Kevin Peikert, MD 1 and Andreas Hermann, MD, PhD 1,2,3
1 Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden,
2 Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden,
3 German Center for Neurodegenerative Diseases (DZNE) Dresden, Dresden, Germany
The “9th International Meeting on Neuroacanthocytosis Syndromes” was held March 23-25, 2018 in Dresden, Germany, also known and famous as “Florence on the Elbe”. The conference followed the tradition of the previous eight international symposia, the last of which was held in Ann Arbor, USA in May, 2016. For the second time , the meeting assembled patients, their families and caregivers along with scientists working in this field - again a tremendously inspiring experience for all participants.
The conference focused on chorea-acanthocytosis (ChAc), one of the “core” diseases of the neuroacanthocytosis (NA) syndromes. It is caused by mutations in the VPS13A gene coding for chorein. It is a neurodegenerative disease that leads to chorea, epilepsy, problems with mood, thinking and memory, and is associated with acanthocytosis of red blood cells. At present there are no treatments that can halt or slow down the progression of the NA diseases.
The abstracts of the scientific talks and posters are under preparation for publication. Here, we give a brief overview of the topics and main messages of the meeting. Both important developments in basic science since 2016 as well as potential clinical translation of experimental treatment approaches developed in vitro were discussed.
The Symposium opened with a joint session attended by scientists, patients and caregivers, chaired by Ginger Irvine (NA Advocacy). Claudia Volger (Leipzig, Germany), mother of two brothers suffering from ChAc, presented an inspiring patient family story which was followed by an overview of the current state of knowledge of ChAc and other NA syndromes by Dr . Adrian Danek (Munich, Germany). Dr. Andreas Hermann (Dresden, Germany), chair of the meeting, provided information on recent developments in basic science and translational research in this field.
Patients and caregivers had the opportunity to address questions and concerns to these two experts along with Drs. Ruth H. Walker (New York, USA) and Hans H. Jung (Zurich, Switzerland).
The VPS13 protein family consists of four related proteins in mammals, VPS13 A-D, but of only one protein in yeast. The scientific part started with an overview of the VPS13 gene family and clinical and genetic features of VPS13A were presented by Dr. Adrian Danek und Dr. Antonio Velayos-Baeza (Oxford, UK). Furthermore, leading experts (Drs. Wenke Seifert (Berlin, Germany), Christine Van Broeckhoven (Antwerp, Belgium) and Catherine Collins (Ann Arbor, USA)) gave an overview of VPS13B-D genes and their respective mutations. Even though the different VPS13 proteins cause distinct neurodegenerative diseases in humans, namely VPS13B Cohen syndrome, VPS13C diffuse Lewy body pathology, VPS13D ataxia and spastic paraplegia phenotypes or childhood movement disorders, the underlying mechanisms clearly show an overlap concentrating on neurodegeneration, problems with autophagy, mitochondrial dysfunction and vesicle trafficking. However, acanthocytosis so far has only been reported in VPS13A/ChAc.
The second day focused on function and dysfunction of the VPS13A gene and its respective protein, chorein, in different models of the disease; including yeast (Drs. Robert Fuller (Ann Arbor, USA), Aaron Nieman (Stony Brook, USA), Teresa Zoladek (Warsaw, Poland)), Dictyostelium (Dr. Ricardo Escalante (Madrid, Spain)), Drosophila (Dr. Ody Sibon (Groningen, Netherlands)), mouse (Drs. Masayuki Nakamura (Kagoshima, Japan) and Birgit Rathkolb (Munich, Germany) ),and in patient derived human neuronal cells (Drs. Hannes Glaß (Dresden, Germany) and Sami J. Barmada (Ann Arbor, USA)). The various roles of VPS13A in health and disease were addressed: cellular transport, autophagy (meaning degradation of cellular components), cytoskeleton (“cell architecture”), calcium balance etc… All those mechanisms are necessary for survival of cells and can lead to diseases when disturbed.
Following that, the conference thoroughly discussed two cellular pathways that seem centrally disturbed in ChAc and which may imply future treatment approaches. Drs. Lucia de Franceschi (Verona, Italy), Florian Lang (Thübingen, Germany) and Giel Bosman (Nijmegen, Netherlands) explained impacts of two disturbed signal proteins, called “Lyn” and “PI3K”, on red blood cells and neurons.
The last session of the day was dedicated to clinical issues. Drs. Ruth H. Walker (New York, USA) and Bernhard Landwehrmeyer (Ulm, Germany) presented symptomatic treatment options including deep brain stimulation, whereas Dr. Christian Beste (Dresden, Germany) provided insights in his work on cognitive function in neurodegenerative diseases and how this could be measured in a more standardized way. The take home message was that up to now no causal therapy is available, and all treatment strategies still concentrate on symptomatic relief. The data on deep brain stimulation (DBS) isare still vague, with some hints that DBS might be beneficial against choreatic movements, but a decision for DBS still warrants intensive discussion between the single patient and the experts in the field. Ginger Irvine (NA Advocacy) closed the session with her talk on patient-centered care by giving examples of daily life with her daughter Alex.
On the third and last day, the scientists discussed possible future treatment approaches focusing on the two main disease pathways introduced the day before. These pathways represent promising “drugable” targets. The workshop based on results from two experimental treatment approaches with two different drugs (FDA/EMA approved for other indications) addressing those targets in overall 5 ChAc patients was performed by a consortium consisting of basic scientists and neurologists led by Dr. Andreas Hermann. The very preliminary results encourage us to further investigate these drug targets and to prepare for possible future clinical trials in parallel. However, it also became clear that the natural history of ChAc in patients differs significantly between the affected individuals and thus makes clinical read-outs for interventions difficult to judge. While the scientific community remains optimistic, this is only the beginning of a long way ahead.
The setting of the meeting encouraged interactions, exchange of ideas and networking opportunities among all participants. Young faculty and students used the opportunity to present their work during the poster session.
Patients and caregivers continue to play a critical role, discussing the next steps, action points, and future studies. This is a collaborative process involving researchers, clinicians, patients, and caregivers, in our quest to advance knowledge and practice.
We acknowledge the financial support by the German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany and the Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Germany and the Advocacy for Neuroacanthocytosis Patients. Finally, we thank the Radisson Blue Hotel for hosting the meeting and covering costs of accommodation for some ChAc patients.
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