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 presentedin 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: ____________________________________________________________________________

Sponsoring Institution: ____________________________________________________________________

Principal Investigator:Last Name: _______________________________ First Name: ______________________ Middle Initial: __

Degree(s): ________________________________ Current Title/Position: ____Associate Professor_____

Department: _____________________________________________________________________________

Address: ________________________________________________________________________________

City: ___________________________________ State: ______________________ Postal Code: _________

____

Phone: ___________________________________ Fax: ____________________________________

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.

GrantApp5222013

©2007 IETF

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

Propranolol & Botulinum Toxin for Essential Vocal Tremor

Emory University School of Medicine

Johns Michael M

MD

Otolaryngology

550 Peachtree Street

Atlanta GA 30308

USACountry: ____ __________________ E-mail address: _______michael.johns2@emory.edu

404-686-1850 404-686-4699

Propranolol and Botulinum Toxin for Essential Vocal Tremor Executive Summary

Investigators: Michael M Johns III, MD, Principal Investigator Edie Hapner, PhD H.A. Jinnah, MD, PhD Natalie Justicz, Study Coordinator Essential tremor is the most common adult-onset movement disorder, and essential voice tremor is the vocal manifestation of essential tremor. While nearly all essential tremor patients experience hand tremor, many also manifest head tremor and voice tremor. Essential voice tremor can lead to increased vocal effort, decreased intelligibility, and misconstrued emotional state. The United States Food and Drug Administration (FDA) has approved only one medication, propranolol, to treat essential tremor. Propranolol is not felt to be nearly as effective for axial tremors (head, trunk, neck) as it is for extremity tremors. However, this has not been studied with any objective assessment in a prospective way for EVT. For patients with essential voice tremor, the limited published data suggests that botulinum toxin has been shown to lead to functional voice improvement. Botulinum toxin, though also not well-studied with objective voice outcomes, is a commonly used clinical therapy for treatment of essential voice tremor. While it is used more often for essential voice tremor than propranolol therapy, botulinum toxin also has not been prospectively studied with validated, objective voice outcome measures. We would like to determine if propranolol has any significant effect on vocal tremor. We would also like to determine, in an objective way, the effect of botulinum toxin on vocal tremor. If effective, propranolol would provide an affordable and non-invasive alternative or addition to botulinum toxin injections for patients with essential voice tremor. Methods: We aim to conduct a prospective study on approximately twenty patients with essential voice tremor to determine the effect of propranolol on vocal tremor in the treatment-seeking population and to determine the effect of botulinum toxin injections on vocal tremor in the treatment-seeking population. Subjects with essential voice tremor will be identified from patients at the Emory Voice Center who have already received or are planning to receive botulinum toxin injections for the treatment of essential voice tremor. Patients are ineligible to participate if they are already on a beta-blocker or have a contraindication to beta-blocker therapy. Patients will undergo three voice evaluations. Each evaluation will consist of patient reported measures as well as a recorded, objective voice assessment. After the first evaluation, the patient will receive a prescription for two weeks of propranolol therapy. At the second evaluation, propranolol therapy will cease and the patient will undergo an injection of botulinum toxin. The third evaluation will take place four weeks after botulinum toxin therapy. Expected Outcomes: We anticipate that botulinum toxin injections will lead to a greater improvement in voice quality than propranolol oral therapy on both objective and patient-reported measures. As this is the first time these outcomes will be objectively measures by validated criteria, if either propranolol or botulinum toxin demonstrates a trend toward improving voice in essential voice tremor, large scale prospective study is warranted. It is likely that some patients may have a greater improvement than others on either propranolol or botulinum toxin therapy. While we anticipate that botulinum toxin injections will lead to patient voice quality improvement, we do not know which patients are most likely to improve. If botulinum toxin injections demonstrate a significant improvement in essential voice tremor, future studies might evaluate trends in patient characteristics that lead to improvement with botulinum toxin therapy. The information received from this study on propranolol and botulinum might also provide a basis for future studies using combined therapy for the treatment of essential voice tremor.

Specific Aims

Determine the effect of propranolol on vocal tremor in the treatment-seeking population. To date, the nonselective beta-blocker propranolol remains the only agent approved by the United States Food and Drug Administration (FDA) for the treatment of essential tremor (ET). For ET, immediate and sustained release formations of propranolol are equally effective, while other beta-blockers like nadolol and timolol are not as effective. While propranolol improves tremor in greater than half of patients with essential tremor, its effects on tremor are not evenly distributed. Improvement in tremor symptoms is greater for limb tremor than axial tremor, and therefore propranolol is not commonly used for the treatment of essential voice tremor (EVT). However, its effect on essential voice tremor has never been objectively, prospectively studied. Our aim is to objectively determine the effect of propranolol on essential voice tremor in the treatment-seeking population by evaluating patients with EVT before and after propranolol therapy.

Determine the effect of botulinum toxin injections on vocal tremor in the treatment-seeking population. More recently, botulinum toxin A has been used for the treatment of EVT. Chemical denervation with botulinum toxin is only modestly effective in reducing limb tremor in ET and complicated by side effects of weakness. However, botulinum toxin seems to be more effective in treating EVT than other manifestations of ET. While prior studies have not enlisted validated assessments of voice quality to measure the effect of botulinum toxin injections on EVT, they have shown subjective improvement in acoustic measures of tremor and ratings of videotaped speech after therapy with botulinum toxin. Our aim is to objectively determine the effect of botulinum toxin on vocal tremor in the treatment-seeking population by evaluating patients with EVT before and after botulinum therapy.

Rationale of the Proposal and Relevance to Essential Tremor Essential tremor (ET) is the most common adult-onset movement disorder, and essential voice tremor (EVT) is the phonatory manifestation of essential tremor [1]. ET is characterized by both postural and kinetic tremor of 4 to 12 Hz. It affects approximately 5% of adults over the age of 65, and, while it was once called “benign essential tremor,” this term has fallen out of favor due to the morbidity associated with the many manifestations of ET [2]. Patients may demonstrate problems with activities of daily living including eating, dressing, and speaking. Approximately 90% of ET patients experience hand tremor, 30% manifest head tremor, and 20% may have voice tremor [2]. While EVT is typically reported to occur in 10-25% of patients with ET, some case series report a prevalence of up to 62% [1]. EVT may be a later-onset manifestation of

