Huntington Disease Flashcards
What is Huntington Disease?
Huntington Disease (HD) is a genetic, hereditary, progressive neurodegenerative disorder caused by a defect in a gene on the short arm of chromosome 4. Caused by a dominant gene that codes for a large brain protein called huntingtin.
Epidemiology of HD
In Canada…
- Approximately 1 in 7,000 people have HD;
- Approximately 1 in 5500 are at-risk of inheriting HD;
- Approximately 1 in 1000 are affected by HD (e.g. spouse, friends, relatives, etc.).
Males and females have equivalent risk of inheriting HD.
Onset of symptoms usually occurs between the ages of 35 and 55.
Juvenile HD accounts for ~10% of all HD cases.
Clinical Symptoms of HD
HD is a particularly insidious disease because its symptoms do not usually appear until later adulthood.
Progressive disease = symptoms begin very subtly, eventually progress to more pronounced involuntary movements (hyperkinetic).
Symptoms may include:
- Abnormal movements (involuntary movements, dystonia,
motor coordination) known has chorea (G. “dance”);
- Cognitive difficulties, including dementia;
- Emotional difficulties (e.g. depression, apathy, irritability, personality disorders)
Eventually the motor and intellectual deterioration become so severe that sufferers are incapable of feeding themselves, controlling their bowels or recognizing their own children.
HD Early Stages:
Face, trunk and limbs move involuntarily and rapidly;
- Not too noticeable, can be disguised by patient fairly easily
As HD disease progresses:
- Muscles begin to contract briefly and rapidly;
- Arms and other body parts suddenly jerk;
- Movements become uncoordinated, and eventually the whole body is affected.
HD Later stages:
- Cognitive changes become pronounced;
- Irritability, excitability, impulse control issues;
- Changes in interests;
- Severe depression, dementia, etc.
- Death usually occurs 13 to 15 years post onset of symptoms.
Normal BG Circuit
Striatum contains groups of specialized neurons called medium spiny neurons (MSN). (Also contains GABA interneurons.)
- MSN are specialized GABAergic cells;
- Represent ~95% of neurons in the human striatum;
two main types of MSN:
There are two main types of MSN: either express D1 (aka direct MSN) or D2 (aka indirect MSN) receptors (some contain both, but we’ll ignore those for now)
- Direct (D1) MSN excite their output structures (e.g. thalamus) and promote associated behaviors;
- Indirect (D2) MSN inhibit output structures (e.g. thalamus) and associated behaviors.
HD Pathology
Damage to neurons in the basal
ganglia (i.e. D2 MSN) and
consequent loss of its inhibitory
output to the thalamus is thought
to account for the disorders of movement in HD patients.
In later stages, cortical degeneration is primarily responsible for the dementia and personality changes associated with HD.
HD Pathology progression
Typically, caudate, putamen and Globus Pallidus are most affected;
However, as disease progresses,
other areas of the brain are also affected (e.g. cerebral cortex shrinking & thinning).
Up to 95% loss of medium spiny (GABA) neurons can be seen in later stages of the HD.
As we’ll see, there are intranuclear inclusion bodies and perinuclear aggregates of huntingtin in HD-affected neurons.
- Causeinterferenceofnormalcellularfunction; - Activationofintrinsicapoptoticpathways.
How can two basal ganglia diseases be so different?
PD and HD are both diseases of the basal ganglia that cause abnormalities in movement due to neurodegeneration.
- Hypokineticvs.hyperkinetic
The primary neurotransmitters in the basal ganglia are GABA
and Acetylcholine (Ach).
These neurotransmitters normally act on the excitatory dopaminergic neurons in the nigrostriatal tract that extend from the substantia nigra to the basal ganglia to inhibit involuntary movements.
Death of these neurons due to aggregates of misfolded Huntingtin proteins causes a significant decrease in GABA and ACh levels, resulting in increased activity in the nigrostriatal pathway.
What causes HD?
It starts with a mutation.
Because HD is passed from generation to generation by a single dominant gene, all of the individuals carrying the gene develop the disorder, as do about 1⁄2 of their offspring.
The dominant gene that is mutated in HD was identified and characterized in 1993 and named huntingtin (HTT) who’s protein product is the huntingtin protein.
mutated huntingtin gene
The mutated huntingtin gene contains an expanded CAG repeat coding for polyglutamine in the huntingtin protein.
- Uninterrupted glutamine residues forming polyglutamine tract;
- Polyglutamine tracts are subject to increased aggregation;
- CAG repeats attract polyglutamine sequences from non-HTT proteins;
CAG repeat lengths between 10-25 are normal. In HD patients we see CAG
repeats above 36X.
The longer the repeat length, the earlier the age of onset of HD.
- Over generations, the mutation seems to add additional CAG codons, and disease presents earlier and earlier.
We don’t fully understand what huntingtin protein does, but it’s thought to be involved with cytoskeletal function, cellular transport, and/or anti-apoptotic functions.
The Huntingtin Protein
Huntingtin proteins are widely expressed throughout the the brain, less prevalent in the peripheral nervous system (concentrated in the testes).
HD patients show misfolded huntingtin proteins that aggregate (i.e. clump) together, particularly in the dorsal striatumàD2 MSN
Big globs of misfolded proteins accumulate and trigger neuronal degeneration.
HD symptoms appear to be due to cell dysfunction, and eventually cell death.
- Celldeathisstronglycorrelatedwithfunctionaldisability;
- Celldeathisthoughttooccurviaapoptoticpathways, with activation of caspases.
Mutated HTT genes
Mutated HTT genes are thought to activate caspase proteins and initiate intrinsic apoptotic pathways.
Caspases are a family of enzymes involved in programmed cell death
- There are 11 or 12 confirmed caspases in humans;
- Each of them function slightly differently, but all initiate apoptotic pathways;
- Caspases are the point of convergence between extrinsic and intrinsic apoptosis.
Activation of caspases ensure that cellular components are degraded in a controlled manner, with minimal effect on surrounding tissues.
