Ataxia-Telangiectasia Clinical Research Workshop Summary

Ataxia-Telangiectasia Clinical Research Workshop Summary
March 10-11, 2006
Bethesda, MD

I.   INTRODUCTION

Ataxia-Telangiectasia (A-T) is a rare, progressive childhood disease that is characterized by progressive neurological motor defects, telangiectasias, blood cancers, immunodeficiency, respiratory dysfunction and radiation sensitivity. The prognosis for individuals with A-T is poor, with death occurring in the teens or early twenties. A-T is due to recessively inherited mutations in an essential DNA damage response protein encoded by the ATM (Ataxia-Telangiectasia Mutated) gene; the pleiotropic phenotype observed in A-T patients is thought to reflect the central cellular role of the ATM protein in the maintenance of genome integrity. The neurological phenotype dramatically impacts the quality of patients lives, so effort has been focused on understanding the observed of ATM-mediated cerebellar degeneration and associated clinical neurological features. In addition pilot clinical trials are underway using anti-oxidants to help alleviate the neurological features of A-T. Given the low prevalence of the A-T, a large scale clinical trial would likely require international collaboration and thus defined standard clinical measures that could be used to define clear endpoints. Therefore the goal of the workshop was to develop diagnostic and molecular assessment measures and a minimal standard protocol for the analysis of patients with A-T.

 

II   BACKGROUND

There are a number of clinical challenges surrounding A-T. First, the primary neurological presentation is quite heterogeneous; it combines a number of different defects in motor function that makes diagnosis difficult as well as confounding efforts to define standard neurological criteria. In addition, the progressive nature of the disease as well as variations in severity increases the challenges in identifying minimal clinical neurological measures. The pleiotropic nature of the disease also requires that clinical assessment measures cover all aspects of the disease. Some aspects of the disease are also not well understood or clinically characterized such as the cancer phenotype and the lung function deficits. Finally since ATM is relatively well characterized molecularly, it is expedient to include molecular and laboratory markers in the standard clinical measures of A-T.

This workshop is part of implementation of the NIH Strategic Research Plan for Ataxia-Telangiectasia (http://www.ninds.nih.gov/about_ninds/plans/a-t_plan.htm) and was sponsored by the National Institute of Neurological Disorders and Stroke, the Office of Rare Diseases and the A-T Children's Project.

Organized by Drs. Jonathan Horsford, Cynthia Rothblum-Oviatt, Giovanna Spinella, and Danilo Tagle, an international group of 43 participants that included NIH staff, basic researchers, clinicians, and industry representatives explored the current state of clinical and molecular measures of A-T, barriers to progress, possible solutions and priorities.

The goals of the workshop were to 1) draft a list of standard A-T clinical criteria in four areas of the disease: neurology, cancer, lung function/ immunology/ endocrinology and molecular/ laboratory markers and 2) to identify challenges in defining minimal clinical standards and focus on approaches to solve these barriers.

 

III.   DISCUSSION

The workshop began with Drs. Tagle and Spinella defining its goals. The first presentations examined the approaches used by other movement disorder communities to define clinical assessment measures (Drs. Pearce and Sanger). The current A-T clinical diagnostic criteria were then presented (Drs. Lederman, Whitehouse, Berkun, Nissenkorn, Waldman and Sandlund). The morning session concluded with a presentation on the extra-cerebellar characteristics of A-T (Dr. Crawford). After lunch the group heard talks on biomakers (Drs. Kaddurah-Daouk and Moore) and A-T translational research (Dr. Shiloh). The final presentations on the first day were on current and recently concluded A-T clinical trials (Drs. Berry and Lederman).

The group then split up into one of four breakout sessions focusing on neurology, cancer, lung function/immunology/endocrinology or molecular/laboratory/biomarkers. On day two the group convened and the chairs from the four breakout sessions presented the draft of clinical assessment measures for the 4 areas identified above as well as challenges that the group encountered, and possible solutions. A very productive discussion ensued from each breakout summation. The final presentations were on international collaborations in A-T using a registry (Dr. Chessa; http://www.e-yes.biz/webat/index.php; active May 1st; please contact Dr. Chessa for further information) and a clinical listservs (Dr. Rothblum-Oviatt; http://www.atcp.org/at_clinician_forum_registration.htm). The workshop concluded with a summary and planning session chaired by Dr. Horsford. The discussions led to the following conclusions and recommendations.

