Genetics of Neurodegenerative Diseases Flashcards
complete
What is the trinuclotide repeat present in Huntington disease? And what does it code for?
- CAG
- encoding for glutamine
Which gene is effected in Huntington disease?
HTT
In which category of diesease does Huntington disease fall?
polyglutamine diseases
What is the mean age of onset for Huntington disease? What is the range?
mean: 30-50
range: 2-85
Huntington Disease
What is the mean duration of disease?
17-20 years
this describes the time from symptom onset to death
What is the mechanism of disease for Huntington disease?
- CAG repeat in HTT gene encodes a polyglutamine stretch in the Huntington protein
- Huntington protein i expressed early in development and is critical for life
- expansion of polyglutamine makes the Huntington protein prone to misfold and then aggregate leading to neuronal loss
What is the mean CAG repeat length in a normal chromosome? In an HD chromosome?
normal ~ 18
HD ~ 42
At what CAG repeat size is an individual affected?
36
Does the trinucleotide repeat expand with paternal or maternal transmission in HD?
paternal
maternal expansion is possible but but less likely and the expansion is smaller
HD
What is the CAG repeat size of a normal allele?
≤ 26
Risk of expansion in this repeat size is essentially zero, but there is one case report of 26 –> 44, so upper end of normal may have some instability
HD
What number of CAG repeats is present in an intermediate allele?
27-35 CAG repeats
HD
What are the risks for someone with an allele with an intermediate number of CAG repeats?
- no personal risk for HD
- risk for HD in offspring
There have been reports of HD symptoms in intermediate allele carriers though.
HD
What factors contribute to risk of expansion in offspring for a carrier of an intermediate number of CAG repeats?
- repeat size: larger intermediate alleles more likely to expand
- sex of carrier: more liekly to expand in paternal transmission
34-35 CAG repeat allele in a male is highest risk
HD
How frequent are intermediate alleles in the general population?
1 in 50
HD
What is the number of CAG repeats in an allele that is considered ‘reduced penetrance’?
36-39 CAG repeats
What do we know about personal risk for HD for individuals with an allele with CAG repeats in the ‘reduced penetrance’ range?
36-39 CAG repeats = reduced penetrance range
- may or may not develop sympotoms of HD
- there is data to correlate current age and number of repeats with likelihood of developing symptoms at a certain age in the future
- eg: 40 yo w/ 39 repeats = 52% chance of developing symptoms by 70
reduced peentrance genes have been observed at high frequency in gen pop
Number of CAG repeats to be full penetrance
40+
full penetrance = will cause HD in lifetime
Number of CAG repeats for juvenile onset HD
60+
Age of onset of HD to be juvenile onset? Symptoms?
- <20 yo
- epilepsy & Parkinsonism
Effect of homozygosity in HD alleles?
- similar age of onset to heterozygotes
- accelerated rate of disease
Loss of interruption variants result in loss of CAA interruption. Results in CAG repeat lengthening by 2. This is associated with what?
- increased somatic instability
- higher frequency of repeat expansions in sperm
Reduced penetrance HD allele with loss of interruption (LOI) variant effect?
reduced penetrance HD allele individuals presented with symptoms 29 years earlier than anticipated
Inheritance pattern of hereditary ataxia/spinocerebellar ataxia
autosomal dominant
heredtiary ataxia when adult onset and AD is AKA
spinocerebellar ataxia