ET, and can lead to increased vocal effort, decreased intelligibility, and misconstrued emotional state [3]. In a study to characterize the signs and symptoms of EVT, it was found to involve kinetic tremor of the muscles of the larynx, pharynx, palate and tongue. It affects women more often than men, and a substantial percentage of affected patients (1/3 to 1/2) have a familial component [1]. The limited published data suggests that botulinum toxin has been shown to lead to functional voice improvement [1], and it is a commonly used clinical treatment. EVT symptoms are often caused by horizontal glottic tremor (94%) or vertical tremor (81%), with 75% having both horizontal and vertical tremor and 31% with pharyngeal tremor [3]. Horizontal glottic tremor can be reduced in amplitude through injecting the thyroarytenoid/lateral cricoarytenoid muscles with botulinum toxin, leading to chemical denervation. Results peak around week four, and in a study of thirteen subjects, all noted an effect [4]. Botulinum injections constitute an invasive procedure that requires repeated treatments and office visits, with side effects that include transient breathiness and dysphagia [3]. The United States Food and Drug Administration (FDA) has approved propranolol, an antihypertensive agent, to treat ET. Propranolol’s effect on ET was discovered by chance. While propranolol is commonly used in ET, there have been few studies on the efficacy of pharmacologic treatment for EVT as a subset of ET [1, 5-7]. Oral medications in general are not considered to be particularly effective for voice tremor [4]. In a small case series of sixteen ET patients, oral medications provided some relief to 70% of hand tremors and 60% of head tremors, but demonstrated limited effect on EVT [3]. Studies are limited by their inconsistent or unquantified outcome measures of oral medication therapy on EVT (5), and therapeutic effects have not been well studied [5-7]. Potential side effects of propranolol therapy include hypotension, bradycardia, and depression [2]. These side effects are more common with aging, a significant concern considering that most patients with EVT are elderly. Propranolol has never been prospectively and objectively evaluated for EVT, and therefore is only infrequently offered. If effective, propranolol would provide an affordable and non-invasive alternative to botulinum toxin injections for patients with EVT. We propose a prospective study to further elucidate the effect of propranolol (oral medication) on EVT patients as compared to botulinum toxin injections for the same patients. This will help establish the best therapy for patients who suffer from EVT. Research Methods and Procedures Participant Selection

A. Eligibility Criteria:

Diagnosis of essential voice tremor

Patients who have received or are planning to receive botulinum toxin injections for essential voice tremor

Patients who give informed consent to be contacted for research

B. Ineligibility Criteria:

Patients who are already on a beta blocker

Patients who suffer from hypotension, bradycardia, or otherwise have a medical contraindication to beta blocker therapy (eg. moderate to severe bronchial asthma)

C. Subjects with essential voice tremor will be identified from patients at the Emory Voice Center who have already received or are planning to receive botulinum toxin injections for the treatment of EVT. These patients will be asked to participate in a study comparing propranolol therapy for the vocal component of essential tremor to botulinum toxin injections.

D. If the patient has received botulinum toxin injections for EVT previously, a three-month washout period is necessary before participation.

Voice Assessment Measures

E. Patient-Reported Measures

Voice-Related Quality Of Life (VRQOL) questionnaire [8] 10 questions for patient to score 1-5; 10-50 raw score

Quality of Life in Essential Tremor (QUEST) questionnaire [9] 30-item, ET-specific quality of life scale

Global voice rating 0-7 ranking

F. Objective Voice Assessment

Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V) tool [10] Sustained vowel, sentences, running speech; 0-100 scale

Acoustic Spectrograms using the Computerized Speech Laboratory speech and voice analysis system (KayPENTAX, Montvale, NJ)

Voice Evaluations and Medications

G. For the first evaluation, a research coordinator will collect demographics and patient reported data. This data will result from providing patient questionnaires and recording the patient’s voice. VRQOL data will be collected by having the patient answer ten statements on a 1-5 scale, such as “I have trouble speaking loudly or being heard in noisy situations” or “I run out of air and need to take frequent breaths.” QUEST data will be also recorded to a 30-item essential tremor-specific questionnaire. Patient will also complete a global voice rating of a 0-7 scoring of “How would you rate your voice today?” After these subjective questionnaires, patient will participate in a vocal recording using prompts and passages from the validated CAPE-V voice assessment tool.

H. After a discussion of the risks and benefits of propranolol therapy, the patient will then be given a prescription by the principal investigator for propranolol. This prescription will consist of a starting dose of generic immediate-release at 10 mg TID (30 mg each day) with an increase in dose in 5-7 days if there is no effect (60 mg each day) and if the patient had demonstrated no side effects. Dose may be increased to 240 mg each day depending on patient improvement and side effect profile.

I. The second evaluation will occur at an office visit two weeks after initiating

propranolol therapy. Again, this will consist of patient-reported V-RQOL, QUEST, and global voice rating data. Patient will participate in a second vocal recording using prompts and passages from the validated CAPE-V voice assessment tool.

J. At this second evaluation, patient will receive botulinum toxin injections. The risks

and benefits of botulinum toxin therapy will be explained to the patient, and bilateral injections will take place.

K. Four weeks after botulinum toxin injection, the patient will undergo the third voice

assessment. Again, this will consist of patient-reported V-RQOL, QUEST, and global voice rating data. Patient will participate in a third vocal recording using prompts and passages from the validated CAPE-V voice assessment tool.

Data Analysis

L. Using a p-value of .05, a power of .8, and an effect size of .8 (significant) for a paired t-test analysis requires a sample size of 15 to detect improvement in the validated Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V) assessment. This power analysis was calculated using G*Power Statistical Power Analysis (G*Power, Dusseldorf, Germany). We will aim to recruit 20 participants.

M. Once data has been collected, trained expert voice listeners from the Emory

Voice Center will listen to and evaluate the three blinded, randomized voice assessments for each patient using the validated CAPE-V tool.

N. Patients voice data will also be analyzed using Acoustic Spectrograms using the

Computerized Speech Laboratory (KayPENTAX, Montvale, NJ). Vocal tremor on spectrographic assessment of the sustained vowel will be determined and rated for severity.

O. Patients will also be analyzed on differences between self-reported measures

over the three evaluations: the Voice-Related Quality of Life (VRQOL), the Quality of Life in Essential Tremor questionnaire (QUEST), as well as 0-7 global voice rating.

Anticipated Results We anticipate less than 50% difference in improvement in voice quality (as measured by CAPE-V score) between baseline voice and voice on propranolol therapy, and a greater than 50% improvement in voice quality (as measured by CAPE-V score) between baseline voice and voice on botulinum toxin therapy. For our other objective measure, acoustic spectrograms using the Computerized Speech Laboratory speech and voice analysis system (KayPENTAX, Montvale, NJ), we anticipate significant improvement between baseline voice and voice on botulinum toxin therapy. For the patient-reported assessments (VRQOL, QUEST, and global voice rating), we also anticipate less than 50% difference in improvement in voice between baseline voice and voice on propranolol therapy, and a greater than 50% improvement in voice quality between baseline voice and voice on botulinum toxin therapy. Significance will be analyzed by paired t-test analysis using SPSS Statistics (IBM, Armonk, NY).

