Huntingtons Disease Flashcards
What is the aetiology of Huntington’s Disease?
- HD is caused by a mutation of the Huntingtin gene (HTT) on the short arm of chromosome 4 (4p16.3)
- The mutation is expressed as an autosomal dominant disease which means any child of an affected parent has a 50% risk of inheriting the disease
A small number of cases of HD are sporadic, that is, they occur even though there is no family history of the disorder. These cases are thought to be caused by a new genetic mutation-an alteration in the gene that occurs during sperm development and that brings the number of CAG repeats into the range that causes disease.
Describe the genetic cause of huntington’s disease
The underlying mutation responsible for the disease involves an improper expansion of a CAG trinucleotide region in the gene HUNTINGTIN-HTT
- In people with HD, the CAG sequence abnormally repeats itself dozens of times
- Scientists have abbreviations for the different amino acids. Glutamine is abbreviated as ‘Q’, so Huntington’s disease is sometimes called a ‘polyglutamine disease’ or a ‘polyQ disease’
Genetic test analyses DNA for the HD mutation by counting the number of CAG repeats in the Huntingtin gene, this relates to risk of developing disease, and severity/age of onset:
- ≤ 28 - Normal range; individual will not develop Huntington’s disease
- 29-34 - Individual will not develop Huntington’s disease but the next generation is at risk
- 35-39 - Some, but not all, individuals in this range will develop Huntington’s disease; next generation is at risk
- ≥ 40 - Individual will develop Huntington’s disease
Describe the normal function of HTT gene
Normal Huntingtin protein is thought to stabilize neurons, preventing apoptosis from occurring and prolonging cell life (Rigamonte, et al. 2000).
The function of Htt is unclear - It interacts with proteins that are involved in transcription, cell signalling and intracellular transporting.
Describe the pathological role of mHTT
- The mutation of the Huntingtin gene codes for an abnormal form of the protein with large glutamine blocks
- Abnormal mHtt protein strands form protein aggregates rather than folding into functional protein
- They coalesce and form inclusion body within the cells. The highest concentrations are in the brain and testes, with moderate amounts in the liver, heart, and lungs.
- This results in gradual damage to neurons possibly by inducing apoptosis in certain types of cell.
- This results in the main pathology: degeneration and death of medium spiny GABAergic neurons in the caudate and putamen.
Describe the neuropathology seen in Huntingtons
You mainly see degeneration and death of medium spiny GABAergic neurons in the caudate and putamen.
This translates macroscopically as caudate and putamen (striatum) atrophy, enlarged ventricles, global cortical atrophy is also seen.
What are the early symptoms of Huntington’s?
The hallmark of the disease is choreic movements: Rapid jerky involuntary movements of the body. These movements usually affect the hands and the face at first.
- Early in the course of the disease patients can mask the involuntary movements by incorporating them into socially acceptable movements (e.g. twiddling thumbs).
Other symptoms include:
- Stumbling and clumsiness
- Lack of concentration
- Short-term memory lapses
- Depression
- Changes of mood, sometimes including aggressive or antisocial behaviour
What are the late symptoms of HD?
Choreic movements gradually increase overtime until the patients become totally incapacitated by them. There is also:
- Loss of coordination and balance
- Difficulty in eating and swallowing
- Later on cognitive decline and dementia
Death usually 10-15 years from symptoms onset
How is Huntington’s Disease tested?
If we have a strong suspicion that the patient arriving from the movement disorders clinic may have Huntington’s disease, we can refer them to a specialist genetic clinic. Genetic test analyses DNA for the HD mutation by counting the number of CAG repeats in the Huntingtin gene, this relates to risk of developing disease, and severity/age of onset:
- ≤ 28 - Normal range; individual will not develop Huntington’s disease
- 29-34 - Individual will not develop Huntington’s disease but the next generation is at risk
- 35-39 - Some, but not all, individuals in this range will develop Huntington’s disease; next generation is at risk
- ≥ 40 - Individual will develop Huntington’s disease
The more repeats, the younger the age of onset
Describe the current tretament strategies for Huntington’s Disease
- Drug treatments - tetrabenazine is the only FDA approved durg for HD (promotes DA degredation).
- Psychiatric symptoms such as depression to be treated by pharmacology such as SSRIs.
- Psychotherapy
- Speech therapy
- Physiotherapy
- Occupational Therapy
Describe the pharmacotherapy available for Huntington’s Disease
Only drug for HD approved by the US Food and Drug administration (2008) is tetrabenazine. It works as VMAT inhibitor (vesicular monoamine transporter) and promotes metabolic degradation of monoamines, particularly Dopamine - Mostly used to reduce choreic movements.
We do not prescribe it often, as it is not a specific drug, and comes with many side effects such as:
- Depression
- Drowsiness, fatigue, dizziness
- Akathisia and anxiety
- Parkinsonism
Compounds such as amantadine or remacemide are still under investigation but have shown preliminary positive results.
Describe how Cell Transplantation Therapy could be used in Huntington’s Disease
Therefore, with cell transplantation therapy, in theory, we can restore down stream basal ganglia- cortical circuits and thus improve HD symptoms
How to transplant cells:
- First, you need to prepare foetal cells from striatal tissue (allogenic tissue - we’re not at the stem cell stage yet)
- Then, you need to stereotactically implant them into the basal ganglia.
Describe the pathopsyhiology of choreic movements in HD
Choreic movements are caused by the degeneration and death of medium spiny GABAergic neurons in the caudate and putamen.
The subsequent lack of inhibitory control of the thalamus generates involuntary movements.
