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C3 CLINICAL > Clinical Presentation and pathology of Huntington’s Disease > Flashcards

Clinical Presentation and pathology of Huntington’s Disease Flashcards

1
Q

What is Huntington’s disease?

A
  1. Inherited
  2. Autosomal dominant
  3. If you have an affected parent, you have a 50% chance of inheriting the 🧬
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2
Q

What is the onset of Huntington’s disease?

A

Typically, mid-adulthood (~37 years)

- Dependent on CAG length

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3
Q

What is the progressive loss of function for Huntington’s disease?

A
  1. Movement disorder
  2. Cognitive deficit
  3. Psychiatric abnormalities
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4
Q

What is the death of Huntington’s disease?

A

15-25 years

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5
Q

How many people are affected with Huntington’s disease in the UK?

A

~8000 affected individuals and 5 times that number at risk of the disease

HD is a disease of families as well as individuals

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6
Q

What is Huntington’s disease caused by?

A

CAG repeat
The length of it determines when you are likely to get it
- Under 35 repeats you are generally thought of as being unaffected
- more than 40 you are considered fully penetrance at some stage of your life

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7
Q

What is reduced penetrance?

A

36-39 repeats

you maybe get it later on in life

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8
Q

Where will the onset of Huntington’s disease by?

A

In the Juvenile years

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9
Q

What is vulnerable to the effect of the Huntington’s gene?

A

The median speed of spinal neurons

- It affects synaptic transmission, mitochondrial function, inflammation

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10
Q

Although Huntington disease is made up of one mutation, what can it produce?

A

A multiple variety of clinical phenotypes

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11
Q

What is Huntington’s disease characterised by?

A

triad of motor, cognitive and behavioural dysfunction

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12
Q

What is chorea?

A

Excessive movements in Huntington’s disease

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13
Q

What are the movement features of HD?

A
  1. Chorea in 90% adult-onset, tails off in advanced disease
  2. Motor incoordination
  3. Dystonia (Muscle contortions)
  4. Oculomotor disturbance
  5. There are additional unwanted movements
  6. Disturbance of eye movements
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14
Q

What the cognitive features of HD?

A

Difficulties with:

  1. Planning
  2. Judgement
  3. Impulse control
  4. Flexibility
  5. Multi-tasking
  6. Emotional processing - Fail to recognise emotions in other people’s faces
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15
Q

What are the psychiatric features of HD?

A
  1. Irritability very common
  2. Depression, anxiety, suicide
  3. Agression
  4. Compulsions
  5. Psychosis
  6. Hypersexuality
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16
Q

What causes the greatest disability, functional decline and distress to relatives?

A

Combination of psychiatric and cognitive features

17
Q

What are the features of onset and early disease of Huntington’s?

A
  1. Onset described age 2-80 years old
  2. Juvenile onset - more aggressive disease, rigidity, dystonia, rapid cognitive decline
  3. Often prior history of mood disorder
  4. Insidious and slow deterioration of intellectual function with mild personality change
  5. Minor motor abnormalities - general restlessness, abnormal eye movement, fidgety movements of fingers, hands and toes during stress or when walking
18
Q

What are the features of mid-course disease?

A
  • ‘Extra-pyramidal signs’ – chorea is seen in 90% of adult-onset, dystonia, parkinsonism, bradykinesia (slowness of movement), rigidity
  • Oculomotor disturbance
  • Impairment of voluntary motor function – clumsiness, disturbances in the fine motor control, motor speed
  • Gait disturbance
  • Dysarthria (speech impairment) and dysphagia (swallowing difficulties)
  • Cognitive and psychiatric problems
19
Q

What are the advanced stage features of the disease

A
  • Patients do not die of HD; they die of causes associated with the disease
  • End-stage disease is dominated by hypokinesia (low movement), rigidity and dystonia
  • Mutism and severe dysphagia (impairment in communication)
  • Severe eye movement abnormalities
  • Agitation common
  • Weight loss and emaciation – metabolic disorder – problem with mitochondria – not processing food well
  • Assisted suicide in HD
20
Q

What are the disease-modifying treatment for Huntington disease?

A

Try to control their depression and their movement but there is nothing slowing down the underlying disease process

  1. Anti-sense anti-oligonucleotide
21
Q

When does an individuals have Huntington’s disease?

A
  • Positive predictive genetic test?
  • Symptoms reported by Individual?
  • Symptoms reported by carer?
  • First motor signs assessed by clinician
  • Huntington’s disease family members are affected by the disease from birth, even if gene negative. When to get a diagnosis is a very personal and individual issue
22
Q

What are the delaying disease onset in HD?

A
  • Disease sign is absent, and they suddenly appear
  • Subjective onset: when people start complaining about problems but before a clinician said yes you have it
  • Health of neurons decline
  • There is a period of neuronal dysfunction after which there is a neuronal death – brain atrophy
  • Shift this along so that if we are having only clinical diagnosis – successful treatment
23
Q

Define biomarker

A

a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention

24
Q

Why is a biomarker useful?

A

Measure of where the disease is up too and whether the treatment has slowed it

  • How much toxic protein is there - causing disease affects
  • Assays are quite variable
25
Q

What do we need in a biomarker?

A
  • Sensitive to disease effects
  • Early HD
  • Premanifest stages
  • Reproducible within and between sites
  • Track change over time
  • Link to clinically meaningful measure of function
26
Q

What are the clinical rating scales?

A
  • very variable according to raUnified Huntington’s Disease Rating Scale
  • Total Functional Capacity
  • Total Motor Score
  • BUT insensitive prior to disease onset, don’t always capture all aspects of the disease and can be ter
27
Q

What is the TRACK-HD study?

A
  • Multi-centre, multi-national, prospective, longitudinal, observational biomarker study with the aim of
  • developing and validating biomarkers to undertake future clinical trials of disease-modifying agents in premanifest and early HD
  • furthering our understanding of the neurobiology of premanifest and early HD
28
Q

What is the TRACK-HD Design?

A 
Baseline, 12, 24 and 36 month assessments in following modalities: 
Clinical
3T MRI
Quantitative motor 
Oculomotor
Cognition
Neuropsychiatry
29
Q

What are the subjects for the TRACK-HD Design

A

123 controls
120 premanifest gene carriers (62 Pre-A:>10.8; 58 Pre-B:<10.8 yrs to diagnosis)
123 early HD (77 Stage 1: TFC range 11-13; 46 Stage 2: TFC range 7-10)
96% retention rate at 12 months, 93% at 24 months

30
Q

What is the Symbol Digit Modalities Test

A

Test of speed and cognitive flexibility

sensitive in early Huntington’s disease

31
Q

What is the application of imaging in HD?

A

Imaging can help us to:
- Understand the natural history of the disease across the spectrum from decades before clinical onset through to manifest disease

-Track disease progression and crucially assess the impact of therapies on this natural decline

32
Q

What do we need in biomarker/?

A 
Sensitive to disease effects
Early HD √
Premanifest stages √
Reproducible within and between sites √
Track change over time √
Link to clinically meaningful measure of function √

C3 CLINICAL (27 decks)

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