• Future research priorities
• Potential collaborations
• Funding strategies

The National Institute of Neurological Disorders and Stroke (NINDS), the Office of Rare Diseases (ORD), and the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) co-sponsored this workshop. This workshop was organized by Dr. Danilo A. Tagle (NINDS), Dr. David Pearce (University of Rochester), Dr. Mark Atkinson (University of Florida), and Dr. Rose-Mary Boustany (Duke University). The workshop addressed key questions and issues regarding key discoveries in Batten Disease research, in particular the recent observation of GAD65 autoimmunity in juvenile ceroid lipofuscinosis (JNCL) patients and in animal models. The workshop served effectively to facilitate the exchange and integration of ideas, information and technologies from experts in Batten disease, type I diabetes, Stiff Person syndrome (SPS), Rasmussen's encephalitis and autoimmunity in the CNS (see Meeting Agenda). The goals of this workshop were to determine the scientific criteria that are necessary to measure the contribution of GAD65 autoantibodies to the pathological consequence of JNCL, to critically evaluate research to date on the autoimmune response in JNCL, to assess the role and contribution that mouse models to JNCL may have on understanding other diseases such as type I diabetes and SPS, to evaluate the efficacy of instituting treatments directed toward a pathological autoantibody in JNCL, to determine if end-points are in place for assessment of a putative-JNCL therapy. The speakers were tasked to consider these points in their presentations and to engage the participants in a meaningful and productive discussion after each session topic.

The purpose of this workshop was to discuss the implications and to follow-up on strategies from research findings by NINDS grantee Dr. David. Pearce of the University of Rochester School of Medicine and Dentistry in New York where he demonstrated that mice lacking the gene that is mutated in juvenile Batten disease have an immune reaction against an important enzyme in the brain. Similar immune reactions were found in children with Batten disease. The enzyme, called glutamic acid decarboxylase 65 (GAD65), normally converts excitatory neurotransmitter glutamate into the inhibitory neurotransmitter GABA. These autoantibodies could be indicative of an autoimmune attack against GAD, which could result in excess excitatory neurotransmitter, leading to the seizures and other symptoms observed in Batten patients. The study is the first to find evidence that the immune system may play a role in Batten disease and provides new insights into the pathogenesis of Batten disease. This study was published in Human Molecular Genetics (Chattopadhyay, S., Ito, M., Cooper, J.D., et al. An autoantibody inhibitory to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease, 2002; 11:1421-1431. An NINDS press release about this finding is available on the web at http://www.ninds.nih.gov/news_and_events/pressrelease_batten_052202.htm. A follow up study was later published in Chattopadhyay, S, Kriscenski-Perry, E., Wenger, D.A., Pearce, D.A. An autoantibody to GAD65 in sera of patients with juvenile neuronal ceroid lipofuscinoses. Neurology. 2002; 59:1816-1817. The redefinition of Batten disease as an autoimmune disorder could have radical implications for the treatment of Batten.

II. Recommendations

The workshop brought together neuroscientists, immunologists and clinicians who work on Batten disease and on a variety of autoimmune diseases, such as multiple sclerosis, Stiff Person Syndrome, Rasmussen's encephalitis, and type I diabetes. The attendees' response to the workshop was overwhelmingly positive. In addition to generating spirited discussion among researchers of different fields, who might not otherwise interact, several new collaborations were forged and valuable resources were offered for sharing.

The group concluded that Pearce's result is intriguing, but will require certain key follow-up experiments in order to conclude that Batten is an autoimmune disease. Autoantibodies can be present in an individual without causing disease-the fundamental question is whether the GAD autoantibodies are activating T-cells to trigger a full-fledged immune response. There are two gold-standard experiments to address this question. The first is to remove the autoantibodies from a patient via plasma exchange and determine if the patient's condition improves (a test of whether the autoantibodies are necessary to develop the disease). The second is to inject the autoantibodies into a healthy mouse and determine whether it then develops the disease (a test of whether the autoantibodies are sufficient to confer the disease). Although there was some discussion of whether such experiments were warranted at this time, most workshop participants seemed satisfied with Dr. Pearce's plans to conduct preliminary experiments using transgenic mouse models. He will cross mouse mutants that carry Batten disease mutations with mice that have an impaired immune system. If the physical effects of Batten are in fact due primarily to an immune response, then these mice should not develop the full Batten phenotype.

The following are the outstanding issues that the group indicated should be addressed in assessing the potential autoimmune nature of Batten Disease:

• What are the specific roles, if any, for humoral and cellular immune responses in the pathogenesis of Batten disease?
• Other than GAD65, what additional neuronal molecules serve as antigenic targets of autoantibodies?
• Are studies of immune based therapies (e.g., plasma exchange, immunosuppression) warranted for Batten patients at this time?
• Are there associations between Batten disease and other putative autoimmune disorders (i.e., is there a clustering with other autoimmune diseases or one autoimmune disorder in particular)?
• What is the exact function of the CLN3 molecule in the pathogenesis of Batten Disease?
• Given their demonstrative ability to inhibit enzymatic activity in vitro, do GAD autoantibodies in Batten disease interfere with GABAergic regulation in vivo?
• If autoimmune in basis, why does the development of Batten disease occur in such a protracted form?
• Why does anti-GAD immunity represent such a common feature to a variety of clinical disorders?

A review of the field and relevant discussions from the workshop is published in the Journal Neurology