 

IV.   RECOMMENDATIONS/CONCLUSIONS

The format of the workshop allowed the group to consider A-T standard clinical criteria separately for the four different aspects of the disease- neurology, cancer, lung function/immunology/endocrinology and molecular/laboratory/biomarkers.

• The lung function/immunology/endocrinology group will draft a list of standard clinical criteria as well as pilot studies in lung and perhaps swallowing function. There is also the possibility of collaborating to write a manuscript on the responses to vaccinations in A-T patients.
• • Participants: Lederman (Chair), Berkun, Stray-Pedersen, Levi, Lefton-Greif, McGrath-Morrow, Weemaes, Horsford, Pietrucha, Reichenbach
• The cancer group will collaborate to define general recommendations for care as well as consider research and a publication on the incidence and characterization of cancers in patients with A-T.
• • Participants: Sandlund (Chair), Waldman, Guinan, Mizutani, Corey, Rothblum-Oviatt
• The molecular/laboratory/biomarkers group will work together to draft a list of common A-T clinical measurements to be used for diagnosis and follow-up assessment of patients with A-T. A proposed A-T translational workshop will incorporate a discussion of biomarkers in A-T.
• • Participants: Chessa (Chair), Gatti, Steinberg, Moore, Kaddurah-Daouk, Stoppa-Lyonnet, Doctrow, Berry, Tagle
• The neurology group will further pursue developing a list of standard A-T neurological criteria. Following the example of the Batten's Disease group (as presented by Dr. Pearce), a more focused meeting will be held in the near future that will bring together neurologists and other A-T health care providers (from the different A-T clinical centers) along with a number of A-T patients to concretely compare, discuss and define neurological measures in A-T.
• • Participants: Crawford (Chair), Nissenkorn, Mandir, Slopis, Shaikh, Sanal, Whitehouse, Rivkin, Brown, Pearce, Sanger, Shiloh, Margus, Spinella

The workshop clarified the challenges in defining the A-T clinical criteria and most importantly set up the foundations and collaborations to reach that goal. The goal is to have lung function/immunology/endocrinology, cancer and molecular/laboratory markers standard measures for A-T completed six months after the workshop in September, 2006.

 

IV  AGENDA

Friday March 10, 2006

8:30 am   Charge to Participants

Danilo Tagle, NINDS/NIH, USA
Giovanna Spinella, ORD/NIH, USA

Diagnostic and Assessment Measures for Movement Disorders in Children

8:40 am      David Pearce, University of Rochester Medical Center, USA
9:00 am      Terry Sanger, Stanford University Medical Center, USA
9:20 am      Discussion- Danilo Tagle

Diagnostic and Assessment Measures for A-T

9:40 am      Howard Lederman, A-T Clinical Center, Johns Hopkins Hospital, USA
9:55 am      William Whitehouse, National A-T Clinic, UK
10:10 am      A-T Clinical Center, Israel
           Yackov Berkun - Overview
           Andrea Nissenkorn - Neurology
           Dalia Waldman - Hematology
10:25 am      Torrey Sandlund, St. Jude Children's Research Hospital, USA
10:40 am      Discussion- Giovanna Spinella

11:05 am      Break - Linden Oak

Extra-Cerebellar Characteristics of A-T

11:20 am      Thomas Crawford, A-T Clinical Center, Johns Hopkins Hospital, USA
12:00 pm      Discussion- Cynthia Rothblum-Oviatt

12:30 pm      Lunch - Linden Oak

Molecular Profiling: Proteomics and Metabolomics in Clinical Research

1:30 pm      Rima Kaddurah-Daouk, Duke University, USA
1:45 pm       Stacy Moore, Ciphergen, USA
2:00 pm      Discussion- Jonathan Horsford