Detailed Budget and Justification

Key Personnel Percent Effort Salary Requested Fringe Benefits Totals

Michael Johns – PI 1.5% $4,711 $1,258 $5,969

Hyder Jinnah – Co-I 0% $0 $0 $0

Edie Hapner – Co-I 0% $0 $0 $0

Natalie Justicz – Study Coordinator

0% $0 $0 $0

Research Assistant 20% $6,396 $1,708 $8104

Research Assistant 16% $5,117 $1,367 $6,484

Subtotal $16,224 $4,333 $20,557

Supplies and Other Costs

Travel and Conference expenses $3,193 $3,193

Participation incentives $1250 (25 participants at $50/each)

$1,250

Grand Total $25,000

Personnel Michael Johns, MD – will devote 1.5% effort (0.18 calendar mos.); he will act as the principal investigator throughout the project’s creation, execution, analysis, and publication; 1.5% salary support requested Hyder Jinnah, MD, PhD – he will act as mentor throughout development, implementation, data analysis, and publication; will recruit study participants. Edie Hapner, MD, MSCR – she will act as mentor throughout development, implementation, data analysis, and publication. Natalie Justicz, MS3 - she will act as project coordinator; will identify patients who meet inclusion criteria; will also perform voice recordings. TBN Research Assistants (2) - will devote 16% & 20% effort (1.92 & 2.40 calendar mos.); the two positions are requested to cover clinic-based recruitment and data entry functions. $15/hr. for a combined base salary of $11513, plus fringe benefits = $3075. Total research assistant compensation = $14,588) Direct Costs Equipment: No new equipment is required to be purchased. These items are already in place or will be covered by other available funds. Travel and Conference Cost: To present study results at national meetings = $3,193. Estimated average costs per meeting for two meetings: 3 days hotel at $200/night and registration $1200; airfare, ground transportation and per diem Total = $1,993. There is no patient travel costs included in this proposal. Study supplies: No supplies needed. Participating incentives: 25 participants at $50/each at a total cost of $1250

Biographic sketch of principal investigator and all professional personnel participating in the project (standard NIH format, including biosketch and other support). Please see attached biosketches for the following professional personnel: Michael M Johns III, MD, Principal Investigator Edie Hapner, PhD H.A. Jinnah, MD, PhD

PHS 398/2590 (Rev. 05/01) Page Biographical Sketch Format Page

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

BIOGRAPHICAL SKETCH Provide the following information for the 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

Johns, Michael Marieb

POSITION TITLE

Associate Professor of Otolaryngology – Head and

Neck Surgery eRA COMMONS USER NAME

johnsmd

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.)

INSTITUTION AND LOCATION DEGREE

(if applicable) YEAR(s) FIELD OF STUDY

University of Virginia B.A. 1992 Economics

Johns Hopkins School of Medicine M.D. 1996 Medicine

University of Michigan 2002 Otolaryngology

Vanderbilt University 2003 Fellowship - Laryngology

A. Positions and Honors.

Positions and Employment 1996-2002 Resident in Otolaryngology – Head and Neck Surgery, University of Michigan, Ann Arbor, MI 2002-2003 Fellowship in Laryngology and Care of the Professional Voice, Vanderbilt University, Nashville,

TN 2002-2003 Instructor in Otolaryngology – Head and Neck Surgery, Vanderbilt University School of

Medicine, Nashville, TN 2003-present Assistant Professor in Otolaryngology – Head and Neck Surgery, Emory University School of

Medicine, Atlanta, GA 2003-present Director – Emory Voice Center, Emory Healthcare, Atlanta, GA 2006-present Chief of Otolaryngology, Emory Crawford Long Hospital

Other Experience and Professional Memberships 1996-present American Academy of Otolaryngology, Head and Neck Surgery member 1999-2000 Research fellow – NIH T32 training grant - University of Michigan Muscle Mechanics

Laboratory, Preceptor: Norman D. Hogikyan, William M. Kuzon. 2003-present Voice Foundation member 2005-present American Bronchoesophagological Association member 2005-present Co-Chair, World Voice Day, American Academy of Otolaryngology, Head and Neck Surgery

Honors 1992 Phi Beta Kappa honor fraternity 1996 Alpha Omega Alpha honor medical society 2000 University of Michigan Plastic Surgery Division Resident Research Award 2001 Merle Lawrence Resident Research Award

B. Selected peer-reviewed publications (in chronological order).

1. Blaugrund JE. Johns MM Jr. Eby YJ. Ball DW. Baylin SB. Hruban RH. Sidransky D. RET proto-oncogene mutations in inherited and sporadic medullary thyroid cancer. Human Molecular Genetics. 3(10):1895-7, 1994, Oct.

2. Gartenhaus R. Johns MM 3rd. Wang P. Rai K. Sidransky D. Mutator phenotype in a subset of chroniclymphocytic leukemia. Blood. 87(1):38-41, 1996, Jan.

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

PHS 398/2590 (Rev. 09/04) Page Continuation Format Page

3. Johns MM 3rd. Westra WH. Califano JA. Eisele D. Koch WM. Sidransky D. Allelotype of salivary glandtumors. Cancer Research. 56(5):1151-4, 1996, Mar.

4. Califano JA. Johns MM 3rd. Westra WH. Lango MN. Eisele D. Saji M. Zeiger MA. Udelsman R. KochWM. Sidransky D. An allelotype of papillary thyroid cancer. International Journal of Cancer. 69(6):442-4, 1996, Dec.

5. Johns MM, Taylor R, Bogdasarian R. Pathology forum: quiz case 2. Diagnosis: fibromatosis. Archivesof Otolaryngology -- Head & Neck Surgery. 126(7):901, 905-6, 2000, Jul.

6. Rosenthal E. Quint DJ. Johns M. Peterson B. Hoeffner E. Diagnostic maxillofacial coronal imagesreformatted from helically acquired thin-section axial CT data. AJR. American Journal of Roentgenology. 175(4):1177-81, 2000, Oct.

7. Johns MM. Hogikyan ND. Simultaneous Vocal Fold and Tongue Paresis Secondary to Epstein-BarrVirus Infection. Archives of Otolaryngology – Head & Neck Surgery. 126(12):1491-1494, 2000, Dec.

8. Hogikyan ND. Johns MM. Urbanchek M. Kileny P. Kuzon WM. Muscle-nerve-muscle neurotization inunilateral vocal fold paralysis. Ann Otol Rhinol Laryngol, 110. 2001, Sep.

