Hereditary Spastic Paraplegia Genes and Gene Testing

Dr Elizabeth ThompsonClinical Geneticist

SA Clinical GeneticsSA Pathology

Women’s and Children’s HospitalNorth 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

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

*

*

06/09/2011

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

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

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

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 weeksRisk 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

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