2:40 pm       Break - Linden Oak

The Gap Between the Bench and the Bedside

2:55 pm      Yossi Shiloh, Tel Aviv University, Israel

3:15 pm      Discussion - Dan Tagle

Current Clinical Trials and Assessment Measures for A-T

4:00 pm      Gerard Berry, Jefferson Medical College, Thomas Jefferson University, USA
4:20 pm      Howard Lederman, A-T Clinical Center, Johns Hopkins Hospital, USA
4:40 pm      Discussion- Giovanna Spinella

Summary and Introduction to Break-out Sessions

5:00 pm      Jonathan Horsford, NINDS/NIH, USA

Break-out Groups: (Meeting Rooms: Linden Oak, Great Falls, Middle Brook, and Timber Lawn)

Neurology, Chair: Tom Crawford

Immunology, Endocrinology and Lung Function, Chair: Howard Lederman

Cancer, Chair: Torrey Sandlund

Laboratory / Molecular Markers, Chair: Luciana Chessa

6:30 pm      Adjourn

7:00 pm       Board bus at entrance of conference center for dinner

7:30 pm      Dinner at Timpano Italian Chophouse, Rockville

Saturday, March 11, 2006

8:30 am      Reports from Break-out Session Chairs- Jonathan Horsford

9:30 am      Discussion: Clinical Collaborations- Cynthia Rothblum- Oviatt

Developing critical data elements (CDEs) and a minimal standard protocol for the longitudinal assessment of patients with A-T

Break during this session

International Registry for A-T
      Luciana Chessa, University of Roma "La Sapienza", Italy

The A-T Clinical Listserve: Maintaining Collaborations
      Cynthia Rothblum-Oviatt, A-T Children's Project, USA

12:30 pm      Lunch - Linden Oak

1:30 pm      Summary and Planning Session- Jonathan Horsford    

3:00 pm      Adjourn

 

V  PARTICIPANTS

Yackov Berkun, M.D.
Senior Pediatrician
Safra Children Hospital and Sheba Medical Center, Israel
Department of Pediatrics
Tel Ha Shomer, 52621
Tel-Hashomer 52621, Israel
Telephone No.:    (972) 5266-66314
Fax No.:               (972) 3635-5178
E-mail Address:    berkun@md.huji.ac.il

Gerard Berry, M.D.
Professor of Pediatrics and Biochemistry
Thomas Jefferson University
Department of Pediatrics
1025 Walnut Street, Suite 700
Philadelphia, PA 19107
Telephone No.:    (215) 955-7806
Fax No.:               (215) 923-9519
E-mail Address:    gerard.berry@jefferson.edu

Luciana Chessa, M.D.
Associate Professor
University "La Sapienza" II Faculty of Medicine
Department of Experimental Medicine and Pathology
Via di Grottarossa 1035
I-00189 Roma, Italy
Telephone No.:    (39) 06 33775258
Fax No.:               (39) 06 33775258
E-mail Address:    luciana.chessa@ospedalesantandrea.it

Seth Corey, M.D., M.P.H.
Associate Professor
UT-MD Anderson Cancer Center
Department of Pediatrics and Leukemia
P.O. Box 853
1515 Holcombe Boulevard
Houston, TX 77030
Telephone No.:    (713) 563-5393
Fax No.:               (713) 563-5407
E-mail Address:    sjcorey@mdanderson.org

Thomas Crawford, M.D.
Associate Professor of Neurology and Pediatrics
Johns Hopkins University
Department of Neurology
600 North Wolfe Street
Baltimore, MD 21287
Telephone No.:    (410) 955-4259
Fax No.:               (410) 614-2297
E-mail Address:    tcrawfo@jhmi.edu

Susan Doctrow, Ph.D.
Vice President of Therapeutics Research
Proteome Systems, Inc.
6 Gill Street, Suite H
Woburn, MA 01801
Telephone No.:    (781) 932-9477, Ext. 3311
Fax No.:               (781) 932-9294
E-mail Address:    susan.doctrow@proteomesystems.com

Phyllis Frosst, Ph.D.
Science Policy Analyst
National Human Genome Research Institute
National Institutes of Health
9000 Rockville Pike
Room 31B/4B09 MSC 2152
Bethesda, MD 20892
Telephone No.:    (301) 402-0955
Fax No.:               (301) 402-0837
E-mail Address:    frosstp@mail.nih.gov

