Transcript cag cag cag cag cag cag cag cag cag cag cag cag cag cag cag cag

Huntington Disease (HD)
This presentation includes:
• Clinical classification and features.
• Structure and molecular basis of the HD gene.
• Clinical photographs showing involuntary movements in HD,
and brain tissue of normal and affected patients.
• Pedigree of an HD family.
• Probability of inheriting the HD gene change.
• Advantages and disadvantages of predictive testing for HD.
Huntington Disease (HD)
• Clinical Classification
• Movement/Cognitive/Psychiatric disorder
• Mean onset age 35-55 years.
• Prevalence
• Incidence >1 in 10,000.
• Genetic Testing
• Diagnostic
• Presymptomatic – counselling protocol.
Huntington Disease (HD)
• Physical features:
- involuntary movements
- weight loss
- abnormal gait
- speech & swallowing difficulties.
• Psychiatric Manifestations:
- personality changes
- depression
- aggression
- early onset dementia.
Structure of the Huntington disease gene
Short vertical bars represent exons.
Huntington disease - a triplet repeat disease
CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG …... CAG
11-34 CAG triplet repeats are
normal:
encodes a run of 11-34 glutamine
amino acid residues in the
protein.
A run of > 34 glutamine residues
causes the protein to aggregate
in the brain cells and
cause progressive cell death.
Runs of >34 CAG repeats in the HD gene expand further (particularly during male
meiosis) causing earlier age of onset in children of men who have the gene –
anticipation.
1 ttg
ggg
61 gca
tgc
121 cgc
gga
181 cgg
tgc
241 att
cgg
301 ggg
aag
361 tcc
cag
421 cag
ccg
ctg
gcg
gag
tgg
ggc
cgc
gtc
ttt
gcc
ccc
cgg
ctg
ttc
cag
cag
ccg
tgt
ggc
tcc
ccg
ccc
aag
caa
tac
ccg
gag
gag
atg
cag
cag
cag
ccg
gag
tgg
gca
gcg
gcc
gcg
gat
ctg
gtg
gcc
acc
aag
cag
cag
caa
ccg
gca
ttc
ggc
tgg
tcc
ccg
gga
cgg
ctg
tcc
gcc
gcc
cag
cag
cag
cct
gaa
cct
tag
ccc
gcc
tgg
cgg
ccc
agc
ggg
atg
ttc
cag
cag
ccg
cct
cct
ggc
ggc
cgc
ggc
ggg
ccg
aga
ggc
gac
gcg
gag
cag
cag
cca
cag
gcg
cag
tgt
ctc
gca
ctg
ctc
gcc
gcc
tgc
acc
tcc
cag
cag
ccg
ctt
ggg
cca
caa
cgc
cgt
ccg
agg
cca
gcg
cgt
ctg
ctc
cag
cag
ccg
cct
gca
ttg
tca
cgg
ctg
gga
ttc
ttc
agt
gcc
gaa
aag
cag
cag
ccg
cag
21 CAG repeats in a “normal”/usual Huntington disease gene
Huntington disease
A patient in the advanced stages of the disease showing involuntary movements
of the head and face. Photos courtesy of Professor Peter Harper, Cardiff.
(b) Post mortem sections comparing normal brain (left) with brain from
Huntington disease patient (right); note the loss of tissue in the Huntington
disease brain. Photos courtesy of Dr David Crauford, St Mary’s Hospital,
Manchester.
Fig. 1.1 ©Scion Publishing Ltd
Photos courtesy of (a) Prof. Peter Harper and (b) Dr David Crauford
Pedigree of John Ashton’s family. This is shown as it might be recorded in the clinic.
Fig. 1.7 ©Scion Publishing Ltd
I:1
60y
Observations show that 40% of people with
the HD gene are asymptomatic at the age of
50
I:2
75y
Intuition says probability of parent having
gene at age 50 = 1/2 x 1/2.5 = 1/5.
Therefore son’s risk is ½ x 1/5 = 1/10.
II:1
56y
II:2
52y
II:3
50y
II:4
49y
Probability: ½ at
birth
III:1
25y
What
his risk?
Probability
ofisinheriting
the
altered HD gene at birth:
½x½=¼
BUT THIS IS INCORRECT! Probabilities
should be multiplied only when they are
completely independent of each other, and
these are not. Developing HD is conditional
on having inherited the gene.
Have to use Bayes theorem:His mother’s probability of having gene for
HD and asymptomatic at age 50 is 1/3.5 His
risk is therefore 1/7.
Advantages of predictive testing for
Huntington disease
• Uncertainty of gene status removed.
• If negative:
• concerns about self and offspring reduced.
• If positive:
• make plans for the future
• arrange surveillance/treatment if any
• inform children/decide whether to have children.
Disadvantages of predictive testing for
Huntington disease
• If positive:
• removes hope
• introduces uncertainty (if and when)
• known risk to offspring
• impact on self/partner/family/friends
• potential problems with insurance/mortgage.
• If negative:
• expectations of a ‘good’ result
• ‘survivor’ guilt.
‫•قطاری که از ریل خارج‬
‫میشود شاید آزاد شده باشد‬
‫اما راه به جایی نمیبرد‪.‬‬
‫ارائه و تنظیم‪:‬سمانه مقیمی‬
‫زیر نظر‪:‬آقای دکتر دستجردی‬