Hereditary Spastic Paraplegia Genes and Gene Testing

1. Hereditary Spastic Paraplegia Genes and Gene Testing Dr Elizabeth Thompson Clinical Geneticist SA Clinical Genetics SA Pathology Women’s and Children’s Hospital North Adelaide

2. What is hereditary spastic paraplegia (HSP)? • A group of conditions that affects the legs with • stiffness (spasticity) • muscle weakness • 1-10 in 100,000 people worldwide have HSP • Can affect people of all ages

3. Pure (uncomplicated) HSP • More common than complicated HSP • Affects the legs only • Bladder symptoms may occur eg “urgency” (you’re desperate to go)

4. Complicated (complex) HSP Spastic paraplegia with a variety of other problems, for example: • Other neurological problems eg ataxia (poor balance) • Intellectual disability/dementia • Seizures

5. What causes HSP? • An error in a gene • We carry about 25,000 genes • They are the “recipe” to make the body and help it work • We inherit a set of genes from our mother and a set from our father • So we have two copies of each gene

6. What is a gene error? • Genes are like a novel • Written in an alphabet of 4 letters, C,A,G,T, in a specific order for each gene • An error could be that a bit of the gene is missing or doubled up • Or the order of letters could be wrong

7. What does a gene error do? • Genes make proteins that do special jobs in the body • If a gene has a bit missing or the sequence of letters is wrong… • The protein might not get made or will be faulty and not do its job

8. Is the gene error always the same in a particular gene? • In some conditions, yes! The gene has a “weak spot” that often goes wrong • In HSP genes, a wide variety of different errors can occur • Often the errors are unique to a particular family

9. Inheritance of HSP • It’s complicated! • At least 18 different genes cause HSP • At least 17 more genes to be discovered • In a particular family, only ONE gene causes HSP • Huge variation in when HSP starts and how severe it is, even for the same gene

10. Genes that cause HSP • Commonest are: • SPG4 (spastin) gene (25%) • SPG3A (atlastin) gene (7%) • SPG31 (REEP1) gene (few %) • These are dominant genes

11. Dominant gene • Genes come in pairs • One gene is faulty and “calls the shots” (is dominant) • We pass one gene of each pair to each child, so parent with HSP passes to each child: • The normal gene (child not affected with HSP) OR • The faulty gene (child will be affected with HSP)

12. Call the gene with the error A And the normal gene a Mum has HSP Chance of passing HSP to each child is 1 in 2 (Passes A or a) Males and females can be affected (Autosomal) Aaaa Aa aa Dominant gene * *

14. Call the normal gene A And the one with the error a Mum and Dad are healthy carriers Child with HSP has two copies of gene error Chance of each child having HSP is 1 in 4 Male and females can be affected (Autosomal) AaAa aaAa Aa AA Recessive gene *

15. Recessive genes • Recessive genes are a much less common cause of HSP • None tested for in Australia

16. Other type of inheritance • X-linked • Faulty gene on the X chromosome • Males are affected • Females can be healthy carriers • Very rare cause of HSP

17. Making a diagnosis of HSP Doctors make a “clinical” diagnosis based on • History: what the person tells them eg toe “catches” when walking, person is having falls, less able to play sports • Family history: any relatives affected? • Examination: leg muscles feel stiff, reflexes too brisk • Tests: MRI brain or spine scan to rule out other causes

18. Diagnosis of HSP • There are many causes of spastic paraplegia • In children, cerebral palsy is more common than HSP • In adults, other diagnoses have to be considered eg multiple sclerosis • Other tests may be needed to rule out other causes

19. The family • A positive family history make HSP more likely • A negative family history does not rule it out! • parent might carry the faulty gene but has very mild or no symptoms • all gene errors have to start in someone, so the error could have started in the person (both rare but do occur)

20. Next step… • A gene test?

21. Gene testing for HSP in Australia Perth: Royal Perth Hospital (Prof Nigel Laing): SPG3 and SPG4 Currently working up SPG31 (REEP1) Cost: $1650 each for sequencing of each $440 to detect a deletion or duplication Sydney: Concord Hospital (Prof Garth Nicholson): SPG3, SPG4, SPG31 (REEP1) Cost: $1800 for the 3 genes or SPG4 only $800 Research:Royal North Shore Hospital (Prof Carolyn Sue)

22. Cost of genetic testing • Genetic testing is expensive • Availability of genetic test depends on local funding issues • Patient can pay if has the funds

