Huntington Disease Flashcards
What is the mode of inheritance for Huntington disease?
Autosomal dominant (with anticipation leading to age-related Penetrance)
What is the incidence of Huntington disease?
3-10 in 100,000
What are the clinical symptoms of HD?
- Involuntary movement: chorea and later dystonia, bradykinesia and decreased voluntary movements
- Psychiatric disturbance - mood swings, paranoid ideation, rigid thought processes and depression
- Dementia
- Slurred speech and swallowing difficulties
- weight loss
how long a course does HD take?
15-20 years
What is the peak age of onset for HD?
40-45 years
What is the term for HD occurring in individuals under 20 yrs?
Juvenile HD (~4.5%) - nearly always paternally inherited and usually have more than 65 rpts (and can be up to 250)
What percentage of HD patients have an age of onset over 60yrs?
~8%
What are 2 potential differential diagnoses for juvenile onset HD?
- Benign familial chorea - onset in early childhood of isolated chorea (autosomal dominant)
- Wilson disease - autosomal recessive - onset in mid childhood
What are the allele classifications for HD?
Normal = less than 27 Intermediate = 27-35 rpts HD allele (reduced penetrance) = 36-39 rpts HD allele = more than 39 rpts
What is difficult about the intermediate range?
May be unstable and expand in future generations
Results that land in what range carry a risk of symptoms in later life?
Reduced Penetrance range
What percentage of individuals at 50% risk of HD come forward for a presymptomatic test?
Only 15-25%
What is the major issue surrounding prenatal testing in HD?
Requires careful ethical and psychosocial consideration as without termination the team have effectively performed a presymptomatic test on an unborn child
What is HD caused by?
- Expansion of a CAG trinucleotide repeat tract in exon 1 of the huntingtin HTT gene
- Translated into a polyglutamine tract which is thought to acquire a novel deleterious function when abnormally expanded
- Leads to neuronal dysfunction and neurodegeneration
How does the CAG rpt number correlate with mean age of onset?
Inverse correlation (i.e. juvenile onset display largest number of rpts)
What percentage of variability in age of onset is related to CAG rpt length?
~70% - remainder likely to be due to modifying genes and environmental factors
Describe the concept of anticipation in Huntington disease
Number of CAG rpts can increase on transmission to offspring resulting in earlier age of onset and/or increased severity of disease in successive generations
Is anticipation in Huntington disease more likely to occur through maternal or paternal transmission?
Paternal transmission due to expansion of unstable CAG rpt during spermatogenesis
What does the risk of expansion for intermediate alleles depend on?
- The rpt length of the intermediate allele in the parent
- Age/sex of transmitting parent (expansion rare in maternal transmission)
- Family history: if intermediate allele already shown to expand in family it is more likely to be unstable and expand again
- Sequence surrounding the HTT CAG expanded region
What genes are linked to differential diagnoses for HD?
- HD-like 1 = PRNP gene
- HD-like 2 = JPH3 gene
- DRPLA = ATN1 gene
- HD-like 4 (SCA17) = TBP gene
- Friedreich ataxia = FXN gene
What is the standard testing procedure for HD?
Cy5 CAG PCR
- Primers flank the CAG rpt region
- Two primer pairs used (HD1A + HD3; HD1alt + HD2)
- Internal controls used for accurate sizing of CAG rpt
When is the primer pair HD1alt + HD2 used?
Used if 1A + 3 shows two close normal alleles or homozygous normal allele
Provide some details on use of HD1A + 3 PCR primers
- Used for accurate sizing of CAG rpt expansions
- HD1A is adapted from the HD1 primer to avoid rare polymorphism at 3’ end which causes allele dropout
- Rare polymorphism in HD3 may also disrupt primer binding and result in false negative result
What can Observation of a single allele from the HD1A+3 assay represent?
- True homozygote
- Normal allele and an unamplifiable large expansion
- Normal allele and small expansion that has not been amplified due to polymorphism present under HD3 primer
Provide details on the HD1alt + HD2 PCR
- CAG rpts in HTT gene are immediately 5’ of a CCG rpt which is also polymorphic in length
- Primers HD1alt and HD2 encompass both the CAG and CCG rpt region
- Incorporation of the CCG rpt region enables two normal alleles to be resolved in cases where both alleles have identical numbers of CAG rpts but different numbers of CCG rpts
- These primers are not used to determine CAG rpt length
When are testing procedures additional to CAG F-PCR needed?
- If patients are homozygous for a normal allele in both PCRs
- This is particularly important in cases of suspected juvenile HD
- Techniques to detect larger alleles = TP-PCR and southern blotting
Predictive (presymptomatic) testing can be only be offered to which individuals?
- Those at 50% or 25% prior risk
- Only accepted from clinical genetics
- requires comprehensive genetic counselling and informed consent
Provided some details on preimplantation genetic diagnosis (PGD) in the context of HD
- Possible option for couples who wish to avoid transmitting the disease without revealing their own status or avoid termination of a pregnancy
- Embryos are cultured to the 8 cell stage
- biopsy and genetic testing are carried out to allow replacement of those with a normal HD gene
- Exclusion testing may also be possible in this scenario
What is exclusion testing and when is it used in context of HD?
- Used for prenatal testing when the foetus is at 25% risk and the future parent is at 50% risk but does not want to be informed of their HD status
- Testing uses polymorphic markers closely linked to HTT gene
- Determine which grandparental haplotype inherited by foetus
- If from the affected grandparent = 50% risk, and from unaffected = 0% risk
What are the risks involved with exclusion testing?
- Risk of recombination across HD gene is ~2%
- Testing may not be informative
- Small risk of double recombination would result in an affected individual with a ‘low risk’ haplotype
- Termination of possibly unaffected pregnancy
