Huntington's disease Flashcards
1
Q
What causes Huntington’s disease?
A
Huntington’s disease is caused by a mutation of a single huntingtin (HTT) gene found on chromosome 4
2
Q
What is the DNA sequence which causes Huntington’s disease?
A
CAG
(cytosine-adenine-guanine)
3
Q
CAG repeat ranges
A
When the CAG repeat exceeds the normal range (more than 35) the formation of mutant huntingtin protein (mHTT) is triggered.
4
Q
What does mutant HTT (mHTT) do?
A
CAG repeat expansion in exon 1 results in a polyglutamine expansion in the mHttt protein (huntingtin protein)
5
Q
What are the three main symptomatic domains of HD?
A
- Motor
- Cognitive
- Behavioural
6
Q
What is the manifest stage of HD?
A
This is the onset of motor symptoms and when individuals typically get diagnosed
7
Q
Which brain areas are particularly affected in patients with HD?
A
The cortex and the striatum
8
Q
what is the normal range for CAG repeat threshold
A
less than 29 CAG repeats
9
Q
CAG repeats between 29 and 35
A
are not pathogenic
rarely expand into disease range
10
Q
CAG repeats between 36 and 39
A
pathogenic
11
Q
what is the risk of HD with 36 CAG repeats?
A
25%
12
Q
what is the risk of HD with 37 CAG repeats?
A
50%
13
Q
what is the risk of HD with 38 CAG repeats?
A
75%
14
Q
True or false. A greater number of CAG repeats is associated with earlier onset of motor symptoms
A
True
15
Q
CAG repeats over 39
A
always causes HD
16
Q
what is the risk of HD with 39 CAG repeats?
A
90%
17
Q
What are the two main types of testing for HD?
A
Predictive and confirmatory
18
Q
Confirmatory testing
A
Confirms HD diagnoses in someone who is showing HD symptoms
19
Q
what type of genetic disease is huntingtons?
A
a genetic inherited autosomal dominant neurodegenerative disease
20
Q
epidemiology of huntingtons disease
A
most common monogenic neurodegenerative disorder
21
Q
what is the prevalence of huntingtons?
A
5-13 cases/ 100,000/ year
22
Q
what is the incidence of huntingtons?
A
4.7-6.9/ 1,000,000
23
Q
when do symptoms typically present?
A
mid adult life
24
Q
what percentage of mutations are de novo
A
5-8%
25
where is the huntingtin protein expressed?
in all tissues
26
where is the huntingtin protein expressed in neurons
extracellular
27
what is the pathology of early disease in HD
GABAergic medium spiny neurons in the basal ganglia, caudate and putamen
28
what is the pathology of early dysregulation in HD?
early dysregulation in the direct and indirect basal ganglia pathways
29
where is early atrophy seen
**caudate**
30
what neuroimaging methods are used to visualise caudate atrophy in HD
axial CT
T2 weighted MRI
T2 FLAIR MRI (fluid attenuated inversion recovery)
31
motor circuit
sensorimotor and premotor cortex
32
associative circuit
dorsolateral prefrontal and lateral orbitofrontal cortex
33
limbic circuit
limbic and paralimbic cortex, hippocampus and amygdala
34
what are the differentials for adult onset neurodegenerative disease?
spinocerebellar ataxias
dentatorubral-pallidoluysian atrophy (DRPLA)
triplet repeat disorders (FRAXTAS)
parkinsons
alzheimers
| ***FRAXTAS (Fragile X-associated tremor/ ataxia syndrome)***
35
what are the neruological differentials for movement disorders
chorea
tics
bradykinesia
tremor
dystonia
36
what are the neurological differentials for disorders of the basal ganglia?
tourettes
parkinsons
dystonia
37
the basal ganglia is also referred to as what brain system?
the extrapyramidal system of the brain
38
discovery of the huntingtin gene lead to which developments in testing?
predictive genetic testing
diagnostic genetic testing
preimplantation genetic testing
39
why is predictive testing important?
decreases uncertainty
future planning
family planning
treatment targets
informing family members of risk
40
what are the considerations of predictive testing?
individual and family emotional impact
cannot unlearn the result
employment and insurance discrimination
long term adjustment (mood and risk)
41
what is the law on army employment applied to HD?
the army can not discriminate against people at 50% risk or insist on testing
| 37 CAG repeats 50% risk
42
what is the law on police employment applied to HD?
at risk individuals are accepted but excluded from firearms and high speed driving
43
driving and HD
the DVLA have to be informed if an individual is symptomatic
44
what are the laws applied to life insurance and HD
weighting and test results have to be disclosed if application is for amounts exceeding £500,000
45
what is preimplantation testing
IVF technique
46
what is the commonest cause of chorea presenting in midlife
huntingtons
47
what is the protocol for genetic testing in an individual presenting with clinical symptoms and a positive family hx?
