European Workshop on Ataxia-Telangiectasia, Frankfurt, 2011

J. Neurogenetics, 25(3): 78–81 Copyright © 2011 Informa Healthcare USA, Inc. ISSN: 0167-7063 print/1563-5260 online DOI: 10.3109/01677063.2011.592553

Workshop Report: European Workshop on Ataxia-Telangiectasia, Frankfurt, 2011 Stefan Zielen and Ralf Schubert

J Neurogenet Downloaded from informahealthcare.com by 202.43.112.106 on 05/20/14 For personal use only.

Children’s Hospital, Department of Allergy, Pneumology and Cystic Fibrosis, Goethe-University, Frankfurt am Main, Germany

Abstract: Ataxia-telangiectasia (A-T) is a devastating human recessive disorder characterized by progressive cerebellar ataxia, immunodeficiency, chromosomal instability, and cancer susceptibility. The European Workshop on Ataxia-Telangiectasia 2011 in Frankfurt focused on status quo of patient care and future clinical research directions. In Europe, approximately 600 patients are registered and many national websites have been established. During the meeting, guidelines of patient care were discussed and all participants agreed to build up an European A-T research network in near future to bring basic research and new therapies into clinical applications. Keywords: Ataxia-telangiectasia (A-T), A-T advocacy organizations, A-T registry, cancer, chromosomal instability, immunodeficiency

On January 28–29, 2011, the Clinical Workshop on Ataxia Telangiectasia (A-T) was held in Frankfurt, Germany. Under the theme “Clinical Science for A-T: Status Quo and Future Directions,” the purpose of the workshop was to bring together European clinical researchers in the field of A-T. The meeting was strengthened by having clinical representatives from Johns Hopkins Hospital, Baltimore, and University of California–Los Angeles (UCLA), Los Angeles. Representatives from the UK’s A-T Society, France’s A-T Europe, Germany’s HeredoAtaxia Society (DGHA), as well as from the USA’s A-T Children’s Project (A-TCP) were also present to express their support. In addition, five A-T families joined the meeting. A-T is a highly pleiotropic, autosomal recessive disorder. Patients suffer from progressive neurodegeneration, severe bronchial complications, cellular as well as humoral immunodeficiency, elevated risk of malignancies, hypersensitivity to radiotherapy, and lung disease (Lavin et al., 2007). In addition, patients often suffer from growth failure and severe dystrophy and cerebellar lesions in A-T go along with deficiency of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis (Schubert et al., 2005; Kieslich et al., 2010). Patients with A-T are frequently wheelchair-bound by their teens. Expected life span is between 15 and 25 years of age and death is caused predominantly by lung failure or cancer (Crawford et al., 2006; McGrath-Morrow et al., 2010). Although a number of potential options for treating A-T patients exist, at present there is no therapy available to cure or prevent the progress of A-T (Lavin et al., 2007).

In this regard, the meeting focused on general guidance for clinical examinations of A-T patients and to define markers that reflects disease progression in order to improve patients care as well as to lay the foundation for future clinical studies and applications. Oral presentations and discussions circled around the topics “A-T Registry and Clinical Centers,” “Therapeutic Approaches—Preclinical Trials,” and the “Therapeutic Approaches—Clinical Trials” were framed by perspective lectures about “mutation-targeted therapies” and “the spectrum of neurodegenerative aspects in A-T” given by Richard Gatti (UCLA, Los Angeles) and Tom Crawford (Johns Hopkins Hospital, Baltimore), respectively. Special work group sessions started to establish a consensus paper documenting current agreement on aspects of outcome parameters for use in clinical trials in regard of neurology, immunodeficiency, cancer, and Ataxia Telangiectasia Mutated (ATM) function. Of course, further work is necessary to reach this goal. The present workshop report summarizes the outcomes of the meeting and will try to give future perspectives of clinical research in the field of A-T.

A-T REGISTRY AND CLINICAL CENTERS In this session the importance of clinical data collection and clinical centers for patients care as well as in clinical trials were discussed. Dr. Luciana Chessa (University La Sapienza, Roma) and Dr. Benjamin Gathmann (Uniklinikum Freiburg) respectively reported about the Italian Registry for A-T (RIAT), which includes medical and

Received 26 May 2011; accepted 26 May 2011 Address correspondence to Ralf Schubert, Children’s Hospital, Department of Allergy, Pneumology and Cystic Fibrosis, Goethe-University, 60590 Frankfurt am Main, Germany. E-mail: [email protected] 78


