Special issue: Molecular basis of the NCLs

TY - JOUR

T1 - Special issue

T2 - Molecular basis of the NCLs

AU - Mole, Sara E.

AU - Williams, Ruth E.

AU - Cooper, Jonathan D.

N1 - Funding Information: Sara E. Mole a b c ⁎ [email protected] Ruth E. Williams d [email protected] Jonathan D. Cooper e [email protected] a MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK MRC Laboratory for Molecular Cell Biology University College London Gower Street London WC1E 6BT UK b Department of Genetics, Evolution and Environment, University College London, Gower Street, London WC1E 6BT, UK Department of Genetics, Evolution and Environment University College London Gower Street London WC1E 6BT UK c Molecular Medicine Unit, UCL Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK Molecular Medicine Unit UCL Institute of Child Health University College London 30 Guilford Street London WC1N 1EH UK d Department of Children's Neurosciences, Guy's and St Thomas' NHS Foundation Trust, Westminster Bridge Road, London SE1 7EH, UK Department of Children's Neurosciences Guy's and St Thomas' NHS Foundation Trust Westminster Bridge Road London SE1 7EH UK e Department of Neuroscience, James Black Centre, Institute of Psychiatry, King's College London, 125 Coldharbour Lane, London SE5 9NU, UK Department of Neuroscience James Black Centre Institute of Psychiatry King's College London 125 Coldharbour Lane London SE5 9NU UK ⁎ Corresponding author at: MRC Laboratory for Molecular Cell Biology, UCL Institute of Child Health, University College London, Gower Street, London WC1E 6BT, UK. The neuronal ceroid lipofuscinoses (NCLs), often known as Batten disease, are a group of rare and devastating neurodegenerative disorders. They commonly affect children but can strike at any age, from before birth up to late in life. They are genetic diseases, usually inherited in an autosomal recessive manner, and at present are incurable. This special issue follows the latest international meeting on the NCLs—the 13th international congress, NCL2012 ( 150 clinical, scientific and professional experts from around the world. There were 50 talks and 64 posters, and 2 outreach workshops for professionals. Additional satellite meetings included those of the DEM-CHILD Consortium, funded by the European Union, which ranged from meetings of those collaborating on work packages, to training for families and professionals, and a gathering of all PhD students. This European Consortium has since expanded to include international clinical collaboration centering on the natural history of the NCLs. http://www.ncl2012.org )—which was held in March 2012 in London, United Kingdom, and attended by a total of > In addition to these scientific and clinical activities, there was a parallel Family Conference hosted by the UK Batten Disease Family Association that was attended by nearly 100 families with some sessions held jointly with the scientific conference, including an innovative and popular shared interactive ‘market place’ event (with 12 ‘stalls’) that shared the wide expertise of all of those present. This integration of science, clinical, professional and lay perspectives without diluting what is essentially a scientific meeting exemplifies a new format of meeting. This can be further built upon in future scientific congresses in this field, for other rare diseases, and adapted for use in other fields. We commissioned a series of reviews from attending experts, deliberately requesting shared co-authorship across different institutions to reflect the excellent cooperative international expertise that exists, a particular feature perhaps of research into a rare disease. The aim of these reviews is to provide articles that summarise the current status of the NCL field. The first review (Haltia and Goebel) deliberately looks to the past since the NCLs were first proposed as a distinct clinical diagnosis in the late 1960s, but are now increasingly defined on the basis of their genetics. This ensures that relevant knowledge and experience built up over these years is not forgotten, but can be integrated with new developments, such as recent changes in disease nomenclature, as well as highlighting key historical landmarks. The genetic basis of the NCLs including the number of genes and mutations, and correlations with phenotype since some mutations cause disease of a very different clinical course, are discussed by Warrier et al., as well as providing links to the updated web-based NCL Mutation and Family Databases. Bioinformatic approaches have become more sophisticated and used to advance research particularly in the areas of establishing the genetic basis of disease in individual families and in predicting the molecular basis of NCL disease. These new and recent approaches in the NCL field are summarised by Kmoch et al. A review on the clinical perspectives of the NCLs summarises features of the different NCLs, such as range of ages at onset and presenting symptoms, and characteristics of progression (including involvement of organs outside the nervous system), together with a recently adopted new nomenclature, and a guide to diagnosis (Schulz et al.). This is complemented by a review on the pathology of NCL, long used in diagnosis and still important in establishing NCL especially when common genetic or biochemical causes have been quickly excluded (Anderson et al.). Those affected with NCL as children may live into adulthood and so attend school for many years. Elmerskog and colleagues review NCL from an educational perspective, a view that many families find extremely helpful as they interact with professionals who support them. An established and productive focus of disease research is the derivation or recognition and use of experimental model organisms, from unicellular models up to large animal models (Bond et al.) and the use of mammalian cell systems and models to understand the molecular basis of the disease itself, by studying the expression, function and regulation of NCL proteins and their impact on lysosomal integrity (Kollman et al.). From these studies comes a further understanding of the disease mechanisms (Palmer et al.), and this knowledge forms the basis for current and future therapeutic development. Hawkins-Salsbury et al. highlight recent advances in studying experimental therapies for CLN1 disease, as well as touching on other forms of NCL. Progress in reaching new treatments or therapy is always of particular interest to families, whether curative or one that halts progression or impacts