9. Johns MM. Urbanchek M. Kuzon WM. Chepeha DB. Hogikyan ND. Thyroarytenoid muscle maintainsnormal contractile force in unilateral vocal fold immobility. Laryngoscope 111:2152-6, 2001, Dec.

10. Johns MM. Concus A. Beals T. Teknos T. Early onset of post-irradiation sarcoma of the head andneck. ENT Journal 81:6, 2002, Jun.

11. Wong A. Johns MM. Teknos TN. Marjolin's ulcer arising in a previously grafted burn of the scalp.Otolaryngology - Head & Neck Surgery. 128(6):915-6, 2003, Jun.

12. Johns MM. Urbanchek M. Kuzon WM. Chepeha DB. Hogikyan ND. Length-tension relationship of thefeline thyroarytenoid muscle. Journal of Voice, 18(3):285-91, 2004, Sep.

13. Johns MM. Update on the etiology, diagnosis, and treatment of vocal fold nodules, polyps, and cysts.Curr Opin Otolaryngology. 11(6):456-61, 2003, Dec.

14. Johns MM, Garrett CG, Hwang J, Ossoff RH, Courey M. Quality of life outcomes following endoscopiclaryngeal surgery for non-neoplastic vocal fold lesions. Annals of Otol Rhinol Laryngol. 13(8): , 2004, Aug.

15. Nehus E, Johns MM. Subglottic synechia. ENT Journal. 84(3):128, 2005, Mar.16. Otto K, Johns MM. Dysphagia following cervical fusion. ENT Journal. 84(6):208, 2005, Jun.17. Stong B, Delgaudio J, Hapner ER, Johns MM. Safety of bilateral posterior criocoarytenoid muscle

botulinum toxin injections for abductor spasmodic dysphonia. Arch Oto Head Neck Surg. 131(9): 793-5, 2005, Sept.

18. Golub JS, Portone CR, Johns MM. Partial esophageal obstruction from anterior cervical spinehardware. In Press. ENT Journal, June, 2005.

19. Golub JS, Johns MM. Esophageal candidiasis. ENT Journal, 84(12):765, 2005, Dec.20. Johns MM, Ossoff RH. Burnout in chairs of Otolaryngology – Head and Neck Surgery. Laryngoscope

115(11):2056-61, 2005 21. Golub JS, Hapner EH, Johns MM. Vocal fold hemorrhage witnessed during laryngoscopy. Ear Nose

Throat J. 2006 Mar;85(3):148. 22. Otto KJ, Hapner ER, Baker M, Johns MM. Blinded evaluation of the effects of high definition and

magnification on perceived image quality in laryngeal imaging. Ann Otol Rhinol Laryngol. 2006 Feb;115(2):110-3.

23. Portone CR, Hapner ER, McGregor L, Otto K, Johns MM. Correlation of the Voice Handicap Index andthe Voice-Related Quality of Life Measure. J Voice. 2007 Nov;21(6):723-7.

24. Golub JS, Chen V, Otto K, Hapner ER, Johns MM. Prevalence of perceived dysphonia in a geriatricpopulation. J Am Geriatr Soc. 2006 Nov;54(11):1736-9.

25. Leu G, Klein AM, Deyrup AT, Johns MM 3rd. Pathology quiz case 1. Laryngeal myxoma. ArchOtolaryngol Head Neck Surg. 2007 Jan;133(1):94, 96.

26. Berg EE, Hapner ER, Klein A, Johns MM. Voice therapy improves quality of life in age-relateddysphonia: a case-control study. J Voice. 2008 Jan;22(1):70-4.

27. Golub JS, Weiss PS, Ramesh AK, Ossoff RH, Johns MM 3rd. Burnout in residents of otolaryngology-head and neck surgery: a national inquiry into the health of residency training. Acad Med. 2007 Jun;82(6):596-601.

28. Portone C, Johns MM 3rd, Hapner ER. A Review of Patient Adherence to the Recommendation forVoice Therapy. J Voice. 2008 Mar;22(2):192-6.

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

PHS 398/2590 (Rev. 09/04) Page Continuation Format Page

29. Shah RN, Parikh SL, Johns MM 3rd. Radiology quiz case 1. Diagnosis: tracheocele. Arch OtolaryngolHead Neck Surg. 2007 Jul;133(7):724, 726

30. Talebi T, Johns MM 3rd, Sequeira J, Saba N. Rosai-Dorfman disease of the epiglottis. J Clin Oncol.2007 Jun 1;25(16):2324-6.

31. Klein AM, Johns MM 3rd. Vocal emergencies. Otolaryngol Clin North Am. 2007 Oct;40(5):1063-80, vii32. Abdelkafy WM, Smith JQ, Henriquez OA, Golub JS, Xu J, Rojas M, Brigham KL, Johns MM. Age-

related changes in the murine larynx: initial validation of a mouse model. Ann Otol Rhinol Laryngol. 2007 Aug;116(8):618-22.

33. Hapner ER, Braden M, Johns MM. Assessing the effectiveness of botulinum toxin injections foradductor spasmodic dysphonia: clinician and patient perception. In Press. J Voice. 8/08.

34. Gilman M, Merati AL, Klein AM, Hapner ER, Johns MM. Performer's Attitudes Toward Seeking HealthCare for Voice Issues: Understanding the Barriers. J Voice. 2007 Nov 21 [Epub ahead of print]

35. Klein AM, Lehmann M, Hapner ER, Johns MM 3rd. Spontaneous Resolution of Hemorrhagic Polyps ofthe True Vocal Fold. J Voice. 2009 Jan;23(1):132-5.

36. Rubin AD, Shah A, Moyer CA Johns MM. The Effect of Topical Anesthesia on Vocal Fold Motion. JVoice. 2009;23(1):128-31

37. Chen PH, Golub JS, Hapner E, Johns MM 3rd. Prevalence of perceived dysphagia and quality of lifeimpairment in a geriatric population. Dysphagia. 2008 Mar 27. [Epub ahead of print]

38. Klein AM, Stong BC, Wise J, Delgaudio JM, Hapner ER, Johns MM 3rd. Vocal outcome measuresafter bilateral posterior cricoarytenoid muscle botulinum toxin injections for abductor spasmodic dysphonia. Otolaryngol Head Neck Surg. 2008 Sep;139(3):421-3

39. Hapner E, Portone-Maira C, Johns MM 3rd. A Study of Voice Therapy Dropout. J Voice. 2008 Jul 30[Epub ahead of print]

40. Contag S, Klein AM, Blount AC, Johns MM 3rd. Validation of a Laryngeal Dissection Module forPhonomicrosurgical Training. Laryngoscope. 2009 Jan;119(1):211-5.

