional funding, including potential NIH mechanisms, to expand the scope of our work, and I will participate in crafting these proposals. We have already initiated discussion with Dr. Lupski on the potential to perform additional sequencing studies of ET families from the PDCMDC cohort, and you have established important links to outside collaborators, such as Dr. Elan Louis at Columbia University Medical Center, that will accelerate future efforts. In conclusion, you have my strongest support in your application for this grant. I am excited to see the initial results from this important research, and to begin working with you to help advance our understanding of ET genetics. Sincerely yours,

Joshua M. Shulman M.D., Ph.D.

March 1, 2014

Catherine Rice

Executive Director

International Essential Tremor Foundation

PO Box 14005

Lenexa, KS 66285-4005

Dear Cathy:

I am delighted to offer my strongest support and mentorship for Dr. Mary Ann

Thenganatt and her grant proposal for the International Essential Tremor Foundation.

Dr. Thenganatt joined the Baylor Parkinson’s Disease Center and Movement Disorders

Clinic (PDCMDC) in 2012, having been highly recommended following a 2-year

movement disorders fellowship with Dr. Stanley Fahn at Columbia University Medical

Center. Besides caring for a diverse patient population with movement disorders at the

PDCMDC, Dr. Thenganatt is beginning to develop her research portfolio, for which she

has protected academic time (20% effort) built into her schedule. I have encouraged her

to take a leadership role on our center’s longstanding effort to advance understanding of

essential tremor (ET) genetics.

This study addresses one of the most important research issues in ET: finding and

understanding the genetic underpinnings of this common, familial disorder. Dr.

Thenganatt proposes to investigate the genetic determinants of ET in 2 large family

pedigrees identified by the PDCMDC. This effort will integrate our clinical experience

with the substantial expertise in human genetics available within the Baylor Department

Joseph Jankovic, M.D. Professor of Neurology Distinguished Chair in Movement Disorders Director, Parkinson’s Disease Center and Movement Disorders Clinic Department of Neurology Parkinson’s Disease Center and Movement Disorders Clinic 6550 Fannin, Suite 1801 Houston, TX 77030 Phone: 713-798-7438 Fax: 713-798-6808 www.jankovic.org

of Molecular and Human Genetics. Two DNA samples from individuals with ET

representing each family have undergone whole exome sequencing. This portion of the

overall project is fully-funded by the NIH Center for Mendelian Genomics grant (see

letter of support by study PI, Dr. James Lupski). Following up on these results, Dr.

Thenganatt will lead our effort to obtain detailed neurologic examinations along with

additional DNA samples from all available family members in these pedigrees.

Subsequent genotyping and analyses will allow refinement of the candidate variant list

based on sequencing and identification of the responsible mutations. In future work, Dr.

Thenganatt will leverage our existing, large collection of ET cases to confirm her

findings and she is also developing pivotal collaborations with other centers.

Besides my supervision and mentorship, Dr. Thenganatt will be supported by our

experienced research nurse, Christine Hunter, RN, and by another PDCMDC faculty

member, Joshua Shulman, MD, PhD, who has joint appointments at Baylor’s

Department of Neurology and Department of Molecular and Human Genetics. Dr.

Shulman’s laboratory, with a wealth of experience in similar projects related to

neurodegenerative disease genetics, will coordinate the preparation of DNA samples

and genotyping, and will assist with the necessary analyses (see letter of support).

In sum, with funding from the IETF, Dr. Thenganatt’s project promises important

progress in our understanding of ET genetics and will further catalyze future research

efforts at PDCMDC and Baylor College of Medicine in this area. I very much hope that

the IETF will recognize the scientific importance of this research and will agree that the

PDCMDC is well suited to carry out the proposed project under the leadership of Dr.

Thenganatt in collaboration with me and Dr. Shulman. I enthusiastically support her

application for this award.

Sincerely,

Joseph Jankovic, MD