Not for duplication or distribution NOT FOR DUPLICATION OR DISTRIBUTION APAC/BRIN/0133 EU/CLN2/0735 US/CLN2/0255 December 2019 APAC/BRIN/0133 EU/CLN2/0735 US/CLN2/0255 December 2019
About this Enduring Webinar NOT FOR DUPLICATION OR DISTRIBUTION • These slides are from a live webinar held on 14 November 2019 with Professor Nicola Specchio and Dr Raman Sankar • Videos are not live in this presentation, and some patient images have been removed for privacy purposes. Images which were once videos will have this symbol 2 2 2 APAC/BRIN/0133 EU/CLN2/0735 US/CLN2/0255 December 2019
Faculty NOT FOR DUPLICATION OR DISTRIBUTION Nicola Specchio, MD, PhD Raman Sankar, MD, PhD Head of the Epilepsy Unit, Professor of Neurology and Pediatrics and Chief of Department of Neuroscience Pediatric Neurology Bambino Gesú Children’s Hospital David Geffen School of Medicine at UCLA Rome, Italy Los Angeles, CA, USA 3 3 APAC/BRIN/0133 EU/CLN2/0735 US/CLN2/0255 December 2019
Faculty disclosures NOT FOR DUPLICATION OR DISTRIBUTION Nicola Specchio, MD, PhD • Consultant: BioMarin Pharmaceutical Inc • Grant / Research support: BioMarin Pharmaceutical Inc Raman Sankar, MD, PhD • Consulting fee, travel support and honoraria from BioMarin Pharmaceutical Inc All photos are used with family permission 4 APAC/BRIN/0133 EU/CLN2/0735 US/CLN2/0255 December 2019
Learning objectives NOT FOR DUPLICATION OR DISTRIBUTION • Understand benefits of early genetic testing in understanding seizure etiology in pediatric epilepsy patients • Recognize how genetic research is rapidly advancing our understanding of the underlying causes of epilepsy • Understand the benefits of epilepsy gene panels in pediatric epilepsy patients to potentially uncover disorders, like CLN2 disease, earlier in the course of the disease • Understand the urgency to provide a definitive diagnosis to patients, which may enable more precise clinical management and improve patient outcomes 5 APAC/BRIN/0133 EU/CLN2/0735 US/CLN2/0255 December 2019
Webinar Agenda NOT FOR DUPLICATION OR DISTRIBUTION Topic Presenter Welcome & Introductions Nicola Specchio Epilepsy and Genetics Raman Sankar CLN2 Disease and the Need for Early Diagnosis Nicola Specchio Genetic Testing and Actionability of Results Raman Sankar Case Study Nicola Specchio Interactive Q&A Session 6 APAC/BRIN/0133 EU/CLN2/0735 US/CLN2/0255 December 2019
NOT FOR DUPLICATION OR DISTRIBUTION Genetic Epilepsy CLN2 Testing & and Case Study Disease Actionability Genetics of Results
Advances In Understanding The Causes of Epilepsy New research demonstrates increasing genetic basis NOT FOR DUPLICATION OR DISTRIBUTION Autoimmune Focal epilepsy with Birth anoxia Birth anoxia MRI-detectable lesions Other Other Congenital lesions Congenital lesions Infectious Infectious Neoplasm Neoplasm Vascular Vascular Trauma Trauma Modifiers and susceptibility alleles Single-gene epilepsies: Familial, Idiopathic de novo Epilepsies with complex inheritance 1975 1 2014 paradigm 2 8 1. Hauser WA, Kurland LT. Epilepsia. 1975;16:1–66; 2. Thomas RH, Berkovic SF. Nat Rev Neurol. 2014;10:283–292. APAC/BRIN/0133 EU/CLN2/0735 US/CLN2/0255 December 2019
The History Of Gene Identifications In Epilepsy Research NOT FOR DUPLICATION OR DISTRIBUTION Channelopathy era Dark ages Next-generation sequencing STX1B SLC6A1 GABRA1 GABRB3 SIK1 KCNA2 ALG13 GRIN2B PURA KCNB1 KCNC1 DNM1 Microdeletions HCN1 CHD2 15q13.3 SCN8A 16p13.11 SCN2A GRIN2A 15q11.2 DEPDC5 KCNT1 PRRT2 TBC1D24 STXBP1 LGI1 PCDH19 GABRA1 CACNA1H GABRG2 NGS demonstrates the spectrum of ARX CDKL5 SCN1A SLC2A1 phenotypes associated with TPP1 KCNQ3 genetic epilepsies CLN3 KCNQ2 SCN1B CHRNA4 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 2017 2018 TPP1: tripeptidyl peptidase 1. Adapted from: Helbig I et al. Epilepsia. 2016;57:861–868; Sleat DE et al. Science. 1997;277:1802–1805; 9 The International Batten Disease Consortium. Cell. 1995; 82:949–957; Trump N et al. J Med Genet. 2016;53:310–317. APAC/BRIN/0133 EU/CLN2/0735 US/CLN2/0255 December 2019
