1. Chapter 14 Huntington’s Disease Imprinting and Genetic Anticipation

2. History of Huntington’s Disease 1630, 3 men escaped to America 1630, 3 men escaped to America Wilke, Nichols, and Jeffers Wilke, Nichols, and Jeffers Families had been persecuted for witchcraft Families had been persecuted for witchcraft One man settled in the Hampton’s(NY) One man settled in the Hampton’s(NY) Offspring were notorious for a strange and frightening disease Offspring were notorious for a strange and frightening disease

3. Initial Symptoms Irritability Irritability Clumsiness Clumsiness Depression Depression Forgetfulness Forgetfulness Mood and personality changes Mood and personality changes Uncontrollable movements Uncontrollable movements Hard to swallow Hard to swallow

4. George Huntington Huntington’s had 3 generations of doctors Huntington’s had 3 generations of doctors Youngest was George Huntington Jr Youngest was George Huntington Jr Made rounds via horseback with father Made rounds via horseback with father 1872, George Huntington Jr wrote a paper “ On Chorea” 1872, George Huntington Jr wrote a paper “ On Chorea”

5. Chorea Chorea means to dance Chorea means to dance “dancing disorder” “dancing disorder” Uncontrollable jerking and moving Uncontrollable jerking and moving People were thought to be possessed by devils People were thought to be possessed by devils One of the “witches” executed in Salem, MA had Huntington’s disease One of the “witches” executed in Salem, MA had Huntington’s disease

6. Ex. Wilke’s Children One of the 3 original British men who fled to America One of the 3 original British men who fled to America Professional carpenter w/ 7 children Professional carpenter w/ 7 children Son marries Elizabeth Warne who returns to England, tried as a witch Son marries Elizabeth Warne who returns to England, tried as a witch child with strange convulsions) child with strange convulsions) Elizabeth's child is tried as the "Groton Witch" Elizabeth's child is tried as the "Groton Witch" http://www.medinfo.ufl.edu/other/histmed/okun/slide27.html

7. Huntington’s Disease Caused by a dominant gene Caused by a dominant gene Diagnosed 35-60 years old Diagnosed 35-60 years old Average age of onset=40 years Average age of onset=40 years Progressive Progressive Continually getting worse Continually getting worse No remission No remission No breaks or getting better No breaks or getting better ALWAYS fatal ALWAYS fatal Usually only 20 more years after diagnosis Usually only 20 more years after diagnosis

8. Interesting Weirdness Maternal Allele Maternal Allele If you inherit huntingtons allele from mom If you inherit huntingtons allele from mom Normal onset(35-50 years) Normal onset(35-50 years) Paternal Allele: Paternal Allele: If you inherit huntingtons allele from dad If you inherit huntingtons allele from dad You show symptoms at earlier age You show symptoms at earlier age Thanks a lot dad!!! Thanks a lot dad!!! MOM MOM H h DAD hHh hh hHh hh hHh hh normal onset normal onsetMOM h h DAD HHh Hh hhh hh hhh hh show symptoms earlier show symptoms earlier

9. Genomic Imprinting In some diseases, it matters which parent gave you the gene!!! In some diseases, it matters which parent gave you the gene!!! A mysterious phenomena A mysterious phenomena We still don’t fully understand it We still don’t fully understand it

10. Genomic Imprinting At least 100 genes are imprinted At least 100 genes are imprinted You must re-imprint genes from you parents before you pass them on to your children You must re-imprint genes from you parents before you pass them on to your children

11. Another weird thing about Huntington’s Disease Example of anticipation Example of anticipation Symptoms start showing up earlier in families Symptoms start showing up earlier in families Genetic anticipation Genetic anticipation

12. Genetic Anticipation in Huntington’s Disease DNA has regions of repeating sequences DNA has regions of repeating sequences Trinucleotide repeats Trinucleotide repeats Makes gene more and more unstable Makes gene more and more unstableEx.CAGCAGCAGCAGCAGCAGCAGCAGCAG or orTCGTCGTCGTCGTCGTCGTCGTCGTCGTCT

13. CAG repeats Huntington’s is caused by too Huntington’s is caused by too much repeats much repeats End of chromosome 4 End of chromosome 4 CAG repeats CAG repeats Normal gene has 11-34 copies of CAG Normal gene has 11-34 copies of CAG Mutation increases it to more than 37 Mutation increases it to more than 37 In HD, Passing on chromosome 4 Increases # of repeats In HD, Passing on chromosome 4 Increases # of repeats Symptoms start showing earlier Symptoms start showing earlier