Richard Gatti, M.D.
Professor
UCLA School of Medicine
Departments Pathology and Laboratory Medicine
Los Angeles, CA 90095-1732
Telephone No.:    (310) 825-7618
E-mail Address:    rgatti@mednet.ucla.edu

Anthony Hayward, M.D., Ph.D.
Director, Division for Clinical Research Resources
National Center for Research Resources
National Institutes of Health
6701 Democracy Boulevard, Room 906
Bethesda, MD 20892-7518
Telephone No.:    (301) 435-0791
Fax No.:              
E-mail Address:    haywarda@mail.nih.gov

D. Jonathan Horsford, Ph.D.
Acting Program Director
National Institute of Neurological Disorders and Stroke
Division of Neurogenetics
National Institutes of Health
6001 Executive Boulevard, Room 2145
Bethesda, MD 20892-9523
Telephone No.:    (301) 496-5745
Fax No.:               (301) 402-1501
E-mail Address:    horsforj@ninds.nih.gov

Rima Kaddurah-Daouk, Ph.D.
Associate Research Professor
Duke University Medical Center
Department of Psychiatry
P.O. Box 3903
Durham, NC 27710
Telephone No.:    (919) 684-2611
Fax No.:               (919) 681-7668
E-mail Address:    rima.kaddurahdaouk@duke.edu

Howard Lederman, M.D., Ph.D.
Johns Hopkins University
Division of Pediatric Immunology
600 North Wolfe Street, CMSC - 1102
Baltimore, MD 21287-3923
Telephone No.:    (410) 955-5883
Fax No.:               (410) 955-0229
E-mail Address:    hlederm1@jhem.jhmi.edu

Maureen Lefton-Greif, Ph.D.
Speech-Language Pathologist
Johns Hopkins University School of Medicine
Department of Pediatrics & Pediatric Pulmonary
600 North Wolfe Street, Park 316
Baltimore, MD 21287-2533
Telephone No.:    (410) 614-5637
Fax No.:               (410) 955-1030
E-mail Address:    mlefton@jhmi.edu

Yonit Levi, R.N., M.H.A.
Coordinating Nurse
Sheba Medical Center
A-T Children's Medical Center
The Edmond and Lily Safra Children's Hospital
Tel Hasomer 52621, Israel
Telephone No.:    (972-3) 635-5176
Fax No.:               (972-3) 635-5178
E-mail Address:    Yonit@sheba.health.gov.il

Brad Margus
Chief Executive Officer
Perlegen Sciences, Inc.
2021 Stierlin Court
Mountain View, CA 94043
Telephone No.:    (650) 625-4500
Fax No.:               (650) 625-4505
E-mail Address:    Brad_Margus@perlegen.com

Sharon McGrath-Morrow, M.D.
Associate Professor
Johns Hopkins University School of Medicine
Division of Pediatric Pulmonary
600 North Wolfe Street, Park 316
Baltimore, MD 21287
Telephone No.:    (410) 614-5637
Fax No.:               (410) 955-1030
E-mail Address:    'SMCGRATH@JHMI.EDU'

Shuki Mizutani, M.D.
Professor
Tokyo Medical and Dental University
1-5-45 Yushima
Tokyo Japan 113-8519
Telephone No.:    (81) 3-5803-5244
Fax No.:               (81) 3-3818-7181
E-mail Address:    smizutani.ped@tmd.ac.jp

Stacy Moore, B.S., Ph.D.
Senior Field Scientist
Ciphergen
Sales Department
6611 Dumbarton Circle
Freemont, CA 94555
Telephone No.:    (410) 371-4226
E-mail Address:    smoore@ciphergen.com

Andreea Nissenkorn, M.D.
Safra Children Hospital and Sheba Medical Center, Israel
Department of Pediatric Neurology
Tel Ha Shomer
Ramat Gan, Israel
Telephone No.:    (972) 9745-2043
Fax No.:               (972) 9745-2043
E-mail Address:   Andreea.Nissenkorn@sheba.health.gov.il