41. Golub JS, Johns MM, Delgaudio JM, Klein AM. Comparison of an oropharyngeal pH probe and astandard dual or triple pH probe for diagnosis of laryngopharyngeal reflux. In Press, Annals of Otology, Rhinology, Laryngology 8/08.

42. Golub JS, Johns MM 3rd, Weiss PS, Ramesh AK, Ossoff RH. Burnout in academic faculty ofotolaryngology-head and neck surgery. Laryngoscope. 2008 Nov;118(11):1951-6..

43. Shewmaker MB, Hapner ER, Gilman M, Klein AM, Johns MM. Analysis of voice change during cellularphone use: a blinded controlled study. In Press, J Voice, May 2008

44. Gilman M, Gilman S, Johns MM. The other risks. In Press, Lancet, Jan 2009.

C. Research Support

Ongoing Research Support

Participating site for Project 3 of the Dystonia Coalition

Completed Research Support:

U54 NS067501 and UL1 RR025008 Pilot Project (PI: Johns)NIH-NCRR, NINDS, and ORDRRole: PI Autoimmune, Neurologic, and Psychiatric Disease in the Focal Dystonias, 8/10 – 7/11 NIH Head and Neck Cancer Spore Grant. Role: Career Development Program Awardee Rejuvenation of the radiation fibrosed larynx. 12/07 – 1/10.

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

PHS 398/2590 (Rev. 09/04) Page Continuation Format Page

Astra-Zenica, 1/06 – present. Role: Co-PI, Clinical trial assessing the diagnostic accuracy of a novel pharyngeal probe measuring oropharyngeal aerosolized pH.

Jahnigen Career Development Scholar Grant, 7/05 – 6/07 Role: PI Awarded by the John A. Hartford Foundation and the American Geriatrics Society to fund a clinical trial investigating treatment of age-related voice disorders.

Geriatrics Education for Specialty Residents Award, $32,000, 7/05 – 6/06 Role: PI Awarded by the American Geriatrics Society/John A. Hartford Foundation to develop a geriatric otolaryngology curriculum at Emory University.

Reynolds Foundation Faculty Scholar Grant. 9/04 – 8/05. Role: PI Awarded to fund development of a durable teaching tool for geriatric dysphagia.

American Laryngological Voice Research and Education Foundation Grant. 7/99-7/00. Role: Participating Investigator Development and utilization of a feline hemilaryngeal denervation model to assess muscle-nerve-muscle neurotization for the treatment of unilateral vocal fold paralysis.

BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors.

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

NAME

Hapner, Edie R POSITION TITLE

Associate Professor, Emory University School of Medicine, Department of Otolaryngology Head and Neck Surgery and Neck Surgery.

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

Vanderbilt University, Nashville, TN PhD 2003 Hearing and Speech Science

Fontbonne College, St. Louis, MO MS 1981 Communication Disorders

University of Missouri-Columbia BS 1980 Communication Disorders

A. Personal Statement

In general, my research foci are in the evaluation and treatment of the aging voice. Most relevant to the current proposal, is the work I have done regarding dysphonia and quality of life impairment as well as work specifically with the Voice Related Quality of Life measure. I am also on the Board of Directors for the American Speech, Language, and Hearing Association. This experience, in addition to my clinical expertise as director of Speech Language Pathology of The Emory Voice Center is integral to my role as a collaborator for Laura White’s proposal “Vocal Outcomes in Patients Treated for Hormone-Secreting Pituitary Adenomas.”

B. Positions and Honors

Positions and Employment September 2003-2010 Assistant Professor-Department of Otolaryngology-Head and Neck Surgery,

Emory University School of Medicine January 2007-2013 Adjunct teaching faculty- University of Georgia, Communication Sciences and

Disorders, Department of Special Education, Athens, GA September 2003-present Division Director-Emory Voice Center, Speech Language Pathology. Emory Honors, Other Experience, and Professional Memberships Clinical Scholars, American Academy of Otolaryngology- Head and Neck Surgery-2006. Outstanding Alumnae, University of Missouri Department of Education-2007 Georgia Speech Language and Hearing Association-Clinician of the Year. 2007 Kathleen Quigley Lectureship. Society for Otolaryngology Nurses. 2008. Students Preparing for Academic and Research Careers (SPARC) award mentor. ASHA,

Christine Williams, Vanderbilt University. 2010-2011.

Committees 1. Council on Academic Accreditation in Audiology and Speech Language Pathology. American Speech

Language and Hearing Association. January 2002- December 2006. 2. American Academy of Otolaryngology- Guidelines for the Evaluation and Treatment of Hoarsenes

(dysphonia). September 2008-September 2009. 3. 4. Head and Neck Cancer Alliance. Head and Neck Cancer Screening Event Chair for national screening

events at Indianapolis Motor Speedway. January –June 2009. 5. Board of Division Coordinators. American Speech Language and Hearing Association.. January 2009-2012.6. ASHA Special Interest Division Voice and Voice Disorders. American Speech Language and Hearing

Association. Coordinator 2009-2012, Associate Coordinator 2008-2009, Member 2006-2008. 7. Oral Head and Neck Cancer Advocacy Foundation of Georgia, dba A Voice For Hope (501 c3). 2010-

present, GA chapter president, national board, national race screening liason.

8. Georgia Division of Public Health Office of Healthy Behavior Georgia Tobacco Cessation Work Plan StudyCommittee. 2008-2009

9. Community Engagement and Research Program, Atlanta Clinical Translational Science Institute. OralHealth Workgroup III. Katherine Erwin, DDS Chair August 2010-2011.

10. American Speech Language and Hearing Association Board of Directors. 2014-2016.

C. Selected Peer-reviewed Publications 1. Portone CR. Hapner ER. McGregor L. Otto K. Johns MM. Correlation of the Voice Handicap Index and the

Voice-Related Quality of Life Measure. Journal of Voice. 21(6): 723-7, 2007, Nov. 2. Berg EE. Hapner ER. Klein AM. Johns MM 3rd . Voice therapy improves quality of life in age-related

dysphonia: a case-control study. Journal of Voice. 22 (1): 70-4, 2008, Jan. 3. Portone CR. Johns MM 3rd. Hapner ER. A review of patient adherence to the recommendation for voice

therapy. Journal of Voice. 22 (2): 192-62, 2008, Mar. 4. Hapner ER. Portone M. Johns MM 3rd. A study of voice therapy dropout. Journal of Voice. 23 (3): 337-40,

2008, May. 5. van Leer E. Hapner ER. Connor N. The transtheoretical model of health behavior change applied to voice

therapy. Journal of Voice. 22(6): 688-98, 2008, Nov. 6. Chen PH. Golub JS. Hapner ER. Johns MM 3rd. Prevalence of perceived dysphonia and quality of life

impairment in a geriatric population. Dysphagia. 24(1): 1-6, 2009, Mar. 7. Shewmaker M. Hapner ER. Gilman M. Klein A. Johns, MM 3rd. Analysis of voice change during cellular

phone use: A blinded controlled study. Journal of Voice. 24(3): 242-9, 2009, June. 8. Hapner, ER, Maira, C., Wise, J., & Johns, MM. Differences in temporal variables between voice therapy

completers and dropouts. Journal of Voice. 25(1): 62-6, 2009, Jul. 9. Schwartz SR. Cohen SM. Dailey SH. Rosenfeld RM. Deutsch ES. Gillespie MB. Hapner ER et al. Clinical

practice guideline: hoarseness (dysphonia). Otolaryngology Head and Neck Surgery, 141: S1-S31, 2009, Sept.

