Transcript Document
Huntington Disease An overview This PowerPoint file contains a number of slides that may be useful for teaching of genetics concepts. You may use these slides and their contents for non-commercial educational purposes. © 2009 NHS National Genetics Education and Development Centre Genetics and Genomics for Healthcare www.geneticseducation.nhs.uk Huntington Disease (HD) This presentation includes: • Clinical classification and features. • Structure and molecular basis of the HD gene. • Clinical photographs showing involuntary movements in HD, and brain tissue of normal and affected patients. • Pedigree of an HD family. • Probability of inheriting the HD gene change. • Advantages and disadvantages of predictive testing for HD. © 2009 NHS National Genetics Education and Development Centre Genetics and Genomics for Healthcare www.geneticseducation.nhs.uk Huntington Disease (HD) • Clinical Classification – Movement/Cognitive/Psychiatric disorder – Mean onset age 35-55 years. • Prevalence – Incidence >1 in 10,000. • Genetic Testing – Diagnostic – Presymptomatic – counselling protocol. © 2009 NHS National Genetics Education and Development Centre Genetics and Genomics for Healthcare www.geneticseducation.nhs.uk Huntington Disease (HD) • Physical features: - involuntary movements - weight loss - abnormal gait - speech & swallowing difficulties. • Psychiatric Manifestations: - personality changes - depression - aggression - early onset dementia. © 2009 NHS National Genetics Education and Development Centre Genetics and Genomics for Healthcare www.geneticseducation.nhs.uk Structure of the Huntington disease gene Short vertical bars represent exons. Fig. 3.7 ©Scion Publishing Ltd © 2009 NHS National Genetics Education and Development Centre Genetics and Genomics for Healthcare www.geneticseducation.nhs.uk Huntington disease - a triplet repeat disease CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG …... CAG 11-34 CAG triplet repeats are normal: encodes a run of 11-34 glutamine amino acid residues in the protein. A run of > 34 glutamine residues causes the protein to aggregate in the brain cells and cause progressive cell death. Runs of >34 CAG repeats in the HD gene expand further (particularly during male meiosis) causing earlier age of onset in children of men who have the gene – anticipation. © 2009 NHS National Genetics Education and Development Centre Genetics and Genomics for Healthcare www.geneticseducation.nhs.uk 1 ttg ggg 61 gca tgc 121 cgc gga 181 cgg tgc 241 att cgg 301 ggg aag 361 tcc cag 421 cag ccg ctg gcg gag tgg ggc cgc gtc ttt gcc ccc cgg ctg ttc cag cag ccg tgt ggc tcc ccg ccc aag caa tac ccg gag gag atg cag cag cag ccg gag tgg gca gcg gcc gcg gat ctg gtg gcc acc aag cag cag caa ccg gca ttc ggc tgg tcc ccg gga cgg ctg tcc gcc gcc cag cag cag cct gaa cct tag ccc gcc tgg cgg ccc agc ggg atg ttc cag cag ccg cct cct ggc ggc cgc ggc ggg ccg aga ggc gac gcg gag cag cag cca cag gcg cag tgt ctc gca ctg ctc gcc gcc tgc acc tcc cag cag ccg ctt ggg cca caa cgc cgt ccg agg cca gcg cgt ctg ctc cag cag ccg cct gca ttg tca cgg ctg gga ttc ttc agt gcc gaa aag cag cag ccg cag 21 CAG repeats in a “normal”/usual Huntington disease gene © 2009 NHS National Genetics Education and Development Centre Genetics and Genomics for Healthcare www.geneticseducation.nhs.uk Huntington disease A patient in the advanced stages of the disease showing involuntary movements of the head and face. Photos courtesy of Professor Peter Harper, Cardiff. (b) Post mortem sections comparing normal brain (left) with brain from Huntington disease patient (right); note the loss of tissue in the Huntington disease brain. Photos courtesy of Dr David Crauford, St Mary’s Hospital, Manchester. Fig. 1.1 ©Scion Publishing Ltd Photos courtesy of (a) Prof. Peter Harper and (b) Dr David Crauford © 2009 NHS National Genetics Education and Development Centre Genetics and Genomics for Healthcare www.geneticseducation.nhs.uk Pedigree of John Ashton’s family. This is shown as it might be recorded in the clinic. Fig. 1.7 ©Scion Publishing Ltd © 2009 NHS National Genetics Education and Development Centre Genetics and Genomics for Healthcare www.geneticseducation.nhs.uk I:1 60y Observations show that 40% of people with the HD gene are asymptomatic at the age of 50 I:2 75y Intuition says probability of parent having gene at age 50 = 1/2 x 1/2.5 = 1/5. Therefore son’s risk is ½ x 1/5 = 1/10. II:1 56y II:2 52y II:3 50y II:4 49y Probability: ½ at birth III:1 25y Whatofisinheriting his risk? Probability the altered HD gene at birth: ½x½=¼ © 2009 NHS National Genetics Education and Development Centre BUT THIS IS INCORRECT! Probabilities should be multiplied only when they are completely independent of each other, and these are not. Developing HD is conditional on having inherited the gene. Have to use Bayes theorem:His mother’s probability of having gene for HD and asymptomatic at age 50 is 1/3.5 His risk is therefore 1/7. Genetics and Genomics for Healthcare www.geneticseducation.nhs.uk Advantages of predictive testing for Huntington disease • Uncertainty of gene status removed. • If negative: – concerns about self and offspring reduced. • If positive: – make plans for the future – arrange surveillance/treatment if any – inform children/decide whether to have children. © 2009 NHS National Genetics Education and Development Centre Genetics and Genomics for Healthcare www.geneticseducation.nhs.uk Disadvantages of predictive testing for Huntington disease • If positive: – removes hope – introduces uncertainty (if and when) – known risk to offspring – impact on self/partner/family/friends – potential problems with insurance/mortgage. • If negative: – expectations of a ‘good’ result – ‘survivor’ guilt. © 2009 NHS National Genetics Education and Development Centre Genetics and Genomics for Healthcare www.geneticseducation.nhs.uk