Mary Oster-Granite, Ph.D.
Health Science Administrator
National Institute of Child Health and Human Development
National Institutes of Health
6100 Executive Boulevard, Room 4B09G
Bethesda, MD 20892-7518
Telephone No.:    (301) 435-6866
Fax No.:               (301) 496-3791
E-mail Address:    Mo96o@nih.gov

David Pearce, Ph.D.
Associate Professor
University of Rochester School of Medicine
Center For Aging and Developmental Biology
601 Elmwood Avenue
P.O. Box 645
Rochester, NY 14642
Telephone No.:    (585) 273-1514
Fax No.:               (585) 276-1972
E-mail Address:    david_pearce@urmc.rochester.edu

Barbara Pietrucha, M.D., Ph.D.
Pediatrician and Clinical Immunologist
The Children's Memorial Health Institute
Departments of Gastroenterology, Hematology & Immunology
Al. Dzieci Polskich 20
04-730 Warsaw, Poland
Telephone No.:    (48-22) 815-73 85
Fax No.:               (48-22) 815-18 39
E-mail Address:    barbara.p@rocketmail.com

Janine Reichenbach, M.D.
Klinikum der J.W. Goethe Universitat Frankfurt am Maine
Department of Pediatrics
60590 Frankfurt am
Main, Germany
Telephone No.:    (49-69) 6301-83611
Fax No.:               (49-69) 6301-83349
E-mail Address:    Janine.reichenbach@kgu.de

Michael Rivkin, M.D.
Associate Professor of Neurology
Children's Hospital of Boston & Harvard Medical School
Department of Neurology
300 Longwood Avenue, Pavilion 154
Boston, MA 02115
Telephone No.:    (617) 355-6073
Fax No.:               (617) 730-0618
E-mail Address:    michael.rivkin@childrens.harvard.edu

Karen Rosquist, R.N.
Research Nurse
Johns Hopkins University
Department of Pediatrics
7117 Bridoon Avenue
Sykesville, MD 21784
Telephone No.:    (410) 614-1922
Fax No.:               (410) 955-0229
E-mail Address:    krosquis@jhmi.edu

Cynthia Rothblum-Oviatt, Ph.D.
Science Coordinator
A-T Children's Project
Research Department
668 South Military Trail
Deerfield Beach, FL 33442
Telephone No.:    (703) 765-1223
Fax No.:               (954) 725-1153
E-mail Address:    cynthia@atcp.org

Ozden Sanal, M.D.
Professor
Hacettepe University Medical School
Pediatric Immunology Division
Ankora, Turkey 06100
Telephone No.:    (90) 312-305-1172
Fax No.:               (90) 312-310-5700
E-mail Address:    sanaloz@tr.net

John Sandlund, M.D.
Member
St. Jude Children's Research Hospital
Departments of Hematology and Oncology
332 North Lauderdale
Memphis, TN 38105
Telephone No.:    (901) 495-3300
Fax No.:               (901) 521-9005
E-mail Address:    john.sandlund@stjude.org

Terence Sanger, M.D., Ph.D.
Assistant Professor of Neurology
Stanford University
Department of Neurology and Movement Disorders
300 Pasteur Drive, Room A-347
Stanford, CA 94305
Telephone No.:    (650) 736-2154
Fax No.:               (650) 725-7459
E-mail Address:    sanger@stanford.edu

Rodney Shackelford, D.O., Ph.D.
Pathology Resident
Louisiana State University at Shreveport
Department of Pathology
1333 Coates Bluff Drive, Suite 1022
Shreveport, LA 71104
Telephone No.:    (318) 865-5907
Fax No.:              (318) 675-7662
E-mail Address:    RdnyShac@aol.com

Aasef Shaikh, M.D, Ph.D.
Fellow
Johns Hopkins University
Department of Neurology
600 North Wolfe Street, Path 2-210
Baltimore, MD 21287
Telephone No.:    (410) 955-2904
Fax No.:              
E-mail Address:    aasefshaikh@gmail.com