10. Venkatesan NN. Johns MM 3rd. Hapner ER. DelGaudio JM. Abductor paralysis after botox injection foradductor spasmodic dysphonia. The Laryngoscope. 120:1177-80, 2010, June.

11. Gilman M., Nix J. Hapner ER. Speech Pathologist, the Singing Teacher and the Singing VoiceSpecialist:Where’s the Line? Journal of Singing, Nov/Dec 2010, vol 67, No2 p 171-178.

12. Hapner ER, Bauer KL, Wise JC. The impact of a community based oral head and neck cancer screeningfor reducing tobacco consumption. Otolaryngology Head and Neck Surgery, November 2011, 145 (5): 778-782. doi:10.1177/0194599811415804

13. White LJ, Klein AM, Hapner ER, Delgaudio JM, Hanfelt HH, JInnah HA, and Johns MM. (2011).Coprevalence of tremor with spasmodic dysphonia. The Laryngoscope, 121: 1752-1755.doi:10.1002/lary.21872

14. White LJ, Chin-Quee AL, Berg CJ, Wise JC, Hapner ER (2012). Differences in Head and Neck CancerRisk Perception between Smoking and Non-Smoking NASCAR Attendees. Otolaryngology Head and NeckSurgery, 47-1, 63-68

15. White LJ, Creighton FP, Wise JC, Hapner ER (2013). Differences in HPV related head and neck cancerrisk Perception between in three populations (in review)

D. Research Support

Ongoing Research Support 1. Dystonia Coalition. #6301-U32 Diagnostic and measurement tools for

spasmodic dysphonia. Rare Diseases Clinical Research Network. NIH, clinical site co-coordinator 2. American Head and Neck Society, Prevention Grant 2012-2013.

Completed Research Support Institutional: Emory University; URC grant, PI. The usefulness of head and neck cancer

screenings in reducing tobacco consumption. 6/08-1/11.

Office of University and Community Partners, PI: Training medical students in tobacco cessation research and completing community based head and neck cancer screenings. 2010 - 2011.

BIOGRAPHICAL SKETCH

NAME

Hyder A. Jinnah POSITION TITLE

Professor Departments of Neurology, Human Genetics & Pediatrics

eRA COMMONS USER NAME

hjinnah1

EDUCATION/TRAINING

INSTITUTION AND LOCATION DEGREE

(if applicable) YEAR(s) FIELD OF STUDY

Duke University, Durham NC BS 1985 Zoology & Psychology University of California, San Diego MD/PhD 1993 Medicine/Neuroscience

A. PERSONAL STATEMENT Dr. Jinnah obtained a joint MD/PhD degree as part of the Medical Scientist Training Program at the University of California in San Diego in 1993, completed a Neurology Residency at Johns Hopkins University in 1997, joined the faculty at Johns Hopkins for 10 years, and moved to Emory University in 2008. He is currently Professor of Neurology, Pediatrics and Human Genetics. Approximately 20% of his time is devoted to clinical service, with 80% devoted to research. His research focuses on clinical and translational issues in movement disorders and genetics. A substantial portion of his work has addressed both the basic and clinical sciences relevant to Lesch-Nyhan disease. Over the years he has conducted basic genetic and biochemical studies, studies of cell and animal models, anatomical and pathological studies of rodent and human brains, descriptive or imaging studies of affected patients, and interventional clinical studies. He recently shared a NIH grant devoted to Lesch-Nyhan disease with Dr. Schretlen under the multi-PI model (R01 HD 053312), a collaboration that was highly successful. He was Founder of the Lesch-Nyhan Disease International Study Group in 2000, has been a member of the Scientific Advisory Board of the Lesch-Nyhan Syndrome Children’s Research Foundation since 1996, and a member of its French counterpart since 2001. Dr. Jinnah also is PI of a consortium of investigators focusing on the dystonias (U54 NS065701), part of the Rare Diseases Clinical Research Network of the National Center for Advancing Translational Sciences. Dr. Jinnah therefore is well suited for the clinical and scientific studies of Lesch-Nyhan disease and its variants described in this proposal.

B. POSITIONS & HONORS

Positions & employment

1993-1994 Intern, Department of Medicine, Milton S. Hershey Medical Center, Hershey PA

1994-1997 Resident, Department of Neurology, Johns Hopkins University, Baltimore MD

1997-1998 Instructor, Department of Neurology, Johns Hopkins University, Baltimore MD

1999-2005 Assistant Professor, Department of Neurology, Johns Hopkins University, Baltimore MD

2005-2008 Associate Professor, Department of Neurology, Johns Hopkins University, Baltimore MD

2008-present Professor, Departments Neurology & Human Genetics, Emory University, Atlanta GA

2009-present Professor, Department of Pediatrics, Emory University, Atlanta GA

Honors & awards

1984 Phi Beta Kappa National Honor Society

1985 BS, Summa Cum Laude, Duke University

1987 Medical Scientist Training Program Award

1997 NINDS Clinical Scientist Development Award

2003 Elected Member, American Neurological Association

2008 Emory Dean’s Clinical Scholar Award

2009 Dystonia Medical Research Foundation Patient Support Group Award

Other relevant activities

1996-present Scientific Advisory Board, Lesch-Nyhan Syndrome Children’s Research Foundation

2001-present Scientific Council, Association Francaise Lesch-Nyhan Action, Paris

2001-present Founder & Director, Lesch-Nyhan Disease International Study Group

2003-present Medical & Scientific Advisory Council, Dystonia Medical Research Foundation

2007-2009 Scientific Advisory Board, Bachmann-Strauss Dystonia & Parkinson’s Foundation

2008-present Task Force on Childhood Motor Disorders

2011-present Scientific Advisory Board, Tyler’s Hope for a Cure

2013-present Scientific Advisory Board, Cure Dystonia Now

C. SELECTED PUBLICATIONS MOST RELEVANT TO THE CURRENT PROPOSAL (from 176 total) 1. Jinnah HA, Visser JE, Harris JC, Verdu A, Larovere L, Ceballos-Picot I, Gonzalez-Alegre P, Neychev

VK, Torres RJ, Dulac O, Desguerre I, Schretlen DA, Robey K, Barabas G, Bloem BR, Nyhan WL,deKremer R, Eddey GE, Puig J, Reich SG. Delineation of the motor disorder of Lesch-Nyhan disease,Brain, 129: 1201-1217, 2006.

