Ataxia-Telangiectasia Clinical Research Workshop Summary

Ataxia-Telangiectasia Clinical Research Workshop Summary

March 10-11, 2006
Bethesda, MD

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.

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.

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.

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.

Agenda

Friday March 10, 2006

Diagnostic and Assessment Measures for Movement Disorders in Children

Diagnostic and Assessment Measures for A-T

Extra-Cerebellar Characteristics of A-T

Molecular Profiling: Proteomics and Metabolomics in Clinical Research

The Gap Between the Bench and the Bedside

Current Clinical Trials and Assessment Measures for A-T

Summary and Introduction to Break-out Sessions

Saturday, March 11, 2006

 

Participants

Yackov Berkun, M.D.
Senior Pediatrician
Safra Children Hospital and Sheba Medical Center, Israel
Department of Pediatrics

Gerard Berry, M.D.
Professor of Pediatrics and Biochemistry
Thomas Jefferson University
Department of Pediatrics

Luciana Chessa, M.D.
Associate Professor
University "La Sapienza" II Faculty of Medicine
Department of Experimental Medicine and Pathology

Seth Corey, M.D., M.P.H.
Associate Professor
UT-MD Anderson Cancer Center
Department of Pediatrics and Leukemia

Thomas Crawford, M.D.
Associate Professor of Neurology and Pediatrics
Johns Hopkins University
Department of Neurology

Susan Doctrow, Ph.D.
Vice President of Therapeutics Research
Proteome Systems, Inc.

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

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
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

Howard Lederman, M.D., Ph.D.
Johns Hopkins University
Division of Pediatric Immunology

Maureen Lefton-Greif, Ph.D.
Speech-Language Pathologist
Johns Hopkins University School of Medicine
Department of Pediatrics & Pediatric Pulmonary

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

Brad Margus
Chief Executive Officer
Perlegen Sciences, Inc.

Sharon McGrath-Morrow, M.D.
Associate Professor
Johns Hopkins University School of Medicine
Division of Pediatric Pulmonary

Shuki Mizutani, M.D.
Professor
Tokyo Medical and Dental University

Stacy Moore, B.S., Ph.D.
Senior Field Scientist
Ciphergen
Sales Department

Andreea Nissenkorn, M.D.
Safra Children Hospital and Sheba Medical Center, Israel
Department of Pediatric Neurology

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

Barbara Pietrucha, M.D., Ph.D.
Pediatrician and Clinical Immunologist
The Children's Memorial Health Institute
Departments of Gastroenterology, Hematology & Immunology

Janine Reichenbach, M.D.
Klinikum der J.W. Goethe Universitat Frankfurt am Maine
Department of Pediatrics

Michael Rivkin, M.D.
Associate Professor of Neurology
Children's Hospital of Boston & Harvard Medical School
Department of Neurology

Karen Rosquist, R.N.
Research Nurse
Johns Hopkins University
Department of Pediatrics

Cynthia Rothblum-Oviatt, Ph.D.
Science Coordinator
A-T Children's Project
Research Department

Ozden Sanal, M.D.
Professor
Hacettepe University Medical School
Pediatric Immunology Division

John Sandlund, M.D.
Member
St. Jude Children's Research Hospital
Departments of Hematology and Oncology

Terence Sanger, M.D., Ph.D.
Assistant Professor of Neurology
Stanford University
Department of Neurology and Movement Disorders

Rodney Shackelford, D.O., Ph.D.
Pathology Resident
Louisiana State University at Shreveport
Department of Pathology

Aasef Shaikh, M.D, Ph.D.
Fellow
Johns Hopkins University
Department of Neurology

Yosef Shiloh, Ph.D.
Professor
Sackler School of Medicine, Tel Aviv University
Departments of Molecular Genetics and Biochemistry

John Slopis, M.D.
Associate Professor
The University of Texas M.D. Anderson Cancer Center
Department of Neurology

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

Dominique Stoppa-Lyonnet, M.D., Ph.D.
Head of Genetics Department of the Institut Curie
Institut Curie
Genetics Department

Asbjørg Stray-Pedersen, M.D., Ph.D.
Rikshopitalet University Hospital
Department of Pediatrics and Medical Genetics

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

Corry Weemaes, M.D., Ph.D.
Associate Professor of Pediatric Immunology
UMC St. Radboud
Department of Pediatrics

William Whitehouse, BSc., F.R.C.P.
University of Nottingham
School of Human Development
Queen's Medical Centre

Yin Yao, Ph.D.
Associate Professor
Johns Hopkins University
Division of Epidemiology