Yosef Shiloh, Ph.D.
Professor
Sackler School of Medicine, Tel Aviv University
Departments of Molecular Genetics and Biochemistry
Tel Aviv 69978 Israel
Telephone No.:    972-3-6409760
Fax No.:               972-3-64-7471
E-mail Address:    yossih@post.tau.ac.il

John Slopis, M.D.
Associate Professor
The University of Texas M.D. Anderson Cancer Center
Department of Neurology
1515 Holcombe Boulevard, Box 431
Houston, TX 77030
Telephone No.:    (713) 792-7255
Fax No.:               (713) 794-4999
E-mail Address:    jmslopis@mdanderson.org

Giovanna Spinella, M.D.
Director, Extramural Research Program
Office of Rare Diseases
Office of the Director
National Institutes of Health
6100 Executive Boulevard, Room 3B01
Bethesda, MD 20892-7518
Telephone No.:    (301) 402-4336
Fax No.:               (301) 480-9655
E-mail Address:    spinellg@od.nih.gov

Steven Steinburg, Ph.D.
Technical Laboratory Director
Johns Hopkins University School of Medicine
Institute of Genetic Medicine
600 North Wolfe Street, CMSC10-04B
Baltimore, MD 21287
Telephone No.:    (410) 502-4797
Fax No.:               (410) 955-0484
E-mail Address:    Steven.Steinberg@KennedyKrieger.org

Dominique Stoppa-Lyonnet, M.D., Ph.D.
Head of Genetics Department of the Institut Curie
Institut Curie
Genetics Department
26 rue d'Ulm
Paris, France F75248
Telephone No.:    (33) 1-44-32-4695
Fax No.:               (33) 1-44-32-4695
E-mail Address:    'dominique.lyonnet@curie.net'

Asbjørg Stray-Pedersen, M.D., Ph.D.
Rikshopitalet University Hospital
Department of Pediatrics and Medical Genetics
Oslo N-0027
Norway
Telephone No.:    (47) 4812-5234
Fax No.:               (47) 2307-5590
E-mail Address:    'asbjorg.stray-pedersen@rikshospitalet.no'

Danilo Tagle, Ph.D.
Program Director
National Institute of Neurological Disorders and Stroke
National Institutes of Health
6001 Executive Boulevard, Room 2133
Bethesda, MD 20892-9523
Telephone No.:    (301) 496-9964
Fax No.:               (301) 402-1501
E-mail Address:    tagled@ninds.nih.gov

Carol Vreim, Ph.D.
Deputy Director
National Heart, Lung, and Blood Institute
Division of Lung Diseases
National Institutes of Health
6701 Rockledge Drive, Rockledge II - Suite 10018
Bethesda, MD 20892
Telephone No.:    (301) 435-0233
Fax No.:               (301) 480-3547
E-mail Address:    vreimc@nhlbi.nih.gov

Dalia Waldman, M.D.
Sheba Medical Center
Departments of Pediatric Hematology and Oncology
52621 Tel Hashomer, Ramat Gan
Telephone No.:    (972-3) 530-3037, Ext. 3019
Fax No.:               (972-3) 530-3040
E-mail Address:    daliawa@sheba.health.gov.il

Corry Weemaes, M.D., Ph.D.
Associate Professor of Pediatric Immunology
UMC St. Radboud
Department of Pediatrics
P.O. Box 9101
Nijmegen, The Netherlands
Telephone No.:    (31) 24-3614412
Fax No.:               (31) 24-3619123
E-mail Address:    c.weemaes@cukz.umcn.nl

William Whitehouse, BSc., F.R.C.P.
University of Nottingham
School of Human Development
Queen's Medical Centre
East Floor East Block
Nottingham, United Kingdom NG7 2UH
Telephone No.:    (44) 115-924-9924, Ext. 44476
E-mail Address:    William.whitehouse@nottingham.ac.uk

Yin Yao, Ph.D.
Associate Professor
Johns Hopkins University
Division of Epidemiology
4634 Learned Sage
Ellicott City, MD 21042
Telephone No.:    (410) 955-1213
Fax No.:               (410) 955-0863
E-mail Address:    yyao@jhsph.edu