The Era of Targeted Therapy for Genetic Epilepsy NOT FOR DUPLICATION OR DISTRIBUTION Patient with unexplained epilepsy Old paradigm Stepwise approach Initial empirical AED treatment Emerging paradigm no underlying cause yet identified Direct, accurate, cost-effective AED Failure Genetic assessment: Genetic assessment: epilepsy gene panel chromosomal microarray UNINFORMATIVE Genetic assessment: Potential for disease-specific management: epilepsy gene panel targeted therapy or clinical trial EpiPM Consortium. Lancet Neurol. 2015;14:1219–1228; Helbig K. A Clinician’s Guide to Genetic Test Selection: Navigating the Wild West. Epilepsygenetics.com. http://epilepsygenetics.net/2016/10/16/a-clinicians-guide-to-genetic-test-selection-navigating-the-wild- 10 west (accessed January 18, 2018). APAC/BRIN/0133 EU/CLN2/0735 US/CLN2/0255 December 2019
Reasons For Considering Genetic Testing NOT FOR DUPLICATION OR DISTRIBUTION 1 Can impact clinical management e.g. choice of AED 2 May avoid unnecessary testing 3 Shortens the diagnostic journey for families Genetic Genetic Genetic testing 4 Allows for specific counseling (family planning) testing testing 5 Opportunity to participate in a clinical study 6 Can allow for targeted therapy: precision medicine 7 Connect families with each other and advocacy groups 11 Berkovic SF. Epilepsy Curr. 2015;15:192–196. APAC/BRIN/0133 EU/CLN2/0735 US/CLN2/0255 December 2019
NOT FOR DUPLICATION OR DISTRIBUTION Genetic Epilepsy CLN2 Testing & and Case Study Disease Actionability Genetics of Results
Features of CLN2 disease NOT FOR DUPLICATION OR DISTRIBUTION 0–1 years 3–4 years • Normal early development • Seizures often more troublesome 1–2 years • Developmental stasis • May have slow language development • Worsening of mobility and fine motor skills 2–3 years 4–5 years • Seizures, often polymorphic • Further loss of skills • Poor mobility • Sleep disorder • Hospital admissions (seizures) • Pain and irritability • Increasing medical and developmental concerns • Increasingly dependent for activities of daily living • Referral for diagnostic investigations 13 CLN2: late-infantile neuronal ceroid lipofuscinosis (NCL) or NCL type 2. APAC/BRIN/0133 EU/CLN2/0735 US/CLN2/0255 December 2019
Late stage may be prolonged NOT FOR DUPLICATION OR DISTRIBUTION >6 years • Gastrostomy dependent • Unsafe swallowing Retain some • Loss of communication understanding and • Loss of voluntary movement personality • Chest infections • Ongoing seizures • Myoclonic status • Spasticity and joint contractures • Spinal scoliosis 14 APAC/BRIN/0133 EU/CLN2/0735 US/CLN2/0255 December 2019
Clinical presentation: Classical late infantile CLN2 disease NOT FOR DUPLICATION OR DISTRIBUTION • Psychomotor decline • Language delay • Death • Bedridden • Blindness • Seizures • Ataxia Age (yr) Birth 1 2 3 4 5 6 7 8 9 10 11 12 Do NOT wait for vision loss to diagnose CLN2 15 All photos / videos used with family permission from Bambino Gesù Children’s Hospital. APAC/BRIN/0133 EU/CLN2/0735 US/CLN2/0255 December 2019
Clinical presentation: Classical late infantile CLN2 disease NOT FOR DUPLICATION OR DISTRIBUTION • Psychomotor decline • Language delay • Death • Bedridden • Blindness • Seizures • Ataxia Age (yr) Birth 1 2 3 4 5 6 7 8 9 10 11 12 Video showing CLN2 patient at 3 years old, who was experiencing some epileptic seizures. This video shows motor development that is still normal 3 yr old Do NOT wait for vision loss to diagnose CLN2 16 All photos / videos used with family permission from Bambino Gesù Children’s Hospital. APAC/BRIN/0133 EU/CLN2/0735 US/CLN2/0255 December 2019
Clinical presentation: Classical late infantile CLN2 disease NOT FOR DUPLICATION OR DISTRIBUTION • Psychomotor decline • Language delay • Death • Bedridden • Blindness • Seizures • Ataxia Age (yr) Birth 1 2 3 4 5 6 7 8 9 10 11 12 The same patient after 1 year, who is starting to present with ataxia and other movement disorders 3 yr old 4 yr old Do NOT wait for vision loss to diagnose CLN2 17 All photos / videos used with family permission from Bambino Gesù Children’s Hospital. APAC/BRIN/0133 EU/CLN2/0735 US/CLN2/0255 December 2019
Clinical presentation: Classical late infantile CLN2 disease NOT FOR DUPLICATION OR DISTRIBUTION • Psychomotor decline • Language delay • Death • Bedridden • Blindness • Seizures • Ataxia Age (yr) Birth 1 2 3 4 5 6 7 8 9 10 11 12 The same patient had a very quick progression of disease – soon suffering continuous myoclonic jerks, is bedridden and almost blind 3 yr old 4 yr old 5 yr, 7 mo old Do NOT wait for vision loss to diagnose CLN2 18 All photos / videos used with family permission from Bambino Gesù Children’s Hospital. APAC/BRIN/0133 EU/CLN2/0735 US/CLN2/0255 December 2019
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