Transcript Liz`s PowerPoint presentation

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)?
 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
Pure (uncomplicated) HSP
 More common than complicated HSP
 Affects the legs only
 Bladder symptoms may occur eg
“urgency” (you’re desperate to go)
Complicated (complex) HSP
Spastic paraplegia with a variety of
other problems, for example:
 Other neurological problems eg ataxia
(poor balance)
 Intellectual disability/dementia
 Seizures
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
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
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
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
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
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Genes that cause HSP
 Commonest are:
 SPG4 (spastin) gene (25%)
 SPG3A (atlastin) gene (7%)
 SPG31 (REEP1) gene (few %)
 These are dominant genes
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)
Dominant gene
 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)
*
Aa
aa
*
Aa
aa
Recessive gene
 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)
Aa
Aa
*
aa
Aa
Aa
AA
Recessive genes
 Recessive genes are a much less
common cause of HSP
 None tested for in Australia
Other type of inheritance
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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
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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
 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
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)
Next step…
 A gene test?
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)
Cost of genetic testing
 Genetic testing is expensive
 Availability of genetic test depends on
local funding issues
 Patient can pay if has the funds
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
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
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
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
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
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
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”
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
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
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
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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
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
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
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
 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
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
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
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)
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
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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