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When does Huntingtons Disease Begin PowerPoint Presentation

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Description : Check out this medical presentation on Neurology, which is titled "When does Huntington’s Disease Begin?", to know about Huntington’s Disease.

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Published on : Aug 18, 2021 | Views : 1185 | Downloads : 0

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Slide 1-

When does Huntington’s Disease Begin? Richard Dubinsky, MD, MPH University of Kansas 11/16/12
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Disclosures Current NIH/NCAM and FDA OPD 2CARE CRESTE CHDI ENROLL-HD Facilitator, redefining HD across the life span Completed: NIH: CARE-HD, PHAROS, PREDICT-HD FDA: RID-HD HSG: Longitudinal database CHDI: COHORT
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HD Gene Cloned 1993,from the Venezuela project Trinucleotide repeat, one of the first three described CAG expansion Gene product huntingtin htt
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Ross C, Lancet Neurology 2011;10:83-98
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CAGn Ranges <26 normal, 17 most common 26-29 rarely expand 30-36 expand, mostly 35 and 36 35-38 unstable expansion HD in future generations 39 and above: HD 80% of people with 39 repeats will develop HD
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What happened? Founder effect, maternal germ cell mosaicism Maternal transmission rarely changes CAGn Paternal transmission usually expands Mean expansion 6.2 Mean contraction 1.3
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Lee JM. Neurology 2012;78:690-5
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Onset of HD Traditionally defined as onset of chorea Always gradual, never sudden Cognitive, behavioral and motor changes can precede chorea
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Determining Clinical Onset Historical data Chorea Other domains: Behavior Cognition
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UHDRS-99 Copyright © HSG Ltd.
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HD: Juvenile Form Predominance of dystonic rigidity Early cognitive problems Prolonged survival
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http://promotingexcellence.org/huntingtons/
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Is the initial symptom disease onset? Frequent phenoconversion after predictive testing 4 x > normal population suicide rate around phenoconversion HD is not protective against other disorders
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HD: Progression Total Functional Capacity Five domains Occupation (3) Fiscal (3) Activities of daily living (3) Household chores (2) Residence (2) T Slope ~ 0.9/y
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HD Disease Models Weir Lancet Neurology 2011;10:573-9
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Ross C, Lancet Neurology 2011;10:83-98
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Ross C, Lancet Neurology 2011;10:83-98
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Ross C, Lancet Neurology 2011;10:83-98
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Lee JM. Neurology 2012;78:690-5
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Brinkman R Am J Hum Genet, 1997;60:1202-10
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Brinkman R Am J Hum Genet, 1997;60:1202-10
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Langbehn D, Am J Med Genet B Neuropscyh 2010;153B:397-408
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PREDICT-HD Prospective cohort study of gene +, asymptomatic subjects and gene – controls Near (onset < 9 years) Mid (onset 9-15 years) Far (onset > 15 years) Yearly neuroimaging, cognitive and psychomotor testing
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Paulsen J, JNNSP 2008;79:874-80
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Paulsen J, JNNSP 2008;79:874-80
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Paulsen J, Brain Res Bull 2010;82:201-7
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Aylward E, JNNSP, 2011;82:405
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COHORT Multi-site, international natural history of HD People with HD, those at risk, family members, some children 2006-2011 Funded by CHDI Dorsey, PLoS 2012
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Dorsey, PLoS 2012
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Dorsey, PLoS 2012
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Dorsey, PLoS 2012
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Dorsey, PLoS 2012
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Symbol Digit Modality / Stroop red green blue blue green red red green blue blue green red
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COHORT: Medication Use Dorsey, PLoS 2012
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Dorsey, PLoS 2012
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TRACK-HD Prospective, longitudinal cohort study Manifest HD Gene + (pre-manifest HD) Burden of pathology score Age x (CAG-35.5) > 250 Gene -, non-matched controls
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HD Cohorts PreHD-A and PreHD-B Dichotomized at median predicted years to diagnosis (Langbehn score) HD1 and HD2 Stage 1 TFC 11-13 Stage 2 TFC 7-10
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TRACK-HD Baseline Characteristics Tabrizi S, Lancet Neurology 2009
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Tabrizi S, Lancet Neurology 2009
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Tabrizi S, Lancet Neurology 2009
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Tabrizi, S Lancet Neurology. 2012,11:42-35 ∆ in Brain Volume
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Tabrizi, S Lancet Neurology. 2012,11:42-35 Striatal volumes
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Tabrizi, S Lancet Neurology. 2012,11:42-35
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Tabrizi, S Lancet Neurology. 2012,11:42-35
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Tabrizi, S Lancet Neurology. 2012,11:42-35 Neuropsychological Tests
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Tabrizi, S Lancet Neurology. 2012,11:42-35
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Tabrizi, S Lancet Neurology. 2012,11:42-35
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HD Clinical Trials Completed CARE-HD RID-HD TETRA-HD TREND-HD MINOS CYTE I PHEND-HD DIMEBOND 1 & 2 HSG Database PHAROS COHORT Ongoing 2CARE CRESTE-HD PRE-CREST REACH-HD PREDICT-HD
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Potential Treatments RNA Silencing Anti-sense oligonucleotides RNA interference
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Delivery Mechanisms RNAi injected into CSF Virus injected into: CSF Putamen Virus inserted into bone marrow Inserted via nanotube and heavy metal through the olfactory bulbs
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Bone Marrow Transplantation? Mutant htt expressed in many cells Inflammatory markers before and at phenoconversion Bone marrow derived cells get into the brain
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Lancet 2004;363:1432-7
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Aronin N NEJM 2012;367-1753
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Conclusion Changes that lead to HD start > 10 years before ‘phenoconversion’ Redefining the onset Research Clinical diagnosis Implications
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Huntington Study Group
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Sleep and HD Insomnia is very common Sun downing Delusions of not sleeping
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