Introduction to Huntington's Disease Flashcards
What kind of inheritance pattern does HD show?
HS shows autosomal dominant inheritance with anticipation leading to age-related penetrance.
What is the frequency of HD?
The frequency of HD is 3-10 / 100,000 in populations of western descent. It is must less frequent in other populations.
In one sentence outline what HD is.
HD is a progressive neurodegenerative disorder which presents with motor dysfunction, e.g. chorea, also cognitive impairment and psychiatric disturbances.
At what age do the first symptoms of HD usually manifest?
The first symptoms of HD usually manifest at approximately 35-50 years of age.
What is the duration of HD?
The duration of HD is usually approximately 15-20 years.
What % of HD cases are diagnosed before the age of 20 years?
Approximately 5-10% of HD cases present before 20 years of age (juvenile onset HD).
What are the symptoms of juvenile HD?
Symptoms of juvenile HD include rigidity, tremor, postural hypotonia, behavioural disturbance and learning difficulties.
What is the age of onset of juvenile HD?
Approximately 2-20 years.
What percentage of HD cases present after 50 years of age?
approximately 20% of HD cases present after 50 years of age.
What causes HD on the genetic level?
HD is caused by expansion of a CAG trinucleotide repeat tract in exon 1 of the huntingtin (HTT) gene (previously named IT15).
HTT is located on chromosome 4p16.3, spanning 180kb; 67 exons.
HTT is widely expressed and is required for normal development.
CAG repeats translated into a polyglutamine tract, which is thought to acquire a novel deleterious function when abnormally expanded - leading to neuronal dysfunction and neuro-degenration.
Where is HTT located?
HTT is located on chromosome 4p16.3, spanning 180kb; 67 exons.
What is a normal HTT allele size?
<27 repeats
What is an intermediate HTT allele size?
27-35 repeats - very unlikely to be affected but can expand into disease range upon transmission (especially paternal transmission).
What is a partial penetrance HTT allele size?
36-39 repeats - some individuals with repeats in this range can be unaffected at age 70-80+.
What is a ‘classic’ HTT allele size?
40-65 repeats.
What is a juvenile HD allele size?
Can be up to approximately 250 repeats (seen in an 18 month year old child).
In HD what does the CAG repeat number in the HTT gene correlate with?
The CAG repeat number correlates inversely with the mean age of onset of symptoms as there is a tendency for repeat length to increase upon meiotic transmission.
However, only 70% of the variability in age of onset is related to the CAG repeat length. The remainder is likely to be due to modifying genes and environmental factors.
What primarily determines the age of onset of HD?
The CAG repeat number correlates inversely with the mean age of onset of symptoms as there is a tendency for repeat length to increase upon meiotic transmission.
However, only 70% of the variability in age of onset is related to the CAG repeat length. The remainder is likely to be due to modifying genes and environmental factors.
What causes anticipation in HD?
The instability in the CAG repeat tract leads to anticipation.
The number of CAG repeats can increase on transmission to offspring, resulting in earlier age of onset and/or increased severity of disease in successive generations.
Anticipation is more likely to occur through paternal transmission due to expansion of unstable CAG repeat during spermatogenesis.
Is anticipation more likely to occur through maternal or paternal transmission? Why?
Anticipation is more likely to occur through paternal transmission due to expansion of unstable CAG repeat during spermatogenesis.
What is anticipation?
The number of CAG repeats can increase on transmission to offspring, resulting in earlier age of onset and/or increased severity of disease in successive generations.
Describe repeat instability in paternal transmission and where expansions may occur during spermatogenesis.
The repeat occurs mainly in expansions in coding regions.
The expansions seem to occur at multiple stages in spermatogenesis.
e.g. Pre-meiotic cell division (mitosis) of spermatogonia.
Many mitotic cell divisions in male germ cell development.
Expansions may also occur in post-meiotic haploid cells.
Expansion is dependent on the replication process.
Therefore, expansions in the sperm could be transmitted from a father with an intermediate allele to his offspring resulting the the onset of HD in the offspring in adulthood.
What is the smallest number of CAG repeats described in patients with confirmed HD?
The smallest number of CAG repeats described in patients with confirmed HD is 36 - observed in more than 6 cases.
What are reduced penetrance HD alleles?
