Huntington's Disease Flashcards
What is Huntington’s Disease?
Progressive neurodegenerative disorder with motor, cognitive, and psychiatric disturbances - movements – memory – mood
What is the movement disorder associated with HD?
chorea, dystonia, bradykinesia, swallowing/ choking, dysarthria
What is the mood disorder associated with HD?
depression, euphoria, apathy, anxiety, aggression, psychotic symptoms
What are the cognitive effects of HD?
loss of executive functioning, rigidity of thought, memory loss, dementia
What is the mean age of onset of HD?
35-44 years
What is the median survival time of HD?
15 to 18 years after onset
What type of inheritance is HD?
Autosomal dominant
HD has complete penetrance. What does this mean?
“Complete” penetrance means the gene or genes for a trait are expressed in all the population who have the genes.
What does a normal HTT gene contain?
What is the HD mutation?
Contains, within exon 1, a run of CAG trinucleotide repeats
An expansion of CAG repeats ≥ 40 triplet repeats
What repeat is expressed in the HD mutation?
CAG repeats (≥ 40 triplet repeats)
A few people will develop HD with 36-39 CAG repeats. What is the result of this?
Reduced penetrance alleles
Where is the HTT gene located?
Chromosome 4
What is the function of the normal Huntington protein?
Widely expressed in different tissues but function is UNKNOWN
What is the effect of the abnormal protein produced by the Huntington’s mutation? What amino acid is produced?
Increased number of glutamine amino acids (CAG)
What does the increased number of glutamine amino acids cause?
Polyglutamine (polyQ) expansion – altering protein structure/properties
PolyQ aggregates in cells
Basal ganglia especially caudate nucleus primarily affected
What is a polyQ expansion?
A portion of a protein consisting of a sequence of several glutamine units caused by CAG repeats
What is anticipation?
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
Why is anticipation associated with triple repeat disorders?
Triplet repeat expansions are unstable and may increase (or contract) when passed to the next generation
Anticipation is often linked to specific parental gender. What is the higher anticipation risk in:
- HD
- Myotonic dystrophy
- Fragile X syndrome
- HD - paternal inheritance (i.e. higher chance of anticipation if father passes it on)
- Myotonic dystrophy - maternal
- Fragile X syndrome - maternal
What is juvenile HD?
- Onset under 20 years
- Rare
- Usually paternally inherited
- Large expansions (CAG repeat length 60+)
What is the clinical presentation of juvenile HD?
Motor – bradykinesia
Memory – decline in school work
Mood – decline in social interactions, friends
What is bradykinesia?
Slowness of movement
Are other siblings at risk during juvenile HD?
Other siblings are at risk HD – may be adult onset
Diagnostic vs predictive genetic testing?
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.
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?
Diagnostic gene test (neurology)
If a patient was asymptomatic, when would you perform a predictive gene test (clinical genetic)?
If there was a positive FHx
What is the difference between diagnostic vs predictive genetic testing in HD?
The same genetic test (count the number of CAG repeats) – but very different counselling needed
Other diseases where predictive testing is possible?
- 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
What is the treatment currently available for HD?
Symptomatic treatment only at present
No prevention or cure
Predictive testing does not save lives
What will the HD predictive test tell you?
- 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
What will the HD predictive test not tell you?
- 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
What is the most common prenatal option?
Just have children
What is predictive testing as a prenatal option?
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.
What is exclusion testing?
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.
What are other prenatal options regarding HD?
Pre-implantation genetic diagnosis (PGD)
Sperm or egg donor
Adoption
What % of people at a 50% risk of HD decide to have predictive gene testing?
15-20%
What amino acid does CAG code for?
Glutamine
