Genetics of Ataxia

1. Genetics of Ataxia Lisa Castillo, MS Genetic Counselor The University of Chicago

2. A little about me…..

3. Objectives • Case example • General principles of genetics & inheritance patterns • Genetic testing options • Symptomatic • Presymptomatic

5. What is Genetics? • Defined: The branch of science concerned with heredity • Focus will be on clinical genetics • The branch of genetics concerned with the diagnosis, prognosis, management, and prevention of genetic diseases

6. Cells • All cells in our body contain structures that run the cell, called organelles • Examples of organelles are mitochondria, golgi bodies, endoplasmic reticulum, ribosomes • All cells contain a nucleus • The genetic material is in the nucleus

7. Inside the nucleus

8. Chromosomes • 23 pairs of chromosomes = 46 chromosomes • 22 autosomal pairs and 1 pair of sex chromosomes

9. What does a chromosome do?

10. Genes • 30,000 to 50,000 genes on the 23 chromosomes • Genes are made up of proteins, the 4 making up the genetic code are called: • Adenine (A) • Tyrosine (T) • Guanine (G) • Cytosine (C) • These 4 letters are repeated in a very specific order and are then translated into a protein based on the order.

11. Gene mutation • Based on the order of the letters, if one or more letters are altered, missing, or repeated, this is called a gene mutation. • Since chromosomes come in pairs, each pair has the same genes, except that one pair comes from mom and the other pair comes from dad, so we each have 2 of each gene.

12. Passing on chromosomes Egg or Sperm Egg or Sperm

13. Inheritance and genetics • 3 main types of inheritance • Autosomal recessive • Autosomal dominant • X-linked

14. Ataxia with Autosomal Recessive Inheritance

15. Friedreich Ataxia • Expansion in intron 1 of both copies of FXN gene • 98% of FA individuals • Point mutation in FXN gene + FXN expansion • 2% of FA individuals

16. Trinucleotide repeats • Repeated nucleotides are normal • Number determines disease GAAGAAGAAGAA GAAGAAGAAGAAGAAGAAGAAGAA In Friedreich ataxia-both genes w/expansion: GAAGAAGAAGAAGAAGAAGAAGAA GAAGAAGAAGAAGAAGAAGAAGAA

17. Autosomal Recessive • A gene mutation must occur in both copies of the gene in order for symptoms to be present • 2 chromosomes Symptoms occur Gene is not working on either chromosome

18. Autosomal Recessive • If a person has one of the two copies that does not work, they are carriers Carrier Parent Carrier Parent 25% 50% carrier 25% Unaffected Unaffected Affected

19. Autosomal Recessive

20. Genetic testing for FA • Useful for other family members to detect carrier status • Carrier frequency 1:60-1:100 • Pregnancy planning options if both parents are carriers • Amniocentesis, CVS, preimplantation genetic diagnosis • Participation in clinical trials

21. Ataxias with Autosomal Dominant Inheritance

22. Majority of the Spinocerebellar ataxias have autosomal dominant inheritance

23. Autosomal Dominant • A gene mutation occurring in one of the two genes is enough to cause symptoms to occur. 2 chromosomes: Symptoms occur Gene is not working Gene is working

24. Autosomal Dominant Affected Parent Unaffected Parent 50% 50% Unaffected Affected

25. Autosomal Dominant

26. Trinucleotide repeats • Genetics • CAG repeats (trinucleotide repeats) • Normal and expanded copies of SCA genes have trinucleotide repeats, number of CTG repeats determines affected status • Sometimes more severe in subsequent generations (anticipation)

27. Genetic testing • Testing is to detect the number of trinucleotide repeats • If not previously done in the family, needs to be performed on someone with SCA diagnosis • ~2-4 weeks • Lab reports # of repeats

28. Genes/loci known in SCA

29. Symptomatic genetic testing • Genetic testing on someone who has symptoms of SCA. • To clarify the type of SCA • Will have genetic information for other family members

30. Presymptomatic Genetic Testing • If genetic testing previously done in family, type of SCA and # of repeats is known: • Can do genetic testing in other family members who are at-risk but do not have ataxia symptoms • Personal decision

31. Presymptomatic Genetic Testing • Points to consider • Timing of testing • Who to tell results to? • Effect on relationships: spouse, siblings, parents, children • Professional support to discuss decision • Insurance issues: have life insurance prior to testing; medical insurance now covered by GINA • Reasons people consider doing presx test • Family planning • Career decisions • Financial planning • Stress of not knowing • Enrollment into clinical trials

32. Presymptomatic Genetic Testing Protocol • Adapted from Huntington Disease Presymptomatic Genetic Testing Protocol • Steps to genetic testing • Neurological examination • Meet with genetic counselor • Psychological examination • Draw blood • Get results in person from neurologist and genetic counselor

33. www.ataxia.org

34. Genetic Counseling • If a family member is affected with a condition, they can be seen by a genetic counselor. • Take family history, give risk assessments, coordinate genetic testing, explain genetic testing results, discuss pregnancy options

35. Questions?Lisa Castillo, MSGenetic Counselor(773) 702-4310Ldellefa@medicine.bsd.uchicago.edu