The HD mutation can be non-penetrant. Some cases with 36-39 repeats fail to show clinical and neuropathological features of disease in their 9th and 10th decades.
Based on a direct observational study of 176 patients, if an individual has a predictive test result in this range, the chance of them being asymptomatic at 65 years of age is >40%, and at 75 years of age is >30%.
If an individual has a CAG repeat length of 36-39, what is the chance of them being asymptomatic at 65 years of age?
> 40%
If an individual has a CAG repeat length of 36-39, what is the chance of them being asymptomatic at 75 years of age?
> 30%
Describe intermediate alleles.
- Range 37-35 repeats.
- Frequency of 1-7% in the general population.
- Defined as being below the affected range, but having the potential to expand into the disease range in the next generation.
- The lower limit is defined as the shortest size ever report to expand into the HD range after 1 transmission. 27 is the smallest repeat shown to expand into the disease range.
- The risk of expansion of an intermediate allele into the disease range has been estimated at between 0.1 and 1% per generation.
- Individuals found to carry an intermediate allele should be counselled about the possibility of PND and about the risk to other family members.
- When intermediate and pathogenic alleles are found in the same individual, the interpretation in the report should clearly distinguish between the risk associated with each allele.
- Intermediate alleles can be coincidentally identified when healthy family members in an HD family undergo CAG repeat sizing.
What has the risk of expansion of an intermediate allele been estimated at?
The risk of expansion of an intermediate allele into the disease range has been estimated at between 0.1 and 1% per generation.
What is the definition of an intermediate allele?
- Range 37-35 repeats.
- Defined as being below the affected range, but having the potential to expand into the disease range in the next generation.
What determines the risk of expansion of an intermediate HD allele?
- Range 37-35 repeats.
- The risk of expansion of an intermediate allele into the disease range depends on a number of factors:
1) . The repeat length of the intermediate allele in the parent.
2) . Age/sex of the transmitting parent - expansion into disease range is rare upon maternal transmission with only 1 case documented.
3) . Family history - If an intermediate allele has already been shown to have expanded in the family then it is more likely to be unstable and expand again.
4) . The sequence surrounding the HTT CAG expanded region is also important. Genetic variability can influence the stability of the repeat tract. A polymorphisms p.Glu2645del is vastly overrepresented on the HD chromosome compared to the general population. Also repeat tracts where the 3’ CAA repeat is changed to a CAG are much more unstable.
What polymorphism is known to be vastly overrepresented on the HD chromosome compared to the general population?
A polymorphisms p.Glu2645del is vastly overrepresented on the HD chromosome compared to the general population.
What is the frequency of HD intermediate alleles in the general population?
1-7%
Can large intermediate alleles be associated with HD symptoms?
There have been some reports of HD symptoms associated with large intermediate alleles, but reports are not conclusive. There are few alleles in this size range and so data is insufficient. Other diagnoses should be considered for symptoms in patients with these intermediate alleles.
What percentage of clinically diagnosed cases of HD are not confirmed by a genetic tests?
Approximately 1% of cases clinically diagnosed as HD are not confirmed by a genetic test - these are the so called phenocopies.
What are phenocopies of HD?
Phenocopies are defined by a clinical diagnosis of HD with chorea, psychiatric and/or other cognitive signs and an AD pattern of inheritance.
A number of genes can be responsible for HD-like symptoms:
1) . HD-like 1 (HDL1) - mutations in the PRNP gene.
2) . HD-like 2 (HDL2) - mutations JPH3 on chr16.
3) . DRPLA - ATN1 mutations.
4) . SCA17 (HDL4) - linked to mutations in the TBP gene.
5) . Friedreich ataxia - FXN gene mutation.
HDL1 is linked to mutations in which gene?
PRNP gene.
HDL2 is linked to mutations in which gene?
JPH3 gene.
DRPLA is linked to mutations in which gene?
ATN1 gene.
SCA17 (HDL4) is linked to mutations in which gene?
TBP gene.
Friedreich Ataxia is linked to mutations in which gene?
FXN gene.
List some of the disorders that can present as phenocopies of HD.
1) . HDL1
2) . HDL2
3) . DRPLA
4) . SCA17
5) . Friedreich Ataxia
All of these disorders are caused by repeat expansions.