2. Shirley TL, Lewers JC, Egami K, Majumdar A, Kelly M, Ceballos-Picot I, Seidman MM, Jinnah HA. Ahuman neuronal tissue culture model for Lesch-Nyhan disease, Journal of Neurochemistry, 101: 841-853, 2007.

3. Lewers JC, Ceballos-Picot I, Shirley TL, Mockel L, Egami K, Jinnah HA. Consequences of impairedpurine recycling in dopaminergic neurons. Neuroscience, 152: 761-772, 2008.

4. Ceballos-Picot I, Mockel L, Potier MC, Dauphinot L, Shirley TL, Torero-Ibad R, Fuchs J, Jinnah HA.Hypoxanthine-guanine phosphoribosyltransferase regulates early developmental programming ofdopamine neurons: Implications for Lesch-Nyhan disease pathogenesis. Human Molecular Genetics,18: 2317-2327, 2009. PMCID: 2694685.

5. Jinnah HA, Ceballos-Picot I, Torres R, Visser J, Schretlen D, Verdu A, Larovere L, Chen CJ, Cossu A,Wu CH, Chang SJ, Dodelson de Kremer R, Nyhan W, Harris J, Reich S, Puig JG. Attenuated variantsof Lesch-Nyhan disease. Brain, 13: 671-689, 2010. PMCID: 2842514.

6. Fu R, Jinnah HA. Genotype-phenotype correlations in Lesch-Nyhan disease and its variants: Movingbeyond the gene. Journal of Biological Chemistry, 287: 2997-3008, 2012. PMCID: 3270957.

7. Albanese A, Del Sorbo F, Comella C, Jinnah HA, Mink JW, Post B, Vidailet M, Volkmann J, Warner T,Leentjens AFG, Martinez-Martin P, Stebbins GT, Goetz CG, Schrag, A. Dystonia rating scales:critique and recommendations. Movement Disorders, 28: 874-883, 2013. PMC Journal – In Process.

8. Fu R, Ceballos-Picot I, Torres RJ, Larovere LE, Yamada Y, Vguyen KV, Hegde M, Visser JE,Schretlen DJ, Nyhan WL, Puig JG, O’Neill PJ, Jinnah HA. Genotype-phenotype correlations inneurogenetics: Lesch-Nyhan disease as a model. Brain, in press, 2013. PMC Journal – In Process.

9. Goettle M, Burhenne H, Sutcliffe D, Jinnah HA. Purine metabolism during neuronal differentiation: therole of purine synthesis and recycling. Journal of Neurochemistry, 127: 805-818, 2013. PMCID:3859826

10. Jinnah HA, Berardelli A, Comella C, Defazio G, DeLong MR, Factor SA, Galpern WR, Hallett M,Ludlow CL, Perlmutter J, Rosen A. The focal dystonias: current views and challenges for futureresearch. Movement Disorders, 28: 926-943 2013. PMCID: 3733486.

11. Kamatani N, Jinnah HA, Hennekam RCM, Kuilenburg ABP. Chapter 99: Purine & PyrimidineMetabolism. In Emery & Rimoin’s Principles and Practice of Medical Genetics, Rimoin D, Pyeritz R,Korf B, Eds, Elsevier Publishers, Elsevier, 2013.

12. Prudente CN, Pardo CA, Xiao J, Hanfelt J, Hess EJ, LeDoux MS, Jinnah HA. Neuropathology ofcervical dystonia. Experimental Neurology, 241: 95-104, 2013. PMCID: 3570661.

13. Schretlen DJ, Varvaris M, Ho TE, Vannorsdall TD, Gordon B, Harris JC, Jinnah HA. Regional brainvolume abnormalities in Lesch-Nyhan disease and its variants: A cross-sectional study. LancetNeurology, 12: 1151-1158, 2013. PMC Journal - In Process.

14. Shaikh AG, Wong AL, Zee DS, Jinnah HA. Keeping your head on target. Journal of Neuroscience,33: 11281-11293, 2013. PMCID: 3718362.

15. Dauphinot L, Mockel L, Cahu J, Jinnah HA, Ledroit M, Poitier MC, Ceballos-Picto I. A transcriptomicapproach to Lesch-Nyhan disease. Nucleosides, Nucleotides, and Nucleic Acids, in press, 2014.

D. RESEARCH SUPPORT

Ongoing research support R01 HD053312-01A2 (Multi-PI model: Jinnah & Schretlen) 7/1/08 - 6/30/14 (NCE) NIH-NICHD Lesch-Nyhan disease: Neuroanatomical & biochemical bases of the neurobehavioral phenotype This multicenter project is devoted to elucidating the biological basis for the neurobehavioral anomalies in Lesch-Nyhan disease including evolution and natural history, biochemical genetics, and neuroanatomical correlates via voxel-based morphometry and diffusion tensor imaging.

U54 NS065701 (PI: Jinnah, CoPI: Perlmutter) 9/30/09 – 8/31/14 NIH-NINDS/ORDR-NCATS The Dystonia Coalition The goal of this project is to establish a multicenter network for clinical and translational studies focusing on primary dystonias.

Bachmann-Strauss Dystonia & Parkinson’s Disease Foundation 8/1/12 – 7/31/14 iPS resource for dystonia The goal of this project is to develop a bank of fibroblasts and induced pluriopotent stem cells from patients with genetically identified forms of dystonia.

Merz Pharmaceuticals, LLC (Site PI: Jinnah) 9/17/12 – 9/16/16 CD-FLEX: An open label study evaluating Xeomin in cervical dystonia The goal of this project is to examine varying dosing intervals for Xeomin in cervical dystonia.

Benign Essential Blepharospasm Research Foundation (PI: Jinnah) 1/1/14 – 12/31/14 Neuropathology of blepharospasm The goal of this project is to examine the histopathology of brains of patients who had blepharospasm.

Completed research support R01 NS40470-04 (PI: Jinnah) 4/1/01 - 3/30/05 NIH/NINDS Neurobiology of dystonia The goal of this project was to develop and characterize several mouse models for dystonia, and to perform a pilot trial of nifedipine for the treatment of generalized dystonia in humans.