confirm clinical dx
only do genetic testing with motor abnormalities are consistent with HD
48
what are the genetic disease differentials for huntingtons
inherited prion disease
HDL2 (triplet repeatexpansion in the JPH3 gene)
HDL3
neuroferritinopathy
NBIA/PKAN (PANK 2 mutations)
SCA17/ HDL4
SCA1-3
DRPLA
neuroacanthocytosis and MacLeod's syndrome
49
what are other acute or sub acute (non neurodegenerative) causes of chorea
medication
stroke
structural pathology
metabolic syndromes
50
what are the phases of the phases of at risk huntington stage?
presymptomatic (unfavourable genetic predictive test)
prodromal phase
manifest huntingtons (motor and psychiatric signs)
51
how are motor symptoms assessed in huntingtons
unified huntington disease rating scale (UHDRS)
52
what percentage of people first present with psychiatric symptoms
30%
53
which individuals are often diagnosed as having a primary psychiatric disorder (without family hx of huntingtons)
broken families
care leavers
single parents
family trauma
54
what are the commonest primary psychiatric misdiagnoses?
personality disorder and neurosis
mood disorder
schizophrenia
other forensic
55
what are the psychiatric features of huntingtons
anxiety and depression
apathy
obsessive compulsive disorder
irritability, impulsivitiy and psychotic symptoms
suicide
56
what is the pharmacological treatment for anxiety and depression in huntingtons?
SSRIs and SNRIs (mirtazepine, citalopram, fluoxetine)
57
what is the pharmacological treatment for ocd in HD
behavioural interventions and SSRIs
58
what is the pharmacological treatment for irritability, impulsivity and psychotic symptoms?
neuroleptics (olanzapine, supiride, amisulpiride, risperidone)
59
what is the lifetime prevalence of suicide risk in huntingtons
5-10% lifetime prevalence
60
when do cognitive symptoms appear
10 years before manifest huntingtons
61
which tests are most sensitive to cognitive impairements in early huntingtons
tests of psychomotor speed
62
which brain areas are associated with dysexecutive syndrome?
frontal, striatal and subcortical
63
what are the features of dysexecutive syndrome
difficulties with planning, reasoning, mental flexibility, decision making, attention and concentration
64
how can dysexecutive syndrome be tested
stroop
symbol digit modality
letter fluency test
65
which symptoms overlap with psychiatry
impulsivity and irritability
loss of emotional response and empathy
66
what are the motor manifestations of huntingtons
eye movements
impersistence of tongue protrusion
speech and swallowing
chorea
motor sequencing
gait and balance
67
what are the features of chorea
impersistence of movement
myoclonus
tics
dystonia
hypokinesia
68
which symptomatic treatments for motor symptoms block dopamine receptors
atypical neuroleptics such as olanzapine, risperidone, supiride and aripirazole
69
which symptomatic treatment depletes presynaptic dopamine
tetrabenazine 25-100mg/ day
70
what is the pharmacological management of akinetic rigid variant of huntingtons
levodopa, baclofen, clonazepam
71
what are other important areas to address
weight loss
swallowing
speech and communication
dental care
mobility
activities of daily living
sleep
driving
social care needs
huntingtons disease association care advisor
research
72
what are the general aims of treatment in huntingtons
preventative
symptomatic
supportive
73
what is the staging system used to measure disease progression in huntingtons
the integrated staging system (ISS)
74
how many stages are there in the integrated staging system for huntingtons?
3
75
integrated staging system stage 1
biomarkers of pathogensis
76
what are the landmark assessments that define stage 1
putamen volume
caudate volume
77
integrated staging system stage 2
clinical signs and symptoms
78
what are the landmark assessments that define stage 2
test motor score (uhdrs)
symbol digit modality test
79
integrated staging system stage 3
functional change
80
what are the landmark assessments of stage 3
total function capacity
independence scale
81
NfL
Neurofilament light chains are a potential biomarker for huntingtons. Studies show elevated levels in blood and CSF are associated with disease progression, atrophy and clinical symptoms
82
what pathological processes are associated with huntingtons progression
oxidative stress
translational dysregulation
mitochondrial damage
excitotoxicity
83
what are potential DNA targets to treat huntingtons
zinc-finger transcription factor targeting
CRISPR/ Cas9
84
what are potential RNA targets to treat huntingtons
antisense oligonucleotides
RNA interference
small-molecule splicing modulators
85
what are some acquired causes of chorea
sydenham's chorea (d2 receptors)
post infectious chorea
anti-phospholipid antidbody syndrome
bachet's diseas
polyarteritis nodosa
paraneoplastic chorea
neuronal surface antibodies
preganancy (chorea gravidarum)
vascular
henoch-sconlein purpura
MS
SLE
86
what are metabolic causes of acquired chorea
hyperthyroidism
hyperglycemia
hyponatremia
87
what are infectious causes of chorea
HIV (primary and opportunistic infection)
borreliosis
88
what percentage of chorea is drug induced
30%
89
what are drug related causes of chorea
anticonvulsants
oral contraceptives
antiparkinsonism drugs
trycyclic antidepressants
stimulants
neuroleptics
carbon dioxide
manganese
mercury
thallium
toluene
