Newsletter. Issue 3, December Welcome to the third newsletter Ataxia Investigators Meeting

Transcription

1 Newsletter Issue 3, December 2014 Welcome to the third newsletter We are pleased to send you the third newsletter of the ataxia study group (ASG). The highlights of this newsletter are a summary of the 2014 Ataxia Investigators Meeting and a presentation of the ataxia centre in Paris. If you have topics of interest for this newsletter please do not hesitate to contact Holm Graessner via his address holm.graessner@med.uni-tuebingen.de 2014 Ataxia Investigators Meeting By Jacqueline M. Ward, B.S., University of California San Diego The Fifth Ataxia Investigator s Meeting (AIM) took place in March 2014 in Las Vegas, Nevada, thanks to the sponsorship of the National Ataxia Foundation. There were more than 150 attendees from 16 countries at this year s AIM, including representation from 10 companies representing industry. Researchers were able to withstand the many temptations of Las Vegas (for the most part), in order to share cutting-edge research in the field of ataxia. On Tuesday evening, the meeting kicked off with a keynote address from Christopher M. Gomez, M.D., Ph.D., University of Chicago, who described his lab s most recent findings on SCA6. In this disease, the pathogenic CAG mutation occurs in the CACNA1A gene that the Gomez lab has recently found to produce two separate protein products, α1a and α1act. The Gomez lab showed that getting rid of the internal ribosome entry site responsible for production of α1act protein reduces cellular toxicity and could serve as a target for future SCA6 therapy. The Wednesday morning session focused on the role of mitochondria in cerebellar function. David C. Chan, M.D., Ph.D., California Institute of Technology, addressed the identification of ataxia and Purkinje cell degeneration in mice caused by a lack of mitofusin 2. Mitofusin 2 is a transmembrane GTPase embedded in the outer mitochondrial membrane. This work serves to highlight the importance of mitochondrial biology in ataxia and cerebellar biology. Other features from this session include an alleviation of motor symptoms in SCA3 mice through caffeine intake, the implication of a mitochondrial defects in ARSACS, and the first report of magnetic resonance spectroscopy in Friedreich s ataxia. After a quick lunch break, Holly Kordasiewicz, Ph.D., from ISIS Pharmaceuticals started off a very exciting session focused on developing therapies in ataxia. ISIS Pharmaceuticals uses antisense oligonucleotides to reduce mutant protein production and ameliorate effects for many diseases. This approach could be applicable to a number of ataxias demonstrated in the retinal degeneration of SCA7 by Chenchen Niu, M.D., Ph.D. and Albert La Spada, M.D., Ph.D. both at University of California San Diego. The theme of reducing mutant protein production was continued throughout the session with further focus on SCA1 and SCA3. Helene Puccio, Ph.D. also discussed the flipside of the coin in Friedreich s ataxia (FRDA). She demonstrated that expression of human frataxin by adeno-associated virus can correct cardiac defects in mice with FRDA.