R01 HD39795-04 (PI: Jinnah) 4/1/02 - 3/31/06 NIH/NICHD Neurobiology of self-injurious behavior The goal of this project was to determine the neuroanatomical and neuropharmacological bases for self-injurious behavior in a novel rodent model relevant to Lesch-Nyhan disease.

Merck & Co., Inc. (Site investigator: Jinnah) 1/1/06 - 4/1/06 Randomized and placebo controlled, double-blind, double-dummy, three-period crossover study of MK-0657 in Parkinson’s disease This was an industry-initiated trial of a novel anti-glutamatergic drug for treatment of Parkinson disease.

Lesch-Nyhan Syndrome Children’s Research Foundation (PI: Jinnah) 7/1/03 - 6/30/07 Clinical trials in Lesch-Nyhan disease The goal of this project was to facilitate the design of clinical trials for Lesch-Nyhan disease and conduct a pilot trial of levodopa therapy.

Research grant (PI: Jinnah) 1/1/07 - 12/30/07 Bachmann-Strauss Dystonia & Parkinson Foundation Why is dystonia more common in females than in males?

The goal of this proposal was to begin to decipher the contributions of ovarian hormones to episodic dystonia that occurs selectively in females of an inbred mouse line carrying a defined mutation.

R21 HD 048881-02 (PI: Jinnah) 4/15/06 - 3/31/08 NIH-NICHD Lesch-Nyhan disease: dissecting the functions of HGprt The aims of this proposal were to use computer graphical modeling and molecular reconstructions to explore the biochemical kinetics of HGprt in relation to the clinical phenotype of Lesch-Nyhan disease.

R21 NS061349-01A2 (PI: Jinnah) 9/1/08 - 8/30/10 NIH-NINDS Gender differences in episodic neurological disease The goal of this project is to delineate hormonal contributions to episodic dystonia exhibited only by females in an inbred mouse line that carries a defined calcium channel defect.

R01 NS040470-08 (PI: Jinnah) 6/1/00 - 3/31/10 NIH-NINDS Neurobiology of dystonia The aim of this project is to determine the relative contributions of basal ganglia and cerebellar pathways to the expression of dystonia in rodent and primate animal models.

Psyadon Pharmaceuticals, LLC (Site PI: Jinnah) 1/1/10 - 12/31/11 PSY-101: Safety & Tolerability Study of Ecopipam in Lesch-Nyhan Disease The aim of this project was to assess the safety and tolerability of a D1-dopamine receptor antagonist (ecopipam) in Lesch-Nyhan disease.

R01 NS033592-11 (PI: Hess, CoPI: Jinnah) 4/1/07 - 4/30/11 NIH-NINDS Pathophysiology of dystonia: animal models The goal of this project was to understand the pathogenesis of dystonia in several mouse models to guide discovery of novel treatments.

R24 DK082840-01 (PI: Friedmann, CoPI: Jinnah) 9/30/08 - 8/28/13 NIH-NIDDK Lesch-Nyhan disease: a model for complex genetic proteomic, and metabolic pathways The goal of this project was to perform a comprehensive assessment of developmental cell models for Lesch-Nyhan disease that addressed genomic, proteomic, and metabolomic aspects.

NIH NCRR UL1 RR025008 (PI: Stephens) 5/1/12 – 4/30/13 Atlanta Clinical & Translational Science Institute Pilot Project Functional imaging in cervical dystonia This was a pilot project aimed collecting preliminary feasibility data for imaging of patients with cervical dystonia.

Psyadon Pharmaceuticals, LLC (PI: Jinnah) 12/12/12 – 12/31/13 PSY-102: Phase 3 study of ecopipam in Lesch-Nyhan disease The goal of this project was to evaluate the efficacy of a D1-dopamine receptor antagonist (ecopipam) for the treatment of Lesch-Nyhan disease.

Copies of relevant abstracts and/or articles that have been published, are in press, or have been submitted for publication. 1. Sulica L, Louis ED. Clinical characteristics of essential voice tremor: a study of 34 cases. Laryngoscope. 2010 Mar; 120(3):516-28. doi: 10.1002/lary.20702. PubMed PMID: 20066728.

2. Zesiewicz TA, Shaw JD, Allison KG, Staffetti JS, Okun MS, Sullivan KL. Update on treatment of essential tremor. Curr Treat Options Neurol. 2013 Aug; 15(4):410-23. doi: 10.1007/s11940-013-0239-4. PubMed PMID: 23881742.

3. Gurey LE, Sinclair CF, Blitzer A. A new paradigm for the management of essential vocal tremor with botulinum toxin. Laryngoscope. 2013 Oct; 123(10):2497-501. doi: 10.1002/lary.24073. Epub 2013 Apr 1. PubMed PMID: 23553653.

4. Adler CH, Bansberg SF, Hentz JG, Ramig LO, Buder EH, Witt K, Edwards BW, Krein-Jones K, Caviness JN. Botulinum toxin type A for treating voice tremor. Arch Neurol. 2004 Sep; 61(9):1416-20. PubMed PMID: 15364688.

5. Warrick P, Dromey C, Irish J, Durkin L. The treatment of essential voice tremor with botulinum toxin A: a longitudinal case report. J Voice 2000; 14:410–421.

6. Koller W, Graner D, Mlcoch A. Essential voice tremor: treatment with propranolol. Neurology 1985; 35:106–108.

7. Massey EW, Paulson GW. Essential vocal tremor: clinical characteristics and response to therapy. South Med J 1985; 78:316–317.

8. Hogikyan ND, Sethuraman G. Validation of an instrument to measure voice-related quality of life (V-RQOL). J Voice. 1999 Dec;13(4):557-69. PubMed PMID: 10622521.

9. Tröster AI, Pahwa R, Fields JA, Tanner CM, Lyons KE. Quality of life in Essential Tremor Questionnaire (QUEST): development and initial validation. Parkinsonism Relat Disord. 2005 Sep;11(6):367-73. PubMed PMID: 16103000.

10. Kempster GB, Gerratt BR, Verdolini Abbott K, Barkmeier-Kraemer J, Hillman RE. Consensus auditory-perceptual evaluation of voice: development of a standardized clinical protocol. Am J Speech Lang Pathol. 2009 May;18(2):124-32. doi: 10.1044/1058-0360(2008/08-0017). Epub 2008 Oct 16. PubMed PMID: 18930908.

Completed conflict of interest questionnaire Please see attached conflict of interest questionnaires for the following professional personnel: Michael M Johns III, MD, Principal Investigator Edie Hapner, PhD H.A. Jinnah, MD, PhD

Questionnaire Appendices Appendix 1: VRQOL [8]

Appendix 2: QUEST [9]

Appendix 3: CAPE-V [10]