Huntingtons disease (HD)

Question 1

what is HD

Answer 1

a progressive neurodegenerative disorder that result in dementia. It may cause movement disorders, cognitive impairment and changes to psychiatric disturbances (changes in mood, character etc).

Question 2

when do symptoms of HD typically manifest

Answer 2

between 35 and 50 years.

there can be a juvenile onset, younger than 20 (5%) and younger than 50 (25%)

Question 3

what is the mode of inheritance for HD

Answer 3

autosomal dominant

Question 4

what is the pathology behind HD

Answer 4

loss of specific neuronal populations.

Question 5

what causes HD

Answer 5

due to instability of CAG repeat in sperm/oocyte

Question 6

where is the huntingtons gene (HTT) located

Answer 6

ch 4p16.3, it is widely expressed and is needed for normal development

Question 7

describe the HTT mutation responsible for HD

Answer 7

it causes an expansion of unstable polymorphic tri nucleotide (CAG)n repeat in exon 1.
It results in the extended polyglutamine tract in HD.

Question 8

Describe the normal allele : include number of CAG repeats, the phenotype and the risk to offspring.

Answer 8

Number of CAG repeats: <26 (26 or less)
phenotype: normal
risk to offspring: no risk to offspring

Question 9

Describe the mutable normal allele: include number of CAG repeats, the phenotype and the risk to offspring.

Answer 9

Number of CAG repeats: 27-35
phenotype: normal
risk to offspring: increased risk to offspring.

Question 10

Describe the HD allele (with 36-39 repeats): include number of CAG repeats, the phenotype and the risk to offspring.

Answer 10

Number of CAG repeats: 36-39
phenotype: HD
May have reduced penetrance, may not develop HD.
risk to offspring: increased risk to offspring.

Question 11

Describe the HD allele (40+ repeats ): include number of CAG repeats, the phenotype and the risk to offspring.

Answer 11

Number of CAG repeats: 40 or more
phenotype: HD
risk to offspring: increased risk to offspring.

Question 12

what number of repeats correlates to juvenile onset

Answer 12

greater than 55

Question 13

true or false: the age on onset correlates with the number of repeats

Answer 13

true

Question 14

Describe the stages of testing involved in HD

Answer 14

1. pre-symptomatic: for individuals at risk involves genetic counselling.
2. diagnostic
3. prenatal testing: CVS and exclusion
4. Pre-implantation genetic diagnosis.

Predictive testing:
* HD is confirmed at 36-39 repeats with “will or will not develop HD”
@ 40 repeats they “will develop HD.”
lower number of repeats: HD not confirmed or denied “will not develop HD”.

Question 15

what is the method of dna analysis

Answer 15

Triplet primed repeat assay

Question 16

true or false: increased number of repeats correlates with a younger onset.

Answer 16

True

Question 17

True or false: there is toxicity from the polyq. repeat lenght

Answer 17

true.

Question 18

What are the three major pathogenic mechanisms of HD.

Answer 18

1. Nuclear trans protein aggregations: leads to intra-nuclear inclusions, nuclear oligomerization and aggregation.
2. protein aggregation: leads to cytoplasmic oligomerization and aggregation and cytoplasmic inclusions.
3. impairment of proteostais network: synaptic dysfunction, mitochondrial toxicity and energy imbalance. and axonal transport impairment.

Question 19

What are suggested functions of HTT

Answer 19

the function is unknown: these are hypothesis:

• transport proteins
• aid in protein folding
• part of transcription

Question 20

what are some possible therapeutic targets

Answer 20

HTT pre mRNA
toxix rna
HTT mRNA RAN proteins
however there is no actual cure.

Question 21

what does predictive testing include and why is it important.

Answer 21

refers to: Presence of the HD gene and counselling and genetic testing.
includes: genetic counselling, physiological assessment and counselling pre and post results, blood testing and neurological assessment pre and pst results.

It is important as HD is currently untreatable.