2 After a poster session and networking and, maybe, some gambling the night before, the scientists reconvened with lots of coffee the next morning to discuss genomic approaches to ataxia. Susan Ackerman, Ph.D., Jackson Laboratories, described her lab s breakthroughs on the contribution of the U2 multigenic functional RNAs in cerebellar degeneration. These RNAs are strongly expressed in the cerebellum, and mutations in one of them cause ataxia. The rest of the session focused on high throughput techniques including screening for therapeutic targets in SCA1, detecting novel mutations that cause ataxia, and contributions of gene expression alterations to different neurodegenerative phenotypes. The afternoon session explored the theme of cerebellar circuitry and its contribution to cerebellar function. Kamran Khodakhah, Ph.D., Albert Einstein College of Medicine delved into information coding by Purkinje cells. Javier Medina, Ph.D., University of Pennsylvania, described his lab s optogenetic approach to alter the firing rate of individual Purkinje cells, which can modulate the kinetics of eye blinking. Disruption in Purkinje cell firing was also implicated in SCA1 by Vikram Shakkottai, M.D., Ph.D., University of Michigan, in the next talk. Peter Todd, M.D., Ph.D, University of Michigan, contributed to a discussion of the burgeoning phenomenon of unconventional translation in repeat disease, specifically in the mutant FMR1 gene in Fragile X-associated Tremor/Ataxia syndrome. The highlight of the meeting for many was the chance to interact with patients during the poster session on Thursday evening. This session was specifically geared to ataxia patients and their families to ask questions of the scientists who are actually doing the research. Afterwards, Alexandra Durr, M.D., University Hospital Salpetriere in Paris, addressed the scientists as a keynote speaker with an update from EUROSCA. She described the evolution from EUROSCA to what is now the Ataxia Study Group. This consortium yielded the implementation of the SARA scale, as well as currently coordinating studies focused on the presymptomatic phase of ataxia, age of onset, and potential biomarkers. The last session on general ataxia biology kicked off Friday morning with a keynote address from Joe Gleeson, M.D., University of California San Diego. He reported on the identification of a novel mutation in CLP1, a kinase implicated in trna maturation, in a patient with pontocerebellar degeneration. Neurons derived from patient cells exhibit decreased mature trnas due to a splicing defect caused by this mutation. This is the first time trna maturation has been implicated in ataxia or cerebellar degeneration. Other highlights included a discussion of the importance of regulating cell cycle control in neurodegeneration, Purkinje cell dendritic excitability, a novel mouse model of SCA23, and the role of glial activation in SCA1. Following the end of the scientific meeting, the researchers had another chance to interact with patients at the Birds of a Feather small group sessions. Patients, families, and researchers grouped themselves together based on what kind of ataxia they have or study. Patients with similar diseases were able to interact with each other and ask more questions of the scientists. The interaction between the patients and scientists is a unique feature to this meeting that allows the researchers to meet the people who are benefitting from their work. This interaction can change the perspective and motivate many scientists. NeurOmics - Invitation to all Ataxia (and SPG) centres to register at the NeurOmics Care and Trail Site Register The Care and Trial Site Registry (CTSR), set up 6 years ago within the neuromuscular community, has now been significantly expanded by NeurOmics (coordinated by Olaf Riess) to include rare neurodegenerative conditions. At the moment there are 294 neuromuscular sites registered across the world and we need to aim for similar coverage amongst those centres which see neurodegenerative patients too. The CTSR has been instrumental in getting the NMD field more trial-ready and has provided information about feasibility and potential trial-sites in response to many enquiries over the past 6 years. For this to also be of benefit to NDD care and research, we really need to get relevant sites registered. The CTSR can be accessed here: Please register your ataxia centre at the CTSR!

3 Highlighting an Ataxia Centre of the ASG: Reference Center for Neurogenetic Diseases, Paris, France The Reference Center for Neurogenetic Diseases ( was created in 2005 under the leadership of Pr. Alexis Brice as part of a national plan for rare diseases. It provides expertise in rare motor diseases of the central nervous system such as cerebellar ataxia, hereditary spastic paraplegia, dystonia, movement disorders, and pediatric neurodegenerative diseases (progressive encephalopathies, leucodystrophies). The center is located in two hospitals in Paris, the Pitié-Salpêtrière (department of Genetics - Pr. Brice, Department of Neurology - Pr. Vidailhet) and the Trousseau Hospitals (Neuropediatric Department - Pr. Billette de Villemeur). It gathers a pluridisciplinary team with different medical experts (geneticists, neurologists, neuropediatricians), working with psychologists, genetic counselors, a social worker, a physiotherapist. Our goal is to provide global care to the patient, form childhood to adulthood, as a resource center for neurologists or general practitioners, at the local, regional and national levels. We organize the care of patients in collaboration with other expert centers in France, and aim at developing collaborations with rehabilitation centers willing to increase their knowledge and expertise on this topic. In the field of cerebellar ataxias, we develop clinical diagnosis and follow-up tools, provide access to molecular diagnosis, and genetic counseling. We have a special interest in prenatal and presymptomatic diagnosis with dedicated weekly clinics and a monthly round gathering the members of the reference center and specialized obstetricians. The reference center is also leading many clinical research projects, particularly on the development of biomarkers (including at the presymptomatic stage) and trials for new therapies. The Reference centers is closely linked with research teams located at the ICM (Institut du Cerveau et de la Moelle Epinière brain and spinal cord Institute) at the Pitié-Salpêtrière Hospital. The ICM, created in 2010, became rapidly a leading institute in neuroscience research. The team of A. Brice, with Alexandra Durr, Giovanni Stevanin and Annie Sittler is focusing on the genetic basis, pathophysiological mechanisms and preclinical treatment of neurodegenerative diseases, in particular spinocerebellar degenerations. This close link is illustrated by the fact that all families with ataxia followed at the neurogenetic reference center clinics are included in the SPATAX network ( coordinated by Pr Alexandra Durr), a large collection of clinical data and biosamples shared with an international network of European and Mediterranean clinicians and scientists, dedicated to the elucidation of the molecular basis of ataxias and hereditary spastic paraplegias. Core research activities Next Generation Sequencing (exomes, gene panels) in cerebellar ataxias Expansion of the SPATAX network Validation of quantitative tools and scales (clinical, imaging or biological) Clinical Trials AOA1 and CoQ10 treatment (ongoing) BIOSCA: Identification of biomarkers in spinocerebellar ataxias 1, 2, 3, and 7 (NCT , ongoing) NEUROMICS : Integrated European Project on Omics Research of Rare Neuromuscular and Neurodegenerative Diseases (ongoining) EFACTS : European Friedreich s Ataxia Consortium for Translational Studies (ongoing) CERMOI : Cerebellum, eye movements and instability (to be started) ORFA : Voice, audition in Friedreich s ataxia