European Workshop on Ataxia-Telangiectasia

laboratory data of 171 A-T patients, and The ESID Online Database for Primary Immunodeficiencies (www.esid.org/ esid_testregistry.php), which can be used as platform for research on A-T. A-T is classified among “other well-defined PID” in the ESID database and represents one of the 10 largest disease entities with 572 registered patients in Europe. Dr. Yonit Levi (Edmond and Lily Safra Children’s Hospital, Tel Ha Shomer) demonstrated the benefits of clinical centers in patients care and collecting relevant demographic, clinical, and laboratory characteristics, especially for rare diseases such as A-T. This was underlined by Prof. Kate Sinclair (Royal Children’s Hospital, Brisbane) who showed in her presentation the establishment and operation of a dedicated team of academic specialist clinicians across multiple disciplines offering patients multidisciplinary care and support as well participation in studies. Assistive technology adjustment in A-T was shown by Dr. Efrat Shenhod (A-T Children National Clinic, Tel Ha Shomer) to promote physical and psychological age-appropriate independence, function, and participation of A-T patients. In his talk Herman Stimm (German Heredo-Ataxia Society, Stuttgart) presented data of a German questionnaire about quality of life of A-T patients. He concluded that general conditions, especially growth failure and lack of weight gain, should be more in the focus of physicians. Table 1 summarizes all websites of international A-T advocacy organizations.

THERAPEUTIC APPROACHES— PRECLINICAL TRIALS Interesting insights into the field of preclinical work and new therapeutic approaches was given by researchers with clinical and scientific background. Sophie Schirmer from the University of Regensburg showed proteomic analysis of the cellular response to ionizing

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radiation in ATM-mutation carriers. Julia Pietzner from the Goethe University, Frankfurt, first presented results from a bone marrow transplantation trial that successfully improved outcome of Atm-deficient mice. Prof. Marcel van Deuren (Radboud University Nijmegen) and Dr. Elizabeth McDermott (Nottingham University Hospitals), both carry out research on the immune deficiency in A-T, showed class switch recombination defects in the B-cell department and influence of ATM kinase activity on the T-cell receptor repertoire in A-T patients, respectively. In a special talk Cédric Anchisi from the organization A-T Europe introduced this charity tool and the new Web page. Founded in France, the aim of this structure is national and international coordination to efficiently finance A-T research and to improve support for the children.

THERAPEUTIC APPROACHES— CLINICAL TRIALS The majority of inputs in the clinical session centered on neurological symptoms of A-T patients. Dr. Michèl Willemsen (Radboud University Nijmegen) showed mixed extrapiramidal syndromes in adulthood as presenting feature of variant A-T. His presentation was followed by a discussion about how consistent cognitive impairments in A-T are, which was initiated by the talk by Dr. Franziska Hoche (Goethe University, Frankfurt). An ongoing trial on amantadine sulfate treatment (ClinicalTrials.gov Identifier: NCT00950196) was presented by Dr. Andreea Nissenkorn (National A-T Clinic, Ramat Gan). Another study using dexamethasone treatment was introduced by Dr. Luciana Chessa from the University La Sapienza, Roma, and controversially discussed by the audience. In addition, Dr. Barbara Pietrucha from Children’s Memorial Health Institute, Warsaw, talked about assessment of humoral immunity and viral markers in Polish patients with A-T and

Table 1. International A-T advocacy organizations. Country Australia Europe France Germany Israel Italy Italy Japan Norway Poland Spain The Netherlands United Kingdom United States

International A-T advocacy organizations

Web address

BRASHAT A-T Europe APRAT A-T Info Association for Fighting A-T Disease Un Vero Sorriso Onlus (A True Smile Association) Gli Amici di Valentina (Friends of Valentina) Team A-T (Jpn) AT-Norge (AT-Norway) Razem Zdazymy (Together We are in Time) AEFAT Stichting A-T A-T Society A-T Children’s Project

www.brashat.org.au www.ateurope.org www.aprat.fr www.info-at.de www.a-t.org.il www.unverosorriso.it www.gliamicidivalentina.eu www.tmd.ac.jp/med/ped/atcp www.at-norge.no www.razemzdazymy.republika.pl www.ataxiatelangiectasia.es www.stichting-at.org http://www.atsociety.org.uk/ http://www.atcp.org/

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Dr. Nadine Andrieu from the INSERM, Paris, showed the characteristics of women with an A-T related to their genetic status. Consensus of the session was that a closer cooperation of European A-T centers is necessary.


WORKGROUPS The aim of the workgroups was to define outcome parameters for use in clinical trials in regard of neurology, immunodeficiency, and cancer. Of course time was short so each topic just touched on the basics, but the fruitful discussions of the workgroups definitely laid the foundation for further meetings.

