Huntington's Disease

Question 1

What is Huntington’s Disease?

Answer 1

Progressive neurodegenerative disorder with motor, cognitive, and psychiatric disturbances - movements – memory – mood

Question 2

What is the movement disorder associated with HD?

Answer 2

chorea, dystonia, bradykinesia, swallowing/ choking, dysarthria

Question 3

What is the mood disorder associated with HD?

Answer 3

depression, euphoria, apathy, anxiety, aggression, psychotic symptoms

Question 4

What are the cognitive effects of HD?

Answer 4

loss of executive functioning, rigidity of thought, memory loss, dementia

Question 5

What is the mean age of onset of HD?

Answer 5

35-44 years

Question 6

What is the median survival time of HD?

Answer 6

15 to 18 years after onset

Question 7

What type of inheritance is HD?

Answer 7

Autosomal dominant

Question 8

HD has complete penetrance. What does this mean?

Answer 8

“Complete” penetrance means the gene or genes for a trait are expressed in all the population who have the genes.

Question 9

What does a normal HTT gene contain?

What is the HD mutation?

Answer 9

Contains, within exon 1, a run of CAG trinucleotide repeats

An expansion of CAG repeats ≥ 40 triplet repeats

Question 10

What repeat is expressed in the HD mutation?

Answer 10

CAG repeats (≥ 40 triplet repeats)

Question 11

A few people will develop HD with 36-39 CAG repeats. What is the result of this?

Answer 11

Reduced penetrance alleles

Question 12

Where is the HTT gene located?

Answer 12

Chromosome 4

Question 13

What is the function of the normal Huntington protein?

Answer 13

Widely expressed in different tissues but function is UNKNOWN

Question 14

What is the effect of the abnormal protein produced by the Huntington’s mutation? What amino acid is produced?

Answer 14

Increased number of glutamine amino acids (CAG)

Question 15

What does the increased number of glutamine amino acids cause?

Answer 15

Polyglutamine (polyQ) expansion – altering protein structure/properties

PolyQ aggregates in cells

Basal ganglia especially caudate nucleus primarily affected

Question 16

What is a polyQ expansion?

Answer 16

A portion of a protein consisting of a sequence of several glutamine units caused by CAG repeats

Question 17

What is anticipation?

Answer 17

The onset of a disorder occurs at an earlier age as it is passed from one generation to the next. Often this is associated with an increase in severity of symptoms

Question 18

Why is anticipation associated with triple repeat disorders?

Answer 18

Triplet repeat expansions are unstable and may increase (or contract) when passed to the next generation

Question 19

Anticipation is often linked to specific parental gender. What is the higher anticipation risk in:

1. HD
2. Myotonic dystrophy
3. Fragile X syndrome

Answer 19

1. HD - paternal inheritance (i.e. higher chance of anticipation if father passes it on)
2. Myotonic dystrophy - maternal
3. Fragile X syndrome - maternal

Question 20

What is juvenile HD?

Answer 20

• Onset under 20 years
• Rare
• Usually paternally inherited
• Large expansions (CAG repeat length 60+)

Question 21

What is the clinical presentation of juvenile HD?

Answer 21

Motor – bradykinesia

Memory – decline in school work

Mood – decline in social interactions, friends

Question 22

What is bradykinesia?

Answer 22

Slowness of movement

Question 23

Are other siblings at risk during juvenile HD?

Answer 23

Other siblings are at risk HD – may be adult onset

Question 24

Diagnostic vs predictive genetic testing?

Answer 24

Predictive testing is used to search for genetic mutations linked with a condition before you show symptoms.

Diagnostic testing is used to find out if you have a condition associated with symptoms you already have.

Question 25

If a patient presented with symptoms of HD and they either had a) No FHx or b) Positive FHx of HD, what test would you do?

Answer 25

Diagnostic gene test (neurology)

Question 26

If a patient was asymptomatic, when would you perform a predictive gene test (clinical genetic)?

Answer 26

If there was a positive FHx

Question 27

What is the difference between diagnostic vs predictive genetic testing in HD?

Answer 27

The same genetic test (count the number of CAG repeats) – but very different counselling needed

Question 28

Other diseases where predictive testing is possible?

Answer 28

• BRCA (familial breast cancer genes)
• HNPCC (Hereditary non-polyposis colon cancer)
• Myotonic dystrophy

Often there are medical reasons to do these tests e.g. detect early disease and initiate treatment early

Question 29

What is the treatment currently available for HD?

Answer 29

Symptomatic treatment only at present

No prevention or cure

Predictive testing does not save lives

Question 30

What will the HD predictive test tell you?

Answer 30

• Complete certainty you will or will not get the illness in normal life span (fully penetrant)
• Your children will or will not be at risk themselves
• Clarify the prenatal options available

Question 31

What will the HD predictive test not tell you?

Answer 31

• The age of onset of symptoms
• The speed of disease progression
• The order or balance of symptoms
• Will not help resolve symptom concerns – the diagnosis is made clinically

Question 32

What is the most common prenatal option?

Answer 32

Just have children

Question 33

What is predictive testing as a prenatal option?

Answer 33

Predictive testing in at risk patient and then test pregnancy at 11-12 weeks (CVS=chorionic villus sampling).

If positive result, expected to terminate pregnancy.

Question 34

What is exclusion testing?

Answer 34

For parents who do not want predictive testing but want to ensure their children are not at risk.

Expected to terminate pregnancies at 50% risk.

Question 35

What are other prenatal options regarding HD?

Answer 35

Pre-implantation genetic diagnosis (PGD)

Sperm or egg donor

Adoption

Question 36

What % of people at a 50% risk of HD decide to have predictive gene testing?

Answer 36

15-20%

Question 37

What amino acid does CAG code for?

Answer 37

Glutamine