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CLN8 Pesaola 2013

What's New on CLN8 in Latin America

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CLN8 Pesaola 2013

  1. 1. D What’s new on CLN8 in Latin America? F. Pesaola, I.A. Cismondi, N. Guelbert, R. Kohan, M.N. Carabelos, G. Alonso, P. Pons, A.M. Oller-Ramírez, I. Noher de Halac Center for the Study of Inborn Errors of Metabolism (CEMECO), Children´s Hospital, Medical Science Department, Universidad Nacional de Córdoba, Córdoba, Argentina, 5014, E-mail: nclcemeco@nclcemeco.com.ar; nclcemeco1789@gmail.com Traslational Program: NCLs in South America The NCL program at Children’s Hospital (Córdoba, Argentina) was initiated in 2003 as a Translational Research Program for the detection of different NCL forms in Latin America. Acknowledgments  NCL families from Latin America for their willingness to help us.  National Council of Research and Technology (CONICET, Argentina)  Science and Technology Secretary (SECyT), Universidad Nacional de Córdoba, Argentina.  Electron Microscopy Center, Universidad Nacional de Córdoba, Argentina.  Batten Disease Support and Research Association, USA. References: FP, fingerprints; CB, curvilinear bodies; GRODs, granular osmiophilic deposits. vLI- Argentina vLI-other countries EPMR- Finland Age of onset 3y 4-6y 5-10y Initial symptoms Psycho- motor retardation Seizures, myoclonus or generalized psychomotor impairment. Tonic-clonic seizures. Symptoms Refractory seizures Yes Yes Yes Myoclonus Yes Yes No Motor impairment Yes Yes Yes Mental retardation Yes Yes Yes Visual failure ? Yes No Magnetic Resonance Imaging (MRI) Cerebellar atrophy Cortical and cerebellar atrophy Cortical and cerebellar atrophy Light microscopy No vacuolated lymphocytes - Globular neurons without vacuoles Electron microscopy FP, CB and mitochon drial atrophy FP, CB and rarely GRODs GRODs Age at death 12y Generally, before 20y Generally, after 50y What is our next step? We aim to investigate the cell biology of the CLN8 lipoprotein studying the metabolic pathway/s involved and the interacting factors that participate in its functionality. We seek to find out new useful biomolecules to follow up the natural history of the disease and potential treatment outcomes. Biomarkers: what are their uses? A biomarker is a measurable characteristic that reflects the severity or presence of some disease state. It can be an endogenous molecule like a gene, protein or lipid, a specific cell or an exogenous substance that is introduced into the subject under study. Biomarkers can help in early diagnosis, disease prevention, drug target identification, drug response, to examine organ function, to evaluate the risk or progression of a disease, or the susceptibility of the disease to a given treatment. What is the status of the CLN8- disease variants? CLN8 mutations, mainly in Finland, underlay Progressive Epilepsy with Mental Retardation Syndrome (red). In other countries, mutations in that gene cause variant Late Infantile forms (blue). Now it was found one index family in Argentina: one new mutation and new polymorphisms were described in this gene, with still unknown function. Where is CLN8 in the World today?1 Child with seizures, developmental standstill Suspiction of other NCL types Skin biopsy for electron microscopy studies CLN 8 Clinical suspiction Normal PPT1 and TPP1 enzymes activities Molecular analysis What is the diagnostic strategy?2 How we did to diagnose the first CLN8 child in Latin America under our Traslational Program? 4 6 Mouse CLN8 -/- shows loss of vision New biomarker Wild type CLN8 1. In vitro cultured neurons Biomarker molecules Isolation Identification Blood Saliva Tissue samples How could biomarkers technology contribute? 2. Experiments: mouse model and human biomarker characterization. 7 New biomarker Myelin sheath Synapsis Axon Golgi Apparatus (GA) Rough Endoplasmic Reticulum (RER) Nucleus Nucleolus Mitochondria Smooth Endoplasmic Reticulum CLN8 The CLN8 protein is located in the RER. It would be related to lipid metabolism. The cell pathways conducing from gene mutations to disease remain unknown. NEURONAL CELL IN THE BRAIN Where is the disease in the cell?3 RER GA CLN8 -/- mouse We screened out the CLN8 gene in the blood DNA from 15 Late Infantile children that remained with no molecular characterization of the disease in spite of having excluded mutations in most of the other NCL genes. A severe mutation, c.1A>G, p.Met1Val, was found. It was considered pathogenic because of its deleterious nature. What is new in molecular biology? The new c.1A>G mutation of Argentina is expected to produce severe pathological changes of the membrane protein CLN8 involving the complete lack of expression and absence of CLN8 protein in the cell. CLN8 gene with known mutationsc.1A>G 5