Neurology Under the chair of Prof. Tom Crawford and Prof. Matthias Kieslich (Goethe University, Frankfurt), the workgroup “Neurology” discussed the wide clinical neurological spectrum of A-T affecting different systems of the central nervous system as well as the peripheral nervous system. To face the neurology of A-T, it is important to understand it as a multisystem neurological disorder. We do not know why and in which patients different neurological presentations are dominant. To understand the underlying pathophysiology and to develop therapeutic approaches and prognostic risk profiles, basic research as well as clinical studies and even clinical observations are mandatory. The attending scientists from more than 10 different countries shared their experiences and approaches covering basic clinical neurological follow-up as well as neurophysiological, neurocognitive, and drug studies. An age-related clinical scale based on the knowledge of the age-correlated neurodegeneration in A-T, mainly between 5 and 15 years, seems necessary. Modern magnetic resonance imaging (MRI) techniques such as tractography, spectroscopy, and functional MRI as well as deep-brain stimulation may be promising tools to examine neurodegeneration. Immunodeficiency and Laboratory Under the chair of Prof. Dr. Asborg Pederson (University of Oslo), and Prof. Stefan Zielen, the workgroup “Immunodeficiency and Laboratory” discussed how different immunoglobulin replacement therapy is used in patients with A-T. It varies widely between the centers, from 10% to 100% as shown in Table 2. Most centers used immunoglobulin replacement therapy only in patients with frequent respiratory infections. However, it is completely unknown whether this restricted approach is the best for our patients. Unfortunately, no

S. Zielen and R. Schubert

Table 2. Use of Immunoglobulin replacement therapy in different centers*. Centers Frankfurt, Germany Düsseldorf, Germany Israel Nottingham, UK Cambridge, UK Norway ESID Registry USA John Hopkins

Number of all patients

Patients (%) treated with immunglobulins

36 8 53 39 40 14 572 320

10 100 60 10 10 8 33 10–15

*

Data from personal communication of workgroup participants.

placebo-controlled studies are available to prove that A-T patients might benefit from early immunoglobulin therapy. Next it was discussed that markers of disease progression have not been established so far. Possible markers could be the following: α-fetoprotein, the number of CD4/CD8 CD45RA-naïve cells, and ATM kinase activity. However, ATM kinase activity may be a marker that reflects different disease progressions in A-T variants versus classic A-T, but is of no value in clinical follow-up. Laboratory work-up has to be split into clinical follow-up/standard patient care and clinical research for proof-of-concept trials for new drugs. In addition, it was discussed whether clinical disease progression and cancer risk in A-T is related to an ongoing inflammatory response as was suggested by data of the John Hopkins group published recently (McGrath-Morrow et al., 2010). Finally, all participants agreed that during future A-T meetings more time is needed for a workshop on “Immunodeficiency and Laboratory” to address all questions around immunodeficiency in more detail. Moreover, all participants would appreciate the development of an A-T Clinical Research Network to facilitate European longitudinal studies on the discussed unsolved research questions. Biologics: Cancer and ATM Function Under the chair of Prof. Malcom Taylor (School of Cancer Sciences, Birmingham) and Dr. Thilo Dörk (Medizinische Hochschule Hannover), the workgroup “Biologics: Cancer and ATM Function” first discussed how to get complete cellular characterization of A-T patients for future trials for defining populations of A-T patients, such as ATM protein level, ATM kinase activity, ATM mutation identification, and quantitative assessment of ATM mRNA. In this regard, it was suggested to determine whether different levels of ATM kinase activity can be defined in order to test quantitation, reliability, and consistency between different laboratories using lymphoblastoid cell lines (LCLs) that express

European Workshop on Ataxia-Telangiectasia

different levels of normal or mutant ATM. For therapies that might improve existing level of ATM activity/ function, it has to be clarified (1) how large an improvement in activity is required, (2) how small an improvement in activity can be measured, and (3) how this can be reliably measured. For therapies that might reinstate ATM expression, “readthrough” methods such as immunoblotting, nuclear foci (IRIF), and FC-Smc1 are considered for monitoring patients in therapy.


CONCLUSIONS The discussion during the meeting was very lively and interesting. It was found to be a good forum to get closer in contact with each other. All participants of the workshops agreed that during future A-T meetings more time is needed for discussions. In addition, all participants agreed to build up an European A-T research network in the near future to help translate basic research into clinical applications closer together. ACKNOWLEDGMENTS We would like to thank all presenters, participants, parents, sponsors, and volunteers of our meeting for their contributions, their engagement, and lively discussions. Special thanks go to Prof. Richard Gatti and Prof. Tom Crawford for supporting the success of the meeting.

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Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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