23. Testing of the 3 common genes • If a fault (“mutation”) is found, it confirms the diagnosis • If a fault is not found, it does not rule out HSP (many other genes can cause HSP) • Specific features might suggest another specific type of HSP • Gene test overseas might be possible

24. The future of genetic testing • Improving technology = able to test more genes for less cost • “Next Generation Sequencing” • Hope is for a “chip” that will allow testing of many genes cheaply • Next 5-10 years will see improvements in availability of genetic testing

25. Genetic testing • Diagnostic • Person is affected with symptoms • Wants to know the cause • Predictive • Person not affected with symptoms • Has a relative eg parent with HSP

26. Why have a diagnostic genetic test? • Confirm the diagnosis • Information about that type of HSP • Prognosis • Anticipate complications • Provides a means of testing relatives (if they want it) • must first identify the particular gene error in an affected person to then be able to offer a test to relatives

27. Why have a diagnostic genetic test? • Genetic counselling about chance that siblings or children could have HSP • Prenatal diagnosis/preimplantation genetic diagnosis • Involvement in clinical trials

28. Predictive genetic test • Relative (usually son/daughter) wants to know if has inherited HSP gene but does not have symptoms • Best conducted through a genetic clinic • Big step to take, condition currently “incurable” • Need to consider pros and cons carefully

29. Pros of a predictive genetic test • “I just want to know if I have inherited it” • Plan for the future • Plan re work • Planning a family • “I want to know for the kids’ sake”

30. Cons of a predictive genetic test • Find it difficult to cope with result if have inherited it • Plans for the future altered • Family planning more complicated • Life insurance difficult to obtain and/or more expensive • “Survivor guilt” if person has not inherited it but sibling has

31. Process of having a predictive genetic test • Referral to clinical genetics service • See non-medical genetic counsellor and clinical geneticist (doctor) over a couple of sessions to discuss: • Coping strategies • How has person dealt with “bad news” in the past? • Family issues eg how will I feel if I have it and my sibling does not or vice versa • Life insurance issues • Testing in pregnancy

32. Process of a predictive genetic test • Sign a consent form • Have blood collected • Advised when result will be ready • Arrange to meet face to face with genetic counsellors to receive result • Receive result with support person • Follow up

33. Genetic testing for children under 18 years • Predictive genetic testing is not recommended • Leave until child can make own decision as an adult • Many adults choose not to have a predictive genetic test • Discrimination eg life insurance and employment

34. Genetic testing in children • Acceptable if child has symptoms • Is then a diagnostic test (not predictive) • We already know child has a problem and want to diagnose the cause

35. I have HSP: can I avoid having a child with HSP? • Prenatal diagnosis • Test pregnancy at 10½ weeks by chorion villus sample (CVS) Or by amniocentesis at 16 weeks • Only possible if we know the gene error in the person with HSP • Arrange though local clinical genetic service

36. Testing the pregnancy by CVS Sample taken at 10½ weeks Take sample of placenta (chorion villi) Chorion villus sample test (CVS) Result usually available in about 2 weeks Risk of miscarriage around 1 in 150

37. Amniocentesis • Sample taken at around 16 weeks • Risk of miscarriage around 1 in 200 • Many couples prefer the earlier test • Most couples only have these tests if plan not to continue affected pregnancy

38. Pre-implantation genetic diagnosis (PGD) • In vitro fertilisation (IVF) • At a reproductive medicine clinic • Take woman’s eggs, man’s sperm • Embryos form “in the dish” • Test a cell from a very early embryo • Known gene error in parent with HSP

39. Pre-implantation Genetic Diagnosis • Transfer to woman’s womb embryo(s) not carrying the HSP gene • Risks of IVF • Cost • CVS to check is correct

40. Genetic counselling • A good idea! • Genetic clinics in all Australian capitals And many smaller centres eg in SA, we go to Mt Gambier, Whyalla, Pt Augusta twice a year • Meet non-medical counsellors, clinical geneticists (doctors)

41. Genetic counselling • More information about HSP • Genetic aspects of HSP in your family • Genetic testing • We offer “non-directive” counselling Give information, help you make best decisions for you and your family • Help arrange predictive genetic testing, prenatal testing, PGD

42. SA Clinical Genetics Service • Based at Women’s and Children’s Hospital • Outreach clinics eg Flinders Med Centre, Llyell McEwin Hosp, Pt Augusta, Whyalla, Mt Gambier • Requires a medical referral • Under SA Pathology • Tel 81617375