1. Huntington’s Disease Case presentation Clinical features Pathology
Neuropsychological profile
Epidemiology
Treatment

2. Susan 55 yo female Cognitive difficulties: Language Memory
Collateral informant:
progressive cognitive difficulties
poor decisions at work, unsafe
Not driving 2 yrs
Demographics
Living with brother ~ 1.5 yrs
Brother manages IADLs

3. Susan Neurological exam progressive gait disturbance, imbalance
dysarthria
Irritability
Cognitive decline
Dx: Huntington’s disease

4. Huntington’s Disease Progressive loss of functional ability and
death within yrs from onset

5. Huntington’s Disease Key clinical features:
Hyperkinetic movement disorder
Psychiatric manifestations
Cognitive impairment/Dementia

6. Clinical Features: Movement Disorder
Chorea - brief, abrupt, irregular movements
Athetosis – writhing, twisting
Motor impersistence
Postural instability
Eye movement abnormalities (early)
Dystonia (late)
Bradykinesia (late)
Less common but seen – tics, tremor, myoclonus

7. Huntington’s Disease Clinical Features
Other motor features:
Impaired dexterity and fine-motor coordination
Dysarthria
Dysphagia and aspiration
Progressive gait disturbance
balance/incoordination
increased risk of falls/injury

8. Pathology in HD Neuronal loss throughout cortex
Most prominent in striatum

9. Huntington’s Disease Clinical Features
Cognitive impairment
loss of recent memory
poor judgment
impaired concentration
Occurs in nearly all patients
May precede onset of motor symptoms
Progresses to global dementia in later stages

10. Huntington’s Disease Clinical Features
Psychiatric impairment
Depression (10x suicide risk)
Personality changes
agitation, irritability, anxiety, apathy, social withdrawal, impulsiveness, mania, paranoia, delusions, hostility, hallucinations, psychosis, and sexual disorders
May precede onset of motor symptoms

11. HUNTINGTON’S DISEASE Autosomal dominant neurodegenerative disorder
Determined by genetic mutation on short arm of chromosome 4 –
Mutation is an expanded and unstable trinucleotide repeat of cytosine-adenosine-guanine (CAG);
< 35 No symptoms
35–39 Variable expression
> 39 Essentially all become symptomatic .

12. HUNTINGTON’S DISEASE
Mutated gene codes for IT15 protein (now known as HTT or ‘huntingtin’)
Function of huntingtin protein unknown, but
critical for development
highly expressed in brain
involved in signalling, transport and protecting against cell death
Higher number of repeats in mutant gene associated with earlier symptom onset

13. Higher number of CAG repeats associated with earlier symptom onset
Age at
Onset

14. Basal Ganglia

15. Huntington’s Disease Neuropsychological Profile
Deficits seen in at-risk patients prior to motor symptom onset
Frontal-subcortical dysfunction due to striatal degeneration
Mechanism of cortical involvement presumably reflects effect of gene defect on neocortical cell death

16. Huntington’s Disease Neuropsychological Profile
Frontal - Subcortical Deficits
Cortical Deficits
Motor speed/dexterity
Dysarthria
Executive
Attention/concentration
Verbal fluency
Programming
Abstraction
Perseveration
Verbal retrieval (vs. preserved recognition)
Language
Dysprosodia (poor modulation of tone)
Reduced syntactic complexity
Visuo-spatial
Object misidentification (BNT)
Visual construction
Mental rotation

17. Epidemiology United States Prevalence: 5-10/100,000
30,000 Americans with HD
~150, ,000 at-risk
Prevalence is geographically heterogeneous
Europe: 1.6-9/100,000
Finland and Japan: <1/100,000
560 per 100,000 (Moray Firth, Scotland)
700 per 100,000 (Lake Maracaibo, Venezuela)

18. Epidemiology Onset is usually between ages 30-45 Mean 37, range 2-80
Mean aoo differs by cohort
Venezuelan kindreds 34.4y
US: 37.5 y
Canada: 40.4 y
Modifying genes and environmental factors influence age of onset
CAG repeat length correlates inversely with aoo
Correlation stronger when onset of sxs occurs earlier

19. Juvenile HD onset of HD in patients younger than 20 y
~5-10% of all affected patients
Most inherit the disease from their father
onset after age 20 y are more likely to have inherited gene from mother
Inheritance through the father can lead to anticipation

20. HD Treatment Currently no pharmacological treatment available
Can treat psychiatric manifestations (i.e., depression, anxiety, psychosis)
No cognitive agents available yet
Use of DA blocking agents will  chorea
Research directions
Reduce huntingtin production
Improve cell survival
neuronal replacement

21. Multidisciplinary rehabilitation improves brain structure in HD
Cruickshank et al 2015 Brain Behav

22. Multidisciplinary rehabilitation improves cognition in HD
Task
Baseline
Post-trial
P-value
CWIT
Color naming
48.4
52.3
.0999
inhibition 91 94
0.452
TMT A
55.7
61.8
0.051
TMT B
61.9
66.2
0.126
HVLT-R
Free Recall
17.7
16.7
0.013*
Delayed recall
4.9
6.3
0.187
Recognition
8.1
9.0
0.079
SDMT 27
26.78

23. Susan’s Results MMSE 21/30 %ile WAIS-III SS Immediate Memory < 0.1
Digit Span 7
Delayed Memory
Letter-Num Seq DC
WMS-III Imm. Memory 1
Trail Making A 2
Trail Making B
RBANS
Phonemic Fluency
Attention
Language 5
Visuospatial
0.1