Triplet Repeat Disorders - Huntingdon Disease & Predictive Testing

Question 1

What is Huntingdon disease?

Answer 1

a progressive neurodegenerative disorder with motor, cognitive and psychiatric disturbances

it affects movement, memory and mood

Question 2

In what ways is HD a movement disorder?

Answer 2

1. chorea
2. dystonia
3. bradykinesia
4. swallowing/choking
5. dysarthria

Question 3

What is meant by chorea?

Answer 3

jerky involuntary movements affecting especially the shoulders, hips, and face

Question 4

What is dystonia?

Answer 4

a movement disorder in which a person’s muscles contract uncontrollably.

The contraction causes the affected body part to twist involuntarily, resulting in repetitive movements or abnormal postures

Question 5

What is meant by bradykinesia?

Answer 5

it is the slowness of movement

this may include weakness, tremor and rigidity

Question 6

What is dysarthria?

Answer 6

difficult or unclear articulation of speech that is otherwise linguistically normal

Question 7

In what ways is HD a mood disorder?

Answer 7

Mood ranges from depression to euphoria

1. apathy
2. anxiety
3. agression
4. psychotic symptoms

Question 8

In what ways does HD affect cognition?

Answer 8

There is loss of executive function and rigidity of thought

It progresses from memory loss to dementia

Question 9

What is the mean age of onset for HD?

What is the median survival time?

Answer 9

mean age of onset is 35 to 44 years

median survival time is 15 to 18 years after onset

Question 10

What type of disorder is HD?

What is the penetrance?

Answer 10

it is an autosomal dominant disorder that shows complete penetrance

Question 11

What gene is present at what location in HD?

Answer 11

The HTT gene is present at 4q16.3

this was the IT15 gene

Question 12

What is the composition of the HTT gene like?

How does this change in HD?

Answer 12

the normal HTT gene contains, within exon 1, a run of CAG trinucleotide repeats

The HD mutation is an expansion of CAG repeats >/= 40 repeats

Question 13

What is the difference between a normal HTT gene and a HTT gene in someone with HD?

Answer 13

the normal gene has <36 CAG repeats

in HD there is expansion of the CAG repeats, meaning there is 40 or more present

Question 14

What does the normal HTT gene code for?

Answer 14

Huntingtin protein

this is widely expressed in different tissues, but its function is unknown

Question 15

How does the abnormal Huntingdin protein vary comparend to the normal one?

Answer 15

it contains an increased number of glutamine amino acids

this leads to a polyglutamine (polyQ) expansion, which alters the protein structure and function

Question 16

What is the effect of polyQ expansion in the abnormal HUntingtin protein?

Answer 16

PolyQ aggregates in cells

this affects basal ganglia, especially the caudate nucleus

Question 17

What is meant by ‘anticipation’ in triplet repeat disorders?

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 the severity of symptoms

Question 18

What type of disorders is anticipation associated with?

Why?

Answer 18

it is associated with triplet repeat disorders

triplet repeat expansions are unstable and may increase when passed to the next generation

Question 19

What is anticipation often linked to?

Answer 19

a specific parental gender

Question 20

complete the following table

Answer 20

Question 21

What is the general link between the HD triplet repeat size and age of onset?

Answer 21

as the triplet repeat size increases, the age of onset of symptoms becomes increasingly young

Question 22

What is the age of onset for juvenile HD?

What are the expansions like?

Answer 22

onset of symptoms starts before 20 years old

it is usually paternally inherited with large expansions

CAG repeat length is 60 or more

Question 23

How are the motor, memory and mood symptoms noticed in someone with juvenile HD?

Answer 23

motor:

• bradykinesia - slow movement and an impaired ability to move the body swiftly on command

memory:

• decline in school work

mood:

• decline in social interactions and friends

Question 24

If someone has juvenile HD, how does this affect the rest of the family?

Answer 24

any other siblings are at risk of HD

this may be adult onset HD

Question 25

What types of genetic tests are used in the following situations?

FHx = family history

Answer 25

Question 26

What is the difference between a diagnostic gene test and a predictive gene test?

Answer 26

the genetic test is the same and counts the number of CAG repeats

the counselling required is different

Question 27

What is meant by HD predictive testing?

Answer 27

It is different to conventional medical testing as the patient is “well”

It involves testing to know in advance about the future

Question 28

When is HD predictive testing often carried out?

Answer 28

often at a transition point in life of the person at risk

it can be a difficult decision to test or not, as the person may not want to know the outcome

Question 29

What is the definition of predictive testing?

Answer 29

the use of a genetic test in an asymptomatic person who is at risk to predict future risk of disease

Question 30

What other 3 diseases is predictive testing possible for?

Answer 30

1. BRCA (familial breast cancer genes)
2. HNPCC (hereditary non-polyposis colon cancer)
3. myotonic dystrophy

Question 31

Why is predictive testing usually carried out?

Answer 31

1. screening to detect early disease - e.g. cancer, arrhythmias
2. to initate treatments early
3. to take prophylactic measures
4. in HD, prenatal testing options can then be offered

Question 32

What is the treatment available currently for HD?

Answer 32

there is no prevention or cure

there is only symptomatic treatment present

Question 33

What reasons may someone choose to undergo HD predictive testing?

Answer 33

1. patients just want to know
2. to plan future care
3. to plan their career
4. to make decisions about their children
5. to inform other relatives whose risk may change

Question 34

What 3 things will a HD predicitive test tell the patient?

Answer 34

1. complete certainty as to whether or not they will get HD in normal life span
2. whether or not their children will be at risk
3. if they need to consider prenatal options - testing a preganacy before having children

Question 35

What 4 things will the HD predictive test not tell the patient?

Answer 35

1. the age of onset of symptoms
2. the speed of disease progression
3. the order or balance of symptoms
4. it will not help with “symptom hunting” if the result is positive

Question 36

If someone was to have a prenatal test for HD, how and when would this be carried out?

Answer 36

during 11-12 weeks of pregnancy via CVS (chorionic villus sampling)

if the result is positive, the pregnancy is often terminated

Question 37

What is meant by ‘exclusion testing’ when undergoing a prenatal HD test?

Answer 37

this is for parents who do not want predictive testing but want to ensure their children are not at risk

most pregnancies are terminated at 50% risk

Question 38

What are the other prenatal options when it comes to testing for HD?

Answer 38

1. have children as normal
2. pre-implantation genetic diagnosis (PGD)
3. sperm or egg donor
4. adoption

Question 39

What is meant by pre-implantation genetic diagnosis?

Answer 39

genetic profiling of embryos prior to implantation

(or sometimes oocytes prior to fertilisation)