1. Genetics and Dementia – what do relatives want to know? Candy Cooley NHS National Genetic Awareness Lead Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

2. Aims of this session: Review current understanding of links between dementia and genes Consider how the health professional can identify those at increased risk Discuss the implications for the family Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

3. “ From past generations we receive a few strands of DNA, sometimes a heritage, a memory of one sort or another” Dan Pollen M.D. Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

4. Dementia affect around 800,000 people in the UK Causative factors include: age, genes, environmental factors, lifestyle and overall general health Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

5. Most dementia is not inherited Age Acquired immunodeficiency syndrome Central nervous system infections Vascular disease Brain tumours Drug toxicity Syphilis Metabolic or nutritional deficiencies Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

6. So how might you identify a family in which there is an inherited condition? Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

7. Diag = Age diagnosed Diag. 57 Diag. 50Diag. 58 Diag. 52 = Female = Male Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

8. Is there a pattern of people with the condition in this family? Diag. 57 Diag. 50Diag. 58 Diag. 52 Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

9. This is suggestive of a type of inheritance called Autosomal Dominant Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

10. Parents Autosomal dominant inheritance where one parent has the condition Sperm or eggs Has condition

11. Parents Sperm or eggs At conception Autosomal dominant inheritance where one parent has the condition

12. Parents Sperm or eggs At conception Autosomal dominant inheritance where one parent has the condition Has the condition Does not have the condition

13. An example of an Autosomal Dominant condition Familial Alzheimer’s disease (FAD) – Amyloid precursor protein (APP) – Presenilin 1 (PSEN1) – Presenilin 2 (PSEN2) If an alteration is present in only one of the two copies of these genes inherited from a person's parents, the person will inevitably develop that form of early-onset Alzheimer's. Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

14. Other Inherited forms of dementia What if you see an individual with a condition known to be inherited but no-one else in the family has it? Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

15. Tay Sachs Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

16. Tay Sachs Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

17. Tay Sachs ?? ?? ? ? ? Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

18. Parents Sperm or eggs Autosomal recessive inheritance where both parents are carriers Carrier for the condition

19. Parents Sperm or eggs At conception Autosomal recessive inheritance where both parents are carriers Carrier for the condition

20. Parents Sperm or eggs At conception Autosomal recessive inheritance where both parents are carriers Carrier for the condition Does not have the condition, non-carrier Carrier for the condition Has the condition Carrier for the condition

21. Examples of Autosomal Recessive inheritance – causing dementia in children Ceroid lipofucinosis Gaugher disease III Lafora disease Neimann-Pick type C Sandoff disease Late onset Tay-Sachs disease Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

22. Sporadic Alzheimer’s disease Genetic alterations known to be associated with sporadic (late onset) dementia Apolipoprotein E – variants (APOE – ε2, ε3, ε4) Recent Research MS4A, CD2AP, CD33 & EPHA1 BIN1 & ABCA7 Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

23. APOE –ε4 One in 100 people between the ages of 65 and 70 have a form of dementia, compared to one in six people over the age of 80. 1 copy – double or triples lifetime risk 2 copies – increases risk five-fold Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

24. Other causes of dementia Frontotemporal dementia – 20-30% hereditary Adrenoleukodystrophy – X linked Kearns-Sayres syndrome - Mitochondrial Inborn errors in metabolism Huntington disease Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

25. ALERT Know the clues that might indicate a genetic condition ASK Collect appropriate family history information ACT Act on the information you have Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

26. General clues Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2012 NHS National Genetics Education and Development Centre Multiple closely related people with the same condition. Disorders which occur at a younger age than usual (eg colon cancer, breast cancer, dementia). Three or more pregnancy losses Medical problems in children of parents related by blood. Congenital anomalies, dysmorphic features and developmental delay.

27. ASK Collect appropriate family history information Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

28. What information should you collect? Information depends on the context and reason for collecting it: Establish biological relationships Clarify the medical conditions that people have 3 generations For each person: Full name Date of birth (or age) Date of death (or age died) Medical information (age at diagnosis) Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

29. Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre Drawing a family tree Male Female Person whose sex is unknown Pregnancy P Marriage / Partnership (horizontal line) Parents and Siblings Offspring (vertical line) Affected Male & Female Carrier Male & Female Partnership that has ended / X weeks Miscarriage

30. Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

31. Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

32. ACT Act on the information you have Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

33. www.geneticseducation.nhs.uk Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Development Centre

34. Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre Implications for the family “My feeling is I’d only want to know if there’s something I can do about it” “For me, it’s pretty scary when I forget where I parked my car. I think, ‘Here it is, here I go.”

35. Reassure – Knowledge of the condition – Local/national referral guidelines Refer – To the GP or clinical genetics service Seek further advice – Trusted sources of information – Clinical Genetics Department On-Call Service Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

38. Clinical Genetics Services Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre

39. www.geneticseducation.nhs.uk Genetics and genomics for healthcare www.geneticseducation.nhs.uk © 2014 NHS National Genetics and Genomics Education Centre