upon part of the disease. The NCLs continue to surprise and intrigue, more than one hundred years after their first description and twenty years after the first genes were identified. New or improved approaches to research, clinical and professional care continue despite the financial climate. NCL non-profit Organisations initiated by parents around the world are also playing an increasingly important role in supporting families as well as research both locally and collaboratively. This is exemplified by their providing additional sources of funding for research into Batten disease in recent years, which has been summarised by Stehr and Forkel. Many of these organisations were well represented at the meeting, and indeed shared their perspectives with the attending scientists, clinicians and other professionals. These articles were commissioned to be helpful to those new to the field, as well as providing useful summaries and perspectives to those long familiar with the NCLs. Useful tables and summaries can also be found on various internet sites, including the NCL Resource that hosts the NCL Mutation database ( www.ucl.ac.uk/ncl ). Social media was active prior to, during and after the conference and can still be accessed (Facebook: NCL2012; Twitter @ncl2012, #ncl2012 and #battendisease). Progress in the NCL field will continue to be reported at biennial international meetings, with the next being the 14th International Conference on NCL and Patient Organisation Meeting planned for Cordoba in Argentina, 22–26 October, 2014. Sara Mole PhD , Reader in Molecular Cell Biology, MRC Laboratory for Molecular Cell Biology and UCL Institute of Child Health, and Dept Genetics, Evolution & Environment, University College London. Dr Mole is a Reader in Molecular Cell Biology at University College London and her research has focused on Batten disease for 20 years. Prior to this she read Natural Sciences at the University of Cambridge, completing research work in the field of cancer research for her PhD and two postdoctoral positions. An appointment as Lecturer in 1992 allowed her to apply the developing field of molecular genetics to the first gene identification for Batten disease. This continues for small groups of families still without a genetic diagnosis, using the latest DNA technologies on a collection of samples from over 600 families. Dr Mole's lab has a special interest in NCL genes that encode membrane proteins, and has specialised in using yeast as a simple cellular model to understand the biology of CLN3 disease and to identify new targets for therapeutic development. They are also developing gene therapy that targets the visual failure of Batten disease, using mouse models, with the ultimate aim of a therapy that will reach and work in the brain. Dr Mole is the senior editor of a specialised book on Batten disease, published in 2011 by Oxford University Press. She set up a web site in 1998 (NCL Resource—a gateway for Batten disease) that includes the mutation database as well as diagnostic advice for clinicians and information for newly diagnosed families. She is scientific advisor to the UK Batten Disease Family Association. Dr Mole co-organised the last international meeting on Batten disease (in 2012, Royal Holloway College, London) that led to the award by the UCL Provost of Public Engager of the Year (senior staff). Dr. Ruth Williams is a Consultant Paediatric Neurologist at Guy's and St Thomas' NHS Foundation Trust in London. She qualified in Medicine from the University of Nottingham in 1985 and went on to train in Paediatrics and Paediatric Neurology in Birmingham, Bath and London. She now specialises in the diagnosis and management of epilepsy in children and leads the Dietary Epilepsy Service at Evelina Children's Hospital. Ruth first encountered Batten disease as a junior doctor. She went on to work alongside Dr Sara Mole and others at University College London on the initial genetic studies of late infantile Batten disease in the early 1990s. She now helps care for a large number of children and families affected by all types of NCL in the UK. She was Medical Advisor to the BDFA from its beginnings until 2012. She co-hosted the NCL-2012 Congress in London and co-edited the second edition of ‘The Neuronal Ceroid Lipofuscinoses (Batten Disease)’, a comprehensive NCL textbook. Jonathan Cooper PhD . Professor of Experimental Neuropathology, Pediatric Storage Disorders Laboratory (PSDL), Institute of Psychiatry, King's College London. Prof Cooper founded the PSDL when he was appointed at the Institute of Psychiatry, King’s College London in 2000. Prior to this he trained in Anatomy and Cell Biology (BSc, Sheffield), and Neuroanatomy (PhD, Bristol), and spent time as a postdoctoral researcher at the University of Cambridge, the Max-Planck-Institute for Psychiatry (Martinsried, Germany), and in California at the University of California, San Francisco and Stanford University. During much of this time he focussed on issues surrounding why particular neuron populations are affected in neurodegenerative diseases, concentrating upon the cholinergic basal forebrain and the influence of neurotrophins upon them. He first encountered the NCLs while in the USA, and when he started a lab chose to focus upon these childhood disorders. The PSDL has described many of the important neuropathological features of the NCLs, defining vulnerable neuron populations and the relationship of storage material accumulation, glial activation and synaptic pathology to this neuron loss. The lab also continues to be involved in a range of pre-clinical studies assessing the efficacy of a range of experimental therapies, and collaborates widely with colleagues around the world. He also works closely with the affected families, and played a major role in co-organising NCL2012, the 13th International Congress on NCL research that was held at the Royal Holloway College in March 2012. For the first time this congress featured a parallel meeting for the Patient Organisations, with shared sessions and novel initiatives to make the science conference accessible to all.

PY - 2013/11

Y1 - 2013/11

UR - http://www.scopus.com/inward/record.url?scp=84881552280&partnerID=8YFLogxK

U2 - 10.1016/j.bbadis.2013.05.025

DO - 10.1016/j.bbadis.2013.05.025

M3 - Editorial

C2 - 23727410

AN - SCOPUS:84881552280

SN - 0925-4439

VL - 1832

SP - 1793

EP - 1794

JO - Biochimica et Biophysica Acta - Molecular Basis of Disease

JF - Biochimica et Biophysica Acta - Molecular Basis of Disease

IS - 11

ER -