2. Paracelsus (1493-1541): 1st to
describe HD patients as having
“chorea”, which implicated the CNS
In 1600’s, patients’ violent jerking
movements (the “San Vitus” dance)
were believed to be signs of
possession by the devil; Salem
witches included at least 1 HD
patient in 1690’s
Zuccato et al, Physiol Rev 2010; 90: 905-981
In 1920’s, eugenicist Charles Davenport generated largest
study of families with HD; in 1950’s, Dr. Amerigo Negrette
found large community of HD families near Lake Maricaibo,
Venezuela
3. George Huntington, MD
First to describe Huntington’s disease
in the late 1800’s
American physician from Long Island
Described the disease in a paper he
wrote in 1872 when he was 22
With his father & grandfather (MD’s), he
noticed the hereditary nature of the
disease in a family in East Hampton, NY
Huntington referred to the disease as
“hereditary chorea”
4. Huntington’s Disease symptoms:
An autosomal dominant, heritable disease
causing uncontrolled movement of the arms,
legs, head, face, and upper trunk.
Cognitive impairments in reasoning skills,
memory, concentration, judgment, and
organization ability
Mood changes, especially depression,
anxiety, and anger/irritability
Frequently, obsessive-compulsive disorder
(OCD) develops
from alz.org
5. Prevalence of HD
Approx. 30,000 Americans have HD
HD affects both males & females, all races & ethnic groups
In whites, 5-7 affected/100,000 (higher in Lake Maracaibo,
VZ & Tasmania)– higher frequency of 28-35 CAG repeats in
whites
In Japan, 0.5 affected/100,000
from hdsa.org/what-is-hd/
and Lancet 2007; 369: 218-28
6. Chorea: irregular, jerky movements; uncontrolled, dance-like
motion of twisting or writhing (from the Greek word
“dance”)
https://youtu.be/KleHA0fv0Eg
6 min video: doctor & patient, Univ College of Dublin
7. HD patient
Jerky, uncontrollable movements of limbs, trunk, and face
Attempt to conceal involuntary movements by adding
voluntary movements
Lesions in the frontal cortex, putamen, GP
HD: excessive DA signaling in the basal ganglia
Normal movement is dependent on balance between
direct/indirect motor pathways
8. Prognosis of HD:
Progressive cognitive, motor, & psychiatric impairments
Drugs manage symptoms, but not the outcome
Death occurs ~18 yrs after onset (between. 30-50 yrs)
Patient chokes (failure to clear lungs/swallow), or dies of
pneumonia, infection, or heart failure
Patient eventually requires complete care
Fasting every other day may improve symptoms & survival
(82Q mouse study: PNAS 2003; 100(5): 2911-16)
10. Stages of HD
Early-stage: subtle changes in coordination
some involuntary movements (chorea)
difficulty thinking about problems
depressed or irritable mood
overall, less productive at work and home
Middle-stage: movement disorder is problematic
medication can relieve chorea
occupational/physical therapists may be
needed for controlling voluntary
movement
diminished speech & difficulty swallowing
from hdsa.org/what-is-HD
11. Late-stage: total dependence on others for care
choking is a major concern
chorea may be severe or absent
inability to walk or speak
language comprehension is intact
awareness of family & friends is intact
death: result of complications, eg. choking or
pneumonia, heart failure
Stages of HD
*All stages of HD: weight loss is a complication
from hdsa.org/what-is-HD
12. Huntington’s chorea: caused by mutations
in the huntingtin gene (IT-15) located on
chromosome 4
Huntingtin has a polyglutamine (“polyQ”)
repeat sequence encoded by a triplet
codon, CAG, which is inherently unstable
In Huntington’s disease, the CAG repeat
becomes abnormally expanded to extend
the number of polyQ repeats
Expansion creates a “sticky” protein which
aggregates and acts as a molecular sink for
interacting factors, generating large
intracellular lumps
14. Juvenile HD (JHD)
Defined by rapid onset of symptoms < 20 yrs
Caused by a large expansion of the polyglutamine tract at
the amino-terminus of Htt; > 60 CAG repeats (genomic DNA)
Prevalence is rare; only 5-10% of all HD cases
Prognosis is poor; death usually within 10 yrs after onset (vs.
10-25 yrs w/ adult HD)
from rarediseases.info.nih.gov/diseases
15. from rarediseases.info.nih.gov/diseases
Juvenile HD (cont’d): Symptoms
Common sign of JHD: rapid decline in school performance
Handwriting changes
Developmental regression
Slow movement, rigidity and tremor (similar to Parkinson’s)
Rapid muscle twitches (myoclonus)
Voice abnormalities
Seizures (tonic-clonic) occur in 25-30% of JHD patients
Younger children are less likely to have chorea, but have
more stiffness
16. How do trinucleotide repeats become expanded?
-DNA polymerase “slipping” on repeats during replication
http://web.stanford.edu/group/hopes
23. Neurobiological aspects & pathology of HD
Progressive neurodegeneration with loss of efferent
GABAergic medium spiny neurons in the striatum, and in
cortical neurons
Pathology of HD (postmortem): described on a scale of 0-4,
with 0= 30-40% neuronal loss in head of caudate nucleus;
1= atrophy & neuron loss in the tail of caudate; 2-3=
progressive, severe gross atrophy of striatum; 4= most
severe HD, with atrophy of striatum & up to 95% neuron
loss
Zuccato et al, Physiol Rev 2010; 90: 905-981
25. Where in the brain is HD?
Neuron loss in HD brain is not limited to the striatum
In grades 3-4 (advanced HD): cerebral cortex (layers III,
V, & VI), GP, thalamus, STN, SN, myelinated tracts, CB,
and hypothalamus are also affected
Caudate
Putamen
HD brain
30. Dopamine binding is reduced in HD patient brain by PET
*SCH 23390: D1 receptor antagonist
31. HD: disinhibition of striatum + more inhibition from thalamus =
slower controlled movement
from web.stanford.edu [HOPES project]
32. HD: increased inhibition of STN+ disinhibited thalamus = net
increased movement
from web.stanford.edu [HOPES project]
33. Why does HD target the striatum?
mRNA and protein of the Htt gene, IT-15, are ubiquitously
expressed in brain and in the body
key could be: interacting factors’ limited expression
selective sensitivity to aggregates & stress
inherent differences in cell death
mechanisms
Overaccumulation of glutamate theory: basal ganglia
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Editor's Notes
Left= neuronal loss
Right= inclusions of htt protein
The basis of the model resides in the striatopallidal
connections via the direct and the
indirect projections (Fig. 5), which have an opposite
functional effect on basal ganglia output
(Albin et al 1989; DeLong 1990). Activation of
GABAergic MSNs that give rise to the direct
pathway inhibits GPi/SNr tonic activity, inducing
a pause of neuronal firing. At the same time,
activation of MSNs of the indirect pathway first
inhibits GPe neurons, followed by disinhibition
of the STN, which then excites GPi/SNr neurons.
Because pauses of neuronal firing in the
basal ganglia output are associated with the
occurrence of an action (e.g., an eye movement
saccade), and discharges are associated with
stopping or halting movement, the direct and
indirect pathways are viewed as opposite functional
projection systems that facilitate and inhibit
movements and behaviors, respectively
main problem: overactivation of striatal neurons
There are fewer binding sites on excitatory dopamine receptors
greater thalamic inhibition, less directed movement/stim MCx
Increased inhibition of striatum, increased inhibition of STN, overexcitation of MCx