4 Research and clinical team of the Reference Center for Neurogenetic Diseases, Paris, France Recent publications in the field of ataxias Tezenas du Montcel S, Durr A, Bauer P, Figueroa KP, Ichikawa Y, Brussino A, Forlani S, Rakowicz M, Schöls L, Mariotti C, van de Warrenburg BP, Orsi L, Giunti P, Filla A, Szymanski S, Klockgether T, Berciano J, Pandolfo M, Boesch S, Melegh B, Timmann D, Mandich P, Camuzat A; Clinical Research Consortium for Spinocerebellar Ataxia (CRC-SCA); EUROSCA network, Goto J, Ashizawa T, Cazeneuve C, Tsuji S, Pulst SM, Brusco A, Riess O, Brice A, Stevanin G. Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes. Brain Sep;137(Pt 9): Alves S, Cormier-Dequaire F, Marinello M, Marais T, Muriel MP, Beaumatin F, Charbonnier-Beaupel F, Tahiri K, Seilhean D, El Hachimi K, Ruberg M, Stevanin G, Barkats M, den Dunnen W, Priault M, Brice A, Durr A, Corvol JC, Sittler A. The autophagy/lysosome pathway is impaired in SCA7 patients and SCA7 knock-in mice. Acta Neuropathol Nov;128(5): Tezenas du Montcel S, Durr A, Rakowicz M, Nanetti L, Charles P, Sulek A, Mariotti C, Rola R, Schols L, Bauer P, Dufaure-Garé I, Jacobi H, Forlani S, Schmitz-Hübsch T, Filla A, Timmann D, van de Warrenburg BP, Marelli C, Kang JS,Giunti P, Cook A, Baliko L, Melegh B, Boesch S, Szymanski S, Berciano J, Infante J, Buerk K, Masciullo M, Di Fabio R, Depondt C, Ratka S, Stevanin G, Klockgether T, Brice A, Golmard JL. Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6. J Med Genet Jul;51(7): Multiple-System Atrophy Research Collaboration. Mutations in COQ2 in familial and sporadic multiplesystem atrophy. N Engl J Med Jul 18;369(3): Lee YC, Durr A, Majczenko K, Huang YH, Liu YC, Lien CC, Tsai PC, Ichikawa Y, Goto J, Monin ML, Li JZ, Chung MY, Mundwiller E, Shakkottai V, Liu TT, Tesson C, Lu YC, Brice A, Tsuji S, Burmeister M, Stevanin G, Soong BW. Mutations in KCND3 cause spinocerebellar ataxia type 22. Ann Neurol Dec;72(6): Marelli C, Figoni J, Charles P, Anheim M, Tchikviladze M, Vincitorio CM, Tezenas du Montcel S, Brice A, Golmard JL, Dürr A. Annual change in Friedreich's ataxia evaluated by the Scale for the Assessment and Rating of Ataxia (SARA) is independent of disease severity. Mov Disord Jan;27(1): Marelli C, van de Leemput J, Johnson JO, Tison F, Thauvin-Robinet C, Picard F, Tranchant C, Hernandez DG, Huttin B, Boulliat J, Sangla I, Marescaux C, Brique S, Dollfus H, Arepalli S, Benatru I, Ollagnon E, Forlani S, Hardy J, Stevanin G,Durr A, Singleton A, Brice A. SCA15 due to large ITPR1 deletions in a cohort of 333 white families with dominant ataxia. Arch Neurol May;68(5):

5 Contact for the ASG Newsletter Holm Graessner, University of Tuebingen, Phone: