Hereditary Spastic Paraplegia Genes and Gene Testing Dr
- Slides: 42
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
What is hereditary spastic paraplegia (HSP)? o A group of conditions that affects the legs with n stiffness (spasticity) n muscle weakness o 1 -10 in 100, 000 people worldwide have HSP o Can affect people of all ages
Pure (uncomplicated) HSP o More common than complicated HSP o Affects the legs only n Bladder symptoms may occur eg “urgency” (you’re desperate to go)
Complicated (complex) HSP Spastic paraplegia with a variety of other problems, for example: o Other neurological problems eg ataxia (poor balance) o Intellectual disability/dementia o Seizures
What causes HSP? o An error in a gene o We carry about 25, 000 genes o They are the “recipe” to make the body and help it work o We inherit a set of genes from our mother and a set from our father o So we have two copies of each gene
What is a gene error? o Genes are like a novel o Written in an alphabet of 4 letters, C, A, G, T, in a specific order for each gene o An error could be that a bit of the gene is missing or doubled up o Or the order of letters could be wrong
What does a gene error do? o Genes make proteins that do special jobs in the body o If a gene has a bit missing or the sequence of letters is wrong… o The protein might not get made or will be faulty and not do its job
Is the gene error always the same in a particular gene? o In some conditions, yes! The gene has a “weak spot” that often goes wrong o In HSP genes, a wide variety of different errors can occur o Often the errors are unique to a particular family
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 o Huge variation in when HSP starts and how severe it is, even for the same gene o o
Genes that cause HSP o Commonest are: n SPG 4 (spastin) gene (25%) n SPG 3 A (atlastin) gene (7%) n SPG 31 (REEP 1) gene (few %) o These are dominant genes
Dominant gene o Genes come in pairs o One gene is faulty and “calls the shots” (is dominant) o We pass one gene of each pair to each child, so parent with HSP passes to each child: n The normal gene (child not affected with HSP) OR n The faulty gene (child will be affected with HSP)
Dominant gene o Call the gene with the error A o And the normal gene a o Mum has HSP o Chance of passing HSP to each child is 1 in 2 (Passes A or a) o Males and females can be affected (Autosomal) * Aa aa
Recessive gene o Call the normal gene A o And the one with the error a o Mum and Dad are healthy carriers o Child with HSP has two copies of gene error o Chance of each child having HSP is 1 in 4 o Male and females can be affected (Autosomal) Aa Aa * aa Aa Aa AA
Recessive genes o Recessive genes are a much less common cause of HSP o None tested for in Australia
Other type of inheritance o o o X-linked Faulty gene on the X chromosome Males are affected Females can be healthy carriers Very rare cause of HSP
Making a diagnosis of HSP o o 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
Diagnosis of HSP o There are many causes of spastic paraplegia o In children, cerebral palsy is more common than HSP o In adults, other diagnoses have to be considered eg multiple sclerosis o Other tests may be needed to rule out other causes
The family o A positive family history make HSP more likely o A negative family history does not rule it out! n parent might carry the faulty gene but has very mild or no symptoms n all gene errors have to start in someone, so the error could have started in the person (both rare but do occur)
Next step… o A gene test?
Gene testing for HSP in Australia Perth: Royal Perth Hospital (Prof Nigel Laing): SPG 3 and SPG 4 Currently working up SPG 31 (REEP 1) Cost: $1650 each for sequencing of each $440 to detect a deletion or duplication Sydney: Concord Hospital (Prof Garth Nicholson): SPG 3, SPG 4, SPG 31 (REEP 1) Cost: $1800 for the 3 genes or SPG 4 only $800 Research: Royal North Shore Hospital (Prof Carolyn Sue)
Cost of genetic testing o Genetic testing is expensive o Availability of genetic test depends on local funding issues o Patient can pay if has the funds
Testing of the 3 common genes o If a fault (“mutation”) is found, it confirms the diagnosis o If a fault is not found, it does not rule out HSP (many other genes can cause HSP) o Specific features might suggest another specific type of HSP o Gene test overseas might be possible
The future of genetic testing o Improving technology = able to test more genes for less cost o “Next Generation Sequencing” o Hope is for a “chip” that will allow testing of many genes cheaply o Next 5 -10 years will see improvements in availability of genetic testing
Genetic testing o Diagnostic n Person is affected with symptoms n Wants to know the cause o Predictive n Person not affected with symptoms n Has a relative eg parent with HSP
Why have a diagnostic genetic test? o Confirm the diagnosis o Information about that type of HSP n Prognosis n Anticipate complications o Provides a means of testing relatives (if they want it) n must first identify the particular gene error in an affected person to then be able to offer a test to relatives
Why have a diagnostic genetic test? o Genetic counselling about chance that siblings or children could have HSP o Prenatal diagnosis/preimplantation genetic diagnosis o Involvement in clinical trials
Predictive genetic test o Relative (usually son/daughter) wants to know if has inherited HSP gene but does not have symptoms o Best conducted through a genetic clinic o Big step to take, condition currently “incurable” o Need to consider pros and cons carefully
Pros of a predictive genetic test o “I just want to know if I have inherited it” o Plan for the future o Plan re work o Planning a family o “I want to know for the kids’ sake”
Cons of a predictive genetic test o Find it difficult to cope with result if have inherited it o Plans for the future altered o Family planning more complicated o Life insurance difficult to obtain and/or more expensive o “Survivor guilt” if person has not inherited it but sibling has
Process of having a predictive genetic test o Referral to clinical genetics service o See non-medical genetic counsellor and clinical geneticist (doctor) over a couple of sessions to discuss: n Coping strategies n How has person dealt with “bad news” in the past? n Family issues eg how will I feel if I have it and my sibling does not or vice versa n Life insurance issues n Testing in pregnancy
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 o Receive result with support person o Follow up o o
Genetic testing for children under 18 years o Predictive genetic testing is not recommended o Leave until child can make own decision as an adult o Many adults choose not to have a predictive genetic test o Discrimination eg life insurance and employment
Genetic testing in children o Acceptable if child has symptoms o Is then a diagnostic test (not predictive) o We already know child has a problem and want to diagnose the cause
I have HSP: can I avoid having a child with HSP? o Prenatal diagnosis o Test pregnancy at 10½ weeks by chorion villus sample (CVS) Or by amniocentesis at 16 weeks o Only possible if we know the gene error in the person with HSP o Arrange though local clinical genetic service
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
Amniocentesis o Sample taken at around 16 weeks o Risk of miscarriage around 1 in 200 o Many couples prefer the earlier test o Most couples only have these tests if plan not to continue affected pregnancy
Pre-implantation genetic diagnosis (PGD) o In vitro fertilisation (IVF) o At a reproductive medicine clinic o Take woman’s eggs, man’s sperm o Embryos form “in the dish” o Test a cell from a very early embryo o Known gene error in parent with HSP
Pre-implantation Genetic Diagnosis o Transfer to woman’s womb embryo(s) not carrying the HSP gene o Risks of IVF o Cost o CVS to check is correct
Genetic counselling o A good idea! o Genetic clinics in all Australian capitals And many smaller centres eg in SA, we go to Mt Gambier, Whyalla, Pt Augusta twice a year o Meet non-medical counsellors, clinical geneticists (doctors)
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 o Help arrange predictive genetic testing, prenatal testing, PGD o o
SA Clinical Genetics Service o Based at Women’s and Children’s Hospital o Outreach clinics eg Flinders Med Centre, Llyell Mc. Ewin Hosp, Pt Augusta, Whyalla, Mt Gambier o Requires a medical referral o Under SA Pathology o Tel 81617375
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